Synthesis method of 2-aryl-9H-pyrimido [4, 5-b] indole derivative

Abstract

The invention mainly relates to a synthesis method of a 2-aryl-9H-pyrimido [4, 5-b] indole derivative, which comprises the following steps: under the combined action of a copper catalyst, a ligand, an oxidant and an additive which are cheap and easy to obtain, carrying out condensation cyclization reaction on an indole-3-formaldehyde compound and an amidine compound to construct two new C-N bonds, and synthesizing the 2-aryl-9H-pyrimido [4, 5-b] indole derivative in one pot. 5-b] indole derivatives. The method provided by the invention overcomes the defects that the existing synthetic method of the 2-aryl-9H-pyrimido [4, 5-b] indole compound has complex synthetic steps and needs to adopt a multi-step synthetic process; the method has the advantages of simple reaction system, less reaction equipment, simplicity and convenience in experimental operation, wide material source, easiness in expansion of users and application, higher product utilization value and the like.

Description

Technical Field

[0001] The invention relates to a synthesis method of 2-aryl-9H-pyrimido[4,5-b]indole derivatives, and belongs to the field of organic synthesis. Background Art

[0002] Pyrimido[4,5-b]indole compounds are an important class of nitrogen-containing heterocyclic compounds, which are widely used in medicine, pesticides and functional materials. The development of high-yield, efficient, economical and environmentally friendly methods for synthesizing pyrimido[4,5-b]indole compounds has broad market prospects. However, the current synthesis of 2-aryl-9H-pyrimido[4,5-b]indole derivatives requires multi-step reactions or the use of pre-functionalized substrates as raw materials. Therefore, the development of efficient methods for synthesizing such substances has important inventive significance.

[0003] References:

[0004] Reaction of 3-(R-Methylidene)-2-ethoxylindolenines with N,N'-Binucleophiles, VP Borovik, Yu.V. Gatilov, and OPShkurko. Summary of the invention

[0005] In view of the above situation, the purpose of the present invention is to provide a method for synthesizing 2-aryl-9H-pyrimido[4,5-b]indole derivatives, which has the advantages of simple process, convenient operation, cheap and easy to obtain raw materials, few reaction steps, and simple required equipment.

[0006] To achieve this purpose, a method for synthesizing 2-aryl-9H-pyrimido[4,5-b]indole derivatives is provided, in which an indole-3-carboxaldehyde derivative, an amidine compound and an organic solvent are mixed and heated to react under the combined action of a catalyst, a ligand, an additive and an oxidant, and the product is purified.

[0007] In order to improve the comprehensive performance of the present invention and optimize the structure and effect, further measures are as follows:

[0008] The catalyst is one of cuprous iodide, cupric acetate, cuprous chloride, cuprous bromide, cuprous cyanide, cupric chloride, cupric bromide, cupric sulfate, copper trifluoromethanesulfonate, and copper powder, preferably cuprous iodide.

[0009] The ligand is one of 2,2'-bipyridine, 2,2'-biquinoline, pyridine, 2-aminopyridine, 4-(dimethylamino)pyridine, 1,10-phenanthroline, 7-azaindole, 4,4'-dimethyl-2,2'bipyridine, 8-hydroxyquinoline, 2-amino-4-methylpyridine, 4,5-diazafluorene-9-one, and 1,10-phenanthroline-5,6-dione, preferably 2,2'-bipyridine.

[0010] The oxidant is one of air and oxygen, preferably oxygen.

[0011] The additive is one of dimethyl sulfoxide, diphenyl sulfoxide, phenylbenzyl sulfoxide and phenylmethyl sulfoxide, preferably dimethyl sulfoxide.

[0012] The organic solvent is one of o-dichlorobenzene, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane, toluene, N-methylpyrrolidone and pyridine, preferably o-dichlorobenzene.

[0013] The molar ratio of the indole-3-carboxaldehyde derivative, the amidine compound, the catalyst, the ligand and the additive is 1:1-3:0.02-0.5:0.02-0.5:1-4, preferably 1:2:0.3:0.3:3.

[0014] The reaction temperature is 120-170°C, preferably 160°C; the reaction time is 12-30h, preferably 24h.

