CN105949106B - A kind of preparation method of the maleimide compound of 3- amino-N- substitutions - Google Patents

Abstract

The present invention relates to a kind of preparation method of 3-amino-N-substituted maleimide compound, it is characterized in that: the structural formula of described compound is: Wherein, R ₁ is phenyl or benzyl, and NR ₂ R ₃ is pyrrolidinyl, morpholinyl, benzylamino or dimethylamino. Preparation: add N-substituted maleimide, amine compound, and catalyst into a solvent, heat to 25°C-140°C for 1-12 hours, and purify to obtain the product. The 3-amino-N-substituted maleimide compound prepared by the invention is simple in reaction operation, high in yield, short in reaction route, less in production of three wastes, and easy in industrialized production.

Description

A kind of preparation method of 3-amino-N-substituted maleimide compounds

technical field

The invention belongs to the field of 3-amino-N-substituted maleimide compounds and preparation methods thereof, in particular to a preparation method of 3-amino-N-substituted maleimide compounds.

Background technique

3-Amino-N-substituted maleimide compounds (I～IV) and their derivatives are important drug synthesis intermediates, and have a wide range of biological activities such as antibacterial and antitumor (Mori, K.; Izawa , T.; Matsui, S. Antifouling N-arylmaleimide derivatives. JP 53032119,1978; Augustin, M.; Koehler, M.; Kazandji, S..Sulfurization of C-substituted maleimide, Tetrahedron, 1984, 40(18), 3499-502.; Patil, N.S.; Deshmukh, G.B.; Patil, S.V.; 497.; Mabrie, A.B.; Robin, M.P.; Quan, W.D.; Willcock, H.; 47): 9733-9736.).

The synthetic method of the maleimide compound of 3-amino-N-substitution of bibliography mainly comprises three kinds:

Method 1: Tourteau et al reported the synthesis of 3-bromo-N-benzylmaleimide by refluxing N-benzylmaleimide and bromine in dichloromethane, and then stirring at room temperature in THF under the action of triethylamine Imide, yield 98%. The target product 3-morpholinyl-N-benzylmaleimide was synthesized with morpholine at room temperature in dichloromethane through the action of triethylamine, and the yield was 82%. (Tourteau, A.; Merlet, E.; Bontemps, A.; Leland, M.; Helissey, P.; Giorgi-Renault, S.; Desbene-Finck, S.. Easy access to 1H-pyrrolo[3'4 ':5,6]pyrido[2,3-d]pyrimidine-2,4-6,8(3H,7H)-tetraone and selectively N ⁷ -substituted analogues through keysynthons.European Journal of Organic Chemistry,2015,2015( 32):7028-7035.)

Method 2: Patil et al. reported the addition reaction of N-phenylmaleimide with bromine in DMF to obtain 3,4-dibromo-N-phenylmaleimide, and then reacted with amine as an intermediate The 3-amino-substituted maleimide compounds were obtained without separation, and the yield was up to 90%. (Patil, N.S.; Deshmukh, G.B.; Mahale, K.A.; Gosavi, K.S.; Patil, S.V.. Synthesis of novel N-aryl-3-dialkyamino-4-substituted maleimides. Indian journal of Chemistry, Section B: Organic Chemistry Medicinal Chemistry, 2015 ,54B(2):272-278.)

Method 3: Tamura et al. reported the synthesis of nucleophile N-alkyldiphenylsulfimide compounds using diphenylsulfimide and alkylhalogenated hydrocarbons as raw materials, and then reacted with maleimide compounds. The addition and elimination reaction gave 3-amino-substituted maleimide compounds with a yield of 79%. (Tamura, Y.; Matsushima, H.; and Ikeda, M. Syntheses and nucleophilic reactions of N-alkyldiphenylsulfilimines. Tetrahedron, 1976, 32(4): 431-435.)

The above three synthetic methods all have the disadvantages of too long reaction route, many by-products, and low yield. Meanwhile, the raw materials used in the third method are difficult to obtain and expensive, which increases the production cost. Therefore, these three methods are not suitable for large-scale synthesis.

Contents of the invention

The technical problem to be solved by this invention is to provide a kind of preparation method of 3-amino-N-substituted maleimide compound, and this method is raw material with N-substituted maleimide and amine compound, with Copper salts such as copper acetate are used as catalysts, heated to 120° C. in chlorobenzene solution for 1-12 hours to obtain 3-amino-N-substituted maleimide compounds with a yield of 55-95%.

A 3-amino-N-substituted maleimide compound of the present invention, the structural formula of the compound is: Wherein, R ₁ is phenyl or benzyl, and NR ₂ R ₃ is pyrrolidinyl, morpholinyl, benzylamino or dimethylamino.

