A method for preparing 1,2-diamines

Abstract

The application provides a preparation method of a 1,2-diamine compound, and the preparation method comprises the following steps: S1, adding imine, N-(tert-butyl)-N-methyl benzamide, quinuclidine, 4-CzIPN and an alkali into an organic solvent, and uniformly mixing to obtain a mixed solution; S2, placing the mixed solution in a light irradiation condition with a wavelength of 450 nm to obtain a reaction solution; and S3, performing separation and purification on the reaction solution to obtain the 1,2-diamine compound. The preparation method uses cheap and easily obtained imine and benzamide as raw materials, 4-CzIPN as a photosensitizer, and 1,2-diamine compound is prepared through a photochemical catalytic reaction. The raw material is easy to obtain, and the reaction condition and the reaction operation are simple, the synthesis requirement of green, economic, mild and high efficiency is met, and the method has high popularization and application value.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, specifically to a method for preparing 1,2-diamine compounds. Background Technology

[0002] 1,2-Diamine compounds are important alkaloid skeletons with wide applications in medicinal chemistry, asymmetric catalysis, and new materials. Japanese Patent Document JP2013014596A discloses novel CB1 receptor antagonists such as Compound 1 and Compound 2. These compounds are CB1 receptor antagonists with the potential to develop treatments for obesity and related metabolic diseases (such as diabetes and hyperlipidemia), as well as smoking cessation aids. US Patent Document US3965114A discloses multi-substituted piperazine derivatives, in which Compound 3 serves as an important precursor in the synthesis of these derivatives, and can be used to construct a piperazine ring core skeleton through a cyclization reaction. These multi-substituted piperazine derivatives exhibit excellent antiserotonin and antihistamine activities, and can be applied in the treatment of migraines and allergy-related diseases.

[0003]

[0004] Both compounds 1 and 2 can be prepared from 1,2-diamine compounds via the following route:

[0005] In recent years, with the continuous development of photochemistry, this strategy has been increasingly widely used in organic synthesis, especially the use of inexpensive and readily available organic dyes as catalysts, which is considered a highly efficient and environmentally friendly method. If the photochemical pathway is used to synthesize 1,2-diamine compounds, achieving a greener, more economical, milder, and more efficient synthesis, its industrial application would be of significant importance. Summary of the Invention

[0006] This invention proposes a method for preparing 1,2-diamine compounds to meet the requirements of green, economical, mild and efficient synthesis, and to promote their application in industrial production.

[0007] The technical solution of this invention is implemented as follows: This invention provides a method for preparing 1,2-diamine compounds, comprising the following steps: S1. The imine shown in Formula II, N-(tert-butyl)-N-methylbenzamide, quinine ring, 4-CzIPN (2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile) and base are added to an organic solvent and mixed to obtain a mixture; S2. The mixture is placed under light irradiation at a wavelength of 450 nm to obtain a reaction solution; S3. The reaction solution was separated and purified to obtain the 1,2-diamine compound shown in Formula I; The structural formulas for Formula I and Formula II are as follows: , ; In the above structural formulas, R1 and R2 are each independently selected from hydrogen, halogen, alkyl, alkoxy, aryl or arylalkoxy.

[0008] Furthermore, the molar ratio of the imine to N-(tert-butyl)-N-methylbenzamide and the base is 1:2-3:2-3.

[0009] Furthermore, the molar ratio of the imine to the quinine ring is 1:0.1; And / or, the molar ratio of the imine to 4-CzIPN is 1:(0.01-0.02).

[0010] Furthermore, the organic solvent is selected from at least one of dichloromethane, dichloroethane, acetonitrile, and N,N-dimethylacetamide; Furthermore, the alkali is selected from at least one of sodium carbonate, cesium carbonate, potassium hydrogen phosphate, and triethylamine.

[0011] Furthermore, the power of the light source used for illumination is 3-20 W, and the reaction time is 24-36 h.

[0012] Furthermore, the separation and purification steps are as follows: S31. Add water and organic extractant to the reaction solution and extract to obtain the organic phase; S32. The organic phase was sequentially dehydrated and the solvent was removed by evaporation, followed by column chromatography to obtain 1,2-diamine compounds.

[0013] Preferably, the organic extractant is selected from at least one of ethyl acetate and methyl acetate.

[0014] Preferably, the eluent used in the column chromatography is petroleum ether and ethyl acetate in a volume ratio of 5-10:1.

[0015] Preferably, after column chromatography separation, hydrochloric acid is added to the eluent obtained from the separation, and the solvent is removed to obtain the ammonium hydrochloride salt of 1,2-diamine compounds.

