CN112851677A - Synthesis method of imidazopyridine or pyrimidine derivative - Google Patents
Synthesis method of imidazopyridine or pyrimidine derivative Download PDFInfo
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- CN112851677A CN112851677A CN201911176537.2A CN201911176537A CN112851677A CN 112851677 A CN112851677 A CN 112851677A CN 201911176537 A CN201911176537 A CN 201911176537A CN 112851677 A CN112851677 A CN 112851677A
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention belongs to the technical field of synthesis, and particularly relates to a synthesis method of an imidazopyridine or pyrimidine derivative. Pyridine or pyrimidine formic acid is used as a synthon, and is subjected to amidation, Hofmann degradation and cyclization reaction to obtain an imidazopyridine or pyrimidine compound, and the obtained imidazopyridine or pyrimidine derivative can be further converted to generate a functional product. The method has the advantages of easily available raw materials, simple and convenient operation, high reaction efficiency, convenient post-treatment and diversity of functional groups.
Description
Technical Field
The invention belongs to the technical field of synthesis, and particularly relates to a synthesis method of an imidazopyridine or pyrimidine derivative.
Background
The imidazopyridine or pyrimidine derivative is a fused nitrogen heterocyclic compound of five-membered ring imidazole and six-membered ring pyridine or pyrimidine, is an important drug intermediate, and has wide application in the fields of medicines, pesticides, chemical industry and the like. Many natural products and biologically active molecules contain an imidazopyridine or pyrimidine core backbone unit, for example drugs containing an imidazopyridine or pyrimidine building block are useful for anti-cancer (US 20100331296 a1), bone morphogenic protein modulation (US 20160068525 a1), treatment or prevention of arenavirus-related viral diseases (WO 2013123215 a2), and the like. The imidazopyridine or pyrimidine derivative is an important structural unit for synthesizing the compound with biological activity, so that the imidazopyridine or pyrimidine derivative has important synthesis value and wide medical application prospect.
Common methods for synthesizing imidazopyridine or pyrimidine derivatives are mainly as follows: one-pot "multi-component" reactions, microwave reactions, solid phase synthesis, etc. (organic chemistry, 2019, 39(5), 1304-1315). However, these synthetic methods have problems such as the need of using a metal catalyst, complicated reaction process, and unfavorable industrial application. Therefore, the research and development of a novel synthesis method of the imidazopyridine or pyrimidine derivative has important research significance.
Disclosure of Invention
The invention aims to provide a new method for synthesizing an important medical intermediate imidazopyridine or pyrimidine derivative by taking cheap and easily-obtained pyridine or pyrimidine formic acid as a raw material and carrying out amidation, Hofmann degradation and cyclization reactions.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method of synthesizing an imidazopyridine or pyrimidine derivative, the method comprising the steps of:
pyridine or pyrimidine formic acid (2) is used as a starting material and reacts with halogenated sulfoxide or halogenated phosphorus, and further ammonolysis is carried out to obtain pyridine or pyrimidine formamide (3) which is shown in a formula (I);
secondly, pyridine or pyrimidine formamide (3) is subjected to Hofmann degradation reaction to obtain pyridine or pyrimidine amine compound (4) shown as a formula (II);
③ pyridine or pyrimidine amine compound (4) and alpha-chlorocarbonyl compound (5) are subjected to cyclization reaction to obtain imidazopyridine or pyrimidine compound (1) and formula (III);
wherein pyridine or pyrimidine formic acid (2) and alpha-chlorocarbonyl compound (5) are synthons, and X is CH or N; r1Is hydrogen, halogen, aromaticA group, alkoxy group, furan ring, thiophene ring or pyridine ring; r2Is hydrogen, halogen or alkoxy; r3Is hydrogen or alkyl with 1-6 carbon atoms; r4Is hydrogen, alkyl with 4-20 carbon atoms, aryl, furan ring, thiophene ring or pyridine ring. The substituent group of the aryl is hydrogen, methyl, methoxy, halogen and trifluoromethyl, and the number of the substituent groups is 1-5.
