CN106008305B - A kind of synthetic method of five substitutions 2- amino-pyrroles derivatives - Google Patents

Abstract

The invention discloses a method for synthesizing pentasubstituted 2-aminopyrrole derivatives. The method is to react the aryl ketone of the ortho-amino halide with malononitrile under the action of a base in a highly polar organic medium. The five-substituted 2-aminopyrrole derivative can be obtained. Compared with traditional methods, the present invention uses cheap common bases as accelerators, which effectively reduces costs, and the synthesis steps are simple and the reaction yield is high. Especially in the construction of drugs with pyrrole rings, the application of this method can avoid The use of heavy metal catalysis leads to the problem that the residual amount of heavy metal in the drug exceeds the standard. In addition, regardless of whether the aromatic ketone of the ortho-amino halide is α-amino-β-haloaryl ketone or α-halogen-β-aminoaryl ketone, the amino group in the synthesized product is at the 2-position of the pyrrole ring, which has a high degree of Regional selectivity. The five-substituted 2-aminopyrrole derivative synthesized by the invention can be used in the research field of synthesis of condensed heterocyclic compounds, natural antibiotics, anticancer drugs and structural transformation of natural products.

Description

A kind of synthetic method of five substituted 2-aminopyrrole derivatives

technical field

The invention belongs to the technical field of synthesis of pentasubstituted 2-aminopyrrole derivatives, and in particular relates to a method for synthesizing pentasubstituted 2-aminopyrrole by one-step reaction of aryl ketone with an ortho-amino halide and malononitrile.

Background technique

Pyrrole and its derivatives are a very important class of five-membered heterocyclic compounds. Pyrrole was first discovered in the 1930s. Since then, the biological activity and pharmacological effects of pyrrole and its derivatives have attracted widespread attention. Today, pyrrole and its derivatives have been widely used in the fields of medicine, pesticide, food, biology, material science and polymer chemistry. Due to the importance of pyrrole and its derivatives, their synthetic methods have been intensively studied. The 2-aminopyrrole structural unit is a part of many compounds with strong biological activity, and has been recognized as the structural unit of many drug molecules. These drugs can exhibit anti-inflammatory, anti-cancer, anti-viral, anti-fungal, insecticidal, anti-radiation, and strong inhibitory effects on MEK, MK2, FAK, KDR, Tie2 and PDE. In addition, 2-aminopyrroles are precursors for the synthesis of purine congeners such as pyrrolopyrimidines, pyrrolopyrimidines, and pyrrolopyridines. So far, although there are many ways to synthesize pyrrole and its derivatives, there are relatively few reports on the synthesis of pentasubstituted 2-aminopyrrole. The reported methods are as follows: (1) under the catalysis of transition metal Pd, Ni, Co and other complexes, the corresponding five-substituted 2-aminopyrrole derivatives are obtained by refluxing alkyne and trimethylcyanosilane; (2) N-benzenesulfonylaminophenyl methyl ketone, N-heteroarylsulfonylamino phenyl methyl ketone, N-alkylsulfonylamino phenyl methyl ketone, etc. and aldehydes, cyano-containing The three components of the active methylene compound are refluxed in ethanol or acetonitrile solvent to obtain the corresponding five-substituted 2-aminopyrrole derivatives; (3) use α, β-unsaturated imide cyanide and nitrile in AlCl _3. Reaction at 90°C under catalysis to obtain the corresponding pentasubstituted 2-aminopyrrole derivatives; (4) Reaction of alkynes and aniline in toluene solvent at 80°C under the catalysis of titanium complexes to obtain 2,3-diaminopyrrole derivatives ; (5) In toluene solvent, the corresponding five-substituted 2-aminopyrrole derivatives were obtained by reacting three components of benzyl-p-toluenesulfonimide, butynedicarboxylic acid dimethyl ester, and cyclohexyl isonitrile. There are some shortcomings in the above methods in varying degrees. If some methods use transition metals as catalysts, excessive heavy metal residues in drug synthesis are difficult problems to solve in drug synthesis; Increase the cost of synthesis; some have to be carried out at higher temperatures, even at reflux temperature, and the requirements for equipment are increased.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the shortcomings existing in the synthesis of the existing five-substituted 2-aminopyrrole derivatives, and to provide a method that can be used under mild conditions, in a polar organic medium, under the promotion of an ordinary weak base , A one-step synthesis of five-substituted 2-aminopyrroles from aryl ketones and malononitriles in the ortho-amino halide.