[0016] The preparation method of the present invention uses inexpensive and readily available imines and N-(tert-butyl)-N-methylbenzamide as raw materials, and inexpensive and readily available 4-CzIPN as a photosensitizer to obtain 1,2-diamine compounds through photochemical catalytic reaction. The raw materials are readily available and the reaction conditions and operation are simple, meeting the requirements of green, economical, mild and efficient synthesis, and has high application value. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0018] Figure 1 This is a schematic diagram of the reaction mechanism of the preparation method described in this invention; Figure 2 The hydrogen spectrum of the product prepared in Example 1 of this invention; Figure 3 The carbon spectrum of the product prepared in Example 1 of this invention; Figure 4 The hydrogen spectrum of the product prepared in Example 2 of this invention; Figure 5 This is the carbon spectrum of the product prepared in Example 2 of the present invention. Detailed Implementation

[0019] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0020] This invention provides a method for preparing 1,2-diamine compounds, comprising the following steps: S1. Add the imine shown in Formula II, N-(tert-butyl)-N-methylbenzamide, quinine ring, 4-CzIPN and base to an organic solvent and mix well to obtain a mixture; S2. The mixture is placed under light irradiation at a wavelength of 450 nm to obtain a reaction solution; S3. The reaction solution was separated and purified to obtain the 1,2-diamine compound shown in Formula I; The structural formulas for Formula I and Formula II are as follows: , ; In the above structural formulas, R1 and R2 are each independently selected from hydrogen, halogen, alkyl, alkoxy, aryl, or arylalkoxy. Preferably, the carbon chain length of the alkyl group is 1-6, such as methyl, ethyl, or cyclohexyl; preferably, the alkoxy group is methoxy or ethoxy; preferably, the aryl group is phenyl, and the arylalkoxy group is benzyloxy.

[0021] In the above preparation method, under photochemical reaction conditions, 4-CzIPN (2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile) absorbs light to form an excited state. The quinine ring is oxidized by 4-CzIPN to generate an amine radical, which abstracts a hydrogen atom from the α-amino group carbon, producing an α-amino radical that combines with an imine to form an amine radical. Subsequently, the amine radical is reduced by 4-CzIPN to form a 1,2-diamine. A schematic diagram of the reaction mechanism of the preparation method is shown below. Figure 1 As shown.

[0022] In a preferred embodiment, the molar ratio of the imine, N-(tert-butyl)-N-methylbenzamide, quinine ring, 4-CzIPN, and base is 1:(2-3):0.1:(0.01-0.02):(2-3). The power of the light source used for illumination is 3-20 W, and the reaction time is 24-36 h. Under these conditions, a product with a yield of 60% or more can be obtained, and more preferably, a product with a yield of 80% or more can be obtained.

[0023] In a preferred embodiment, the organic solvent is selected from at least one of dichloromethane, dichloroethane, acetonitrile, and N,N-dimethylacetamide; the base is selected from at least one of sodium carbonate, cesium carbonate, potassium hydrogen phosphate, and triethylamine.

[0024] It is understood that the N-(tert-butyl)-N-methylbenzamide can be obtained by reacting N-methyl-tert-butylamine with benzoyl chloride under acid-binding conditions.

[0025] In a preferred embodiment, the separation and purification step is as follows: S31. Add water and organic extractant to the reaction solution and extract to obtain the organic phase; S32. The organic phase was sequentially dehydrated and the solvent was removed by evaporation, followed by column chromatography to obtain 1,2-diamine compounds.

[0026] The above separation and purification methods can yield 1,2-diamine compounds with a purity of over 98%.

[0027] More preferably, the organic extractant is selected from at least one of ethyl acetate and methyl acetate.

[0028] More preferably, the eluent used in the column chromatography is petroleum ether and ethyl acetate in a volume ratio of 5-10:1. After the column chromatography separation, hydrochloric acid is added to the eluent, and the solvent is removed to obtain the ammonium hydrochloride salt of the 1,2-diamine compound. The addition of hydrochloric acid converts it into a solid ammonium hydrochloride salt, which facilitates separation and helps improve the purity of the product.

[0029] The following are preferred embodiments of the present invention. Unless otherwise specified, the reagents used in the embodiments are commercially available standards in the art or are prepared in the laboratory by combining common synthesis methods in the art, and the experimental methods used are those that are well mastered by those skilled in the art.