In the technical scheme, the solvent for the reaction of the pyridine or pyrimidine formic acid (2) and the sulfoxide halide or the phosphorus halide in the step (i) is toluene, N-dimethylformamide or excessive sulfoxide halide or phosphorus halide; the molar ratio of the pyridine or pyrimidine formic acid (2) to the halogenated sulfoxide or the halogenated phosphorus is 1:1-1:20, the reaction temperature is 20-110 ℃, and the reaction time is 1-24 hours.
In the technical scheme, the ammonia water in the step (i) is 1-20 equivalents of pyridine or pyrimidine formic acid (2).
In the technical scheme, further, when the pyridine or pyrimidine formamide (3) is subjected to degradation reaction in the step II, the molar ratio of the pyridine or pyrimidine formamide (3) to the used liquid bromine is 1:1-1: 3; the molar ratio of the pyridine or pyrimidine carboxamide (3) to the potassium hydroxide or sodium hydroxide used is 1:2 to 1: 20; the reaction temperature is 20-100 ℃; the reaction time is 1-12 hours.
In the technical scheme, further, in the step (c), the solvent for cyclization reaction of the pyridine or pyrimidine amine compound (4) and the alpha-chlorocarbonyl compound (5) is one or more than two mixed solvents of methanol, ethanol, toluene or tetrahydrofuran or 1, 4-dioxane; the molar ratio of the pyridine or pyrimidine amine compound (4) to the alpha-chlorocarbonyl compound (5) is 1:1 to 1: 1.5; the reaction temperature is 20-100 ℃; the reaction time is 2-24 hours.
The invention has the beneficial effects that:
1) the structures of the synthesized pyridine or pyrimidine formic acid and the alpha-chlorocarbonyl compound have diversity, and the synthesized pyridine or pyrimidine formic acid and alpha-chlorocarbonyl compound can be used for synthesizing imidazopyridine or pyrimidine derivatives with different types and structures.
2) The preparation raw materials are cheap and easy to obtain, the operation is simple and convenient, the cost is low, the reaction yield is high, the post-treatment is simple, and the industrial production is easy to realize.
3) The product imidazopyridine or pyrimidine derivatives have a wide variety of functional groups and a wide range of applications, and R in this structure1、R2、R3、R4Part of the groups can be further functionalized, and the structure can be used as an intermediate of a drug structure.
Detailed Description
The invention is further illustrated but is not in any way limited by the following specific examples.
Example 1
A100 mL three-necked reaction flask was charged with 20mL of thionyl chloride and 30mL of toluene, and 4-chloro-2-pyridinecarboxylic acid (2a) (15.8g,100mmol) was added thereto in portions under stirring for 10 minutes. After the addition, the reaction mixture was reacted at 80 ℃ for 6 hours in an oil bath, thionyl chloride and most of toluene were distilled off, and 10mL of toluene was added to the residue to dissolve it.
In addition, 70mL of ammonia water (25-28% content) was added to a 250mL three-necked reaction flask, cooled in an ice-water bath, and the above acid chloride solution was added dropwise at constant pressure, followed by reaction at room temperature for 1 hour after completion of the addition. After the reaction was completed, filtration was carried out, and the solid was washed with 3X 20mL of water and dried to obtain 4-chloropyridine-2-carboxamide (3a) (14.7g, yield 94%) as a brown solid product. The target product is confirmed by nuclear magnetic resonance spectroscopy.
Example 2
30mL of phosphorus pentachloride was added to a 100mL three-necked reaction flask, and 4-methoxy-2-pyridinecarboxylic acid (2b) (15.3g,100mmol) was added thereto in portions under stirring for 10 minutes. After the addition, the reaction mixture was subjected to oil bath at 100 ℃ for 4 hours, phosphorus pentachloride was removed by distillation under the reduced pressure, and the residue was dissolved in 10mL of toluene.
In addition, 100mL of ammonia water (25-28% content) was added to a 250mL three-necked reaction flask, cooled in an ice-water bath, and the above acid chloride solution was added dropwise at constant pressure, followed by reaction at room temperature for 1 hour after completion of the addition. After the reaction was completed, filtration was carried out, and the solid was washed with 3X 20mL of water and dried to obtain 4-methoxy-pyridine-2-carboxamide (3b) (14.2g, yield 93%) as a solid product. The target product is confirmed by nuclear magnetic resonance spectroscopy.