The technical solution adopted to solve the above-mentioned technical problems is: in a relatively polar organic solvent, the aryl ketone of the ortho amino halide shown in formula I or formula II is mixed with malononitrile and alkali in a molar ratio of 1:1 ～1.5:0.5～2 mixed evenly, stirred at 40～60°C for 6～24 hours, separated and purified the product, and obtained the pentasubstituted 2-aminopyrrole derivative represented by formula III or formula IV;

In formulas I~IV, Ar ₁ and Ar ₂ independently represent phenyl, C ₁ ~C ₄ alkyl substituted phenyl, C ₁ ~C ₄ alkoxy substituted phenyl, halogen and C ₁ ~C ₄ alkoxy Any one of substituted phenyl, halogenated phenyl, nitro substituted phenyl, preferably Ar ₁ and Ar ₂ independently represent phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-halo-4,5-dimethoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-bromobenzene Any one of base, 4-fluorophenyl, 4-chlorophenyl, 4-nitrophenyl, X represents Cl, Br or I.

The molar ratio of the aryl ketone, malononitrile, and base of the above-mentioned ortho-amino halide is preferably 1:1˜1.5:1˜1.5.

The above-mentioned relatively polar organic solvent is any one of methanol, ethanol, propanol, N,N-dimethylformamide, acetonitrile, and dimethyl sulfoxide, preferably methanol.

The above-mentioned base is any one of sodium acetate, K ₂ CO ₃ , KHCO ₃ , Na ₂ CO ₃ , K ₃ PO ₄ , NaOH, KOH, ethylenediamine, and triethylamine, preferably Na ₂ CO ₃ .

In the synthetic method of the five-substituted 2-aminopyrrole derivatives of the present invention, no matter what substituent is on the aromatic ring of the aromatic ketone of the ortho-position amino halide and what position the substituent is in the aromatic ring, no matter the position of the ortho-amino halide is Whether the aryl ketone is α-amino-β-halogen or α-halogen-β-amino, the five-substituted 2-aminopyrrole derivatives are highly regioselective, and the amino group is at the 2-position of the pyrrole ring. That is, the synthesized pyrrole ring has the structural characteristics of 1,4-dipole, and this structure can further undergo 4+1 or 4+2 ring-closing reactions, which can be used for the total synthesis and structural modification of alkaloids and natural products, and the synthesis of antibiotics , anti-cancer, anti-viral drugs and other fields, providing new technologies for the synthesis of drug molecules and the total synthesis and structural modification of natural products.

The inventor found through experiments that in order to make the reaction fast and efficient, it must be realized under the promotion of alkali, and the reaction cannot occur without adding alkali, and the type and amount of alkali play a decisive role in the reaction. In addition, the solvent also plays an important role in controlling the reaction. In the aqueous medium, malononitrile will be hydrolyzed, so that the reaction cannot occur. Therefore, the reaction must be carried out in an organic medium. However, due to the different types of organic solvents, their polarity is different, and the ability to control the reaction is also different. Experiments have shown that the greater the polarity of the organic solvent, the greater the ability to control the reaction. The reaction temperature has a great influence on the product structure and yield. If the temperature is low (such as room temperature), the reaction tends to generate pyrroline. If the temperature is too high, the product will be complicated and the product yield will decrease.

The advantages of the present invention are:

1. The present invention provides a method for synthesizing pentasubstituted 2-aminopyrrole derivatives in various solvents, such as methanol, ethanol, propanol, N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide etc., where the preferred solvent is methanol.

