CN113620946A - Preparation method of 2-chloro-1, 8-naphthyridine derivatives - Google Patents
Preparation method of 2-chloro-1, 8-naphthyridine derivatives Download PDFInfo
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Abstract
The invention discloses a preparation method of a 2-chloro-1, 8-naphthyridine derivative, which comprises the following steps: (1) substituted 2-aminopyridine is taken as an initial raw material, and is coupled with ethyl acrylate through carbon-carbon bonds under the action of alkali through a palladium catalyst to obtain an intermediate product, namely 2-amino-3-ethyl acrylate pyridine; (2) further intramolecular amidation of the 2-amino-3-ethyl acrylate pyridine under the action of sodium ethoxide to obtain an intermediate product of di-1, 8-naphthyridine-2 (8H) -ketone; (3) the 1, 8-naphthyridine-2 (8H) -ketone is chlorinated by using thionyl chloride and organic base to obtain a final product 2-chloro-1, 8-naphthyridine derivative. The invention adopts the preparation method of the 2-chloro-1, 8-naphthyridine derivative with the structure, takes the 2-aminopyridine compound as the initial raw material, and realizes the new path preparation of the 2-chloro-1, 8-naphthyridine compound through a series of unit reactions such as carbon-carbon bond activation, cyclization, chloro and the like.
Description
Technical Field
The invention relates to the technical field of 2-chloro-1, 8-naphthyridine compounds, in particular to a preparation method of a 2-chloro-1, 8-naphthyridine derivative.
Background
The 1, 8-naphthyridine compounds have important applications in the fields of drug molecule design, novel ligand construction and fluorescent probe preparation, but relatively few reports about the synthesis of the compounds are provided, and reports about introducing halogen atoms and functional groups such as aromatic rings into the structure are rare. The invention provides a novel preparation method of a 2-chloro-1, 8-naphthyridine compound, which is used as an important intermediate of a naphthyridine derivative, wherein the chlorine atom is an important functional group for carrying out structure expansion, and is used for expanding the preparation method of the functionalized 1, 8-naphthyridine compound.
Disclosure of Invention
The invention aims to provide a preparation method of 2-chloro-1, 8-naphthyridine derivatives, which takes 2-aminopyridine compounds as initial raw materials and realizes the high-efficiency preparation of the 2-chloro-1, 8-naphthyridine compounds through a series of unit reactions such as carbon-carbon bond activation, cyclization, chlorination and the like.
In order to achieve the above object, the present invention provides a preparation method of 2-chloro-1, 8-naphthyridine derivatives, comprising the following steps:
(1) substituted 2-aminopyridine is taken as an initial raw material, and is coupled with ethyl acrylate through carbon-carbon bonds under the action of alkali through a palladium catalyst to obtain an intermediate product, namely 2-amino-3-ethyl acrylate pyridine;
(2) further intramolecular amidation of the 2-amino-3-ethyl allylate pyridine under the action of sodium ethoxide to obtain intermediate di-1, 8-naphthyridine-2 (8H) -ketone;
(3) the 1, 8-naphthyridine-2 (8H) -ketone is chlorinated by using thionyl chloride and organic alkali to obtain a final product 2-chloro-1, 8-naphthyridine derivative;
preferably, the carbon-carbon bond coupling reaction in step (1) is carried out in an aprotic dipolar solvent, which is one or more of N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, pyridine, N-dimethylacetamide, and the like.
Preferably, in step (1), the substituted 2-aminopyridine, the ethyl acrylate and the base are dissolved in the aprotic dipolar solvent, the palladium catalyst is added under stirring, and the mixture is refluxed under air for 24 hours.
Preferably, the step (1) further comprises cooling the reaction solution to room temperature after the reaction is finished, filtering out insoluble solid substances, performing rotary evaporation on the reaction solution to 10mL, and pouring the reaction solution into ice water under stirring; and (4) carrying out suction filtration, washing a filter cake by using normal hexane and ethylbenzene, and then carrying out vacuum drying to obtain a yellow solid, namely the intermediate product I.
