CN114560862A - Synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivative thereof - Google Patents
Synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivative thereof Download PDFInfo
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Abstract
The invention relates to pyrrolo [1, 2-A)]A synthetic method of quinoxaline-4 (5H) -ketone and derivatives thereof belongs to the technical field of organic chemistry. The synthetic route is as follows:
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivatives thereof.
Background
Pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivatives thereof have wide application in drug development, and in most cases, the compounds have broad biological activity and drug action and have good expression in anticancer activity, protein inhibitors and the like.
The existing synthetic routes of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone compounds comprise the following steps:
route 1:
in the prior art, a route 1 is mostly used for synthesis, 2-iodo (or bromo) aniline is used as a raw material, amino is protected, then the amino reacts with 2-methyl pyrrolidone through Ullmann reaction, and then deprotection and cyclization are carried out to prepare pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone compounds. The raw materials used in route 1 are expensive; the second step reports that the yield of Ullmann reaction is about 5% at best, and this step is catalyzed by cuprous iodide and L-proline, and the work-up after the reaction is cumbersome.
Route 2:
o-iodoaniline is used as a starting material, amino groups are not protected, and the Ullmann reaction is directly carried out, so that the product can be obtained in one step. However, the yield of scheme 2 is very low, only about 15%. And the o-iodoaniline is used as a raw material, so that the reaction is disordered, and the post-treatment difficulty is high.
Route 3:
o-iodoaniline is used as a starting material, and an Ullmann reaction is firstly carried out, and then cyclization is carried out. However, in the route 3, highly toxic raw materials such as triphosgene and the like are required during cyclization, and the reaction conditions are harsh, so that the method is not suitable for industrial production.
Route 4:
in patent WO2018204370a1 a process for the synthesis of pyrrolo [1,2-a ] quinoxalin-4 (5H) -one derivatives is disclosed, which discloses the following synthetic route:
in the above route, when compound 3 is synthesized, microwave reaction is required, and the reaction temperature is 200 ℃. Firstly, a microwave reactor is needed for microwave reaction, and most enterprises do not have the condition; meanwhile, the reaction temperature of 200 ℃ is harsh. The above two points restrict the production scale and are not favorable for the amplification of the reaction.
In summary, there are many reports of methods for synthesizing pyrrolo [1,2-A ] quinoxaline-4 (5H) -ones, but all have various problems. It is a primary object of the present invention to find a suitable synthetic method.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a synthesis method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivatives thereof, which aims to solve the problems. The invention takes anthranilic acid or methyl anthranilate derivatives as raw materials, and the 1- (2-carbonyl benzene) pyrrole or the derivatives thereof are generated by cyclization; then carrying out Curtius rearrangement to obtain the final product. The synthetic route operation and the post-treatment method are simple and safe, the generated waste liquid is less, and the large-scale production is easy.
The technical scheme of the invention is as follows:
a synthetic method of pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivatives thereof comprises the following steps:
wherein R is hydrogen, fluorine or trifluoromethyl.
The specific method comprises the following steps:
(1) dissolving the compound shown in the formula (II ') in acetic acid, stirring, adding 2, 5-dimethoxy tetrahydrofuran, heating a reaction system to 115-120 ℃ after the addition is finished, reacting for 5-8 hours, and monitoring the complete reaction of the compound shown in the formula (II') by LC-MS; concentrating the reaction solution, distilling the concentrate under reduced pressure, and collecting fractions at 90-95 ℃ to obtain a compound shown in a formula (III);
adding a compound shown in the formula (III) and a 20% sodium hydroxide aqueous solution into methanol, heating a reaction solution to 55-60 ℃, and reacting for 4-8 h; TLC monitoring the compound of formula (III) for complete reaction; then cooling the reaction liquid to room temperature, concentrating under reduced pressure to remove methanol, adjusting the pH value of the reaction liquid to 3-4 by using 6N hydrochloric acid aqueous solution, separating out a large amount of solids, filtering, washing a filter cake twice by using water, and drying in vacuum to obtain a compound shown in the formula (I);
or the like, or a combination thereof,
dissolving a compound shown in the formula (II), 2, 5-dimethoxytetrahydrofuran and pyridine hydrochloride in 1, 4-dioxane, heating to reflux for 24 hours, and monitoring the complete reaction of the compound shown in the formula (II) by LC-MS; concentrating the reaction solution, and carrying out column chromatography on the concentrate to obtain the compound shown in the formula (I).
