CN111533697A - 4-Aminopyridazinone compound and preparation method thereof - Google Patents

Abstract

The invention discloses a class of 4-amino pyridazinone compounds, belongs to the technical field of organic chemical synthesis, and also discloses a preparation method of such compounds. The ester precursor is used for [4+2] cyclization to construct 4-aminopyridazinone compounds. This method not only fills the gap in the synthesis of 4-aminopyridazinone compounds, but also helps to enrich the types of pyridazine alkaloids , thereby providing more selectable compound sources for the screening of drug activity and enriching the compound library for drug screening; the method has the advantages of mild reaction conditions, readily available raw materials, simple operation and high yield.

Description

4-Aminopyridazinone compound and preparation method thereof

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 technique

Pyridazinone structure constitutes the core skeleton of many natural products and drugs, some of which have been approved for marketing as drugs, such as Zardaverine, Imazodan, Pimobendan, etc. 4-Aminopyridazinone is a member in the pyridazinone skeleton, and the molecular structure of the existing report containing the 4-aminopyridazinone skeleton is as follows:

According to existing reports, the above-mentioned compounds containing 4-aminopyridazinone skeleton have a wide range of biological activities, many of which have been proved to have antibacterial, anti-inflammatory, anti-cancer, anti-tumor and other activities, and have huge potential application value. . Therefore, it is of great significance to provide novel 4-aminopyridazinone compounds and develop effective methods to synthesize compounds containing 4-aminopyridazinone skeleton.

Through literature research, we found that there is no method for synthesizing 4-aminopyridazinones. The most common method based on the pyridazinone backbone is the condensation of γ-carbonyl acids or esters with hydrazine. The aforementioned 4-aminopyridazinone skeleton-containing compounds are also synthesized by hydrazine hydrate as the key synthetic pyridazinone skeleton. For another example, Chinese patent application CN106146404A discloses a typical synthetic method of pyridazinone parent (skeleton):

However, the above-mentioned method for synthesizing pyridazinone skeleton has obvious shortcomings, such as: (1) hydrazine reagent with high toxicity and high price is required; (2) the reaction conditions are harsh, often requiring heating and refluxing, and there are many problems in industrial production. (3) It is often necessary to use a large amount of strong acid such as concentrated hydrochloric acid, which leads to serious corrosion of the equipment and also has potential safety hazards. Therefore, the invention of a simple and practical method, and the synthesis of pyridazinone skeleton from non-toxic raw materials, especially the method of one-step synthesis of 4-aminopyridazinone core has very important value.

SUMMARY OF THE INVENTION

One of the objectives of the present invention is to provide a class of 4-aminopyridazinone compounds to solve the above problems.

In order to achieve the above object, the technical solution adopted in the present invention is as follows: a class of 4-aminopyridazinone compounds is compound (4) having the following structure, or a stereoisomer of compound (4) and its Pharmaceutically acceptable salts:

In the above structure, R ¹ group represents an acyl group or a sulfonyl group; R ² group represents an alkyl group or an aryl group; R ³ group represents an aryl group; R ⁴ represents an alkyl group or an aryl group.

The second object of the present invention is to provide the preparation method of the above-mentioned compound, and the technical scheme adopted is, preparation method one:

Include the following steps:

Dissolving α-halogenated hydrazone (1) and azlactone (2) in an organic solvent, adding an inorganic base or an organic base, and stirring the reaction at room temperature under the protection of an inert gas; after completion of the reaction, separation and purification are performed to obtain 4-amino Pyridazinone compounds (4); wherein,

The α-halogenated hydrazone (1) has the following structure:

Described azlactone (2) has following structure:

Preparation method two:

Include the following steps:

The α-halogenated hydrazone (1), the azlactone precursor (3) and the carbodiimide are dissolved in an organic solvent, an inorganic base or an organic base is added, and the reaction is stirred at room temperature under the protection of an inert gas; after the reaction is completed, separation and purification to obtain 4-aminopyridazinone compound (4); wherein

The α-halogenated hydrazone (1) has the following structure:

Described azlactone precursor (3) has following structure:

As a preferred technical solution: the method for separation and purification is column chromatography.

