阅读说明：本技术 一种3-酰基吡咯类化合物的合成方法 (Synthetic method of 3-acyl pyrrole compound ) 是由 熊彪 刘明元 潘铭时 于 2021-09-06 设计创作，主要内容包括：本发明涉及医药化工合成技术领域,具体为一种3-酰基吡咯类化合物的合成方法,合成方法为：在反应器中,加入α-氨基醇和α,β-不饱和炔酮,十二羰基三钌催化剂,4-甲基-1,10菲罗琳配体,乙醇,碱和适量溶剂,在80℃氮气保护下搅拌1.5小时。然后升温到150℃反应18小时,最后经分离提纯得到目标产物。该方法属于醇氢转移偶联反应,具有极高的原子和步骤经济性,操作简单,原料易得,催化剂效率高、成本低。(The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a synthetic method of a 3-acyl pyrrole compound, which comprises the following steps: in a reactor, adding alpha-amino alcohol, alpha, beta-unsaturated alkynone, dodecacarbonyl triruthenium catalyst, 4-methyl-1, 10 phenanthroline ligand, ethanol, alkali and a proper amount of solvent, and stirring for 1.5 hours at 80 ℃ under the protection of nitrogen. Then heating to 150 ℃ for reaction for 18 hours, and finally separating and purifying to obtain the target product. The method belongs to alcohol-hydrogen transfer coupling reaction, has extremely high atom and step economy, is simple to operate, has easily obtained raw materials, and has high catalyst efficiency and low cost.)

1. A synthetic method of 3-acyl pyrrole compounds is characterized in that: the method comprises the following steps:

adding the compound 1 and the compound 2, a catalyst, a ligand, a hydrogen source, an alkali and a proper amount of solvent into a reactor, and stirring for 1.5 hours at the temperature of 80 ℃ under the protection of nitrogen; heating to 150 ℃ for reacting for 18 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, distilling under reduced pressure to obtain a crude product, and purifying by column chromatography to obtain the 3-acylpyrrole compound;

the reaction equation involved in the above synthesis method is as follows:

the compound 1 refers to a compound with a structure shown in a formula (1): alpha, beta-unsaturated alkynones; the compound 2 refers to a compound with a structure shown in a formula (2): an alpha-amino alcohol;

wherein R is₁Is methyl, methoxy, trifluoromethyl, cyano, a halogen substituent or hydrogen; r₂Is the same or different polysubstituted phenyl and phenyl; r₃Is methyl, ethyl, isopropyl, phenyl or hydrogen.

2. The method for synthesizing 3-acylpyrrole compounds according to claim 1, wherein the method comprises the following steps: the molar ratio of compound 1 to compound 2 is 1 (mmol): 1 (mmol).

3. The method for synthesizing 3-acylpyrrole compounds according to claim 1, wherein the method comprises the following steps: the ligand is 4-methyl-1, 10 phenanthroline; the mol ratio of the added 4-methyl-1, 10 phenanthroline to the compound 1 is 1: 10.

4. the method for synthesizing 3-acylpyrrole compounds according to claim 1, wherein the method comprises the following steps: the hydrogen source is ethanol; the molar ratio of the added ethanol to the compound 1 is 2: 1.

5. the method for synthesizing 3-acylpyrrole compounds according to claim 1, wherein the method comprises the following steps: the catalyst is dodecacarbonyl triruthenium; the molar ratio of the added dodecacarbonyl triruthenium to the compound 1 is 0.02: 1.

6. the method for synthesizing 3-acylpyrrole compounds according to claim 1, wherein the method comprises the following steps: the solvent is tert-amyl alcohol, and the ratio of the addition amount of the tert-amyl alcohol to the compound 1 is 1 (mL): 0.1 (mmol).

7. The method for synthesizing 3-acylpyrrole compounds according to claim 1, wherein the method comprises the following steps: the alkali is potassium carbonate; the molar ratio of the added potassium carbonate to the compound 1 is 1: 1.