(2) Dissolving a compound shown in a formula (I) in dichloromethane, stirring and adding Diisopropylethylamine (DIPEA), adding diphenyl phosphorazidate (DPPA), heating a reaction system to 40-45 ℃, reacting for 6-8h, monitoring by LC-MS that the residual amount of raw materials is less than or equal to 0.5%, cooling the reaction system to room temperature, directly filtering and washing if solid is separated out, and drying to obtain a target product; if no solid is precipitated, the solvent is evaporated to dryness, water and ethyl acetate are added into the concentrate, and the target product is obtained after the mixture is stirred, filtered, washed and dried.
Preferably, the molar ratio of the compound of formula (II') to 2, 5-dimethoxytetrahydrofuran is 1:1.5 to 2.0, preferably 1: 1.5. When the feeding amount of the 2, 5-dimethoxytetrahydrofuran is less than 1.5eq, the reaction yield is low, and when the feeding amount of the 2, 5-dimethoxytetrahydrofuran is more than 1.5eq, the yield and the product purity are not influenced, but the waste of the raw material of the 2, 5-dimethoxytetrahydrofuran is caused.
Preferably, the molar ratio of the compound of formula (iii) to sodium hydroxide is 1: 3.5. When the amount of sodium hydroxide is 3.5eq, the reaction is best, and when the amount of sodium hydroxide is more than 3.5eq or less than 3.5eq, a large amount of impurities are produced.
Preferably, the molar ratio of the compound of formula (II) to 2, 5-dimethoxytetrahydrofuran is 1: 1.0-2.0, preferably 1: 1.5.
Preferably, the molar ratio of the compound of formula (II) to the pyridine hydrochloride is 1: 1.2-1.5, preferably 1: 1.5.
Preferably, the feeding molar ratio of the compound of the formula (I) to the diphenylphosphoryl azide is 1: 1.0-2.0, preferably 1: 1.3. The inventors found that the amount of diphenylphosphorylazide used in the reaction of step (2) is critical to the success of the reaction and the purification of the product. When the dosage of the diphenyl phosphorazidate is less than or equal to 1.0eq, the compound of the formula (I) can not be reacted completely; when the dosage of the diphenyl azide is more than or equal to 1.5eq, more impurities are generated; when the dosage of the diphenyl azide is more than or equal to 1.5eq, the dosage is not changed much compared with 1.5eq, but the original waste is serious; the conclusion is that 1.3eq reaction is best. Once more impurities are generated, the product cannot be separated out after the reaction is finished and the temperature is reduced, or impurities can be carried in the separated product. Once more impurities are formed, the purification of the product is complicated. The selection of the solvent is also very critical, methylene dichloride is used as the solvent to react better than other solvents, and after the reaction, water and an organic solvent are pulped to obtain a pure product.
Preferably, the dosage of the dichloromethane is 5-10 mL/g based on the dosage of the compound of the formula (I).
The invention has the beneficial effects that:
the invention provides a new method for synthesizing pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivatives thereof, which takes anthranilic acid or methyl anthranilate derivatives as raw materials to generate 1- (2-carbonyl benzene) pyrrole or derivatives thereof through cyclization; and carrying out Curtius rearrangement to obtain the final product. When the compound of formula (I) is prepared, the invention skillfully utilizes acetic acid as a reaction solvent, and the product can be obtained at the temperature of 115-120 ℃. No microwave reactor is needed, and the reaction condition is effectively simplified. The synthetic route operation and the post-treatment method are simple and safe, the generated waste liquid is less, and the large-scale production is easy.