Preferably, the ratio of the n-hexane to the ethylbenzene is 1: 1-2: 3.
preferably, the reaction conditions of the step (2) are stirring at 85 ℃ for 6 hours; and pouring into ice water after the reaction is finished, performing suction filtration, washing the filtrate with ice methanol, and performing vacuum drying to obtain a yellow crystal, namely the intermediate product II.
Preferably, the reaction conditions of step (3) are stirring at 25 ℃ for 6 hours; after the reaction is finished, pouring into ice water, adding saturated sodium carbonate solution to adjust the pH value to 8.0, performing suction filtration, and washing the filtrate with water to obtain yellow crystals, namely the final product.
Preferably, in the step (1), the alkali is one of silver carbonate, strontium carbonate and the like.
Preferably, in the step (3), the organic base is one of 4, 4-dimethylaminopyridine, 4-methyl-4-isopropylaminopyridine, 1, 8-bisdimethylaminonaphthalene, and the like.
The invention has the beneficial effects that:
(1) the invention takes 2-aminopyridine compounds as starting raw materials to prepare a series of 2-chloro-1, 8-naphthyridine compounds containing different functional groups, the method has definite route, simple operation and higher purification efficiency of intermediates, can prepare high-purity target products in a larger amount, and provides a new synthesis module for developing novel drug molecules and materials such as ligands, probes and the like.
(2) The method shortens the reaction steps, reduces the use of toxic and harmful reagents, reduces the operation of high-temperature reaction, and reduces the risk possibly generated in the operation process. Meanwhile, the method has better structural universality and enlarges the application range of the substrate.
(3) According to the invention, the preparation of the 1, 8-naphthyridine compound connected with different modification units is realized by selecting the starting raw materials containing different substituted functional groups, so that the application of the naphthyridine compound is further expanded.
The technical solution of the present invention is further described in detail by the following examples.
Detailed Description
The present invention will be further described with reference to examples, in which various chemicals and reagents are commercially available unless otherwise specified.
Example 1
Step (1): 100mmol of 2-aminopyridine, 120mmol of ethyl acrylate, 20-300mmol of strontium carbonate and 100ml of N, N-dimethylformamide are dissolved, 1-200mg of palladium acetate are added under stirring, and the mixture is refluxed for 24 hours under the air. After the reaction, the reaction solution was cooled to room temperature, insoluble solid materials were filtered off, the reaction solution was evaporated to 10mL by rotation, and the solution was poured into 300mL of ice water with stirring. Performing suction filtration, washing a filter cake with 20mL of normal hexane and 30mL of ethylbenzene, and performing vacuum drying to obtain a yellow solid intermediate product I;
step (2): the intermediate product one obtained in the above step (40mmol) was dissolved in 150mL of 18% sodium ethoxide-ethanol solution and stirred at 85 ℃ for 6 hours. Pouring the mixture into 300mL of ice water after the reaction is finished, carrying out suction filtration, washing the filtrate with 15mL of ice methanol, and carrying out vacuum drying to obtain a yellow crystal intermediate product II;
and (3): 20mmol of the intermediate product were redissolved in 10mL of thionyl chloride, 10-100 mg of 4-methyl-4-isopropylaminopyridine were added, and stirred at 25 ℃ for 6 hours. After the reaction, the mixture was poured into 300mL of ice water, saturated sodium carbonate solution was added to adjust the pH to 8.0, the mixture was filtered with suction, and the filtrate was washed with 100mL of water to obtain a yellow crystalline final product.