[0030] Example 1

[0031] A method for synthesizing 1,2-diamine compounds, comprising the following steps: S1. Add 0.2 mmol of 1-(4-fluorophenyl)-N-phenylmethylimine, 0.4 mmol of N-(tert-butyl)-N-methylbenzamide, 2 mL of acetonitrile, 0.4 mmol of sodium carbonate, 0.002 mmol of 4-CzIPN, and 0.02 mmol of quinine ring to a 10 mL Shrek tube; place the reaction flask under a 20 W 450 nm light source and stir for 36 h. S2. After the reaction, add 10 mL of water to the reaction system, add ethyl acetate and mix, and extract multiple times; S3. The extracted organic phase was dried with anhydrous sodium sulfate, and the solvent was evaporated using a rotary evaporator. The product system was purified by column chromatography using petroleum ether:ethyl acetate = 10:1 as the eluent. 1 mL of hydrochloric acid (0.5 M) was added to the obtained product, and excess solvent was removed by rotary evaporation to finally obtain 68.4 mg of pure N-(2-(N-tert-butylbenzoylamino)-1-(4-fluorophenyl)ethyl)aniline onium chloride with an HPLC purity of 98.9%.

[0032] The structural formula of 1-(4-fluorophenyl)-N-phenylmethylimine is:

[0033] The structural formula of N-(tert-butyl)-N-methylbenzamide is: ; The structural formula of the product N-(2-(N-tert-butylbenzoamide)-1-(4-fluorophenyl)ethyl)aniline onium chloride is: .

[0034] like Figure 2 , Figure 3 The product N-(2-(N-tert-butylbenzoamide)-1-(4-fluorophenyl)ethyl)aniline onium chloride is characterized as follows: 1H NMR (400 MHz, Chloroform-d) δ 9.60 (d, J = 69.2 Hz, 2H), 7.36 –7.26 (m, 2H), 7.20 – 7.09 (m, 3H), 7.06 (d, J = 7.5 Hz, 7H), 6.90 (t, J = 8.3Hz, 2H), 6.15 (dd, J = 9.9, 3.5 Hz, 1H), 4.08 (dd, J = 13.8, 7.0 Hz, 1H), 3.57 – 3.42 (m, 1H), 1.50 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 173.04, 162.95, 160.47, 138.40, 134.11,130.75, 130.72, 129.67, 129.58, 129.40, 128.94, 127.89, 127.45, 126.91,126.65, 114.86, 114.64, 59.83, 57.16, 44.08, 25.00. Example 2 The difference between this embodiment and Example 1 is that the imine compound in step S1 is 4-fluorobenzaldehyde acetal p-methoxyaniline, and the amount used is 0.2 mmol. All other conditions are the same as in Example 1. The obtained 1,2-diamine is N-(2-(N-tert-butylbenzoylamino)-1-(4-fluorophenyl)ethyl)-4-methoxyaniline onium chloride, with a mass of 75 mg and an HPLC purity of 99.0%.

[0035] The structural formula of 4-fluorobenzaldehyde acetal p-methoxyaniline is: ; The structural formula of N-(2-(N-tert-butylbenzoamide)-1-(4-fluorophenyl)ethyl)aniline onium chloride is: .

[0036] like Figure 4 , Figure 5 The characterization of N-(2-(N-tert-butylbenzoamide)-1-(4-fluorophenyl)ethyl)aniline onium chloride is shown below: 1H NMR (400 MHz, Chloroform-d) δ 9.69 (d, J = 242.4 Hz, 2H), 7.28 (d,J = 7.5 Hz, 2H), 7.12 (s, 1H), 7.08 (d, J = 7.1 Hz, 4H), 6.90 (t, J = 8.2 Hz,3H), 6.50 (d, J = 7.9 Hz, 2H), 6.06 (d, J = 9.4 Hz, 1H), 4.38-3.02 (m, 6H),1.50 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 173.69, 162.99, 160.51, 157.78, 134.04,130.74, 130.64, 130.60, 130.35, 129.76, 129.68, 128.93, 127.41, 126.73,114.92, 114.71, 112.95, 59.62, 57.13, 54.17, 44.08, 25.00. Example 3 A method for synthesizing 1,2-diamine compounds, comprising the following steps: S1. Add 5 mmol of 1-(4-fluorophenyl)-N-phenylmethylimine, 10 mmol of N-(tert-butyl)-N-methylbenzamide, 50 mL of acetonitrile, 10 mmol of sodium carbonate, 0.05 mmol of 4-CzIPN, and 0.5 mmol of quinine ring to a 200 mL solvent storage bottle; place the reaction bottle under four 20 W 450 nm light rings and stir for 30 h; S2. After the reaction, add 100 mL of water to the reaction system, add ethyl acetate and mix, and extract multiple times; S3. The extracted organic phase was dried with anhydrous sodium sulfate, and the solvent was evaporated using a rotary evaporator. The product system was purified by column chromatography using petroleum ether:ethyl acetate = 10:1 as the eluent. 10 mL of hydrochloric acid (0.5 M) was added to the obtained product, and excess solvent was removed by rotary evaporation to finally obtain 1.78 g of pure N-(2-(N-tert-butylbenzoylamino)-1-(4-fluorophenyl)ethyl)aniline onium chloride with an HPLC purity of 99.1%.