Detailed Description
In order to make those skilled in the art better understand the technical solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all 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
Synthesis of pyrrolo [1,2-A ] quinoxalin-4 (5H) -one
1.1) Synthesis of methyl 2- (1-pyrrolyl) benzoate
Methyl anthranilate (250.0g,1.65mol) is dissolved in acetic acid (900mL), after stirring, 2, 5-dimethoxytetrahydrofuran (219g,2.47mol) is added dropwise, the reaction mixture is heated to 115-120 ℃ for 6 hours, and LC-MS monitors the completion of the reaction. After the reaction solution was concentrated, the residue was distilled under reduced pressure (-0.09-0.1MPa) to collect fractions at 90-95 ℃ to obtain 282.3g of the objective compound as a pale yellow oily substance in yield: 85%, LCMS: 98.9 percent.
1HNMR(400MHz,CDCI3):δ3.71(s,3H),6.31(t,2H),6.81(t,2H),7.37-7.42(m,2H),7.53-7.57(m,1H),7.78-7.80(dd,1H).
LCMS:m/z calculated for C12H11NO2:201.2；found:202.1。
1.2) Synthesis of 2- (1-pyrrolyl) benzoic acid
Methyl 2- (1-pyrrolyl) benzoate (195.0g,0.97mol) and 20% sodium hydroxide (680mL,3.40mol) were added to methanol (1300mL), and the reaction mixture was heated to 55-60 ℃ for 4 hours. TLC showed the reaction was complete, cooled to room temperature, concentrated under reduced pressure to remove methanol, adjusted pH to 3-4 with 6N aqueous hydrochloric acid, precipitated a large amount of solid, filtered, washed twice with water, and the filter cake was dried under vacuum to give the target product (175.2g), white solid, yield: 96%, LCMS: 99.1 percent.
HNMR(400MHz,CDCI3):δ6.32(t,2H),6.84(t,2H),7.37-7.44(m,2H),7.58-7.62(m,1H),7.93-7.95(dd,1H)。
LCMS:m/z calculated for C11H9NO2:187.2；found:188.1
1.3) Synthesis of pyrrolo [1,2-A ] quinoxalin-4 (5H) -one
2- (1-pyrrolyl) benzoic acid (152.0g,0.81mol) and diisopropylethylamine (209.7g,1.62mol) were dissolved in dichloromethane (800mL), diphenyl azidophosphate (358.4g,1.30mol) was added, the reaction mixture was heated to 40-45 ℃ for about 8 hours, and LCMS indicated complete reaction. After cooling to room temperature, the reaction solution had a large amount of solid, and was filtered, and then washed with dichloromethane (300mL) and tert-butyl methyl ether (300mL), respectively, and the filter cake was dried to obtain the target product (125.0kg), a white solid, yield: 83.6%, LCMS: 99.0 percent.
HNMR(400MHz,DMSO-d6):δ6.69(m,1H),7.04(dd,1H),7.19-7.23(m,1H),7.27-7.32(m,2H),8.05(d,1H),8.19(m,1H),11.27(s,1H)。
LCMS:m/z calculated for C11H8N2O:184.2；found:185.0。
Example 2
Synthesis of 8-trifluoromethyl-pyrrolo [1,2-A ] quinoxalin-4 (5H) -one
2.1) Synthesis of 4-trifluoromethyl-2- (1-pyrrolyl) benzoic acid
4-trifluoromethyl-2-aminobenzoic acid (14.0g,68.3mmol), 2, 5-dimethoxytetrahydrofuran (13.5g,102.5mol) and pyridine hydrochloride (11.9g,102.5mol) were dissolved in 1, 4-dioxane (140mL), heated to reflux for 24 h and LCMS monitored for reaction completion. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. And (2) washing the organic layer with water, washing with saturated salt water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product, diluting the crude product with ethyl acetate, filtering the diluted crude product through a sand core funnel filled with silica gel (10g), leaching with ethyl acetate, and concentrating the filtrate to obtain a target product 15.0g, a yellow solid, and the yield: 86%, LCMS: 99.2 percent.