Example 2
Step (1): 100mmol of 5-methyl-2-aminopyridine, 120mmol of ethyl acrylate, 20-300mmol of strontium carbonate and 100ml of N, N-dimethylformamide, 1-200mg of palladium acetate are added with stirring and refluxed under air for 24 hours. After the reaction, the reaction solution was cooled to room temperature, insoluble solid materials were filtered off, the reaction solution was evaporated to 10mL by rotation, and the solution was poured into 300mL of ice water with stirring. Performing suction filtration, washing a filter cake with 20mL of normal hexane and 30mL of ethylbenzene, and performing vacuum drying to obtain a yellow solid intermediate product I;
step (2): the intermediate product one obtained in the above step (40mmol) was dissolved in 150mL of 18% sodium ethoxide-ethanol solution and stirred at 85 ℃ for 6 hours. Pouring the mixture into 300mL of ice water after the reaction is finished, carrying out suction filtration, washing the filtrate with 15mL of ice methanol, and carrying out vacuum drying to obtain a yellow crystal intermediate product II;
and (3): 20mmol of the intermediate product were redissolved in 10mL of thionyl chloride, 10-100 mg of 4-methyl-4-isopropylaminopyridine were added, and stirred at 25 ℃ for 6 hours. After the reaction, the mixture was poured into 300mL of ice water, saturated sodium carbonate solution was added to adjust the pH to 8.0, the mixture was filtered with suction, and the filtrate was washed with 100mL of water to obtain a yellow crystalline final product.
Example 3
Step (1): 100mmol of 6-methyl-2-aminopyridine, 120mmol of ethyl acrylate, 20-300mmol of strontium carbonate and 100ml of N, N-dimethylformamide, 1-200mg of palladium acetate are added with stirring and refluxed under air for 24 hours. After the reaction, the reaction solution was cooled to room temperature, insoluble solid materials were filtered off, the reaction solution was evaporated to 10mL by rotation, and the solution was poured into 300mL of ice water with stirring. Performing suction filtration, washing a filter cake with 20mL of normal hexane and 30mL of ethylbenzene, and performing vacuum drying to obtain a yellow solid intermediate product I;
step (2): the intermediate product one obtained in the above step (40mmol) was dissolved in 150mL of 18% sodium ethoxide-ethanol solution and stirred at 85 ℃ for 6 hours. Pouring the mixture into 300mL of ice water after the reaction is finished, carrying out suction filtration, washing the filtrate with 15mL of ice methanol, and carrying out vacuum drying to obtain a yellow crystal intermediate product II;
and (3): 20mmol of the intermediate product were redissolved in 10mL of thionyl chloride, 10-100 mg of 4-methyl-4-isopropylaminopyridine were added, and stirred at 25 ℃ for 6 hours. After the reaction, the mixture was poured into 300mL of ice water, saturated sodium carbonate solution was added to adjust the pH to 8.0, the mixture was filtered with suction, and the filtrate was washed with 100mL of water to obtain a yellow crystalline final product.
Comparative example 1
Step (1): 100mmol of 2-aminopyridine, 120mmol of ethyl acrylate, 20-300mmol of alkali and 100ml of N, N-dimethylformamide are dissolved, 1-200mg of palladium acetate are added under stirring, and the mixture is refluxed for 24 hours under the air. After the reaction, the reaction solution was cooled to room temperature, insoluble solid materials were filtered off, the reaction solution was evaporated to 10mL by rotation, and the solution was poured into 300mL of ice water with stirring. Performing suction filtration, washing a filter cake with 20mL of normal hexane and 30mL of ethylbenzene, and performing vacuum drying to obtain a yellow solid intermediate product I; wherein the base is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate, strontium carbonate, lithium hydroxide, sodium hydroxide, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] -5-nonene, tetramethylguanidine, hexamethyldisilazane-amido lithium, or triethylene diamine; the influence of the kind of base on the conversion of the C-C bond condensation reaction is shown in Table 1;
step (2): the intermediate product one obtained in the above step (40mmol) was dissolved in 150mL of 18% sodium ethoxide-ethanol solution and stirred at 85 ℃ for 6 hours. Pouring the mixture into 300mL of ice water after the reaction is finished, carrying out suction filtration, washing the filtrate with 15mL of ice methanol, and carrying out vacuum drying to obtain a yellow crystal intermediate product II;
and (3): 20mmol of the intermediate product were redissolved in 10mL of thionyl chloride, 10-100 mg of 4-methyl-4-isopropylaminopyridine were added, and stirred at 25 ℃ for 6 hours. After the reaction, the mixture was poured into 300mL of ice water, saturated sodium carbonate solution was added to adjust the pH to 8.0, the mixture was filtered with suction, and the filtrate was washed with 100mL of water to obtain a yellow crystalline final product.
