Preparation method of benzimidazopyrimidine derivative

Abstract

The invention relates to the technical field of biological pharmacy, in particular to a preparation method of a benzimidazopyrimidine derivative. The method comprises the following steps: reacting 2-aminobenzimidazole and acetophenone in DMSO (dimethylsulfoxide) serving as a solvent under the action of alkali and an oxidizing agent to obtain the benzimidazopyrimidine derivative. The invention provides a method for synthesizing the benzo [4, 5] imidazo [1, 2-a] pyrimidine derivative by providing a carbon source with a low-cost solvent, in the presence of CH3COONa and (NH4) 2S2O8, the (3 + 2 + 1) cascade reaction of 2-aminobenzimidazole, acetophenone and DMSO is smoothly carried out to generate a corresponding product, and the yield is good.

Description

Technical Field

[0001] The present invention relates to the technical field of biopharmaceuticals, and in particular to a method for preparing a benzimidazolinone pyrimidine derivative. Background Art

[0002] Nitrogen-containing heterocyclic compounds are widely present in nature. Various enzymes and proteins from the smallest prokaryotes to the largest eukaryotes are composed of nitrogen heterocyclic rings [Debnath, S.; Parveen, S.; Pradhan, P.; Das, I.; Das, T., New Journal of Chemistry 2022, 46(22), 10504-10534.]. Among nitrogen heterocycles, the benzo[4,5]imidazo[1,2-a]pyrimidine skeleton has been shown to be a structure with relevant biological properties [Marcus, AJ; Iezhitsa, I.; Agarwal, R.; Vassiliev, P.; Spasov, A.; Zhukovskaya, O.; Anisimova, V.; Johari, B.; Mohd Ismail, N., European Journal of Pharmaceutical Sciences 2018, 114, 245-254.], such as antibacterial [Fedotov, VV; Rusinov, VL; Ulomsky, EN; Mukhin, EM; Gorbunov, EB; Chupakhin, ON, Chemistry Heterocyclic Compound(NY)2021,57(4),383-409.], anticancer [Bharate, SB; Mahajan, TR; Gole, YR; Nambiar, M.; Matan, TT; Kulkarni-Almeida, A.; Balachandran, S.; Junjappa, H.; Balakrishnan, A.; Vishwakarma, RA,. Bioorganic & Medicinal Chemistry 2008,16(15),7167-76.]etc.

[0003] In addition, benzo[4,5]imidazo[1,2-a]pyrimidine as a conjugated planar pyrimidine scaffold has good photophysical properties and is often used in optoelectronics and optical lasers. At the same time, this scaffold is also widely used in organometallic catalysis, coordination chemistry and catalysis [anna, SK; Das, T.; Samanta, S., Chemistry Select 2019, 4 (30), 8781-8790.]

[0004] To this end, the present invention proposes a method for synthesizing benzo[4,5]imidazo[1,2-a]pyrimidine derivatives by providing a carbon source from a cheap solvent with good yield, providing a new method with low cost and good yield for the production and preparation of benzo[4,5]imidazo[1,2-a]pyrimidine. Summary of the invention

[0005] The purpose of the present invention is to provide a method for preparing a benzimidazolopyrimidine derivative, which is used to provide a new method with low cost and good yield for the production and preparation of benzo[4,5]imidazo[1,2-a]pyrimidine.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A method for preparing a benzimidazolinylpyrimidine derivative comprises the following steps:

[0008] The benzimidazolopyrimidine derivative is prepared by reacting 2-aminobenzimidazole and acetophenone in the presence of a base and an oxidant using DMSO as a solvent;

[0009] The molecular formula of the 2-aminobenzimidazole is as follows:

[0010]

[0011] The molecular formula of the acetophenone is as follows:

[0012]

[0013] The molecular formula of the DMSO is as follows:

[0014]

[0015] Furthermore, the oxidant is selected from TBHP, H 2 O 2 、Na 2 S 2 O 8 NH 4 ) 2 S 2 O 8 One or a combination of .

[0016] Furthermore, the oxidant is Na 2 S 2 O 8 .

[0017] Further, the base is selected from Et 3 N.K 2 CO 3 , NaOH, CH3 One or a combination of COONa.

[0018] Further, the base is CH 3 COONa.

[0019] Furthermore, the amount of the oxidant is 1-3 equivalents.

[0020] Furthermore, the reaction temperature is 110-130°C.