2.2) Synthesis of 8-trifluoromethyl-pyrrolo [1,2-A ] quinoxalin-4 (5H) -one
4-trifluoromethyl-2- (1-pyrrolyl) benzoic acid (15.0g,58.8mmol) and diisopropylethylamine (15.2g,117.6mol) were dissolved in dichloromethane (100mL) and diphenyl azidophosphate (17.8g,64.7mol) was added. The reaction was heated to 40 ℃ for about 5h and LCMS showed the reaction was complete. Cooled to room temperature and concentrated under reduced pressure to remove the solvent dichloromethane. The residue was diluted with water (100mL) and ethyl acetate (20mL) and stirred for 20 minutes, filtered, and the filter cake was washed twice with water and ethyl acetate, respectively. The filter cake was dried to give the target product (11.0g), a white solid, two-step overall yield: 73%, LCMS: 98.8 percent.
1HNMR(400MHz,DMSO-d6):δ6.73(t,1H),7.09(m,1H),7.45(d,1H),7.63(d,1H),8.42(d,1H),8.47(s,1H),11.56(s,1H)。
LCMS:m/z calculated for C12H7F3N2O:252.2；found:253.0。
Example 3
Synthesis of 8-fluoro-pyrrolo [1,2-A ] quinoxalin-4 (5H) -one
3.1) Synthesis of 4-fluoro-2- (1-pyrrolyl) benzoic acid
4-fluoro-2-aminobenzoic acid (50.0g,0.32mol), 2, 5-dimethoxytetrahydrofuran (63.75g,0.48mol) and pyridine hydrochloride (56.4g,0.48mol) were dissolved in 1, 4-dioxane (500mL), heated to reflux for 24 h and LCMS monitored for reaction completion. After the reaction solution was concentrated, the residue was diluted with ethyl acetate and filtered through a sand core funnel filled with silica gel (10g), after ethyl acetate was washed, the filtrate was concentrated to obtain 61.5g of the target product as a pale yellow oil, LCMS: 77% the crude product was used directly in the next reaction.
3.2) Synthesis of 8-fluoro-pyrrolo [1,2-A ] quinoxalin-4 (5H) -one
Crude 4-fluoro-2- (1-pyrrolyl) benzoic acid from the previous step (61.5g,0.30mol) and diisopropylethylamine (76.7g,0.60mol) were dissolved in dichloromethane (350mL) and diphenyl azidophosphate (80.0g,0.39mol) was added. The reaction was heated to 40 ℃ for 5 hours and LCMS showed completion. Cooled to room temperature and concentrated under reduced pressure to remove the solvent dichloromethane. The residue was diluted with water (200mL) and ethyl acetate (50mL) and stirred for 20 minutes, filtered, and the filter cake was washed twice with water and ethyl acetate, respectively. The filter cake was dried to give the target product (36.0g) as a light brown solid in two total yields: 54%, LCMS: 98.7 percent.