[0015] The general formula of the indole-3-carboxaldehyde derivative is Ⅰ:

[0016]

[0017] Among them, R 1 is selected from hydrogen atom, alkyl, alkoxy, halogen, ester group; R 2 Selected from hydrogen atom, alkyl group, phenyl group; further selected from: indole-3-carboxaldehyde, 4-methyl-indole-3-carboxaldehyde, 5-methyl-indole-3-carboxaldehyde, 6-methyl-indole-3-carboxaldehyde, 7-methyl-indole-3-carboxaldehyde, 6-methoxy-indole-3-carboxaldehyde, 6-fluoro-indole-3-carboxaldehyde, 4-chloro-indole-3-carboxaldehyde, 5-chloro-indole-3-carboxaldehyde, 6-chloro-indole-3-carboxaldehyde, 7-chloro-indole-3-carboxaldehyde, 5-bromo-indole-3-carboxaldehyde, 6-bromo-indole-3-carboxaldehyde, 5-methylformyl-indole-3-carboxaldehyde, N-methyl-indole-3-carboxaldehyde, N-ethyl-indole-3-carboxaldehyde, N-phenyl-indole-3-carboxaldehyde.

[0018] The general formula of the amidine compound is II:

[0019]

[0020] Among them, R 3 Substituted or unsubstituted phenyl, pyridyl; further selected from: benzamidine hydrochloride, 2-methylbenzamidine hydrochloride, 3-methylbenzamidine hydrochloride, 4-methylbenzamidine hydrochloride, 2-ethoxybenzamidine hydrochloride, 3-methoxybenzamidine hydrochloride, 4-methoxybenzamidine hydrochloride, 4-hydroxybenzamidine hydrochloride, 4-fluorobenzamidine hydrochloride, 4-chlorobenzamidine hydrochloride, 2-bromobenzamidine hydrochloride, 4-bromobenzamidine hydrochloride, 4-trifluoromethylbenzamidine hydrochloride, 4-nitrobenzamidine hydrochloride, 2-amidinopyridine hydrochloride, 3-amidinopyridine hydrochloride, 4-amidinopyridine hydrochloride. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to prove the products of the present invention, the present invention provides hydrogen NMR spectra and carbon NMR spectra of some embodiments.

[0022] Figure 1a H NMR spectrum of the product of Example 1.

[0023] Figure 1b The NMR carbon spectrum of the product of Example 1.

[0024] Figure 2a H NMR spectrum of the product of Example 13.

[0025] Figure 2b NMR carbon spectrum of the product of Example 13.

[0026] Figure 3a H NMR spectrum of the product of Example 14.

[0027] Figure 3b The NMR carbon spectrum of the product of Example 14.

[0028] Figure 4a H NMR spectrum of the product of Example 18.

[0029] Figure 4b NMR carbon spectrum of the product of Example 18.

[0030] Figure 5a H NMR spectrum of the product of Example 21.

[0031] Figure 5b NMR carbon spectrum of the product of Example 21.

[0032] Figure 6a H NMR spectrum of the product of Example 25.

[0033] Figure 6b NMR carbon spectrum of the product of Example 25.

[0034] Figure 7a H NMR spectrum of the product of Example 28.

[0035] Figure 7b NMR carbon spectrum of the product of Example 28.

[0036] Figure 8a H NMR spectrum of the product of Example 32.

[0037] Figure 8b NMR carbon spectrum of the product of Example 32.

[0038] Figure 9a H NMR spectrum of the product of Example 35.

[0039] Figure 9b NMR carbon spectrum of the product of Example 35.

[0040] Fig.10 It is the general formula of the reaction system of the method for synthesizing 2-aryl-9H-pyrimido[4,5-b]indole and its derivatives of the present invention. DETAILED DESCRIPTION

[0041] The technical solution of the present invention will be described clearly and completely below in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0042] The technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0043] Combined with the synthesis route of the compound of the present invention, the synthesis method of 2-aryl-9H-pyrimido[4,5-b]indole and its derivatives is that under the joint action of cheap and readily available copper catalysts, oxidants and additives, indole-3-carboxaldehyde compounds and amidine compounds undergo condensation cyclization reaction to construct two new CN bonds, and 2-aryl-9H-pyrimido[4,5-b]indole derivatives are synthesized in one pot. This method overcomes the shortcomings of the existing synthesis method of 2-aryl-9H-pyrimido[4,5-b]indole compounds, such as complex synthesis steps, the need to adopt a multi-step synthesis process to complete, and the need for highly pre-functionalized reaction raw materials; it maintains atom economy to the greatest extent; it has the advantages of simple reaction system, mild reaction conditions, less reaction equipment, simple experimental operation, wide source of materials, easy expansion of users and applications, and high product utilization value.