When the reaction is in milligram level, the separation and purification is performed by silica gel column chromatography.

As a preferred technical solution: after the reaction system after the reaction is concentrated, add an alkane solvent and make a slurry; filter, concentrate the filtrate, add an alcohol solvent, and make a second slurry; filter to obtain a white solid, which is 4-aminopyridazine Ketones (4).

When the reaction is at the gram level, the separation and purification can be achieved by crystallization, which is simpler and easier to implement; while when the reaction is at the milligram level, it is not easy to crystallize because the amount is too small and the yield is inaccurate due to sample loss caused by operation, so it is not recommended. using the method of crystallization.

As a preferred technical solution: the organic solvent is selected from toluene, xylene, mesitylene, chlorobenzene, dichloromethane, chloroform, 1,1,1-trichloroethane, 1,2-dichloroethane, At least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, acetonitrile, and ethyl acetate.

The novel 4-aminopyridazinone compounds provided by the present invention enrich the types of pyridazine alkaloids, and the existing pyridazinone molecules have a large number of functions including antibacterial, anti-inflammatory, anti-tumor, insecticidal According to the reports of biological activities, it can be reasonably predicted that the new large class of compounds provided by the present invention also have certain biological activities, thereby providing sufficient compound sources for the screening of drug activities.

Compared with the prior art, the advantages of the present invention are: (1) the present invention uses α-halogenated hydrazone compounds and azlactone or azlactone precursors for the [4+2] cyclization reaction for the first time to construct 4- Aminopyridazinone compounds, this method not only makes up for the blank of 4-aminopyridazinone compound synthesis, but also helps to enrich the types of pyridazine alkaloids, so as to provide more selectable compound sources for the screening of drug activity, Enriching the compound library for drug screening; (2) Compared with the prior art, the present invention synthesizes pyridazinone skeleton from non-toxic raw materials, avoiding the use of hydrazine raw materials with high toxicity and high price; (3) the present invention The reaction conditions for synthesizing pyridazinone are mild, avoiding the harsh conditions of high-temperature reflux in the existing method; (4) the substrate of the present invention has wide applicability and high yield.

Description of drawings

Fig. 1 is the hydrogen spectrum of 4a that embodiment 1 makes;

Fig. 2 is the carbon spectrum of 4a that embodiment 1 makes;

FIG. 3 is the high-resolution mass spectrum of 4a prepared in Example 1. FIG.

FIG. 4 is a single crystal structure diagram of 4a prepared in Example 1. FIG.

Detailed ways

The present invention will be further described below with reference to the embodiments.

method one)

Example 1:

Synthesis of compound 4a: take a dry rigid reaction tube, add α-bromohydrazone 1a (36.6 mg, 0.1 mmol) to the reaction tube, add azlactone 2a (35.6 mg, 0.15 mmol), and then add anhydrous carbonic acid Sodium (10.6 mg, 0.1 mmol), and finally anhydrous toluene (2 mL) was added to replace nitrogen, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After the completion of the reaction, the solvent was concentrated under reduced pressure, and separated and purified by column chromatography (volume ratio: petroleum ether/ethyl acetate=10/1-3/1) to obtain compound 4a as a white solid. The purity detected by HPLC was 99%, and the yield was 99%. is 98%.

Scale-up reaction: scale up the reaction to 1.0 g of α-halogenated hydrazone 1a, after the reaction, concentrate under reduced pressure, and recover the reaction solvent, toluene. After concentrating to dryness, add CH ₂ Cl ₂ (50 mL) to the system, beating at room temperature for 30 min, suspend a large amount of white solids in the system, filter, rinse the filter cake with CH ₂ Cl ₂ (5 mL), combine the filtrates and concentrate them, Anhydrous methanol (10 mL) was added to the concentrate, and slurried at room temperature for 30 min. A large amount of white solid was precipitated. The solid obtained by filtration was pure product 4a. The purity detected by HPLC was >99%, and the yield was 86%. Its single crystal structure is shown in Figure 4; mp: 225.1-226.0°C. ¹ H NMR (300MHz, CDCl ₃ )δ7.91-7.88(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 Figure 1; ¹³ C NMR (75MHz, CDCl ₃ )δ166.1, 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 Figure 2; HRMS(ESI)Calcd.for C ₃₀ H ₂₅ N ₃ NaO ₄ S[ M+Na] ⁺ : 546.1458; found: 546.1454, as shown in Figure 3.