1HNMR(400MHz,DMSO-d6):δ6.70(m,1H),7.04(s,1H),7.14-7.19(m,1H),7.28-7.32(m,1H),8.04-8.18(m,1H),8.19(m,1H),11.27(s,1H)。
LCMS:m/z calculated for C11H7FN2O:202.2；found:203.1。
Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made on the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and these modifications or substitutions are within the scope of the present invention/any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. A method for synthesizing pyrrolo [1,2-A ] quinoxaline-4 (5H) -ketone and derivatives thereof is characterized in that the synthetic route is as follows:
wherein R is hydrogen, fluorine or trifluoromethyl;
the specific method comprises the following steps:
(1) dissolving the compound shown in the formula (II ') in acetic acid, stirring, adding 2, 5-dimethoxy tetrahydrofuran, heating a reaction system to 115-120 ℃ after the addition is finished, concentrating reaction liquid after the compound shown in the formula (II') completely reacts, carrying out reduced pressure distillation on the concentrate, and collecting fractions at 90-95 ℃ to obtain a compound shown in the formula (III);
adding a compound shown in the formula (III) and a 20% sodium hydroxide aqueous solution into methanol, heating a reaction solution to 55-60 ℃, and reacting for 4-8 h; then cooling the reaction solution to room temperature, concentrating under reduced pressure to remove methanol, adjusting the pH value of the reaction solution to 3-4 by using 6N hydrochloric acid aqueous solution, filtering, and drying to obtain a compound shown in the formula (I);
or the like, or, alternatively,
dissolving a compound of formula (II), 2, 5-dimethoxytetrahydrofuran and pyridine hydrochloride in 1, 4-dioxane, and heating to reflux for 24 hours; concentrating the reaction solution, and carrying out column chromatography on the concentrate to obtain a compound shown as a formula (I);
(2) dissolving a compound shown in a formula (I) in dichloromethane, stirring, adding diisopropylethylamine, adding diphenyl phosphorazidate, heating a reaction system to 40-45 ℃, reacting for 6-8 hours, cooling the reaction system to room temperature, filtering, washing and drying to obtain a target product; or evaporating the solvent to dryness, adding water and ethyl acetate into the concentrate, stirring, filtering, washing, and drying to obtain the target product.
2. The method for synthesizing pyrrolo [1,2-a ] quinoxalin-4 (5H) -one and derivatives thereof according to claim 1, wherein the molar ratio of the compound of formula (ii') to 2, 5-dimethoxytetrahydrofuran is 1:1.5 to 2.0.
3. The process for the synthesis of pyrrolo [1,2-a ] quinoxalin-4 (5H) -one and derivatives thereof according to claim 1, wherein the molar ratio of the compound of formula (ii') to 2, 5-dimethoxytetrahydrofuran is 1: 1.5.
4. The process for the synthesis of pyrrolo [1,2-a ] quinoxalin-4 (5H) -one and derivatives thereof according to claim 1, wherein the molar ratio of the compound of formula (iii) to sodium hydroxide is 1: 3.5.
5. The method for synthesizing pyrrolo [1,2-a ] quinoxalin-4 (5H) -one and derivatives thereof according to claim 1, wherein the molar ratio of the compound of formula (ii) to 2, 5-dimethoxytetrahydrofuran is 1:1.0 to 2.0.
6. The process for the synthesis of pyrrolo [1,2-a ] quinoxalin-4 (5H) -one and derivatives thereof according to claim 1, wherein the molar ratio of the compound of formula (ii) to 2, 5-dimethoxytetrahydrofuran is 1: 1.5.
7. The method for synthesizing pyrrolo [1,2-a ] quinoxalin-4 (5H) -one and derivatives thereof according to claim 1, wherein the molar ratio of the compound of formula (ii) to the pyridine hydrochloride is 1: 1.2-1.5.
8. The method for synthesizing pyrrolo [1,2-a ] quinoxalin-4 (5H) -one and derivatives thereof according to claim 1, wherein the feeding molar ratio of the compound of formula (i) to diphenylphosphoryl azide is 1: 1.0-2.0.
9. The method for synthesizing pyrrolo [1,2-a ] quinoxalin-4 (5H) -one and its derivatives according to claim 1, wherein the molar ratio of the compound of formula (i) to diphenyl azidophosphate is 1: 1.3.
10. The method for synthesizing pyrrolo [1,2-A ] quinoxalin-4 (5H) -one and derivatives thereof according to claim 1, wherein the amount of dichloromethane is 5 to 10mL/g based on the amount of the compound of formula (I).
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