[0044] The general reaction system of the synthesis method of 2-aryl-9H-pyrimido[4,5-b]indole and its derivatives is as follows: Fig.10 Shown

[0045] The following steps are involved:

[0046] (1) adding an indole-3-carboxaldehyde derivative, an amidine compound, a catalyst, a ligand, an additive, an oxidant (oxygen-containing gas) and an organic solvent into a reaction vessel;

[0047] (2) After the reactants are fully mixed, heating is performed;

[0048] (3) purifying the product after the reaction;

[0049] Wherein, the catalyst is one of cuprous iodide, cupric acetate, cuprous chloride, cuprous bromide, cuprous cyanide, cupric chloride, cupric bromide, copper sulfate, copper trifluoromethane sulfonate, and copper powder, preferably cuprous iodide;

[0050] The ligand is one of 2,2'-bipyridine, 2,2'-biquinoline, pyridine, 2-aminopyridine, 4-(dimethylamino)pyridine, 1,10-phenanthroline, 7-azaindole, 4,4'-dimethyl-2,2'bipyridine, 8-hydroxyquinoline, 2-amino-4-methylpyridine, 4,5-diazafluorene-9-one, and 1,10-phenanthroline-5,6-dione, preferably 2,2'-bipyridine;

[0051] The oxidant is one of air and oxygen, preferably oxygen;

[0052] The additive is one of dimethyl sulfoxide, diphenyl sulfoxide, phenyl benzyl sulfoxide, and phenyl methyl sulfoxide, preferably dimethyl sulfoxide;

[0053] The organic solvent is one of o-dichlorobenzene, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane, toluene, N-methylpyrrolidone, and pyridine, preferably o-dichlorobenzene;

[0054] The molar ratio of the indole-3-carboxaldehyde derivative, the amidine compound, the catalyst, the ligand, and the additive is 1:1-3:0.02-0.5:0.02-0.5:1-4, preferably 1:2:0.3:0.3:3;

[0055] The reaction temperature is 120-170°C, preferably 160°C; the reaction time is 12-30h, preferably 24h.

[0056] Table 1 Reactants, catalysts, ligands, oxidants, additives, organic solvents, molar ratios, reaction temperatures and reaction times of Examples 1-35

[0057]

[0058]

[0059]

[0060]

[0061] * is the molar ratio of indole-3-carboxaldehyde derivative, amidine compound, catalyst, oxidant and additive

[0062] Table 2 Yield and product structure of Example 1-41 reaction

[0063]

[0064]

[0065]

[0066] The NMR data of the products of some embodiments are as follows:

[0067] NMR data of the product of Example 1:

[0068] 1 H NMR (400 MHz, DMSO-d 6 )δ12.38(br,1H,NH),9.53(s,1H),8.52(d,J=6.8Hz,2H),8.23(d,J=7.6Hz,1H),7.58-7.52(m,5H),7.33(t,J=7.2Hz,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ159.7,156.1,149.0,139.0,138.3,130.2,128.6,127.8,127.6,121.6,121.0,119.1,112.4,111.9.HRMS(ESI)m / z calcd.For C 16 H 12 N 3 + (M+H) + 246.1026, found 246.1038.

[0069] NMR data of the product of Example 13:

[0070] 1 H NMR (400 MHz, DMSO-d 6 )δ12.20(br,1H,NH),9.47(s,1H),8.51(dd,J 1 =8.0Hz,J 2=1.6Hz,2H),8.02(s,1H),7.56-7.50(m,3H),7.45(d,J=8.0Hz,1H),7.345(dd,J 1 =8.4Hz,J 2 =0.8Hz,1H),2.48(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ159.5,156.1,148.7,138.3,137.1,130.1,129.9,128.8,128.6,127.7,121.3,119.1,112.2,111.5,21.0.HRMS(ESI)m / z calcd.For C 17 H 14 N 3 + (M+H) + 260.1182, found 260.1194.

[0071] NMR data of the product of Example 14:

[0072] 1 H NMR (400 MHz, DMSO-d 6 )δ12.23(br,1H,NH),9.41(s,1H),8.46(d,J=7.2Hz,2H),8.05(d,J=8.0Hz ,1H),7.51-7.46(m,3H),7.23(s,1H),7.11(d,J=8.0Hz,1H),2.45(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ159.2,156.2,148.3,139.4,138.3,137.5,130.1,128.6,127.7,122.5,121.3,116.6,112.5,111.8,21.8.HRMS(ESI)m / z calcd.For C 17 H 14 N 3 + (M+H) + 260.1182, found 260.1195.