Example 3
50mL of thionyl chloride was added to a 100mL three-necked reaction flask, and 2-chloro-pyrimidine-4-carboxylic acid (2c) (15.9g,100mmol) was added thereto in portions under stirring for 10 minutes. After the completion of the addition, the reaction mixture was refluxed for 10 hours, thionyl chloride was distilled off, and 10mL of N, N-dimethylformamide was added to the residue to dissolve it.
In addition, 150mL of ammonia water (25-28% content) was added to a 250mL three-necked reaction flask, cooled in an ice-water bath, and the above acid chloride solution was added dropwise at constant pressure, followed by reaction at room temperature for 1 hour after completion of the addition. After the reaction was completed, filtration was carried out, and the solid was washed with 3X 20mL of water and dried to obtain 2-chloro-pyrimidine-4-carboxamide (3c) (14.5g, yield 92%) as a solid product. The target product is confirmed by nuclear magnetic resonance spectroscopy.
Example 4
A100 mL three-necked reaction flask was charged with 50mL of water and potassium hydroxide (85% content) (13.2g,200mmol), dissolved, cooled in an ice-water bath, and after dropping liquid bromine (6.4g,40mmol) was added thereto at a constant pressure, the reaction was continued for 1 hour. At room temperature, 2-carboxamide-4-chloropyridine (3a) (3.1g,20mmol) was further added thereto, and the reaction was continued at 90 ℃ for 2 hours. After the reaction, concentrated hydrochloric acid was added dropwise thereto to adjust the pH to 2 while cooling in an ice-water bath. Insoluble matter was removed by suction filtration, the filtrate was neutralized with potassium hydroxide to pH 8, and extracted with 3X 30mL of ethyl acetate, and the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and volatile matter was removed under reduced pressure to give 2-amino-4-chloropyridine (4a) (2.2g, yield 84%) as a solid product. The target product is confirmed by nuclear magnetic resonance spectroscopy.
Example 5
A100 mL three-necked reaction flask was charged with 40mL of water and sodium hydroxide (9.6g,240mmol), dissolved, cooled in an ice-water bath, and after dropping liquid bromine (4.8g,30mmol) was added thereto at a constant pressure, the reaction was continued for 2 hours. At room temperature, 2-chloro-pyrimidine-4-carboxamide (3c) (3.2g,20mmol) was added thereto and the reaction was continued at 60 ℃ for 8 hours. After the reaction, concentrated hydrochloric acid was added dropwise thereto to adjust the pH to 2 while cooling in an ice-water bath. The insoluble material was removed by suction filtration, the filtrate was neutralized with sodium hydroxide to pH 8, extracted with 3X 30mL ethyl acetate, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the volatile components were removed under reduced pressure to give the solid product 2-chloro-pyrimidin-4-amine (4c) (2.3g, yield 90%). The target product is confirmed by nuclear magnetic resonance spectroscopy.
Example 6
A500 mL three-necked reaction flask was charged with 2-amino-4-chloropyridine (4a) (12.8g,100mmol) and 200mL of absolute ethanol, followed by dropping a chloroacetaldehyde aqueous solution (5a) (40% in content) (21.6g,110mmol) at constant pressure, and after dropping, the reaction was refluxed for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, the volatile components were removed under reduced pressure, and the residue was poured into a saturated aqueous sodium hydrogencarbonate solution, suction-filtered, and the solid was washed with 3X 30mL of water and dried to give 7-chloroimidazo [1,2-a ] pyridine (1aa) (13.5g, yield 89%). The target product is confirmed by nuclear magnetic resonance spectroscopy.
Example 7
A500 mL three-necked reaction flask was charged with 2-chloro-4-aminopyrimidine (4c) (12.9g, 100mmol) and 300mL of toluene, followed by dropping 2-chlorophenylacetone (5b) (23.6g, 140mmol) at constant pressure, and the mixture was allowed to react in an oil bath at 60 ℃ for 20 hours. After the reaction was completed, the mixture was cooled to room temperature, the volatile components were removed under reduced pressure, and the residue was poured into a saturated aqueous sodium bicarbonate solution, filtered with suction, washed with 3X 30mL of water as a solid, and dried to give 5-chloro-3-methyl-2-phenylimidazo [1,2-c ] pyrimidine (1cb) (22.2g, yield 91%). The target product is confirmed by nuclear magnetic resonance spectroscopy.