Said compound is: One of.

A kind of preparation method of the maleimide compound of a kind of 3-amino-N-substituted of the present invention comprises:

Add N-substituted maleimide, amine compound, and catalyst into the solvent, heat to 25°C-140°C for 1-12 hours, and purify to obtain 3-amino-N-substituted maleimide compound; wherein the molar ratio of maleimide, amine compound and catalyst is 1.0:1.0～2.0:0.1～1.0.

The catalyst is copper salt.

The copper salt is one or more of cuprous iodide, cuprous chloride, cuprous bromide and copper acetate.

The solvent is chlorobenzene and/or dimethyl sulfoxide; the amine compound is one of pyrrolidine, morpholine, benzylamine and dimethylamine. The weight-to-volume ratio of the N-substituted maleimide to the solvent is 1 gram: 1 milliliter to 100 milliliters.

The purification is as follows: add water and stir for 3-5 minutes, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and recrystallize the obtained solid.

The weight-to-volume ratio of N-substituted maleimide, water, and ethyl acetate is 1 gram: 4 milliliters to 100 milliliters: 4 milliliters to 100 milliliters.

The solvent used for recrystallization was 95% ethanol.

The specific preparation reaction formula of the 3-amino-N-substituted maleimide compounds of the present invention is as follows:

Synthetic routes of 3-amino-N-substituted maleimides

The structural formula of the compound (I) is:

Melting point: 98～100℃;

Properties: yellow solid;

¹ H NMR (400MHz, CDCl ₃ ) δ: 2.02(s, 4H), 3.35(s, 2H), 3.94(s, 2H), 4.89(s, 1H), 7.32(dd, J=18.4, 7.7Hz, 3H), 7.43(t, J=7.5Hz, 2H)

¹³ C NMR (101MHz, CDCl ₃ ) δ: 24.08, 26.35, 49.11, 50.45, 86.04, 126.30 (2C), 127.18, 128.86 (2C), 132.12, 148.18, 165.60, 170.42;

The structural formula of the compound (II) is:

Melting point: 120～122℃;

Properties: yellow solid;

¹ H NMR (400MHz, CDCl ₃ ) δ: 3.70(s, 4H), 3.79(s, 4H), 4.64(s, 2H), 4.98(s, 1H), 7.30(d, J=12.6Hz, 2H) ,7.37(d,J=7.2Hz,3H)

¹³ C NMR (101MHz, CDCl ₃ ) δ: 40.99(2C), 47.14(2C), 66.28, 89.76, 127.59, 128.36(2C), 128.59(2C), 136.83, 150.06, 166.90, 170.34

The structural formula of the compound (III) is:

Melting point: 110～112℃;

Properties: yellow solid;

¹ H NMR (400MHz, CDCl ₃ )δ: 4.39(d, J=5.0Hz, 2H), 5.01(s, 1H), 5.90(s, 1H), 7.38(m, 10H)

¹³ C NMR (101MHz, CDCl ₃ ) δ: 48.52, 85.71, 125.90 (2C), 127.38, 127.79 (2C), 128.39, 128.97 (2C), 129.08 (2C), 131.82, 135.56, 148.74, 166.35, 171.01;

The structural formula of the compound (IV) is:

Melting point: 132～134℃;

Properties: yellow solid;

¹ H NMR (400MHz, CDCl ₃ )δ: 3.25(s, 6H), 4.97(s, 1H), 7.33(d, J=7.5Hz, 3H), 7.44(t, J=7.2Hz, 2H)

¹³ C NMR (101MHz, CDCl ₃ ) δ: 39.69(2C), 87.71, 126.43(2C), 127.33, 128.88(2C), 131.96, 150.47, 165.74, 169.68.

Beneficial effect

In the process of preparing 3-amino-N-substituted maleimide compounds, the present invention uses copper salt as a catalyst, which shortens the reaction time and improves the yield; Low, simple reaction operation, short reaction route, easy industrial production.

Description of drawings

Fig. 1 is the proton nuclear magnetic resonance spectrum of compound 3-pyrrolidinyl-N-phenylmaleimide (I);

Fig. 2 is the carbon nuclear magnetic resonance spectrum of compound 3-pyrrolidinyl-N-phenylmaleimide (I).