2, the present invention has used common alkali such as sodium acetate, potassium acetate, sodium bicarbonate, potassium carbonate, sodium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, ethylenediamine, triethylamine etc. as promotor, wherein Sodium carbonate is the preferred accelerator. The accelerator is stable and easy to obtain, and the price is low. Compared with the traditional method, it avoids the use of expensive noble metal palladium or other excessive metal complexes, not only effectively reduces the synthesis cost, but also avoids the amount of metal residues in the drug synthesis. Possibility of excess.

3. In the present invention, under the promotion of alkali, the substitution reaction of the halogen in the aryl ketone of the ortho amino halide by malononitrile, the nucleophilic addition reaction of the amino group to the cyano group in the molecule to form pyrroline and the formation of pyrroline by oxygen in the air The oxidative dehydrogenation reaction of morpholino was completed at one time, and five-substituted 2-aminopyrrole derivatives were efficiently synthesized. In the process of oxidative dehydrogenation, oxygen in the air is used for oxidative dehydrogenation, which avoids the use of traditional oxidants such as DDQ, and makes the synthesis of pentasubstituted 2-aminopyrroles cleaner.

4. The synthesis steps of the present invention are simple, and three reactions (nucleophilic substitution/intramolecular nucleophilic addition/oxidative dehydrogenation reaction) are completed in one step, and the reaction yield is high, and the highest yield can reach 91%.

5. The method of the present invention has a high degree of regioselectivity, regardless of whether the aromatic ketone of the ortho-amino halide has an electron-donating substituent or an electron-withdrawing substituent, no matter whether the aryl ketone of the ortho-amino halide is α-amino- β-halogen type or α-halo-β-amino type, the amino group of all products is in the 2-position of pyrrole, and the 2-position amino group and the electron-deficient group at the 3-position can form a 1,4-even The extremely special structure can undergo 4+1 or 4+2 ring-closing reactions, which provides a new route for the synthesis of other complex heteropolycyclic compounds.

Detailed ways

The present invention will be described in further detail below in conjunction with the examples, but the protection scope of the present invention is not limited to these examples.

Example 1

Taking the synthesis of 1-p-toluenesulfonyl-2-amino-3-cyano-4-phenyl-5-benzoylpyrrole with the following structural formula as an example, the specific synthesis method is as follows:

Add 0.457g (1mmol) 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1, 0.066g (1mmol) propylene glycol to a 50mL round bottom flask successively Nitrile, 0.106g (1mmol) sodium carbonate, 5mL methanol, magnetic stirring reaction at 50°C for 8 hours, then add 25mL ethyl acetate, wash with saturated brine three times (each 25mL), and then wash with water three times (each 25mL) , the organic phase was dried overnight with anhydrous sodium sulfate, filtered to remove the desiccant, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (with a mixture of petroleum ether and ethyl acetate volume ratio of 5:1 as eluent), 1-p-toluenesulfonyl-2-amino-3-cyano-4-phenyl-5-benzoylpyrrole was obtained in a yield of 89%, recrystallized from absolute ethanol to obtain a light yellow solid with a melting point of 188.8- 190.2°C, the structural characterization data are as follows:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.48-7.41 (m, 7H), 7.24 (dd, J=14.3, 4.0 Hz, 4H), 7.12 (m, 5H), 2.42 (s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 190.2, 150.7, 146.5, 136.2, 133.4(2), 131.3(2), 130.2(2), 129.3(2), 128.9(2), 128.5, 128.2( 2), 128.0, 127.0(2), 126.9(2), 124.9, 114.5, 72.6, 21.2.

High resolution mass spectrum HRMS: Calcd. for C ₂₅ H ₁₉ N ₃ O ₃ S ([M+Na] ⁺ ) 464.1039, found 464.1047.

Example 2

Taking the synthesis of 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-chlorophenyl)-5-benzoylpyrrole as an example, the specific synthesis method is as follows:

In Example 1, the 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-phenyl-3-(4 -Chlorophenyl)-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was replaced, the reaction time was extended to 14 hours, and other steps were the same as in Example 1 to obtain yellow solid 1-p-toluenesulfonate Acyl-2-amino-3-cyano-4-(4-chlorophenyl)-5-benzoylpyrrole has a yield of 70%, a melting point of 198.8-199.9°C, and structural characterization data as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.47(m, 7H), 7.27(dd, J=14.2, 6.5Hz, 4H), 7.19(d, J=8.4Hz, 2H), 7.11(d, J=8.4Hz, 2H), 2.42(s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 190.0, 150.8, 146.7, 136.2, 133.4, 133.2, 133.0(2), 130.3(2), 129.0(2), 128.3(2), 128.3(2), 127.2(2), 126.9(2), 126.7(2), 125.30, 114.4, 72.7, 21.2.

