CN111533697B - 4-aminopyridazinone compound and preparation method thereof - Google Patents
4-aminopyridazinone compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a 4-aminopyridazinone compound, belongs to the technical field of organic chemical synthesis, and also discloses a preparation method of the compoundαApplication of a halogenated hydrazone compound and azlactone or an azlactone precursor to [4+2 +]The 4-aminopyridazinone compound is constructed through cyclization reaction, the method not only makes up the blank of synthesis of the 4-aminopyridazinone compound, but also is beneficial to enriching the types of pyridazine alkaloids, thereby providing more selectable compound sources for screening the activity of the medicament and enriching the compound library for screening the medicament; the method has the advantages of mild reaction conditions, easily obtained raw materials, simple operation and high yield.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a 4-aminopyridazinone compound and a preparation method thereof.
Background
Pyridazinone structures constitute the core skeleton of many natural products and drugs, some of which have been approved for marketing as pharmaceuticals, such as Zardaverine, imazodan, pimobendan, and the like. The 4-aminopyridazinone is a member of the pyridazinone skeleton, and the molecular structure containing the 4-aminopyridazinone skeleton is reported as follows:
according to the existing reports, the compounds containing the 4-aminopyridazinone skeleton have wide biological activity, and a plurality of molecules in the compounds are proved to have antibacterial, anti-inflammatory, anticancer, antitumor and other activities, so that the compounds have great potential application value. Therefore, it is of great importance to provide novel 4-aminopyridazinone compounds and to develop effective methods for synthesizing compounds containing 4-aminopyridazinone skeleton.
Through literature research, we find that no method for synthesizing 4-aminopyridazinone compounds exists at present. Whereas the most common method based on pyridazinone backbones is the condensation reaction of gamma-carbonyl acids or esters with hydrazine. The aforementioned compounds containing a 4-aminopyridazinone skeleton are also synthesized by using hydrazine hydrate as a key synthetic pyridazinone skeleton. For another example, chinese patent application CN106146404A discloses a typical method for synthesizing a pyridazinone parent body (skeleton):
however, the above-mentioned method for synthesizing a pyridazinone skeleton has significant disadvantages such as: (1) The use of a highly toxic and expensive hydrazine reagent is required; (2) The reaction conditions are harsh, heating reflux is often required, and great potential safety hazards exist in industrial production; (3) A large amount of strong acid such as concentrated hydrochloric acid is often used, so that the equipment is seriously corroded and has safety hazards. Therefore, the invention provides a simple and practical method, and the method for synthesizing the pyridazinone skeleton from non-toxic raw materials, in particular the method for synthesizing the 4-aminopyridazinone mother nucleus in one step has very important value.
Disclosure of Invention
An object of the present invention is to provide a class of 4-aminopyridazinone compounds to solve the above problems.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a4-aminopyridazinone compound is a compound (4) with a structure shown as the following or a stereoisomer of the compound (4) and pharmaceutically acceptable salt thereof:
in the above structure, R 1 The group represents acyl or sulfonyl; r 2 The radical represents alkyl or aryl; r 3 The radicals represent aryl radicals; r 4 Represents an alkyl group or an aryl group.
The second object of the present invention is to provide a method for preparing the above compound, which comprises the following steps:
the method comprises the following steps:
dissolving alpha-halogenated hydrazone (1) and azlactone (2) in an organic solvent, adding inorganic base or organic base, and stirring for reaction at room temperature under the protection of inert gas; after the reaction is finished, separating and purifying to obtain a 4-aminopyridazinone compound (4); wherein the content of the first and second substances,
the alpha-halohydrazone (1) has the following structure:
the azlactone (2) has the following structure:
the second preparation method comprises the following steps:
the method comprises the following steps:
dissolving alpha-halogenated hydrazone (1), azlactone precursor (3) and carbodiimide in an organic solvent, adding inorganic base or organic base, and stirring at room temperature under the protection of inert gas for reaction; after the reaction is finished, separating and purifying to obtain a 4-aminopyridazinone compound (4); wherein
The alpha-halohydrazone (1) has the following structure:
the azlactone precursor (3) has the following structure:
as a preferred technical scheme: the separation and purification method is column chromatography.
When the reaction is in milligram grade, silica gel column chromatography is adopted for separation and purification.
As a preferred technical scheme: concentrating the reaction system after the reaction is finished, adding an alkane solvent, and pulping; filtering, concentrating the filtrate, adding alcohol solvent, and pulping for the second time; filtering to obtain a white solid, namely the 4-aminopyridazinone compound (4).
When the reaction is in gram level, a crystallization method can be adopted for separation and purification, and the method is simple and easy to implement; and when the reaction is in the milligram grade, the crystallization method is not recommended because the amount is too small to be crystallized and the yield is not accurate due to the loss of the sample caused by the operation.