Example 2:

Synthesis of compound 4b: take a dry rigid reaction tube, add α-bromohydrazone 1b (35.2 mg, 0.1 mmol) to the reaction tube, add azlactone 2a (35.6 mg, 0.15 mmol), and then add anhydrous carbonic acid Potassium (13.8 mg, 0.1 mmol), and finally anhydrous chloroform (2 mL) was added to replace nitrogen, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4b. White solid, 81% yield; mp: 221.8-222.0°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.95 (d, J=7.9 Hz, 2H), 7.88 (d, J=6.5 Hz, 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 ) δ 166.1, 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 C29H23N3NaO4S} [ _{M +} Na] ⁺ :532.1301;found:532.1319.

Example 3:

Synthesis of compound 4c: take a dry rigid reaction tube, add α-chlorohydrazone 1c (35.2 mg, 0.1 mmol) into the reaction tube, add azlactone 2a (35.6 mg, 0.15 mmol), and then add anhydrous carbonic acid Potassium hydrogen (10.0 mg, 0.1 mmol), and finally anhydrous toluene (2 mL) was added to replace nitrogen, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4c. White solid, 84% yield. mp: 189.0-191.5°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88-7.85 (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 ) δ 166.6, 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.forC ₂₄ H ₂₁ N ₃ NaO ₄ S[M+ Na] ⁺ :470.1145; found:470.1131.

Example 4:

Synthesis of compound 4d: take a dry hard reaction tube, add α-bromohydrazone 1d (38.0 mg, 0.1 mmol) to the reaction tube, add azlactone 2a (35.6 mg, 0.15 mmol), and then add triethylamine (10.1 mg, 0.1 mmol), and finally anhydrous toluene (2 mL) was added to replace nitrogen, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4d. White solid, 88% yield; mp: 159.4-161.1°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83-7.73 (m, 7H), 7.50 (t, J=7.4 Hz, 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 ) δ 166.1, 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 _{C31H27N3NaO4S} [ _{M +} Na] ⁺ : _560.1614 ; found:560.1611.

Example 5:

Synthesis of compound 4e: take a dry rigid reaction tube, add α-bromohydrazone 1e (39.6 mg, 0.1 mmol) to the reaction tube, add azlactone 2a (35.6 mg, 0.15 mmol), and then add N,N - Diisopropylethylamine (12.9 mg, 0.1 mmol), and finally anhydrous toluene (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4e. White solid, yield 85%; White solid, mp: 208.0-209.5°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88-7.80 (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 for _{C31H27N3NaO5S} [ _M +Na] ⁺ : _576.1564 ; found: _576.1560 .

Example 6:

Synthesis of compound 4f: take a dry rigid reaction tube, add α-bromohydrazone 1f (39.6 mg, 0.1 mmol) into the reaction tube, add azlactone 2a (35.6 mg, 0.15 mmol), and then add anhydrous carbonic acid Sodium (10.6 mg, 0.1 mmol), and finally anhydrous chlorobenzene (2 mL) was added to replace nitrogen, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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, 94% yield; mp: 179.1-180.3°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.81 (d, J=8.3 Hz, 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=17.6 Hz, 1H), 2.43 (s, 3H). ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.1, 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 _NaO5S [M+Na] ⁺ : 576.1564; found: 576.1569.