High resolution mass spectrum HRMS: calculated for C ₂₅ H ₁₆ ClN ₃ O ₃ S ([M+Na] ⁺ ) 498.0650, found 498.0652.

Example 3

Taking the synthesis of 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-bromophenyl)-5-benzoylpyrrole as an example with the following structural formula, the specific synthesis method is as follows:

In Example 1, the 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-phenyl-3-(4 -Bromophenyl)-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was replaced, the reaction time was extended to 9 hours, and other steps were the same as in Example 1 to obtain yellow solid 1-p-toluenesulfonate Acyl-2-amino-3-cyano-4-(4-bromophenyl)-5-benzoylpyrrole has a yield of 84%, a melting point of 201.8-202.8°C, and structural characterization data as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.48 (m, 7H), 7.37-7.22 (m, 6H), 7.06 (dd, J=8.2, 2.4Hz, 2H), 2.40 (s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 190.0, 150.8, 146.6, 136.2, 133.2, 130.3(2), 130.1(4), 129.0(2), 128.7(2), 128.3(2), 126.9( 2), 126.8, 125.3, 122.1(2), 114.3, 72.8, 21.2.

High resolution mass spectrum HRMS: Calcd. for C ₂₅ H ₁₆ BrN ₃ O ₃ S ([M+Na] ⁺ ) 542.0144, found 542.0145.

Example 4

Taking the following 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-fluorophenyl)-5-(4-methoxybenzoyl)pyrrole as an example, the specific synthetic method as follows:

In Example 1, the 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-(4-methoxybenzene Base)-3-(4-fluorophenyl)-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 replacement, the reaction time was extended to 18 hours, other steps were the same as in Example 1, and obtained Pale yellow solid 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-fluorophenyl)-5-(4-methoxybenzoyl)pyrrole in 69% yield, The melting point is 156.1-157.2°C, and the structural characterization data are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.48(d, J=7.4Hz, 6H), 7.21(s, 2H), 7.14～7.09(m, 2H), 7.00(t, J=8.7Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 2.42 (s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 188.8, 163.8, 161.7, 151.1, 147.0, 133.9, 133.9(2), 132.1(2), 130.8(2), 129.4(2), 127.4(2), 126.5, 126.1, 115.0, 114.8, 114.6, 114.2(2), 73.1, 56.0, 21.2.

High resolution mass spectrum HRMS: Calcd. for C ₂₆ H ₂₀ FN ₃ O ₄ S ([M+Na] ⁺ ) 512.1051, found 512.1048.

Example 5

Taking the synthesis of 1-p-toluenesulfonyl-2-amino-3-cyano-4-phenyl-5-(4-chlorobenzoyl)pyrrole as an example, the specific synthesis method is as follows:

In Example 1, 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-(4-chlorophenyl) -3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was replaced, the reaction time was shortened to 6 hours, other steps were the same as in Example 1, and yellow solid 1-p-toluene was obtained Sulfonyl-2-amino-3-cyano-4-phenyl-5-(4-chlorobenzoyl)pyrrole has a yield of 91%, a melting point of 200.1-201.9°C, and structural characterization data as follows:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.44 (m, 6H), 7.29-7.17 (m, 5H), 7.16-7.02 (m, 4H), 2.41 (s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 189.0, 150.7, 146.6, 137.7, 135.1, 133.4, 131.6(2), 130.7(2), 130.3(2), 129.1(2), 128.8, 128.7, 128.2 (2), 127.1(2), 127.0(2), 124.2, 114.5, 72.4, 21.2.