Typical compound characterization data
4-chloropyridine-2-carboxamide (3a), brown solid.1H NMR(CDCl3,400MHz,25℃)δ8.48(d,J＝5.2Hz,1H),8.20(s,1H),7.87(br,m,1H),7.46(d,J＝5.2Hz,1H),6.49(br,s,1H).
2-amino-4-chloropyridine (4a), yellow solid.1H NMR(CDCl3,400MHz,25℃)δ7.96(d,J＝5.2Hz,1H),6.68(d,J＝5.2Hz,1H),6.54(s,1H),4.61(br,s,2H).
7-chloroimidazo [1,2-a ]]Pyridine (1aa), white solid.1H NMR(CDCl3,400MHz,25℃)δ8.02(d,J＝7.2Hz,1H),7.61(m,2H),7.54(s,1H),6.74(d,J＝7.2Hz,1H).13C{1H}NMR(CDCl3,100MHz,25℃)δ145.3,134.5,130.9,126.1,116.8,114.1,112.7.
It will be apparent to those skilled in the art from this disclosure that many changes and modifications can be made, or equivalents modified, in the embodiments of the invention without departing from the scope of the invention. Therefore, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention shall still fall within the protection scope of the technical solution of the present invention, unless the contents of the technical solution of the present invention are departed.
Claims (5)
1. A method for synthesizing an imidazopyridine or pyrimidine derivative, comprising the steps of:
pyridine or pyrimidine formic acid (2) is used as a starting material, reacts with halogenated sulfoxide or halogenated phosphorus, and is further aminolyzed to obtain pyridine or pyrimidine formamide (3);
② pyridine or pyrimidine carboxamide (3) is subjected to Hofmann degradation reaction to obtain pyridine or pyrimidine amine compound (4);
③ pyridine or pyrimidine amine compound (4) and alpha-chlorocarbonyl compound (5) are subjected to cyclization reaction to obtain imidazopyridine or pyrimidine compound (1);
wherein X is CH or N; r1Is hydrogen, halogen, aryl, alkoxy, furan ring, thiophene ring or pyridine ring; r2Is hydrogen, halogen or alkoxy; r3Is hydrogen or alkyl with 1-6 carbon atoms; r4Is hydrogen, alkyl with 4-20 carbon atoms, aryl, furan ring, thiophene ring or pyridine ring; the substituent group of the aryl is hydrogen, methyl, methoxy, halogen and trifluoromethyl, and the number of the substituent groups is 1-5.
2. The method of synthesis according to claim 1,
in the step I, the solvent for the reaction of the pyridine or pyrimidine formic acid (2) and the halogenated sulfoxide or the halogenated phosphorus is toluene, N-dimethylformamide or excessive halogenated sulfoxide or halogenated phosphorus; the molar ratio of the pyridine or pyrimidine formic acid (2) to the halogenated sulfoxide or the halogenated phosphorus is 1:1-1:20, the reaction temperature is 20-110 ℃, and the reaction time is 1-24 hours.
3. The synthesis method according to claim 1, wherein the amount of the ammonia water used in step (i) is 1 to 20 equivalents of pyridine or pyrimidine carboxylic acid (2).
4. The method of synthesis according to claim 1,
in the step II, when the pyridine or pyrimidine formamide (3) is subjected to degradation reaction, the molar ratio of the pyridine or pyrimidine formamide (3) to the used liquid bromine is 1:1-1: 3; the molar ratio of the pyridine or pyrimidine carboxamide (3) to the potassium hydroxide or sodium hydroxide used is 1:2 to 1: 20; the reaction temperature is 20-100 ℃; the reaction time is 1-12 hours.
5. The method of synthesis according to claim 1,
in the step (c), the solvent for cyclization reaction of the pyridine or pyrimidine amine compound (4) and the alpha-chlorocarbonyl compound (5) is one or more than two of methanol, ethanol, toluene or tetrahydrofuran or 1, 4-dioxane; the molar ratio of the pyridine or pyrimidine amine compound (4) to the alpha-chlorocarbonyl compound (5) is 1:1 to 1: 1.5; the reaction temperature is 20-100 ℃; the reaction time is 2-24 hours.
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