8. the method for synthesizing 3-acylpyrrole compounds according to claim 1, wherein the method comprises the following steps: the eluent used for column chromatography purification is petroleum ether: the volume ratio of the ethyl acetate is (5-20): 1.

9. The method for synthesizing 3-acylpyrrole compounds according to claim 1, wherein the method comprises the following steps: the reactor is a schlank tube.

Technical Field

The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a synthetic method of a 3-acyl pyrrole compound.

Background

The pyrrole structure is one of the most common skeletons in numerous heterocyclic compounds, and as an important five-membered nitrogen heterocyclic compound, the pyrrole structure has various biological activities and pharmacological activities and is often found in natural products and some drug structures on the market. For polysubstituted pyrrole compounds, the 3-acyl pyrrole structure has wide application in the aspects of medicines and functional materials, and is a star molecule in the pyrrole family. For example, potent histone deacetylase inhibitors, HIV-1 transcriptase and COX-1/COX-2 cyclooxygenase. Furthermore, some 3-acylpyrrole derivatives are potent cholesterol-lowering drugs inhibiting HMG-CoA reductase (JanNordmann and Thomas J.J.Muller, Org Biomol Chem,2013,11(38), 6556-. In addition, the existence of acyl is beneficial to various derivatization synthesis, and can be used as an important synthon to participate in the preparation of complex functional molecules.

Because of the unique biological activity and wide application of the 3-acyl pyrrole compounds, the high-efficiency synthesis of the 3-acyl pyrrole compounds is always a research hotspot in organic synthetic chemistry. In recent years, some effective synthetic methods have been established for the synthesis of 3-acylpyrrole compounds. For example: IBX mediated intramolecular oxidative cyclization of N-hydroxyalkylenamines to the corresponding 2, 3-disubstituted pyrrole and pyridine products (Peng Gao, Huai-Juan Chen, Zi-lacing Bai, Mi-Na ZHao, Desuo Yang, Juan Wang, Ning Wang, Lele Du, and Zheng-Hui Guan, J.org.chem,2020,85(12), 7939-. Palladium dichloride and bis (1-adamantyl) benzylphosphonium bromide catalyzed one-pot three-component acidic chlorides, terminal alkynes and aminoacetaldehyde diacetals to synthesize 2-substituted acylpyrroles (JanNordmann and Thomas J.J.Muller, Org Biomol Chem,2013,11(38), 6556-. The two-step reaction of a β -aminoenone with an α -aminoketone gives 2-or 3-acylpyrroles (Angel Alberola, Jose EI. Andres, Alfonso Gonadlez, Rafael Pedrosa, and Martina Yonte, Heterocycles,1989,29(10), 1983-91). The above reaction can efficiently produce 3-acylpyrrole derivatives, but most of them have some disadvantages. For example: the raw materials are not easy to obtain, the reaction process is complicated, toxic reagents and precious metals are used, the reaction conditions are harsh, and the like, so that the method is difficult to apply to industrial production.

Disclosure of Invention

The invention aims to provide a synthetic method of a 3-acyl pyrrole compound to solve the problems in the background technology.

In order to achieve the purpose, the invention provides the following technical scheme: a synthetic method of a 3-acyl pyrrole compound comprises the following steps:

adding the compound 1 and the compound 2, a catalyst, a ligand, a hydrogen source, an alkali and a proper amount of solvent into a reactor, and stirring for 1.5 hours at the temperature of 80 ℃ under the protection of nitrogen; heating to 150 ℃ for reacting for 18 hours, cooling to room temperature after the reaction is finished, diluting the reaction solution, filtering, distilling under reduced pressure to obtain a crude product, and purifying by column chromatography to obtain the 3-acylpyrrole compound;

the reaction equation involved in the above synthesis method is as follows:

the compound 1 refers to a compound with a structure shown in a formula (1): alpha, beta-unsaturated alkynones; the compound 2 refers to a compound with a structure shown in a formula (2): an alpha-amino alcohol;

wherein R is₁Is methyl, methoxy, trifluoromethyl, cyano, a halogen substituent or hydrogen; r₂Is the same or different polysubstituted phenyl and phenyl; r₃Is methyl, ethyl, isopropyl, phenyl or hydrogen.