Example 7:

Synthesis of compound 4g: take a dry hard reaction tube, add α-bromohydrazone 1g (43.4mg, 0.1mmol) into the reaction tube, add azlactone 2a (35.6mg, 0.15mmol), then add anhydrous carbonic acid Sodium (10.6 mg, 0.1 mmol), and finally anhydrous toluene (2 mL) was added to replace nitrogen, and the reaction was carried out at room temperature for 24 h 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 4g. White solid, 99% yield; mp: 180.0-181.0°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.99 (d, J=8.1 Hz, 2H), 7.83 (d, J=8.2 Hz, 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 ) δ 166.3, 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=270.0 Hz, 1C), 58.8, 32.3, 21.7. HRMS (ESI) Calcd. for _{C31H24F3N3NaO4S [ M +} Na] ⁺ : _614.1332 ; found: 614.1333.

Example 8:

Synthesis of compound 4h: take a dry rigid reaction tube, add α-bromohydrazone 1h (40.0 mg, 0.1 mmol) into the reaction tube, add azlactone 2a (35.6 mg, 0.15 mmol), and then add anhydrous carbonic acid Sodium (10.6 mg, 0.1 mmol), and finally anhydrous xylene (2 mL) was added to replace nitrogen, and the reaction was carried out at room temperature for 24 h 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 4h. White solid, 93% yield; mp: 228.3-229.4°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.84-7.80 (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 ) δ 166.2, 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 4i: take a dry hard reaction tube, add α-bromohydrazone 1i (38.4 mg, 0.1 mmol) into the reaction tube, add azlactone 2a (35.6 mg, 0.15 mmol), and then add anhydrous carbonic acid Sodium (10.6 mg, 0.1 mmol), and finally anhydrous tetrahydrofuran (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h 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 4i. White solid, 85% yield; mp: 212.1-213.0°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91-7.81 (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 (75 MHz, CDCl ₃ ) δ 166.1, 164.3 (d, J=224.3 Hz, 1C), 151.6, 145.5, 134.6, 133.9, 133.5, 132.1, 130.5 (d, J=3.0 Hz , 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 C30H24FN3NaO 4} S[M+Na] ⁺ : 564.1364; found: 564.1370.

Example 10:

Synthesis of compound 4j: take a dry rigid reaction tube, add α-bromohydrazone 1j (41.1 mg, 0.1 mmol) into the reaction tube, add azlactone 2a (35.6 mg, 0.15 mmol), and then add anhydrous carbonic acid Sodium (10.6 mg, 0.1 mmol), and finally anhydrous toluene (2 mL) was added to replace nitrogen, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4j. White solid, 99% yield; mp: 198.8-199.8°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59 (s, 1H), 8.33 (d, J=8.3 Hz, 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 ) δ 166.3, 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 Two)

Example 11:

Synthesis of compound 41: Take a dry rigid reaction tube, add α-bromohydrazone 11 (41.6 mg, 0.1 mmol) into the reaction tube, add azlactone precursor 3a (30.6 mg, 0.12 mmol), dicyclohexyl Carbodiimide (30.9 mg, 0.15 mmol) was then added with anhydrous sodium carbonate (12.7 mg, 0.12 mmol), and finally anhydrous toluene (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 41. White solid, 99% yield; mp: 175.9-176.8°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 8.10 (d, J=8.0 Hz, 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) _The ^_ 127.0, 126.9, 126.1, 123.2, 58.7, 31.9, 21.7. HRMS (ESI) Calcd. for _{C34H27N3NaO4S} [ _{M +} Na] ⁺ : _596.1614 ; found: 596.1616.

Example 12:

Synthesis of compound 4n: take a dry rigid reaction tube, add α-bromohydrazone 1a (35.6 mg, 0.1 mmol) to the reaction tube, add azlactone precursor 3n (34.7 mg, 0.12 mmol), dicyclohexyl Carbodiimide (30.9 mg, 0.15 mmol) was then added with anhydrous sodium carbonate (12.7 mg, 0.12 mmol), and finally anhydrous toluene (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4n. White solid, 95% yield; mp: 192.0-193.2°C. ¹ H NMR (300 MHz, 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 ) δ 166.1, 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 4p: take a dry rigid reaction tube, add α-bromohydrazone 1a (35.6 mg, 0.1 mmol) into the reaction tube, add azlactone precursor 3p (32.8 mg, 0.12 mmol), dicyclohexyl Carbodiimide (30.9 mg, 0.15 mmol) was then added with anhydrous sodium carbonate (12.7 mg, 0.12 mmol), and finally anhydrous toluene (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4p. White solid, 96% yield; mp: 216.5-217.2°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92-7.89 (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 ) δ 166.1, 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 = 21.8 Hz, 2C), 58.0, 32.1, 21.7. HRMS (ESI) Calcd. for _{C30H24FN3NaO4S} [ _{M +} Na] ⁺ : _564.1364 ; found: 564.1363.

Example 14:

Synthesis of compound 4q: Take a dry rigid reaction tube, add α-bromohydrazone 1a (35.6 mg, 0.1 mmol) to the reaction tube, add azlactone precursor 3q (32.3 mg, 0.12 mmol), dicyclohexyl Carbodiimide (30.9 mg, 0.15 mmol) was then added with anhydrous sodium carbonate (12.7 mg, 0.12 mmol), and finally anhydrous dichloromethane (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4q. White solid, 56% yield; mp: 221.8-222.7°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91-7.88 (m, 2H), 7.83 (d, J=8.3 Hz, 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 ) δ 166.1, 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)Calcdfor _{C31H27N3NaO4S} [ _{M +} Na] ⁺ : _560.1614 ; found: 560.1633.

Example 15:

Synthesis of compound 4s: Take a dry rigid reaction tube, add α-bromohydrazone 1a (35.6 mg, 0.1 mmol) to the reaction tube, add azlactone precursor 3s (32.3 mg, 0.12 mmol), dicyclohexyl Carbodiimide (30.9 mg, 0.15 mmol) was then added with anhydrous sodium carbonate (12.7 mg, 0.12 mmol), and finally anhydrous toluene (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h 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 4s. White solid, 76% yield; mp: 224.8-226.0°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91-788 (m, 2H), 7.82 (d, J=8.2 Hz, 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=17.6 Hz, 1H), 2.44 (s, 3H), 2.37 (s, 3H). ¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.3, 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 4t: take a dry rigid reaction tube, add α-bromohydrazone 1a (35.6 mg, 0.1 mmol) into the reaction tube, add azlactone precursor 3t (40.0 mg, 0.12 mmol), dicyclohexyl Carbodiimide (30.9 mg, 0.15 mmol) was then added with anhydrous sodium carbonate (12.7 mg, 0.12 mmol), and finally anhydrous toluene (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4t. White solid, 94% yield; mp: 225.0-226.1°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.89-7.81 (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) _The ^_ 128.7, 126.6, 126.1, 125.5, 122.8, 58.8, 32.0, 21.7. HRMS (ESI) Calcd. for _{C30H24BrN3NaO4S} [ _{M +} Na] ⁺ : _624.0563 ; found: 624.0573.

Example 17:

Synthesis of compound 4u: take a dry rigid reaction tube, add α-bromohydrazone 1a (35.6 mg, 0.1 mmol) into the reaction tube, add azlactone precursor 3u (36.6 mg, 0.12 mmol), dicyclohexyl Carbodiimide (30.9 mg, 0.15 mmol) was then added with anhydrous sodium carbonate (12.7 mg, 0.12 mmol), and finally anhydrous toluene (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4u. White solid, 84% yield; mp: 206.8-207.6°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15-8.12 (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=17.5 Hz, 1H), 2.43 (s, 3H). ¹³ C NMR (75MHz, CDCl ₃ ) δ 168.8, 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 4w: take a dry hard reaction tube, add α-bromohydrazone 1a (35.6 mg, 0.1 mmol) into the reaction tube, add azlactone precursor 3w (31.3 mg, 0.12 mmol), dicyclohexyl Carbodiimide (30.9 mg, 0.15 mmol) was then added with anhydrous potassium bicarbonate (12.7 mg, 0.12 mmol), and finally anhydrous toluene (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h 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 4w. White solid, 91% yield; mp: 224.5-225.1°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.89-7.80 (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 ) δ 165.9, 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, 5, 8.6.1, , 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 4x: take a dry rigid reaction tube, add α-bromohydrazone 1a (35.6 mg, 0.1 mmol) to the reaction tube, add azlactone precursor 3x (30.7 mg, 0.12 mmol), dicyclohexyl Carbodiimide (30.9 mg, 0.15 mmol) was then added with anhydrous sodium carbonate (12.7 mg, 0.12 mmol), and finally anhydrous toluene (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4x. White solid, 96% yield; mp: 186.5-187.8°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.39 (s, 1H), 8.54-8.53 (m, 1H), 8.05 (d, J=7.8 Hz , 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 ) δ 165.5, 163.7, HRMS(ESI)Calcd.for C ₂₉ HRMS(ESI)Calcd. _24N4NaO4S [M ₊ Na] ⁺ : _547.1410 ; found: 547.1429.

Example 20:

Synthesis of compound 4y: Take a dry rigid reaction tube, add α-bromohydrazone 1a (35.6 mg, 0.1 mmol) to the reaction tube, add azlactone precursor 3y (26.8 mg, 0.12 mmol), dicyclohexyl Carbodiimide (30.9 mg, 0.15 mmol) was then added with anhydrous sodium carbonate (12.7 mg, 0.12 mmol), and finally anhydrous ethyl acetate (2 mL) was added, nitrogen was replaced, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After completion of the reaction, 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 4y. White solid, 37% yield; mp: 138.7-139.4°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85-7.81 (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) _The ^_ 59.2, 58.4, 32.2, 21.7. HRMS (ESI) Calcd. for _{C26H25N3NaO5S} [ _M +Na] ⁺ : _514.1407 ; found: _514.1418 .

The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.

Claims (6)

1. A class of 4-aminopyridazinone compounds, characterized in that the compound (4) having the structure shown in the following formula, or a stereoisomer of the compound (4) and a pharmaceutically acceptable salt thereof:

In the above structure, R ¹ group represents an acyl group or a sulfonyl group; R ² group represents an alkyl group or an aryl group; R ³ group represents an aryl group; R ⁴ represents an alkyl group or an aryl group. 2. the preparation method of 4-amino pyridazinone compound according to claim 1, is characterized in that, comprises the following steps: The α-halogenated hydrazone (1) and azlactone (2) of the following formula are dissolved in an organic solvent, an inorganic base or an organic base is added, and the reaction is stirred at room temperature under the protection of an inert gas; after the completion of the reaction, separation and purification, The compound 4-aminopyridazinone compound (4) is obtained; wherein, The α-halogenated hydrazone (1) has the following structure:

Described azlactone (2) has following structure:

3. the preparation method of 4-amino pyridazinone compound according to claim 1, is characterized in that, comprises the following steps: Dissolve the α-halogenated hydrazone (1), azlactone precursor (3) and carbodiimide of the following formula in an organic solvent, add an inorganic base or an organic base, and stir the reaction at room temperature under the protection of an inert gas ; After the completion of the reaction, separation and purification to obtain 4-aminopyridazinone compound (4); wherein, The α-halogenated hydrazone (1) has the following structure:

Described azlactone precursor (3) has following structure:

4. The preparation method according to claim 2 or 3, wherein the method for separation and purification is column chromatography. 5. preparation method according to claim 2 or 3, is characterized in that: the method for described separation and purification is: after the reaction system after the completion of the reaction is concentrated, add alkane solvent, beating; Filtration, the filtrate is concentrated, add Alcohol solvent, beating twice; filtering to obtain white solid, which is 4-aminopyridazinone compound (4). 6. preparation method according to claim 2 or 3 is characterized in that: described organic solvent is selected from toluene, xylene, mesitylene, chlorobenzene, methylene chloride, chloroform, 1,1,1-trichloro At least one of ethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, acetonitrile, and ethyl acetate.

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