High resolution mass spectrum HRMS: calculated for C ₂₅ H ₁₆ ClN ₃ O ₃ S ([M+Na] ⁺ ) 498.0650, found 498.0654.

Example 6

Taking the synthesis of 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-fluorophenyl)-5-benzoylpyrrole as an example with the following structural formula, the specific synthesis method is as follows:

In Example 1, the 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-phenyl-3-(4 -Fluorophenyl)-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was replaced, the reaction time was extended to 16 hours, other steps were the same as in Example 1, and yellow needle crystal 1-para Tosyl-2-amino-3-cyano-4-(4-fluorophenyl)-5-benzoylpyrrole has a yield of 70% and a melting point of 189.9-190.2°C. The structural characterization data are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.46(m, 7H), 7.23(d, J=34.3Hz, 4H), 7.11(s, 2H), 6.98～6.87(m, 2H), 2.42( s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 190.5, 163.4, 151.1, 147.1, 136.9, 134.3, 134.2, 134.0, 133.5, 130.8(2), 129.5(2), 128.7(2), 127.7, 127.4( 2), 126.2, 126.2, 125.4, 115.0, 114.6, 114.5, 73.1, 21.2.

High resolution mass spectrum HRMS: calculated for C ₂₅ H ₁₈ FN ₃ O ₃ S ([M+Na] ⁺ ) 482.0945, found 482.0943.

Example 7

Taking the synthesis of 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-fluorophenyl)-5-(4-chlorobenzoyl)pyrrole as an example, the specific synthesis method is as follows:

In Example 1, 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-(4-chlorophenyl) -3-(4-fluorophenyl)-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was replaced, the reaction time was extended to 10 hours, other steps were the same as in Example 1, and yellow needles were obtained 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-fluorophenyl)-5-(4-chlorobenzoyl)pyrrole as crystals, with a yield of 76% and a melting point of 199.4 ~201.8°C, the structural characterization data are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.49～7.43(m, 6H), 7.29(d, J=8.4Hz, 2H), 7.21(s, 2H), 7.11(dd, J=8.7, 5.5 Hz, 2H), 6.96 (t, J=8.8Hz, 2H), 2.40 (s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 188.9, 163.4, 161.0, 150.6, 146.6, 137.7, 135.2, 134.0, 134.0, 133.4, 130.8, 130.3, 128.2(2), 127.9, 126.9(2), 125.5 , 125.5, 124.4, 114.5, 114.2, 21.2.

High resolution mass spectrum HRMS: Calcd. for C ₂₅ H ₁₇ FN ₃ O ₃ S ([M+Na] ⁺ ) 516.0555, found 516.0563.

Example 8

Taking the synthesis of 1-p-toluenesulfonyl-2-amino-3-cyano-4-benzoyl-5-(4-methoxyphenyl)pyrrole as an example, the specific synthesis method is as follows:

In Example 1, the 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-phenyl-3-(4 -Methoxyphenyl)-3-(4-methylbenzenesulfonylamino)-2-bromoacetone-1 was replaced, the reaction time was extended to 24 hours, and other steps were the same as in Example 1 to obtain yellow solid 1-para Tosyl-2-amino-3-cyano-4-benzoyl-5-(4-methoxyphenyl)pyrrole has a yield of 49%, a melting point of 196.8-198.8°C, and structural characterization data as follows :

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.49～7.42(m, 7H), 7.26(t, J=7.8Hz, 2H), 7.15(s, 2H), 6.96(d, J=8.7Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 3.66 (s, 3H), 2.41 (s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 190.2, 159.4, 150.5, 146.4, 136.4, 133.5, 133.0, 130.2(2), 129.0(4), 128.4, 128.2, 126.9(2), 124.2(2) , 121.2, 114.6, 112.5(2), 72.4, 55.0, 21.2.

High resolution mass spectrum HRMS: Calcd. for C ₂₆ H ₂₁ N ₃ O ₄ S ([M+Na] ⁺ ) 494.1145, found 494.1149.