Preferably, the molar ratio of compound 1 to compound 2 is 1 (mmol): 1 (mmol).

Preferably, the ligand is 4-methyl-1, 10 phenanthroline; the mol ratio of the added 4-methyl-1, 10 phenanthroline to the compound 1 is 1: 10.

preferably, the hydrogen source is ethanol; the molar ratio of the added ethanol to the compound 1 is 2: 1.

preferably, the catalyst is dodecacarbonyl triruthenium; the molar ratio of the added dodecacarbonyl triruthenium to the compound 1 is 0.02: 1.

preferably, the solvent is tert-amyl alcohol, and the ratio of the addition amount of the tert-amyl alcohol to the compound 1 is 1 (mL): 0.1 (mmol).

Preferably, the base is potassium carbonate; the molar ratio of the added potassium carbonate to the compound 1 is 1: 1.

preferably, the eluent used for the column chromatography purification is petroleum ether: the volume ratio of the ethyl acetate is (5-20): 1.

Preferably, the reactor is a schlenk tube.

Compared with the prior art, the invention has the beneficial effects that: the synthesis method of the 3-acyl pyrrole compound provided by the invention takes the alpha-amino alcohol compound and the alpha, beta-unsaturated alkynone as raw materials, and synthesizes the 3-acyl pyrrole compound by a tandem one-pot method, and has the advantages of simple synthesis steps, easily obtained raw materials, safe synthesis operation, good functional group compatibility and the like.

Drawings

FIG. 1 is a hydrogen spectrum of a product 3a obtained in example 1 of the present invention;

FIG. 2 is a carbon spectrum of the product 3a obtained in example 1 of the present invention;

FIG. 3 is a hydrogen spectrum of the product 3b obtained in example 2 of the present invention;

FIG. 4 is a carbon spectrum of the product 3b obtained in example 2 of the present invention;

FIG. 5 is a hydrogen spectrum of the product 3c obtained in example 3 of the present invention;

FIG. 6 is a carbon spectrum of the product 3c obtained in example 3 of the present invention;

FIG. 7 is a hydrogen spectrum of product 3d obtained in example 4 of the present invention;

FIG. 8 is a carbon spectrum of the product 3d obtained in example 4 of the present invention;

FIG. 9 is a hydrogen spectrum of product 3e obtained in example 5 of the present invention;

FIG. 10 is a carbon spectrum of the product 3e obtained in example 5 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

0.3 mmol of m-fluorophenone alkynylbenzene, 0.3 mmol of 2-amino-1-butanol, 0.006 mmol of triruthenium dodecacarbonyl, 0.03 mmol of 4-methyl-1, 10 phenanthroline, 0.6 mmol of ethanol, 0.3 mmol of potassium carbonate and 3 ml of t-amyl alcohol were added to a schlenk tube, and the mixture was reacted at 80 ℃ for 1.5 hours under nitrogen protection, followed by heating to 150 ℃ for 18 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, and distilling under reduced pressure to remove the solvent. And (3) performing column chromatography separation and purification to obtain a target product 3a, wherein the volume ratio of column chromatography eluent is 15: 1 petroleum ether: ethyl acetate mixed solvent, yield 77%.

The hydrogen spectrum and the carbon spectrum of the obtained product 3a are respectively shown in fig. 1 and fig. 2, and the structural characterization data are as follows:

¹H NMR(400MHz,CDCl₃)δ8.51(s,1H),7.41(dd,J＝7.6,1.6Hz,1H),7.33(dt,J＝9.4,2.0Hz,1H),7.29–7.24(m,2H),7.19–7.09(m,4H),6.99(td,J＝8.3,2.6Hz,1H),6.20(d,J＝2.8Hz,1H),2.56(q,J＝7.6Hz,2H),1.20(t,J＝7.5Hz,3H).