[0073] NMR data of the product of Example 18:

[0074] 1 H NMR (400 MHz, DMSO-d 6)δ12.70(br,1H,NH),9.57(s,1H),8.50(d,J=6.8Hz,2H),7.53-7.51(m,5H),7.36(d,J=6.4Hz,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ160.1,156.0,149.8,140.1,137.9,130.4,128.6,128.5,127.9,127.8,121.1,117.1,111.3,110.8.HRMS(ESI)m / z calcd.For C 16 H 11 C1N 3 + (M+H) + 280.0636, found 280.0651.

[0075] NMR data of the product of Example 21:

[0076] 1 H NMR (400 MHz, DMSO-d 6 )δ12.53(br,1H,NH),9.57(s,1H),8.51(dd,J 1 =7.2Hz,J 2 =2.0Hz,2H),8.21(d,J=8.4Hz,1H),7.57-7.51(m,5H). 13 C NMR (100 MHz, DMSO-d 6 )δ160.1,156.3,149.5,139.9,138.0,130.4,128.6,127.8,123.9,123.4,120.2,116.3,114.5,111.9.HRMS(ESI)m / z calcd.For C 16 H 11 C1N 3 + (M+H) + 324.0131, found 324.0146.

[0077] NMR data of the product of Example 25:

[0078] 1 H NMR (400 MHz, DMSO-d 6)δ12.38(br,1H,NH),9.52(s,1H),8.23(d,J=7.6Hz,1H),8.11(d,J=7.6Hz,1H),8.0 6(s,1H),7.58-7.51(m,2H),7.45(t,J=8.0Hz,1H),7.33(t,J=7.2Hz,1H),7.08(dd,J 1 =8.0Hz,J 2 =2.0Hz,1H),3.87(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ159.5,159.4,156.0,148.8,139.7,139.0,129.7,127.6,121.6,121.0,120.2,119.0,116.2,112.5,112.4,111.8,55.1.HRMS(ESI)m / z calcd.For C 17 H 14 N 3 O + (M+H) + 276.1131, found 276.1147.

[0079] NMR data of the product of Example 28:

[0080] 1 H NMR (400 MHz, DMSO-d 6 )δ12.36(br,1H,NH),9.51(s,1H),8.56-8.52(m,2H),8.23(d,J=7.6Hz,1H),7.57-7.50(m,2H),7.37-7.33(m,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ163.6(d,J=245.7Hz),158.8,156.0,149.0,139.0,134.75(d,J=2.6Hz),130.02(d,J=8.7H z),127.6,121.6,121.0,119.0,115.5(d,J=21.5Hz),112.3,111.9.HRMS(ESI)m / zcalcd.For C 16 H 11 FN 3 + (M+H) + 264.0932, found 264.0947.

[0081] NMR data of the product of Example 32:

[0082] 1 H NMR (400 MHz, DMSO-d 6 )δ12.55(br,1H,NH),9.57(s,1H),8.68(d,J=8.0Hz,2H),8.255(d,J=8.0Hz,1H),7. 89(d,J=8.4Hz,2H),7.61-7.59(m,1H),7.55(t,J=7.6Hz,1H),7.34(t,J=7.4Hz,1H). 13 CNMR (100MHz, DMSO-d 6 )δ158.1,155.8,149.0,142.0,139.2,130.0(q,J=31.4Hz),128.3,127.9,125.5(q, J=3.4Hz),124.3(q,J=274.5Hz),121.8,121.1,118.8,112.9,112.0.HRMS(ESI)m / z calcd.For C 17 H 11 F 3 N 3 + (M+H) + 314.0900, found 314.0922.

[0083] NMR data of the product of Example 35:

[0084] 1 H NMR (400 MHz, DMSO-d 6 )δ12.54(br,1H,NH),9.61(s,1H),8.77(s,2H),8.36(d,J=4.8Hz,2H),8.28(d,J=7.6Hz,1H),7.61-7.55(m,2H),7.36(t,J=6.8Hz,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ157.5,155.8,150.4,149.0,145.3,139.3,128.2,122.0,121.7,121.3,118.8,113.5,112.0.HRMS(ESI)m / z calcd.For C 15 H 11 N 4 + (M+H) + 247.0978, found 247.0993.