Detailed ways

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Example 1

Take 17.3g (0.1mol) of N-phenylmaleimide, 10.6g (0.15mol) of pyrrolidine and 3.6g (0.02mol) of copper acetate into a 250mL round bottom flask, then add 100mL of chlorobenzene and heat to Stir at 120°C for 6 hours, after the reaction is complete, add 50 mL of water, stir for 5 minutes, extract with ethyl acetate 200 mL×3, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and recrystallize the obtained solid with 95% ethanol to obtain 3-pyrrole as a yellow solid Alkyl-N-phenylmaleimide 15.0g, yield 62%, mp: 98-100°C. ¹ H NMR (400MHz, CDCl ₃ ) δ: 2.02(s, 4H), 3.35(s, 2H), 3.94(s, 2H), 4.89(s, 1H), 7.32(dd, J=18.4, 7.7Hz, 3H), 7.43 (t, J=7.5Hz, 2H); ¹³ C NMR (101MHz, CDCl ₃ ) δ: 24.08, 26.35, 49.11, 50.45, 86.04, 126.30 (2C), 127.18, 128.86 (2C), 132.12, 148.18, 165.60, 170.42.

Example 2

Take 8.65g (0.05mol) of N-phenylmaleimide, 5.3g (0.075mol) of pyrrolidine and 9.1g (0.05mol) of copper acetate into a 250mL round bottom flask, then add 100mL of chlorobenzene and heat to Stir at 120°C for 8 hours, after the reaction is complete, add 50 mL of water, stir for 5 minutes, extract with 150 mL of ethyl acetate x 3, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and recrystallize the obtained solid with 95% ethanol to obtain 3-pyrrole as a yellow solid Alkyl-N-phenylmaleimide 11.5g, yield 95%, mp: 98-100°C.

Example 3

Get N-phenylmaleimide 8.65g (0.05mol), pyrrolidine 5.3g (0.075mol), copper acetate 9.1g (0.05mol) and join in the 250mL round bottom flask, then add dimethyl sulfoxide (DMSO ) 100mL, heated to 120°C and stirred for 12h, after the reaction was completed, added 50mL of water, stirred for 5 minutes, extracted with 300mL×3 ethyl acetate, dried the organic phase with anhydrous sodium sulfate, evaporated the solvent, and recrystallized the obtained solid with 95% ethanol to obtain Yellow-brown solid 3-pyrrolidinyl-N-phenylmaleimide 9.68g, yield 80%, mp: 98-100°C.

Example 4

Take 1.73g (0.01mol) of N-phenylmaleimide, 1.07g (0.075mol) of pyrrolidine, and 0.99g (0.01mol) of cuprous chloride and add them to a 250mL round bottom flask, then add 20mL of chlorobenzene, Heat to 120°C and stir for 12 hours. After the reaction is complete, add 50 mL of water, stir for 5 minutes, extract with 50 mL of ethyl acetate x 3, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and recrystallize the obtained solid with 95% ethanol to obtain a yellow solid 3 -Pyrrolidinyl-N-phenylmaleimide 1.57g, yield 65%, mp: 98-100°C.

Example 5

Take 1.73g (0.01mol) of N-phenylmaleimide, 1.07g (0.075mol) of pyrrolidine, and 1.43g (0.01mol) of cuprous bromide into a 250mL round bottom flask, then add 20mL of chlorobenzene, Heat to 120°C and stir for 12 hours. After the reaction is complete, add 50 mL of water, stir for 5 minutes, extract with 50 mL of ethyl acetate x 3, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and recrystallize the obtained solid with 95% ethanol to obtain a yellow solid 3 -Pyrrolidinyl-N-phenylmaleimide 1.65g, yield 68%, mp: 98-100°C.

Example 6

Take 5.0g (0.03mol) of N-phenylmaleimide, 4.3g (0.06mol) of pyrrolidine and 1.90g (0.01mol) of cuprous iodide into a 250mL round bottom flask, then add 60mL of chlorobenzene, Heat to 120°C and stir for 12 hours. After the reaction is complete, add 50 mL of water, stir for 5 minutes, extract with ethyl acetate 100 mL×3, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and recrystallize the obtained solid with 95% ethanol to obtain a yellow solid 3 -Pyrrolidinyl-N-phenylmaleimide 5.4g, yield 75%, mp: 98-100°C.

Example 7

Take 18.7g (0.1mol) of N-benzylmaleimide, 13.05g (0.15mol) of morpholine, and 18.16g (0.1mol) of copper acetate into a 250mL round bottom flask, then add 100mL of chlorobenzene and heat to Stir at 120°C for 12 hours, after the reaction is complete, add 50 mL of water, stir for 5 minutes, extract with 200 mL of ethyl acetate x 3, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and recrystallize the obtained solid with 95% ethanol to obtain a yellow solid 3-mol Linyl-N-benzylmaleimide 22.0g, yield 81%, mp: 120-122°C. ¹ H NMR (400MHz, CDCl ₃ ) δ: 3.70(s, 4H), 3.79(s, 4H), 4.64(s, 2H), 4.98(s, 1H), 7.30(d, J=12.6Hz, 2H) , 7.37 (d, J=7.2Hz, 3H); ¹³ C NMR (101MHz, CDCl ₃ ) δ: 40.99 (2C), 47.14 (2C), 66.28, 89.76, 127.59, 128.36 (2C), 128.59 (2C), 136.83, 150.06, 166.90, 170.34.