¹³C NMR(101MHz,CDCl₃)：δ190.08,162.42,159.97,140.84,135.55,133.55,131.02,128.33,127.36,126.80,124.24,118.98,117.27,117.06,115.36,115.14,108.21,19.45,12.21.

MS(EI,m/z):293[M]⁺.

HRMS(ESI):Calcd.for C19H16FNO[M+H]⁺:294.1289；found:294.1284.

the structure of the resulting product is deduced from the above data as shown in the following formula:

example 2

0.3 mmol of p-methylbenzophenone alkynylbenzene, 0.3 mmol of 2-amino-1-butanol, 0.006 mmol of triruthenium dodecacarbonyl, 0.03 mmol of 4-methyl-1, 10 phenanthroline, 0.6 mmol of ethanol, 0.3 mmol of potassium carbonate and 3 ml of t-amyl alcohol were added to a schlenk tube, and the mixture was reacted at 80 ℃ for 1.5 hours under nitrogen protection, then heated to 150 ℃ for 18 hours, cooled to room temperature, diluted with ethyl acetate, filtered, and the solvent was distilled off under reduced pressure. And (3) performing column chromatography separation and purification to obtain a target product 3b, wherein the volume ratio of column chromatography eluent is 15: 1 petroleum ether: ethyl acetate mixed solvent, yield 70%.

The hydrogen spectrum and the carbon spectrum of the obtained product 3b are respectively shown in fig. 3 and fig. 4, and the structural characterization data are as follows:

¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),7.31(d,J＝4.8Hz,2H),7.24–7.07(m,5H),7.03(d,J＝7.4Hz,1H),6.94(t,J＝7.4Hz,1H),6.09(d,J＝2.9Hz,1H),2.53(q,J＝7.6Hz,2H),2.28(s,3H),1.17(t,J＝7.5Hz,3H).

¹³C NMR(101MHz,CDCl₃)：δ193.17,139.76,135.60,135.08,133.20,131.06,129.41,128.28,127.48,127.40,127.04,126.79,123.72,120.59,108.29,19.44,18.82,12.14.

MS(EI,m/z):289[M]⁺.

HRMS(ESI):Calcd.for C20H19NO[M+H]⁺:290.1539；found:290.1538.

the structure of the resulting product is deduced from the above data as shown in the following formula:

example 3

0.3 mmol of benzophenonynylbenzene, 0.3 mmol of 2-amino-1-butanol, 0.006 mmol of triruthenium dodecacarbonyl, 0.03 mmol of 4-methyl-1, 10-phenanthroline, 0.6 mmol of ethanol, 0.3 mmol of potassium carbonate and 3 ml of t-amyl alcohol were added to a schlenk tube, and the mixture was reacted at 80 ℃ for 1.5 hours under nitrogen protection, followed by heating to 150 ℃ for 18 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, and distilling off the solvent under reduced pressure. And (3) performing column chromatography separation and purification to obtain a target product 3c, wherein the volume ratio of column chromatography eluent is 15: 1 petroleum ether: ethyl acetate mixed solvent, yield 72%.

The hydrogen spectrum and the carbon spectrum of the obtained product 3c are respectively shown in fig. 5 and 6, and the structural characterization data are as follows:

¹H NMR(400MHz,CDCl₃)δ8.30(s,1H),7.68(d,J＝7.3Hz,2H),7.31(d,J＝7.1Hz,3H),7.25–7.12(m,5H),6.22(d,J＝2.4Hz,1H),2.59(q,J＝7.6Hz,2H),1.21(t,J＝7.5Hz,3H).

¹³C NMR(101MHz,CDCl₃)：δ192.58,139.74,136.07,134.23,132.28,131.41,129.63,128.36,128.29,127.77,127.70,120.49,109.55,20.57,13.30.