As a preferred technical scheme: the organic solvent is at least one selected from toluene, xylene, mesitylene, chlorobenzene, dichloromethane, chloroform, 1-trichloroethane, 1, 2-dichloroethane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, acetonitrile and ethyl acetate.
The novel 4-aminopyridazinone compound enriches the types of pyridazine alkaloids, and the existing pyridazinone molecules have a large number of reports of biological activities including antibiosis, anti-inflammation, antitumor, disinsection and the like, so that a novel large class of compounds provided by the invention can be reasonably predicted to have certain biological activity, and a sufficient compound source is provided for screening of the pharmaceutical activity.
Compared with the prior art, the invention has the advantages that: (1) The invention uses the alpha-halogenated hydrazone compound and azlactone or an azlactone precursor for [4+2] cyclization reaction to construct the 4-aminopyridazinone compound for the first time, and the method not only makes up the blank of synthesizing the 4-aminopyridazinone compound, but also is beneficial to enriching the types of pyridazine alkaloids, thereby providing more selectable compound sources for screening the pharmaceutical activity and enriching the chemical compound library for screening the drugs; (2) Compared with the prior art, the pyridazinone skeleton is synthesized from nontoxic raw materials, so that hydrazine raw materials with high toxicity and high price are avoided; (3) The reaction condition for synthesizing the pyridazinone is mild, and the harsh condition of high-temperature reflux in the existing method is avoided; and (4) the substrate has wide applicability and high yield.
Drawings
FIG. 1 is a hydrogen spectrum of 4a obtained in example 1;
FIG. 2 is a carbon spectrum of 4a obtained in example 1;
FIG. 3 is a high resolution mass spectrum of 4a obtained in example 1.
FIG. 4 is a view showing the structure of a single crystal of 4a obtained in example 1.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1:
synthesis of compound 4 a: a dry hard reaction tube was taken, and α -bromohydrazone 1a (36.6 mg, 0.1mmol) was added to the reaction tube, azlactone 2a (35.6 mg, 0.15mmol) was added, then anhydrous sodium carbonate (10.6 mg, 0.1mmol) was added, and finally anhydrous toluene (2 mL) was added, nitrogen gas was replaced, and the reaction was carried out at room temperature for 24 hours under nitrogen protection. After the reaction is finished, the solvent is concentrated under reduced pressure, and the compound 4a is separated and purified by column chromatography (volume ratio: petroleum ether/ethyl acetate = 10/1-3/1) to obtain a white solid with the purity of 99% and the yield of 98% through HPLC detection.
Amplification reaction: the reaction was amplified until the amount of the alpha-halohydrazone 1a charged was 1.0g, and after the reaction was completed, the reaction solvent was concentrated under reduced pressure and toluene was recovered. After concentrating to dryness, CH was added to the system 2 Cl 2 (50 mL), slurrying at room temperature for 30min, suspending a large amount of white solid in the systemFiltering, with CH 2 Cl 2 (5 mL) leaching the filter cake, combining the filtrates, concentrating, adding anhydrous methanol (10 mL) into the concentrate, pulping at room temperature for 30min to separate out a large amount of white solid, filtering to obtain solid, namely pure product 4a, and detecting the purity of the solid by HPLC>99% and yield 86%. The single crystal structure is shown in FIG. 4; m.p. 225.1-226.0 ℃. 1 H NMR(300MHz，CDCl 3 ) δ 7.91-7.88 (m, 2H), 7.83 (d, J =8.4hz, 2h), 7.75-7.73 (m, 3H), 7.52-7.38 (m, 6H), 7.27-7.18 (m, 3H), 7.14-7.07 (m, 4H), 4.97 (d, J =17.6hz, 1h), 3.42 (d, J =17.6hz, 1h), 2.44 (s, 3H), as shown in fig. 1; 13 C NMR(75MHz，CDCl 3 ) δ 166.1, 165.9, 152.6, 145.5, 134.6, 134.3, 134.0, 133.6, 132.1, 131.0, 129.5, 129.0, 128.9, 128.8, 128.7, 128.6, 127.0, 126.6, 126.1, 58.7, 32.2, 21.7 as shown in fig. 2; HRMS (ESI) Calcd 30 H 25 N 3 NaO 4 S[M+Na] + 546.1458; found:546.1454, as shown in FIG. 3.