[0021] Further, the H of the 2-aminobenzimidazole can be replaced by: one or more C 1-6 Alkyl, one or more OC 1-6 Alkoxy, halogenated C 1-6 alkyl.

[0022] Furthermore, the molecular formula of the product of the benzimidazolopyrimidine derivative prepared by the method is as follows:

[0023]

[0024] The present invention has at least the following beneficial effects:

[0025] The present invention provides a method for synthesizing benzo[4,5]imidazo[1,2-a]pyrimidine derivatives by providing a carbon source from a cheap solvent. 3 COONa and (NH 4 ) 2 S 2 O 8 In the presence of , the (3+2+1) cascade reaction of 2-aminobenzimidazole, acetophenone and DMSO proceeded smoothly to generate the corresponding products in good yields. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying any creative work.

[0027] Figure 1 Schematic diagram of the reaction of the present invention. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0029] Example 1

[0030] The main purpose of the present invention is to provide a method for preparing a benzimidazolinone pyrimidine derivative, which is specifically as follows:

[0031] It is prepared by reacting a compound of formula I, a compound of formula II and a compound of formula III under the action of a base and an oxidant. The synthetic route is as follows Figure 1 shown.

[0032] The molecular formula of the compound of formula I (2-aminobenzimidazole) is as follows:

[0033]

[0034] The molecular formula of the compound of formula II (acetophenone) is as follows:

[0035]

[0036] The molecular formula of formula III (DMSO) is as follows:

[0037]

[0038] In one embodiment, R is H, one or more C 1-6 Alkyl, one or more OC 1-6 Alkoxy, halogenated C 1-6 alkyl.

[0039] In a specific embodiment, the oxidant is selected from TBHP, H 2 O 2 、Na 2 S 2 O 8 NH 4 ) 2 S 2 O 8 One or a combination of .

[0040] In a specific embodiment, the base is selected from Et 3 N.K 2 CO 3 , NaOH, CH 3 One or a combination of COONa;

[0041] In a specific embodiment, preferably, the base is selected from Et 3 N.K 2 CO 3 , NaOH, CH 3 One or a combination of COONa.

[0042] In a specific embodiment, preferably, the base is selected from CH3 COONa, the oxidant is selected from (NH 4 ) 2 S 2 O 8 .

[0043] In a specific embodiment, preferably, the amount of the catalyst is 0.1-0.2 mol.

[0044] In a specific embodiment, preferably, the amount of the oxidant is 1-3 equivalents.

[0045] In a specific embodiment, in the above method, the reaction temperature is 110-130°C.

[0046] At the same time, this reaction also generates some derivatives, the specific molecular formula is as follows:

[0047]

[0048] Example 2

[0049] See also Figure 1 In the preliminary test, K 2 CO 3 As base, DMSO as solvent, in Na 2 S 2 O 8 In the presence of , acetophenone and 2-aminobenzimidazole were treated and the reaction progress was monitored by TLC. However, under this condition, the yield of benzo[4,5]imidazo[1,2-a]pyrimidine was only 38% (Table 1, entry 1).

[0050] We then explored the effects of other conditions on the reaction (Table 1, entries 2-4). It can be seen from the table that CH 3 COONa had the best effect (Table 1, entries 2-4).

[0051] Next, we focus on the effects of oxidant and temperature on the reaction (Table 1, entries 5-11). Experiments show that when 2 equivalents (NH 4 ) 2 S 2 O 8 The best reaction effect was shown when oxidized, and the best reaction effect was achieved when the temperature was 120°C.

[0052] Finally, the optimal reaction conditions were determined as follows: 2-aminobenzimidazole, acetophenone in (NH 4 ) 2 S 2 O 8 The reaction was stirred at 120 °C for 3 h.

[0053] Table 1. Optimization of reaction conditions

[0054]

[0055]

[0056] In order to verify the universality of the reaction scheme, a variety of aldehydes were studied under the optimized reaction conditions. 3 ,-OCH 3 ) or electron withdrawing groups (-Cl and -CF 3 ) were well tolerated and afforded the corresponding products in moderate to excellent yields.

[0057] It can be seen that in the present invention, in CH 3 COONa and (NH 4 ) 2 S 2 O 8 In the presence of , the three-component cascade reaction of acetophenone, DMSO and 2-aminobenzimidazole proceeded smoothly to generate the corresponding products in good yields.