TABLE 1 influence of the type of base on the conversion of the C-C bond condensation reaction.
Note: represents no product formation
Experimental data show that silver carbonate and strontium carbonate have obvious promotion effect on carbon-carbon bond condensation of a system, and are alkaline additives with relatively good effects. However, the price of silver carbonate is relatively high, so strontium carbonate is preferably used as the basic additive.
Comparative example 2
Step (1): 100mmol of 2-aminopyridine, 120mmol of ethyl acrylate, 20-300mmol of strontium carbonate and 100ml of N, N-dimethylformamide are dissolved, 1-200mg of palladium acetate are added under stirring, and the mixture is refluxed for 24 hours under the air. After the reaction, the reaction solution was cooled to room temperature, insoluble solid materials were filtered off, the reaction solution was evaporated to 10mL by rotation, and the solution was poured into 300mL of ice water with stirring. Performing suction filtration, washing a filter cake with 20mL of normal hexane and 30mL of ethylbenzene, and performing vacuum drying to obtain a yellow solid intermediate product I;
step (2): the intermediate product one obtained in the above step (40mmol) was dissolved in 150mL of 18% sodium ethoxide-ethanol solution and stirred at 85 ℃ for 6 hours. Pouring the mixture into 300mL of ice water after the reaction is finished, carrying out suction filtration, washing the filtrate with 15mL of ice methanol, and carrying out vacuum drying to obtain a yellow crystal intermediate product II;
and (3): 20mmol of the intermediate product are redissolved in 10mL of thionyl chloride, 10-100 mg of an organic base are added and stirred at 25 ℃ for 6 hours. Pouring the mixture into 300mL of ice water after the reaction is finished, adding a saturated sodium carbonate solution to adjust the pH value to 8.0, carrying out suction filtration, and washing the filtrate with 100mL of water to obtain a yellow crystal final product; wherein the organic base is selected from 4, 4-dimethylaminopyridine, 4-methyl-4-isopropylaminopyridine, 2, 6-diaminopyridine, 1, 8-bisdimethylaminonaphthalene, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] -5-nonene, tetramethylguanidine; the effect of the type of organic base on the conversion of the chlorination reaction is shown in table 2.
TABLE 2 influence of the type of organic base on the conversion of the chlorination reaction
Note: represents no product formation
As shown in Table 2, the 4-methyl-4-isopropylaminopyridine is used for catalyzing and converting the carbonyl group at the 2-position in 1, 8-naphthyridin-2 (8H) -ketone into chlorine with high efficiency by screening various organic bases, and the reaction is carried out at room temperature, so that the risk in the heating process is reduced.
Therefore, the preparation method of the 2-chloro-1, 8-naphthyridine derivative with the structure is adopted, the 2-chloro-1, 8-naphthyridine derivative is prepared through simple carbon-carbon bond coupling, lactamization and other standard organic unit reactions, and the intermediate and the target product generated by the reaction can be purified through simple extraction and recrystallization operations.
Claims (9)
1. A preparation method of 2-chloro-1, 8-naphthyridine derivatives is characterized by comprising the following steps:
(1) substituted 2-aminopyridine is taken as an initial raw material, and is coupled with ethyl acrylate through carbon-carbon bonds under the action of alkali through a palladium catalyst to obtain an intermediate product, namely 2-amino-3-ethyl acrylate pyridine;
(2) further intramolecular amidation of the 2-amino-3-ethyl allylate pyridine under the action of sodium ethoxide to obtain intermediate di-1, 8-naphthyridine-2 (8H) -ketone;
(3) the 1, 8-naphthyridine-2 (8H) -ketone is chlorinated by using thionyl chloride and organic base to obtain a final product 2-chloro-1, 8-naphthyridine derivative.