Example 2:
synthesis of compound 4 b: a dry hard reaction tube was taken, and α -bromohydrazone 1b (35.2mg, 0.1mmol) was added to the reaction tube, azlactone 2a (35.6mg, 0.15mmol) was added, followed by anhydrous potassium carbonate (13.8mg, 0.1mmol), and finally anhydrous chloroform (2 mL) was added, and the reaction was carried out at room temperature for 24 hours under nitrogen atmosphere with replacement of nitrogen. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4b. White solid, yield 81%; m.p. 221.8-222.0 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.95(d，J＝7.9Hz，2H)，7.88(d，J＝6.5Hz，2H)，7.75-7.71(m，3H)，7.64(t，J＝7.9Hz，1H)，7.53-7.38(m，8H)，7.22-7.18(m，1H)，7.11-7.09(m，4H)，4.94(d，J＝17.5Hz，1H)，3.47(d，J＝17.4Hz，1H). 13 C NMR(75MHz，CDCl 3 )δ166.1，166.0，152.8，136.9，134.5，134.2，133.5，132.1，131.1，129.1，128.90，128.87，128.65，128.64，127.0，126.6，126.0，58.8，32.2.HRMS(ESI)Calcd.for C 29 H 23 N 3 NaO 4 S[M+Na] + :532.1301；found:532.1319。
Example 3:
synthesis of compound 4 c: a dry, hard reaction tube was taken, and α -chlorohydrazone 1c (35.2mg, 0.1mmol) was added to the reaction tube, azlactone 2a (35.6mg, 0.15mmol) was added, then anhydrous potassium bicarbonate (10.0mg, 0.1mmol) was added, and finally anhydrous toluene (2 mL) was added, nitrogen gas was replaced, and the reaction was carried out at room temperature for 24 hours under nitrogen protection. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4c. White solid, yield 84%. m.p. 189.0-191.5 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.88-7.85(m，2H)，7.80-7.77(m，2H)，7.56-7.42(m，9H)，7.34-7.32(m，3H)，4.70(d，J＝17.4Hz，1H)，3.79(d，J＝17.5Hz，1H)，3.39(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.6，166.5，153.1，134.9，134.2，133.5，132.2，131.1，129.6，129.4，128.9，128.7，127.0，126.5，126.2，59.2，41.3，32.7.HRMS(ESI)Calcd.for C 24 H 21 N 3 NaO 4 S[M+Na] + :470.1145；found:470.1131。
Example 4:
synthesis of compound 4 d: a dry, hard reaction tube was taken, and α -bromohydrazone 1d (38.0 mg, 0.1mmol) was added to the reaction tube, azlactone 2a (35.6 mg, 0.15mmol) was added, triethylamine (10.1mg, 0.1mmol) was added, and finally anhydrous toluene (2 mL) was added to replace nitrogen, and the reaction was carried out at room temperature for 24 hours under nitrogen protection. After the reaction is finished, the solvent is concentrated under reduced pressure and is separated and purified by column chromatography (stone)Oleyl ether/ethyl acetate = 10/1-3/1) gave compound 4d. White solid, yield 88%; m.p. 159.4-161.1 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.83-7.73(m，7H)，7.50(t，J＝7.4Hz，1H)，7.43-7.38(m，2H)，7.28-7.17(m，5H)，7.14-7.06(m，4H)，4.97(t，J＝17.6Hz，1H)，3.36(d，J＝17.6Hz，1H)，2.44(s，3H)，2.42(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.1，166.0，152.6，145.4，141.5，134.7，134.0，133.6，132.0，131.5，129.6，129.4，128.9，128.8，128.7，128.6，127.0，126.6，126.1，58.7，32.1，21.7，21.4.HRMS(ESI)Calcd.for C 31 H 27 N 3 NaO 4 S[M+Na] + :560.1614；found:560.1611。
Example 5:
synthesis of compound 4 e: a dry, hard reaction tube was taken, and α -bromohydrazone 1e (39.6 mg, 0.1mmol) was added to the reaction tube, azlactone 2a (35.6 mg, 0.15mmol) was added, then N, N-diisopropylethylamine (12.9 mg, 0.1mmol) was added, and finally anhydrous toluene (2 mL) was added, nitrogen gas was replaced, and the reaction was carried out at room temperature for 24 hours under nitrogen protection. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4e. White solid, yield 85%; white solid, m.p. 208.0-209.5 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.88-7.80(m，5H)，7.74(t，J＝7.3Hz，2H)，7.50(t，J＝7.4Hz，1H)，7.43-7.38(m，2H)，7.26-7.18(m，3H)，7.14-7.06(m，4H)，6.96(d，J＝8.8Hz，2H)，4.97(d，J＝17.4Hz，1H)，3.87(s，3H)，3.33(d，J＝17.5Hz，1H)，2.43(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.0，161.9，152.3，145.4，134.7，134.1，133.6，132.2，129.4，128.9，128.8，128.7，128.6，128.3，127.0，126.7，126.1，114.2，58.7，55.4，31.9，21.7.HRMS(ESI)Calcd.for C 31 H 27 N 3 NaO 5 S[M+Na] + :576.1564；found:576.1560。