[0085] Based on the above ideal embodiments of the present invention, the relevant staff can make various changes and modifications without departing from the technical concept of the present invention through the above description. The technical scope of the present invention is not limited to the contents of the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A method for synthesizing 2-aryl-9H-pyrimido[4,5-b]indole and its derivatives, characterized in that: The synthesis method comprises the following steps: adding indole-3-carboxaldehyde derivatives, amidine compounds, catalysts, ligands, additives, oxidants and organic solvents into a reaction container; fully mixing the reactants and heating them; and purifying them after the reaction to obtain a product.

2. The method according to claim 1, characterized in that The general formula of the indole-3-carboxaldehyde derivative is Ⅰ: Among them, R 1 is selected from hydrogen atom, alkyl, alkoxy, halogen, ester group; R 2 Selected from hydrogen atom, alkyl group, phenyl group; further selected from: indole-3-carboxaldehyde, 4-methyl-indole-3-carboxaldehyde, 5-methyl-indole-3-carboxaldehyde, 6-methyl-indole-3-carboxaldehyde, 7-methyl-indole-3-carboxaldehyde, 6-methoxy-indole-3-carboxaldehyde, 6-fluoro-indole-3-carboxaldehyde, 4-chloro-indole-3-carboxaldehyde, 5-chloro-indole-3-carboxaldehyde, 6-chloro-indole-3-carboxaldehyde, 7-chloro-indole-3-carboxaldehyde, 5-bromo-indole-3-carboxaldehyde, 6-bromo-indole-3-carboxaldehyde, 5-methylformyl-indole-3-carboxaldehyde, N-methyl-indole-3-carboxaldehyde, N-ethyl-indole-3-carboxaldehyde, N-phenyl-indole-3-carboxaldehyde.

3. The method according to claim 1, characterized in that The general formula of the amidine compound is II: Among them, R 3 Substituted or unsubstituted phenyl, pyridyl; further selected from: benzamidine hydrochloride, 2-methylbenzamidine hydrochloride, 3-methylbenzamidine hydrochloride, 4-methylbenzamidine hydrochloride, 2-ethoxybenzamidine hydrochloride, 3-methoxybenzamidine hydrochloride, 4-methoxybenzamidine hydrochloride, 4-hydroxybenzamidine hydrochloride, 4-fluorobenzamidine hydrochloride, 4-chlorobenzamidine hydrochloride, 2-bromobenzamidine hydrochloride, 4-bromobenzamidine hydrochloride, 4-trifluoromethylbenzamidine hydrochloride, 4-nitrobenzamidine hydrochloride, 2-amidinopyridine hydrochloride, 3-amidinopyridine hydrochloride, 4-amidinopyridine hydrochloride.

4. The method according to claim 1, characterized in that The catalyst is one of cuprous iodide, cupric acetate, cuprous chloride, cuprous bromide, cuprous cyanide, cupric chloride, cupric bromide, cupric sulfate, copper trifluoromethanesulfonate, and copper powder, preferably cuprous iodide.

5. The method according to claim 1, characterized in that The ligand is one of 2,2'-bipyridine, 2,2'-biquinoline, pyridine, 2-aminopyridine, 4-(dimethylamino)pyridine, 1,10-phenanthroline, 7-azaindole, 4,4'-dimethyl-2,2'bipyridine, 8-hydroxyquinoline, 2-amino-4-methylpyridine, 4,5-diazafluorene-9-one, and 1,10-phenanthroline-5,6-dione, preferably 2,2'-bipyridine.

6. The method according to claim 1, characterized in that The oxidant is an oxygen-containing gas, such as air or oxygen, preferably oxygen.

7. The method according to claim 1, characterized in that The additive is one of dimethyl sulfoxide, diphenyl sulfoxide, phenylbenzyl sulfoxide and phenylmethyl sulfoxide, preferably dimethyl sulfoxide.

8. The method according to claim 1, characterized in that The organic solvent is one of o-dichlorobenzene, chlorobenzene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane, toluene, N-methylpyrrolidone and pyridine, preferably o-dichlorobenzene.

9. The method according to claim 1, characterized in that: The molar ratio of the indole-3-carboxaldehyde derivative, the amidine compound, the catalyst, the ligand and the additive is 1:1-3:0.02-0.5:0.02-0.5:1-4, preferably 1:2:0.3:0.3:

3.

10. The method according to claim 1, characterized in that The reaction temperature is 120-170°C, preferably 160°C; the reaction time is 12-30h, preferably 24h.

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