Example 9

Taking the synthesis of 1-p-toluenesulfonyl-2-amino-3-cyano-4-benzoyl-5-(4-methylphenyl)pyrrole as an example with the following structural formula, the specific synthesis method is as follows:

In Example 1, the 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-phenyl-3-(4 -Methylphenyl)-3-(4-methylbenzenesulfonylamino)-2-bromoacetone-1 replacement, other steps are the same as in Example 1, to obtain yellow needle crystal 1-p-toluenesulfonyl-2- Amino-3-cyano-4-benzoyl-5-(4-methylphenyl)pyrrole has a yield of 59%, a melting point of 196.2-197.8°C, and structural characterization data as follows:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.46 (m, 7H), 7.27 (s, 2H), 7.18 (s, 2H), 6.94 (s, 4H), 2.42 (s, 3H), 2.19 ( s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 190.7, 151.1, 146.9, 138.5, 136.8, 134.0, 133.6, 131.7(2), 130.7(2), 129.5(2), 128.8(2), 128.6, 128.2 (2), 127.4(2), 126.9, 125.1, 115.0, 73.1, 21.7, 21.3.

High resolution mass spectrum HRMS: Calculated for C ₂₆ H ₂₁ N ₃ O ₃ S ([M+Na] ⁺ ) 478.1196, found 478.1193.

Example 10

Taking the following 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-chlorobenzoyl)-5-(4-methoxyphenyl)pyrrole as an example, the specific synthetic method as follows:

In Example 1, 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-(-chlorophenyl)- 3-(4-methoxyphenyl)-3-(4-methylbenzenesulfonylamino)-2-bromoacetone-1 was replaced, the reaction time was extended to 24 hours, and other steps were the same as in Example 1 to obtain yellow Solid 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-chlorobenzoyl)-5-(4-methoxyphenyl)pyrrole in 43% yield, melting point 206.2～207.5℃, the structural characterization data are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.47～7.39(m, 6H), 7.28(d, J=8.5Hz, 2H), 7.15(s, 2H), 6.94(d, J=8.7Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 3.68 (s, 3H), 2.40 (s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 189.1, 159.6, 150.4, 146.5, 137.4, 135.3, 133.5, 133.2(2), 130.7(2), 130.2(2), 129.3, 128.2(2), 126.9 (2), 123.7, 121.0, 114.7, 112.6(2), 72.2, 55.1, 21.2.

High resolution mass spectrum HRMS: Calcd. for C ₂₆ H ₂₀ N ₃ O ₄ S ([M+Na] ⁺ ) 528.0755, found 528.0754.

Example 11

Taking the following 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-nitrobenzoyl)-5-(4-methoxyphenyl)pyrrole as an example, the specific synthesis Methods as below:

In Example 1, the 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-(4-nitrophenyl )-3-(4-methoxyphenyl)-3-(4-methylbenzenesulfonylamino)-2-bromoacetone-1 was replaced, the reaction time was extended to 24 hours, and other steps were the same as in Example 1, 1-p-Toluenesulfonyl-2-amino-3-cyano-4-(4-nitrobenzoyl)-5-(4-methoxyphenyl)pyrrole was obtained as a yellow solid in 35% yield , the melting point is 199.1～200.4℃, and the structural characterization data are as follows:

¹ H NMR (600MHz, DMSO-d ₆ ) δ: 7.93(d, J=6.8Hz, 2H), 7.58～7.37(m, 6H), 7.15(s, 2H), 6.90(d, J=6.8Hz, 2H), 6.56 (d, J = 6.3 Hz, 2H), 3.60 (s, 3H), 2.38 (s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 189.4, 160.3, 151.0, 149.1, 147.1, 143.0, 134.2, 134.1(2), 131.8, 130.8(2), 130.4(2), 127.5(2), 123.8 , 123.3(2), 121.1, 115.2, 113.0(2), 72.6, 55.6, 21.2.

High resolution mass spectrum HRMS: Calcd. for C ₂₆ H ₂₀ N ₄ O ₆ S ([M+Na] ⁺ ) 539.0996, found 539.0998.