Example 6:
synthesis of compound 4 f: a dry, hard reaction tube was taken, and α -bromohydrazone 1f (39.6 mg, 0.1mmol) was added to the reaction tube, azlactone 2a (35.6 mg, 0.15mmol) was added, then anhydrous sodium carbonate (10.6 mg, 0.1mmol) was added, and finally anhydrous chlorobenzene (2 mL) was added, nitrogen gas was replaced, and the reaction was carried out at room temperature for 24 hours under nitrogen protection. After the reaction was completed, the solvent was concentrated under reduced pressure, and separated and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4f. White solid, yield 94%; m.p. 179.1-180.3 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.81(d，J＝8.3Hz，2H)，7.75-7.72(m，3H)，7.52-7.34(m，6H)，7.26-7.17(m，3H)，7.15-7.08(m，4H)，7.02(dd，J＝8.1，1.7Hz，1H)，4.89(d，J＝17.6Hz，1H)，3.84(s，3H)，3.44(d，J＝17.6Hz，1H)，2.43(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.1，165.9，159.9，152.3，145.4，135.6，134.6，133.9，133.5，132.0，129.8，129.4，129.0，128.8，128.7，128.6，127.0，126.1，119.1，116.8，111.7，58.7，55.4，32.3，21.7.HRMS(ESI)Calcd.for C 31 H 27 N 3 NaO 5 S[M+Na] + :576.1564；found:576.1569。
Example 7:
synthesis of Compound 4 g: 1g (43.4 mg, 0.1mmol) of α -bromohydrazone was added to a dry rigid reaction tube, azlactone 2a (35.6 mg, 0.15mmol) was added thereto, anhydrous sodium carbonate (10.6 mg, 0.1mmol) was added thereto, and finally anhydrous toluene (2 mL) was added thereto, and the reaction was carried out at room temperature for 24 hours under nitrogen atmosphere with replacement of nitrogen. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain 4g of the compound. White solidThe yield is 99%; m.p. 180.0-181.0 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.99(d，J＝8.1Hz，2H)，7.83(d，J＝8.2Hz，2H)，7.75-7.68(m，5H)，7.50(t，J＝7.5Hz，1H)，7.43-7.38(m，2H)，7.28-7.21(m，3H)，7.14-7.07(m，4H)，4.91(d，J＝17.6Hz，1H)，3.52(d，J＝17.6Hz，1H)，2.45(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.3，165.6，151.0，145.7，137.6，134.5，133.9，133.5，132.6(q，J＝33.0Hz，1C)，132.1，129.6，129.2，129.0，128.8，128.7，127.0，126.9，126.0，125.9(q，J＝3.8Hz，2C)，123.8(q，J＝270.0Hz，1C)，58.8，32.3，21.7.HRMS(ESI)Calcd.for C 31 H 24 F 3 N 3 NaO 4 S[M+Na] + :614.1332；found:614.1333。
Example 8:
synthesis of compound 4 h: a dry hard reaction tube was taken, and α -bromohydrazone (40.0 mg, 0.1mmol) was added to the reaction tube for 1h, azlactone 2a (35.6 mg, 0.15mmol) was added, anhydrous sodium carbonate (10.6 mg, 0.1mmol) was then added, and finally anhydrous xylene (2 mL) was added to displace nitrogen, and the reaction was carried out at room temperature for 24h under nitrogen protection. After the reaction is finished, the solvent is concentrated under reduced pressure, and the compound is separated and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain the compound for 4h. White solid, yield 93%; m.p. 228.3-229.4 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.84-7.80(m，4H)，7.74-7.71(m，3H)，7.50(t，J＝7.3Hz，1H)，7.44-7.38(m，4H)，7.27-7.19(m，3H)，7.13-7.07(m，4H)，4.90(t，J＝17.6Hz，1H)，3.42(d，J＝17.6Hz，1H)，2.44(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.2，165.7，151.4，145.6，137.2，134.5，133.9，133.5，132.7，132.1，129.5，129.12，129.07，128.9，128.7，128.6，127.9，127.0，126.0，58.7，32.1，21.7.HRMS(ESI)Calcd.for C 30 H 24 ClN 3 NaO 4 S[M+Na] + :580.1068；found:580.1054。
Example 9:
synthesis of compound 4 i: taking a dry hard reaction tube, adding alpha-bromohydrazone 1i (38.4 mg, 0.1mmol) into the reaction tube, adding azlactone 2a (35.6 mg, 0.15mmol), then adding anhydrous sodium carbonate (10.6 mg, 0.1mmol), finally adding anhydrous tetrahydrofuran (2 mL), replacing nitrogen, and reacting at room temperature for 24h under the protection of nitrogen. After the reaction is completed, the solvent is concentrated under reduced pressure, and the compound 4i is obtained by column chromatography separation and purification (petroleum ether/ethyl acetate = 10/1-3/1). White solid, yield 85%; m.p. 212.1-213.0 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.91-7.81(m，4H)，7.74-7.72(m，3H)，7.50(t，J＝7.2Hz，1H)，7.43-7.38(m，2H)，7.27-7.09(m，9H)，4.91(d，J＝17.5Hz，1H)，3.42(d，J＝17.6Hz，1H)，2.44(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.1，164.3(d，J＝224.3Hz，1C)，151.6，145.5，134.6，133.9，133.5，132.1，130.5(d，J＝3.0Hz，1C)，129.5，129.0，128.8，128.7，128.6，127.0，126.0，116.0(d，J＝21.8Hz，2C)，58.7，32.2，21.7.HRMS(ESI)Calcd.for C 30 H 24 FN 3 NaO 4 S[M+Na] + :564.1364；found:564.1370。
Example 10:
synthesis of compound 4 j: a dry hard reaction tube was taken, and α -bromohydrazone 1j (41.1mg, 0.1mmol) was added to the reaction tube, azlactone 2a (35.6 mg, 0.15mmol) was added, then anhydrous sodium carbonate (10.6 mg, 0.1mmol) was added, and finally anhydrous toluene (2 mL) was added, and the reaction was carried out at room temperature for 24 hours under nitrogen atmosphere with replacement of nitrogen. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4j. White solid, yield 99%; m.p. 198.8-199.8℃. 1 H NMR(300MHz，CDCl 3 )δ8.59(s，1H)，8.33(d，J＝8.3Hz，1H)，8.21(d，J＝7.8Hz，1H)，7.85(d，J＝8.3Hz，2H)，7.74(d，J＝7.3Hz，2H)，7.69-7.63(m，2H)，7.52(t，J＝7.3Hz，1H)，7.44-7.39(m，2H)，7.32-7.23(m，3H)，7.17-709(m，4H)，4.84(d，J＝17.6Hz，1H)，3.65(d，J＝17.6Hz，1H)，2.47(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.3，165.4，150.1，148.6，145.9，136.1，134.4，133.6，133.3，132.2，130.0，129.6，129.3，129.0，128.8，128.6，127.0，125.9，125.3，121.2，58.8，32.4，21.7.HRMS(ESI)Calcd.for C 30 H 24 N 4 NaO 6 S[M+Na] + :591.1309；found:591.1315。
Method 2
Example 11:
synthesis of Compound 4 l: a dry, hard reaction tube was taken, 1l (41.6 mg, 0.1mmol) of α -bromohydrazone was added to the reaction tube, azlactone precursor 3a (30.6 mg, 0.12mmol), dicyclohexylcarbodiimide (30.9mg, 0.15mmol), anhydrous sodium carbonate (12.7 mg, 0.12mmol), and finally anhydrous toluene (2 mL) was added thereto, and the mixture was reacted at room temperature for 24 hours under nitrogen atmosphere with replacement of nitrogen. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain 4l of the compound. White solid, yield 99%; m.p. 175.9-176.8 ℃. 1 H NMR(300MHz，CDCl 3 )δ8.34(s，1H)，8.10(d，J＝8.0Hz，1H)，7.97-7.94(m，1H)，7.90-7.84(m，5H)，7.77(d，J＝7.1Hz，2H)，7.61-7.49(m，3H)，7.45-7.40(m，2H)，7.28-7.25(m，2H)，7.22-7.16(m，3H)，7.11-7.06(m，2H)，5.21(d，J＝17.6Hz，1H)，3.46(d，J＝17.5Hz，1H)，2.44(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.2，166.0，152.1，145.5，134.54，134.50，134.0，133.6，132.9，132.1，131.6，129.5，129.0，128.9，128.8，128.74，128.67，127.8，127.1，127.0，126.9，126.1，123.2，58.7，31.9，21.7.HRMS(ESI)Calcd.for C 34 H 27 N 3 NaO 4 S[M+Na] + :596.1614；found:596.1616。
Example 12:
synthesis of compound 4 n: a dry, hard reaction tube was taken, and α -bromohydrazone 1a (35.6 mg, 0.1mmol) was added to the reaction tube, azlactone precursor 3n (34.7 mg, 0.12mmol), dicyclohexylcarbodiimide (30.9mg, 0.15mmol), anhydrous sodium carbonate (12.7 mg, 0.12mmol), and finally anhydrous toluene (2 mL) was added thereto, and the mixture was reacted at room temperature for 24 hours under nitrogen atmosphere with replacement of nitrogen gas. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4n. White solid, yield 95%; m.p. 192.0-193.2 ℃. 1 HNMR(300MHz，CDCl 3 )7.93-7.90(m，2H)，7.83-7.80(m，3H)，7.75-7.72(m，2H)，7.54-7.40(m，6H)，7.29-7.26(m，2H)，7.18-7.02(m，3H)，6.93(t，J＝1.7Hz，1H)，5.03(d，J＝17.6Hz，1H)，3.32(d，J＝17.7Hz，1H)，2.44(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.1，165.4，152.7，145.9，136.3，134.8，134.0，133.5，133.3，132.2，131.2，129.8，129.6，129.2，129.0，128.7，128.6，127.0，126.6，126.4，124.6，58.2，31.8，21.8.HRMS(ESI)Calcd.for C 30 H 24 ClN 3 NaO 4 S[M+Na] + :580.1068；found:580.1072。
Example 13:
synthesis of compound 4 p: a dry, hard reaction tube was taken, and α -bromohydrazone 1a (35.6 mg, 0.1mmol) was added to the reaction tube, and azlactone precursor 3p (32.8mg, 0.12mmol), dicyclohexylcarbodiimide (30.9mg, 0.15mmol) and then anhydrousSodium carbonate (12.7 mg, 0.12mmol) was added to the reaction solution, and anhydrous toluene (2 mL) was added to the reaction solution to replace nitrogen and the reaction solution was reacted at room temperature for 24 hours under nitrogen atmosphere. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4p. White solid, yield 96%; m.p. 216.5-217.2 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.92-7.89(m，2H)，7.84-7.81(m，3H)，7.75-7.69(m，2H)，7.54-7.39(m，6H)，7.28-7.26(m，2H)，7.13-7.08(m，2H)，6.79-6.74(m，2H)，5.01(d，J＝17.6Hz，1H)，3.32(d，J＝17.7Hz，1H)，2.45(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.1，165.8，162.7(d，J＝248.3Hz，1C)，152.4，145.7，134.1，133.8，133.4，132.2，131.2，130.3(d，J＝3.8Hz，1C)，129.5，129.0，128.7，128.2(d，J＝8.3Hz，2C)，127.0，126.6，115.7(d，J＝21.8Hz，2C)，58.0，32.1，21.7.HRMS(ESI)Calcd.for C 30 H 24 FN 3 NaO 4 S[M+Na] + :564.1364；found:564.1363。
Example 14:
synthesis of compound 4 q: a dry, hard reaction tube was taken, and α -bromohydrazone 1a (35.6 mg, 0.1mmol) was added to the reaction tube, and azlactone precursor 3q (32.3 mg, 0.12mmol), dicyclohexylcarbodiimide (30.9mg, 0.15mmol) and then anhydrous sodium carbonate (12.7 mg, 0.12mmol) were added, and finally anhydrous dichloromethane (2 mL) was added, and the mixture was reacted at room temperature for 24 hours under nitrogen atmosphere while replacing nitrogen. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4q. White solid, yield 56%; m.p. 221.8-222.7 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.91-7.88(m，2H)，7.83(d，J＝8.3Hz，2H)，7.75-7.72(m，3H)，7.52-7.38(m，6H)，7.27-7.24(m，2H)，7.01(d，J＝8.3Hz，2H)，6.90(d，J＝8.2Hz，2H)，4.92(d，J＝17.6Hz，1H)，3.41(d，J＝17.6Hz，1H)，2.45(s，3H)，2.23(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.1，166.0，152.5，145.4，138.9，134.3，134.0，133.6，132.0，131.6，131.0，129.5，129.4，128.8，128.7，128.6，127.0，126.6，126.0，58.5，32.2，21.7，21.0.HRMS(ESI)Calcd.for C 31 H 27 N 3 NaO 4 S[M+Na] + :560.1614；found:560.1633。
Example 15:
synthesis of compound 4 s: a dry, hard reaction tube was taken, and α -bromohydrazone 1a (35.6 mg, 0.1mmol) was added to the reaction tube, azlactone precursor 3s (32.3mg, 0.12mmol), dicyclohexylcarbodiimide (30.9mg, 0.15mmol), anhydrous sodium carbonate (12.7mg, 0.12mmol), and finally anhydrous toluene (2 mL) was added thereto, and the mixture was reacted at room temperature for 24 hours under nitrogen atmosphere with replacement of nitrogen. After the reaction is completed, the solvent is concentrated under reduced pressure, and the compound is separated and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain the compound 4s. White solid, yield 76%; m.p. 224.8-226.0 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.91-788(m，2H)，7.82(d，J＝8.2Hz，2H)，7.75(s，1H)，7.55-7.46(m，5H)，7.30-7.18(m，5H)，7.11-7.06(m，4H)，4.97(d，J＝17.6Hz，1H)，3.41(d，J＝17.6Hz，1H)，2.44(s，3H)，2.37(s，3H). 13 C NMR(75MHz，CDCl 3 )δ166.3，166.0，152.6，145.5，138.5，134.6，134.2，134.0，133.5，132.8，131.0，129.5，128.9，128.84，128.77，128.7，128.5，127.6，126.6，126.1，124.0，58.7，32.2，21.7，21.3.HRMS(ESI)Calcd.for C 31 H 27 N 3 NaO 4 S[M+Na] + :560.1614；found:560.1615。
Example 16:
synthesis of compound 4 t: taking a dry hard reaction tube, and adding alpha-bromineThe substituted hydrazone 1a (35.6mg, 0.1mmol) was added to a reaction tube, and 3t (40.0mg, 0.12mmol) of the azlactone precursor, dicyclohexylcarbodiimide (30.9mg, 0.15mmol), anhydrous sodium carbonate (12.7mg, 0.12mmol) and finally anhydrous toluene (2 mL) were added to replace nitrogen, and the reaction was carried out at room temperature for 24 hours under nitrogen protection. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4t. White solid, yield 94%; m.p. 225.0-226.1 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.89-7.81(m，5H)，7.70(s，1H)，7.66-7.60(m，2H)，7.52-7.43(m，3H)，7.31-7.19(m，4H)，7.10-7.09(m，4H)，4.91(d，J＝17.5Hz，1H)，3.41(d，J＝17.6Hz，1H)，2.44(s，3H). 13 C NMR(75MHz，CDCl 3 )δ165.7，164.6，152.5，145.5，135.5，135.0，134.2，134.1，133.9，131.1，130.2，130.1，129.5，129.1，128.9，128.7，126.6，126.1，125.5，122.8，58.8，32.0，21.7.HRMS(ESI)Calcd.for C 30 H 24 BrN 3 NaO 4 S[M+Na] + :624.0563；found:624.0573。