MS(EI,m/z):275[M]⁺.

HRMS(ESI):Calcd.for C19H17NO[M+H]⁺:276.1383；found:276.1380.

the structure of the resulting product is deduced from the above data as shown in the following formula:

example 4

0.3 mmol of p-trifluoromethylphenonynylbenzene, 0.3 mmol of 2-amino-1-butanol, 0.006 mmol of triruthenium dodecacarbonyl, 0.03 mmol of 4-methyl-1, 10 phenanthroline, 0.6 mmol of ethanol, 0.3 mmol of potassium carbonate and 3 ml of t-amyl alcohol were added to a schlenk tube, and the mixture was reacted at 80 ℃ for 1.5 hours under nitrogen protection, and then heated to 150 ℃ for 18 hours, cooled to room temperature, diluted with ethyl acetate, filtered, and the solvent was distilled off under reduced pressure. And (3) performing column chromatography separation and purification to obtain a target product 3d, wherein the volume ratio of column chromatography eluent is 15: 1 petroleum ether: ethyl acetate mixed solvent, yield 80%.

The hydrogen spectrum and the carbon spectrum of the obtained product 3d are respectively shown in fig. 7 and 8, and the structural characterization data are as follows:

¹H NMR(400MHz,CDCl₃)δ8.54(s,1H),7.68(d,J＝8.1Hz,2H),7.43(d,J＝8.2Hz,2H),7.28–7.21(m,2H),7.15–7.09(m,3H),6.20(d,J＝2.8Hz,1H),2.56(q,J＝7.6Hz,2H),1.20(t,J＝7.5Hz,3H).

¹³C NMR(101MHz,CDCl₃)：δ191.29,142.96,137.05,134.78,132.74,132.41,131.93,129.62,128.56,128.29,128.03,124.76,120.04,109.21,20.51,13.24.

MS(EI,m/z):343[M]⁺.

HRMS(ESI):Calcd.for C20H16F3NO[M+H]⁺:344.1257；found:344.1255.

the structure of the resulting product is deduced from the above data as shown in the following formula:

example 5

0.3 mmol of p-methylbenzophenone alkynyl benzene, 0.3 mmol of leucinol, 0.006 mmol of dodecacarbonyl triruthenium, 0.03 mmol of 4-methyl-1, 10 phenanthroline, 0.6 mmol of ethanol, 0.3 mmol of potassium carbonate and 3 ml of tert-amyl alcohol were added to a schlenk tube, and the mixture was reacted at 80 ℃ for 1.5 hours under nitrogen protection, followed by heating to 150 ℃ for 18 hours, cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, and distilling under reduced pressure to remove the solvent. And (3) performing column chromatography separation and purification to obtain a target product 3e, wherein the volume ratio of column chromatography eluent is 15: 1 petroleum ether: ethyl acetate mixed solvent, yield 65%.

The hydrogen spectrum and the carbon spectrum of the obtained product 3e are respectively shown in fig. 1 and fig. 2, and the structural characterization data are as follows:

¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),7.33(d,J＝7.3Hz,2H),7.22(d,J＝7.5Hz,1H),7.17–7.08(m,4H),7.03(d,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),6.07(d,J＝2.8Hz,1H),2.35(d,J＝7.1Hz,2H),2.28(s,3H),1.79(dt,J＝13.5,6.7Hz,1H),0.87(d,J＝6.6Hz,6H).

¹³C NMR(101MHz,CDCl₃)：δ193.25,135.42,135.43,135.13,131.09,130.81,129.43,128.32,127.57,127.40,127.06,126.77,123.75,120.67,110.09,76.32,76.00,75.68,35.67,27.87,21.36,18.87.

MS(EI,m/z):317[M]⁺.

HRMS(ESI):Calcd.for C22H23NO[M+H]⁺:318.1852；found:318.1848.

the structure of the resulting product is deduced from the above data as shown in the following formula:

the invention is not described in detail, but is well known to those skilled in the art.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.