[0037] The structural formula of 1-(4-fluorophenyl)-N-phenylmethylimine is: ; The structural formula of N-(tert-butyl)-N-methylbenzamide is: ; The structural formula of the product N-(2-(N-tert-butylbenzoamide)-1-(4-fluorophenyl)ethyl)aniline onium chloride is: .

[0038] Example 4

[0039] The difference between this embodiment and Example 1 is that the imine compound in step one is N-(4-benzyloxyphenyl)-1-(4-fluorophenyl)methylimine, and the amount used is 61 mg. All other conditions are the same as in Example 1. The resulting 1,2-diamine is 4-benzyloxy-N-(2-(N-(tert-butyl)benzoylamino)-1-(4-fluorophenyl)ethyl)aniline chloride, with a mass of 92.1 mg and an HPLC purity of 99.6%.

[0040] The structural formula of N-(4-benzyloxyphenyl)-1-(4-fluorophenyl)methylimine is: ; The structural formula of 4-benzyloxy-N-(2-(N-(tert-butyl)benzoylamino)-1-(4-fluorophenyl)ethyl)aniline chloride is: .

[0041] The characterization of 4-benzyloxy-N-(2-(N-(tert-butyl)benzoylamino)-1-(4-fluorophenyl)ethyl)aniline chloride is as follows: 1 H NMR (400 MHz, CDCl3) δ 10.3 – 9.86 (m, 1H), 9.66 – 9.26 (m, 1H), 7.42 – 7.36 (m, 7H), 7.25 – 7.13 (m, 5H), 7.07 – 6.92 (m, 3H), 6.78 – 6.47(m, 2H), 6.35 – 6.06 (m, 1H), 5.06 – 4.62 (m, 2H), 4.32 – 3.95 (m, 1H), 3.63 – 3.28 (m, 1H), 2.53 – 2.18 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.82 162.87 (d, J = 250.48 Hz), 158.07, 136.32, 135.30, 131.90, 130.89 (d, J = 8.1 Hz), 130.85, 130.01, 128.59, 128.13, 127.86, 127.56, 124.42, 123.52, 119.14,115.94 (d, J = 21.2 Hz), 115.11, 70.06, 60.66, 58.29, 45.26, 26.19.

[0042] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a 1,2-diamine compound, characterized in that the step... include: S1. Add the imine shown in Formula II, N-(tert-butyl)-N-methylbenzamide, quinine ring, 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile and base to an organic solvent and mix well to obtain a mixture; S2. The mixture is placed under light irradiation at a wavelength of 450 nm to obtain a reaction solution; S3. The reaction solution was separated and purified to obtain the 1,2-diamine compound shown in Formula I; The structural formula of the N-(tert-butyl)-N-methylbenzamide is as follows: ; The structural formulas for Formula I and Formula II are as follows: 、 ； In the above structural formulas, R1 and R2 are para-substitutions, and each is independently selected from hydrogen, halogen, alkyl, alkoxy, phenyl or benzyloxy. The molar ratio of the imine, N-(tert-butyl)-N-methylbenzamide, quinine ring, 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile and the base is 1:(2-3):0.1:(0.01-0.02):(2-3).

2. The preparation method according to claim 1, characterized in that, The organic solvent is selected from at least one of dichloromethane, dichloroethane, acetonitrile, and N,N-dimethylacetamide.

3. The preparation method according to claim 1, characterized in that, The alkali is selected from at least one of sodium carbonate, cesium carbonate, potassium hydrogen phosphate, and triethylamine.

4. The preparation method according to claim 1, characterized in that, The power of the light source used for illumination is 3-20 W, and the reaction time is 24-36 h.

5. The preparation method according to claim 1, characterized in that, The separation and purification steps are as follows: Water and an organic extractant were added to the reaction solution, and the organic phase was obtained by extraction. The organic phase was subjected to dehydration and solvent removal by evaporation, followed by column chromatography to obtain 1,2-diamine compounds.

6. The preparation method according to claim 5, characterized in that, The organic extractant is selected from at least one of ethyl acetate and methyl acetate.

7. The preparation method according to claim 5, characterized in that, The eluent used in the column chromatography was petroleum ether and ethyl acetate in a volume ratio of 5-10:

1.

8. The preparation method according to claim 5, characterized in that, After column chromatography separation, hydrochloric acid is added to the eluent obtained from the separation, and after removing the solvent, ammonium hydrochloride salts of 1,2-diamine compounds are obtained.

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