Example 17:
synthesis of compound 4 u: a dry, hard reaction tube was taken, and α -bromohydrazone 1a (35.6 mg, 0.1mmol) was added to the reaction tube, azlactone precursor 3u (36.6 mg, 0.12mmol), dicyclohexylcarbodiimide (30.9mg, 0.15mmol), anhydrous sodium carbonate (12.7mg, 0.12mmol) and finally anhydrous toluene (2 mL) were added thereto, and the mixture was reacted at room temperature for 24 hours under nitrogen atmosphere with replacement of nitrogen. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4u. White solid, yield 84%; m.p. 206.8-207.6 ℃. 1 H NMR(300MHz，CDCl 3 )δ8.15-8.12(m，1H)，7.93-7.82(m，6H)，7.59(d，J＝7.1Hz，1H)，7.53-7.40(m，6H)，7.34(s，1H)，7.27-7.13(m，7H)，4.91(d，J＝17.4Hz，1H)，3.74(d，J＝17.5Hz，1H)，2.43(s，3H). 13 C NMR(75MHz，CDCl 3 )δ168.8，165.5，152.5，145.4，134.7，134.3，134.1，133.6，133.2，131.2，131.0，130.0，129.5，129.2，129.0，128.9，128.7，128.3，127.3，126.6，126.5，126.1，125.2，125.1，124.5，59.4，32.4，21.7.HRMS(ESI)Calcd.for C 34 H 27 N 3 NaO 4 S[M+Na] + :596.1614；found:596.1619。
Example 18:
synthesis of compound 4 w: a dry, hard reaction tube was taken, and α -bromohydrazone 1a (35.6 mg, 0.1mmol) was added to the reaction tube, azlactone precursor 3w (31.3mg, 0.12mmol), dicyclohexylcarbodiimide (30.9mg, 0.15mmol), then anhydrous potassium hydrogencarbonate (12.7mg, 0.12mmol), and finally anhydrous toluene (2 mL) was added, and the mixture was reacted at room temperature for 24 hours under nitrogen atmosphere with replacement of nitrogen. After the reaction is finished, the solvent is concentrated under reduced pressure, and the compound 4w is obtained through column chromatography separation and purification (petroleum ether/ethyl acetate = 10/1-3/1). White solid, yield 91%; m.p. 224.5-225.1 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.89-7.80(m，5H)，7.55(s，1H)，7.52-7.42(m，3H)，7.35-7.16(m，5H)，7.10-7.08(m，4H)，4.95(d，J＝17.6Hz，1H)，3.38(d，J＝17.6Hz，1H)，2.44(s，3H). 13 C NMR(75MHz，CDCl 3 )δ165.9，161.7，152.5，145.5，136.7，134.5，134.2，133.9，131.0，129.5，129.1，129.0，128.9，128.8，128.7，126.8，126.6，126.1，125.9，58.6，32.2，21.7.HRMS(ESI)Calcd.for C 28 H 23 N 3 NaO 4 S 2 [M+Na] + :552.1022；found:552.1021。
Example 19:
synthesis of compound 4 x: the dried rigid reaction tube was taken and α -bromohydrazone 1a (35) was added.6mg, 0.1mmol) was added to the reaction tube, 3x (30.7mg, 0.12mmol) of azlactone precursor, dicyclohexylcarbodiimide (30.9mg, 0.15mmol) and then anhydrous sodium carbonate (12.7mg, 0.12mmol) were added, and finally anhydrous toluene (2 mL) was added, nitrogen gas was replaced, and the reaction was carried out at room temperature under nitrogen atmosphere for 24 hours. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4x. White solid, yield 96%; m.p. 186.5-187.8 ℃. 1 H NMR(300MHz，CDCl 3 )δ9.39(s，1H)，8.54-8.53(m，1H)，8.05(d，J＝7.8Hz，1H)，7.89-7.85(m，4H)，7.80(td，J＝7.7，1.6Hz，1H)，7.49-7.39(m，4H)，7.27-7.19(m，3H)，7.14-7.07(m，4H)，4.76(d，J＝17.4Hz，1H)，3.61(d，J＝17.4Hz，1H)，2.44(s，3H). 13 C NMR(75MHz，CDCl 3 )δ165.5，163.7，152.4，149.2，148.2，145.3，137.3，134.8，134.4，134.1，130.9，129.4，129.0，128.9，128.8，128.7，126.6，126.1，121.9，58.7，32.2，21.7.HRMS(ESI)Calcd.for C 29 H 24 N 4 NaO 4 S[M+Na] + :547.1410；found:547.1429。
Example 20:
synthesis of compound 4 y: a dry, hard reaction tube was taken, and α -bromohydrazone 1a (35.6 mg, 0.1mmol) was added to the reaction tube, azlactone precursor 3y (26.8mg, 0.12mmol), dicyclohexylcarbodiimide (30.9mg, 0.15mmol) and then anhydrous sodium carbonate (12.7mg, 0.12mmol) were added, and finally anhydrous ethyl acetate (2 mL) was added, and the mixture was reacted at room temperature for 24 hours under nitrogen atmosphere with replacement of nitrogen. After the reaction was completed, the solvent was concentrated under reduced pressure and purified by column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to obtain compound 4y. White solid, yield 37%; m.p. 138.7-139.4 ℃. 1 H NMR(300MHz，CDCl 3 )δ7.85-7.81(m，5H)，7.45-7.43(m，3H)，7.27-7.19(m，3H)，7.12-7.02(m，4H)，4.63(d，J＝17.3Hz，1H)，3.87-3.73(m，2H)，3.50(d，J＝17.3Hz，1H)，3.38(s，3H)，2.44(s，3H). 13 C NMR(75MHz，CDCl 3 )δ169.0，165.4，152.4，145.4，134.6，134.3，134.1，130.9，129.4，128.9，128.8，128.7，126.5，126.0，71.9，59.2，58.4，32.2，21.7.HRMS(ESI)Calcd.for C 26 H 25 N 3 NaO 5 S[M+Na] + :514.1407；found:514.1418。
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (5)
- A method for preparing a 4-aminopyridazinone compound, which is characterized by comprising the following steps:dissolving alpha-halogenated hydrazone (1) and azlactone (2) in an organic solvent, adding an inorganic base or an organic base, and stirring for reaction at room temperature under the protection of inert gas; after the reaction is finished, separating and purifying to obtain a compound 4-aminopyridazinone compound (4); wherein the content of the first and second substances,the α -halohydrazone (1) has the following structure:；
the azlactone (2) has the following structure:；
the compound 4-aminopyridazinone compound (4):；
wherein, R is as defined above 1 The group represents p-toluenesulfonyl, benzenesulfonyl or methanesulfonyl;R 2 the radical represents phenyl, p-methylphenyl, p-methoxyphenyl or m-methoxyphenylPhenyl, p-trifluoromethylphenyl, p-chlorophenyl, p-fluorophenyl or m-nitrophenyl;R 3 the radical represents phenyl;R 4 the radical represents phenyl. - A method for preparing a 4-aminopyridazinone compound, which is characterized by comprising the following steps:dissolving alpha-halogenated hydrazone (1) with the following formula, azlactone precursor (3) and dicyclohexylcarbodiimide in an organic solvent, adding inorganic base, and stirring for reaction at room temperature under the protection of inert gas; after the reaction is finished, separating and purifying to obtain a 4-aminopyridazinone compound (4); wherein the content of the first and second substances,the alpha-halohydrazone (1) has the following structure:；
the azlactone precursor (3) has the following structure:；
the compound 4-aminopyridazinone compound (4):；
wherein, R is as defined above 1 The radical represents p-toluenesulfonyl;R 2 the radical represents phenyl or 2-naphthyl;R 3 the radical represents phenyl, m-chlorophenyl, p-fluorophenyl or p-methylphenyl;R 4 the radical represents phenyl, m-methylphenyl, m-bromophenyl, 1-naphthyl, 3-thienyl, 2-pyridyl or methoxymethylene. - 3. The production method according to claim 1 or 2, characterized in that: the separation and purification method is column chromatography.
- 4. The production method according to claim 1 or 2, characterized in that: the separation and purification method comprises the following steps: concentrating the reaction system after the reaction is finished, adding an alkane solvent, and pulping; filtering, concentrating the filtrate, adding alcohol solvent, and pulping for the second time; filtering to obtain a white solid, namely the 4-aminopyridazinone compound (4).
- 5. The production method according to claim 1 or 2, characterized in that: the organic solvent is at least one selected from toluene, xylene, mesitylene, chlorobenzene, dichloromethane, chloroform, 1-trichloroethane, 1, 2-dichloroethane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, acetonitrile and ethyl acetate.
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