[0058] Among them, the molecular formula and NMR data of products 3a-3h are as follows:

[0059]

[0060] 2-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine Yellow solid(0.19g,77%)

[0061] 1 H NMR (600 MHz, CDCl 3 )δ8.76(d,J=7.1Hz,1H),8.31–8.20(m,2H),7.98(dt,J=8.3,0.9Hz,1H),7 .87(dt,J=8.2,0.9Hz,1H),7.59–7.49(m,4H),7.41(dd,J=7.1,1.1Hz,2H). 13 C NMR (151 MHz, CDCl 3 )δ161.72,150.97,144.89,136.62,133.10,131.46,129.02,127.82,126.45,121.96,120.39,110.45,104.08.

[0062]

[0063] 2-(o-tolyl)benzo[4,5]imidazo[1,2-a]pyrimidine Yellow solid(0.19g,74%).

[0064] 1 H NMR(600MHz,CDCl 3 )δ8.78(d,J=7.0Hz,1H),8.03(d,J=8.3Hz,1H),7.91(dt,J=8.2,0.9Hz,1H),7.69–7.50(m,2H),7.46–7.37(m,2H),7.34(dd,J=7.8,6.4Hz,2H),7.13(d,J=7.0Hz,1H). 13 CNMR(151MHz,CDCl 3 )δ165.25,144.76,137.92,137.00,132.54,131.56,129.91,129.74,126.89,126.42,126.15,121.98,120.58,110.44,108.00,20.94.

[0065]

[0066] 2-(4-ethylphenyl)benzo[4,5]imidazo[1,2-a]pyrimidine Yellow solid(0.19g,71%).

[0067] 1H NMR(600MHz,CDCl3)δ8.74(d,J=7.2Hz,1H),8.21(d,J=8.3Hz,2H),7.99(d,J=8.2Hz,1H),7.86(d,J=8.1Hz,1H),7.56(t,J=7.7Hz,1H),7.43–7.36(m,3H),2.75(q,J=7.6Hz,2H),1.30(t,J=7.6Hz,3H).13C NMR(151MHz,CDCl3)δ161.69,151.12,148.33,134.14,132.91,128.59,127.91,127.02,126.30,121.79,120.36,110.35,103.96,28.86,15.33.

[0068]

[0069] 2-(4-butylphenyl)benzo[4,5]imidazo[1,2-a]pyrimidine Yellow solid(0.22g,73%).

[0070] 1 H NMR(600MHz,CDCl 3 )δ8.72(d,J=7.2Hz,1H),8.20(d,J=8.3Hz,2H),7.98(d,J=8.2Hz,1H),7.85(d,J=8.2Hz,1H),7.57–7.53(m,1H),7.41–7.37(m,2H),7.35(d,J=8.3Hz,2H),2.72–2.67(m,2H),1.66(p,J=7.6Hz,2H),1.42–1.36(m,2H),0.99–0.92(m,3H). 13 CNMR(151MHz,CDCl 3 )δ161.64,151.15,147.02,145.01,134.12,132.88,129.12,128.60,128.16,127.81,127.05,126.25,120.38,110.33,103.89,35.61,33.37,22.38,13.96,13.94.

[0071]

[0072] 2-(4-ethoxyphenyl)benzo[4,5]imidazo[1,2-a]pyrimidine Yellow solid(0.19g,73%).

[0073] 1 H NMR(600MHz,CDCl 3 )δ8.68(d,J=7.2Hz,1H),8.24(d,J=8.8Hz,2H),7.97(d,J=8.1Hz,1H),7.83(d,J=8.2Hz,1H),7.54(t,J=7.7Hz,0H),7.39–7.33(m,1H),7.02(d,J=8.9Hz,2H),4.12(q,J=7.0Hz,2H),1.47(t,J=7.0Hz,3H). 13 C NMR(151MHz,CDCl 3)δ161.96,161.21,151.61,132.74,129.56,128.91,126.17,121.62,120.22,114.88,114.83,110.24,103.60,63.74,14.76.

[0074]

[0075] 2-(3,5-dimethoxyphenyl)benzo[4,5]imidazo[1,2-a]pyrimidine Yellowsolid(0.21g,70%).

[0076] 1 H NMR(600MHz,CDCl 3 )δ8.75(d,J=7.2Hz,1H),8.00(dd,J=8.2,0.9Hz,1H),7.88(dt,J=8.2,0.9Hz,1H),7.58(ddd,J=8.3,7.2,1.1Hz,1H),7.48–7.35(m,4H),6.64(s,1H),3.91(s,6H). 13 C NMR(151MHz,CDCl 3 )δ161.26,161.23,144.97,138.65,132.97,126.44,121.99,120.47,110.45,105.73,104.18,103.86,77.24,77.02,76.81,55.72.