2. The preparation method of 2-chloro-1, 8-naphthyridine derivatives according to claim 1, wherein: the carbon-carbon bond coupling reaction in the step (1) is carried out in an aprotic dipolar solvent, wherein the aprotic dipolar solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, pyridine, N-dimethylacetamide and the like.
3. The preparation method of 2-chloro-1, 8-naphthyridine derivatives according to claim 2, wherein: dissolving the substituted 2-aminopyridine, the ethyl acrylate and the base in the aprotic dipolar solvent in the step (1), adding the palladium catalyst under stirring, and refluxing for 24 hours under air.
4. The preparation method of 2-chloro-1, 8-naphthyridine derivatives according to claim 3, wherein: after the reaction in the step (1) is finished, cooling the reaction liquid to room temperature, filtering out solid insoluble substances, performing rotary evaporation on the reaction liquid to 10mL, and pouring the reaction liquid into ice water under stirring; and (4) carrying out suction filtration, washing a filter cake by using normal hexane and ethylbenzene, and then carrying out vacuum drying to obtain a yellow solid, namely the intermediate product I.
5. The preparation method of 2-chloro-1, 8-naphthyridine derivatives according to claim 4, wherein: the ratio of the n-hexane to the ethylbenzene is 1: 1-2: 3.
6. the preparation method of 2-chloro-1, 8-naphthyridine derivatives according to claim 1, wherein: the reaction condition of the step (2) is stirring for 6 hours at 85 ℃; and pouring into ice water after the reaction is finished, performing suction filtration, washing the filtrate with ice methanol, and performing vacuum drying to obtain a yellow crystal, namely the intermediate product II.
7. The preparation method of 2-chloro-1, 8-naphthyridine derivatives according to claim 1, wherein: the reaction condition of the step (3) is that the mixture is stirred for 6 hours at the temperature of 25 ℃; after the reaction is finished, pouring into ice water, adding saturated sodium carbonate solution to adjust the pH value to 8.0, performing suction filtration, and washing the filtrate with water to obtain yellow crystals, namely the final product.
8. The preparation method of 2-chloro-1, 8-naphthyridine derivatives according to claim 1, wherein: in the step (1), the alkali is one of silver carbonate, strontium carbonate and the like.
9. The preparation method of 2-chloro-1, 8-naphthyridine derivatives according to claim 1, wherein: in the step (3), the organic base is one of 4, 4-dimethylamino pyridine, 4-methyl-4-isopropylaminopyridine, 1, 8-bis-dimethylamino naphthalene, and the like.
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Citations (3)
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| CN105061421A (en) * | 2015-07-20 | 2015-11-18 | 中国石油大学(华东) | Method for preparing 2-chloro-1, 8-naphthyridine derivative |
| CN106810550A (en) * | 2017-01-10 | 2017-06-09 | 湖南华腾制药有限公司 | A kind of preparation method of 7-naphthyridine derivatives |
| CN109294314A (en) * | 2018-09-06 | 2019-02-01 | 中国海洋石油集团有限公司 | A kind of epoxy acrylic cathode electrophoresis dope resin emulsion and preparation method thereof |
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Patent Citations (3)
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| CN105061421A (en) * | 2015-07-20 | 2015-11-18 | 中国石油大学(华东) | Method for preparing 2-chloro-1, 8-naphthyridine derivative |
| CN106810550A (en) * | 2017-01-10 | 2017-06-09 | 湖南华腾制药有限公司 | A kind of preparation method of 7-naphthyridine derivatives |
| CN109294314A (en) * | 2018-09-06 | 2019-02-01 | 中国海洋石油集团有限公司 | A kind of epoxy acrylic cathode electrophoresis dope resin emulsion and preparation method thereof |
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| SEUNG HWAN CHO等: "Palladium-Catalyzed C-H Functionalization of Pyridine N-Oxides: Highly Selective Alkenylation and Direct Arylation with Unactivated Arenes", 《J. AM. CHEM. SOC.》 * |
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