Example 8

Take 17.3g (0.1mol) of N-phenylmaleimide, 16.05g (0.15mol) of benzylamine and 18.16g (0.1mol) of copper acetate into a 250mL round bottom flask, then add 100mL of chlorobenzene and heat to Stir at 120°C for 12 hours, after the reaction is complete, add 50 mL of water, stir for 5 minutes, extract with 300 mL of ethyl acetate × 3, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and recrystallize the obtained solid with 95% ethanol to obtain a yellow solid 3-benzyl Amino-N-phenylmaleimide 14.18g, yield 51%, mp: 110-112°C. ¹ H NMR (400MHz, CDCl ₃ ) δ: 4.39 (d, J=5.0Hz, 2H), 5.01 (s, 1H), 5.90 (s, 1H), 7.38 (m, 10H); ¹³ C NMR (101MHz, CDCl ₃ ) δ: 48.52, 85.71, 125.90 (2C), 127.38, 127.79 (2C), 128.39, 128.97 (2C), 129.08 (2C), 131.82, 135.56, 148.74, 166.35, 171.0.

Example 9

Take 17.3g (0.1mol) of N-phenylmaleimide, 20.45g (0.15mol) of 33% dimethylamine aqueous solution, and 18.16g (0.1mol) of copper acetate into a 250mL round bottom flask, then add chlorobenzene 100mL, heated to 120°C and stirred for 12h, after the reaction was completed, add 50mL of water, stirred for 5 minutes, extracted with 200mL×3 ethyl acetate, dried the organic phase with anhydrous sodium sulfate, evaporated the solvent, and recrystallized the obtained solid with 95% ethanol to obtain yellow Solid 3-dimethylamino-N-phenylmaleimide 10.6g, yield 49%, mp: 132-134°C. ¹ H NMR (400MHz, CDCl ₃ ) δ: 3.25(s, 6H), 4.97(s, 1H), 7.33(d, J=7.5Hz, 3H), 7.44(t, J=7.2Hz, 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ: 39.69 (2C), 87.71, 126.43 (2C), 127.33, 128.88 (2C), 131.96, 150.47, 165.74, 169.68.

Example 10

Take 17.3g (0.1mol) of N-phenylmaleimide, 20.45g (0.15mol) of 33% dimethylamine aqueous solution, and 9.9g (0.1mol) of cuprous chloride, and add them to a 250mL round bottom flask, then add Dimethylsulfoxide (DMSO) 100mL, heated to 120°C and stirred for 12h, after the reaction was completed, 50mL of water was added, stirred for 5 minutes, extracted with 200mL×3 ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, the solvent was evaporated, and the obtained solid was used Recrystallization from 95% ethanol gave 13.2 g of yellow solid 3-dimethylamino-N-phenylmaleimide, yield 61%, mp: 132-134°C.

Claims (7)

1. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions, it is characterised in that：The compound Structural formula is：Wherein, R₁For phenyl or benzyl, NR₂R₃For pyrrolidinyl, morpholinyl, benzamido group or diformazan Amido；

Preparation method includes：Maleimide, aminated compounds, the catalyst that N- is replaced are added in solvent, are heated to 25 DEG C ~140 DEG C are reacted 1~12 hour, and the maleimide compound to get the-N- substitutions of 3- amino is purified；Wherein maleimide Amine, aminated compounds, catalyst molar ratio be 1.0:1.0~2.0:0.1~1.0；Wherein catalyst is cuprous iodide, chlorination One or more of cuprous, cuprous bromide, copper acetate；Solvent is chlorobenzene and/or dimethyl sulfoxide (DMSO).

2. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 1, special Sign is：The compound is：

In one kind.

3. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 1, special Sign is：The aminated compounds is one kind in pyrrolidines, morpholine, benzylamine, dimethylamine.

4. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 1, special Sign is：The w/v of N- substituted maleimides amine and solvent is 1 gram：1 milliliter~100 milliliters.

5. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 1, special Sign is：The purification is：Water is added to stir 3-5min, ethyl acetate extraction, organic phase anhydrous sodium sulfate is dry, it is molten to boil off Agent, obtained solid are recrystallized.

6. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 5, special Sign is：N- substituted maleimides amine, water, ethyl acetate w/v be 1 gram：4 milliliters~100 milliliters：4 milliliters~ 100 milliliters.

7. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 5, special Sign is：Recrystallization solvent for use is 95% ethyl alcohol.