Example 12

Taking 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-methoxybenzoyl)-5-(4-methoxyphenyl)pyrrole as an example with the following synthetic structural formula, the specific The synthesis method is as follows:

In Example 1, the 1-phenyl-3-phenyl-2-(4-methylbenzenesulfonylamino)-3-bromoacetone-1 was used with equimolar 1-(4-methoxybenzene Base)-3-(4-methoxyphenyl)-3-(4-methylbenzenesulfonylamino)-2-bromoacetone-1 replacement, the reaction time was extended to 24 hours, other steps were the same as in Example 1 , to obtain 1-p-toluenesulfonyl-2-amino-3-cyano-4-(4-methoxybenzoyl)-5-(4-methoxyphenyl)pyrrole as a yellow solid in a yield of 40%, the melting point is 188.9-190.2°C, and the structural characterization data are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 7.51～7.42 (m, 6H), 7.13 (s, 2H), 6.97 (d, J=6.7Hz, 2H), 6.76 (dd, J=68.5, 7.1 Hz, 4H), 3.76(s, 3H), 3.68(s, 3H), 2.41(s, 3H).

¹³ C NMR (100MHz, DMSO-d ₆ ) δ: 189.0, 163.7, 159.8, 150.9, 146.8, 133.2(2), 132.1(2), 130.7(2), 129.5(2), 127.4, 125.3(2), 122.0, 114.2, 113.2(4), 73.0, 56.0, 55.5, 21.7.

High resolution mass spectrum HRMS: Calcd. for C ₂₇ H ₂₃ N ₃ O ₅ S ([M+Na] ⁺ ) 524.1251, found 524.1245.

In the above-mentioned Examples 1-12, _{the Na2CO3} used can also be replaced by equimolar sodium acetate, _{K2CO3 , KHCO3} , _K3PO4 , NaOH, KOH, ethylenediamine or triethylamine _. Methanol can also be replaced by an equal volume of ethanol, propanol, N,N-dimethylformamide, acetonitrile, and dimethyl sulfoxide, and other steps are the same as in the corresponding examples.

Claims (6)

1. a synthetic method of five substituted 2-aminopyrrole derivatives, characterized in that: in a more polar organic solvent, the aryl ketone and malononitrile of the ortho amino halide shown in formula I or formula II , The molar ratio of alkali is 1:1～1.5:0.5～2, mix evenly, stir at 40～60°C for 6～24 hours, separate and purify the product, and obtain the pentasubstituted 2-aminopyrrole derivative represented by formula III or formula IV; In formulas I~IV, Ar ₁ and Ar ₂ independently represent phenyl, C ₁ ~C ₄ alkyl substituted phenyl, C ₁ ~C ₄ alkoxy substituted phenyl, halogen and C ₁ ~C ₄ alkoxy Any one of phenyl substituted by radical, halophenyl, nitro substituted phenyl, X represents Cl, Br or I; The above-mentioned highly polar organic solvent is any one of methanol, ethanol, propanol, N,N-dimethylformamide, acetonitrile, and dimethyl sulfoxide. 2. the synthetic method of five substituted 2-aminopyrrole derivatives according to claim 1 is characterized in that: described Ar ₁ and Ar ₂ independently represent phenyl, 4-methylphenyl, 4-formyl Oxyphenyl, 2-halo-4,5-dimethoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl , 4-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, and 4-nitrophenyl. 3. according to the synthetic method of claim 1 or 2 described five substituted 2-aminopyrrole derivatives, it is characterized in that: the mol ratio of the aryl ketone of described ortho amino halide and malononitrile, alkali is 1:1 ~1.5:1~1.5. 4. The synthetic method of the five-substituted 2-aminopyrrole derivatives according to claim 1, characterized in that: the more polar organic solvent is methanol. 5. The synthesis method of pentasubstituted 2-aminopyrrole derivatives according to claim 1, characterized in that: the base is sodium acetate, K ₂ CO ₃ , KHCO ₃ , Na ₂ CO ₃ , K ₃ PO ₄ , NaOH, KOH, ethylenediamine, triethylamine in any one. 6. The synthesis method of pentasubstituted 2-aminopyrrole derivatives according to claim 1, characterized in that: the base is Na ₂ CO ₃ .