[0077]

[0078] 2-(2-chlorophenyl)benzo[4,5]imidazo[1,2-a]pyrimidine Yellow solid(0.19g,69%).

[0079] 1 H NMR(600MHz,Chloroform-d)δ8.79(d,J=7.1Hz,1H),8.05(d,J=8.3Hz,1H),7.99–7.86(m,2H),7.60(t,J=7.2Hz,1H),7.55–7.49(m,1H),7.48–7.37(m,4H). 13 C NMR(151MHz,CDCl 3)δ162.23,144.75,137.18,132.27,132.07,132.05,131.26,130.42,127.41,126.56,122.22,120.67,110.62,108.57.

[0080]

[0081] 2-(3-chlorophenyl)benzo[4,5]imidazo[1,2-a]pyrimidine Yellow solid(0.21g,75%).

[0082] 1 H NMR(600MHz,CDCl 3 )δ8.81(d,J=7.2Hz,1H),8.30(s,1H),8.16(d,J=7.5Hz,1H),8.02(d,J=8.2Hz,1H),7.90(d,J=8.2Hz,1H),7.60(t,J=8.1Hz,1H),7.54–7.46(m,2H),7.46–7.41(m,1H),7.40(d,J=7.2Hz,1H). 13 C NMR(151MHz,CDCl 3 )δ160.05,145.10,138.45,135.24,133.38,131.30,130.25,127.94,126.94,126.63,125.87,122.20,120.64,110.51,103.75.

[0083]

[0084] 2-(3-(trifluoromethyl)phenyl)benzo[4,5]imidazo[1,2-a]pyrimidineYellowsolid(0.22g,72%).

[0085] 1 H NMR(600MHz,CDCl 3)δ8.84(d,J=7.2Hz,1H),8.55(s,1H),8.48(d,J=7.8Hz,1H),8.03(d,J=8.3Hz,1H),7.91(d,J=8.2 Hz,1H),7.80(d,J=7.7Hz,1H),7.68(t,J=7.8Hz,1H),7.60(t,J=7.7Hz,1H),7.45(t,J=6.6Hz,2H). 13 C NMR (151 MHz, CDCl 3 )δ159.85,150.55,145.01,137.41,133.57,131.69,131.47,130.92,129.59,127.87,127.85,12 7.82,127.80,126.89,126.74,124.71,124.69,124.66,124.64,122.34,120.66,110.59,103.65

[0086] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions only describe the principles of the present invention. The present invention may be subject to various changes and improvements without departing from the spirit and scope of the present invention. These changes and improvements fall within the scope of the present invention. The scope of protection claimed by the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for preparing a benzimidazolinylpyrimidine derivative, characterized in that: The following steps are involved: The benzimidazolopyrimidine derivative is prepared by reacting 2-aminobenzimidazole and acetophenone in the presence of a base and an oxidant using DMSO as a solvent; The molecular formula of the 2-aminobenzimidazole is as follows: The molecular formula of the acetophenone is as follows: The molecular formula of the DMSO is as follows:

2. The method for preparing a benzimidazolopyrimidine derivative according to claim 1, characterized in that: The oxidant is selected from one or a combination of TBHP, H2O2, Na2S2O8, (NH4)2S2O8.

3. The method for preparing a benzimidazolopyrimidine derivative according to claim 2, characterized in that: The oxidant is Na2S2O8.

4. The method for preparing a benzimidazolopyrimidine derivative according to claim 1, characterized in that: The base is selected from one or a combination of Et3N, K2CO3, NaOH, and CH3COONa.

5. The method for preparing a benzimidazolopyrimidine derivative according to claim 4, characterized in that: The base is CH3COONa.

6. The method for preparing a benzimidazolopyrimidine derivative according to claim 1, characterized in that: The amount of the oxidant used is 1-3 equivalents.

7. The method for preparing a benzimidazolopyrimidine derivative according to claim 1, characterized in that: The reaction temperature is 110-130°C.

8. The method for preparing a benzimidazolopyrimidine derivative according to claim 1, characterized in that: The H of the 2-aminobenzimidazole can be replaced by: one or more C 1-6 Alkyl, one or more OC 1-6 Alkoxy, halogenated C 1-6 alkyl.

9. The method for preparing a benzimidazolopyrimidine derivative according to claim 8, characterized in that: The molecular formula of the product of the benzimidazolopyrimidine derivative prepared by the method is as follows:

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