CN1651416A - Preparation method of 5-fluoro-3(2H)-pyridazinone compound - Google Patents

Abstract

A process for preparing 5-fluoro-3(2H)-pyridazinone includes such steps as reaction of halopyridazinone on the fluoride of alkali metal in ionic liquid at 20-150 deg.C for 1-30 hr while stirring, and post-treating.

Description

Preparation method of 5-fluoro-3(2H)-pyridazinone compound

(1) Technical field

The invention relates to a preparation method of 5-fluoro-3(2H)-pyridazinone compound.

(2) Background technology

Fluoropyridazinones have high anticonvulsant, antiplatelet aggregation, antiviral, anticancer, insecticidal, and plant growth-regulating activities. Many pyridazinone compounds have been listed as drugs, and fluoropyridazinone and fluorine Uracil is an isomer, so it has been valued by chemists in the field of medicine and pesticide research.

Before the present invention was made, the methods for introducing fluorine atoms into the pyridazine ring mainly included melting method, diazotization method, condensation method and halogen exchange method. The melting method is that the compound is carried out in a molten state. At this time, polyfluorinated products are generally obtained, with poor selectivity, high reaction temperature, and difficult product separation. The diazotization method can prepare compounds with relatively complex structures, but there are not many reports on this research, and the prospect of industrial production needs further research. The condensation method is a method for preparing fluoropyridazinone compounds through ring closure reaction of hydrocarbon fluorides, but it is difficult to popularize and apply due to the limitation of the synthesis of hydrocarbon fluorides. Halogen exchange methods are mostly performed in aprotic polar solvents with good results.

As an emerging green chemical solvent, ionic liquid is a liquid compound composed entirely of ions, usually composed of alkylimidazole or alkylpyridinium quaternary ammonium cations and acid anions such as tetrafluoroboric acid, hexafluorophosphoric acid and chloroaluminic acid. Compared with organic solvents, ionic liquids are non-volatile, non-flammable and explosive, have good solubility to organic and inorganic substances, enable the reaction to proceed in a homogeneous phase, are stable to water and air, are convenient for reaction operation and treatment, and are easy to recycle. Ionic liquids can also catalyze and accelerate the process of chemical reactions and improve the selectivity of reactions. Therefore, using ionic liquids to improve traditional processes is a promising green chemical synthesis technology.

(3) Contents of the invention

The purpose of the present invention is to provide a green chemical synthesis method of fluoropyridazinone compound with easy control of reaction conditions, low cost and recyclable reaction system.

The 5-fluoro-3(2H)-pyridazinone compound of the present invention is represented by formula (I). The preparation method is carried out as follows: the halogenated pyridazinone compound represented by the formula (II) and the alkali metal fluoride are stirred and reacted at 20° C. to 150° C. for 1 to 30 hours in an ionic liquid, and the post-treatment The 5-fluoro-3(2H)-pyridazinone compound was obtained.

Among them, in formulas (I) and (II), R ¹ is a hydrogen atom, C ₁ -C ₆ alkyl, benzyl, substituted benzyl, substituted phenyl or substituted naphthyl, preferably a hydrogen atom, phenyl, benzyl Base, halobenzyl, naphthyl or tert-butyl; R ² is a hydrogen atom or a halogen atom, preferably chlorine or bromine; X is chlorine, bromine or iodine;

The alkali metal fluoride is preferably potassium fluoride, sodium fluoride or cesium fluoride, most preferably potassium fluoride.

The ionic liquid is 3-methylimidazole inorganic acid salt or 1-alkyl-3-methylimidazole inorganic acid salt [Bmim] ⁺ L ^- as shown in formula (III), and R in formula (III) represents H or an alkyl group containing 1 to 18 carbon atoms, L is one of the following: BF ₄ , PF ₆ , OA _C , CF ₃ SO ₃ , N(SO ₂ CF ₃ ) ₂ ; the ionic liquid is preferably 3-methylimidazolium tetrafluoroborate or 1-alkyl-3-methylimidazolium tetrafluoroborate, wherein the alkyl group is an alkyl group with n=1-18 carbon atoms. More preferred is 1-butyl-3-methylimidazolium tetrafluoroborate or 1-ethyl-3-methylimidazolium tetrafluoroborate.

The above post-treatment may be: extract the reaction solution with an organic solvent, and then purify to obtain the product 5-fluoro-3(2H)-pyridazinone compound.

The reaction temperature is preferably 50°C-120°C, and the reaction time is preferably 2-10 hours.

The molar ratio of the halogenated pyridazinone to the alkali metal fluoride is preferably 1:2-8, and the amount of the ionic liquid is preferably 1-20 times the mass of the halogenated pyridazinone compound.

The 5-fluoro-3(2H)-pyridazinone compound described in the present invention is preferably prepared according to the following steps:

Put 1 mmol of halogenated pyridazinone, 2 to 5 mmol of metal fluoride, and 10 ml of 1-butyl-3-methylimidazolium tetrafluoroborate into a 50 ml three-necked flask, stir and heat, and heat at 20 ℃～150℃ to react for 1～20 hours. After the reaction is finished, it is cooled and post-treated, and the product is identified by melting point and mass spectrometry.

The reaction formula of the above reaction is:

The ionic liquid and the reactive fluoride can be recovered and recycled after post-treatment.

The preparation method of the invention has the advantages of simple preparation process, high yield, easy operation and little environmental pollution, and is a green chemical synthesis technology.

(4) Specific implementation methods

The present invention will be further described below in conjunction with specific examples, but the protection scope of the present invention is not limited thereto.

Example 1 Synthesis of 4-chloro-5-fluoro-2-phenyl-3(2H)-pyridazinone

0.24 g of 4,5-dichloro-2-phenyl-3(2H)-pyridazinone (1 mmol), 0.29 g of potassium fluoride (5 mmol), 1-butyl-3-methyl Put 2 ml of imidazolium tetrafluoroborate into a 50 ml three-neck flask, stir and heat, and react at 100° C. for 5 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.2 g of a white powdery solid product with a yield of 89%. The melting point is 145-146°C. MS (m/z): 224 (M ⁺ ).

Example 2 Synthesis of 4-bromo-5-fluoro-2-phenyl-3(2H)-pyridazinone

0.33 g (1 mmol) of 4,5-dibromo-2-phenyl-3 (2H)-pyridazinone, 0.29 g (5 mmol) of potassium fluoride, 1-butyl-3-methylimidazole Put 2 milliliters of tetrafluoroborate in a 50 milliliter three-neck flask, stir and heat, and react at 100° C. for 5 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.25 g of a white powdery solid product with a yield of 88%. The melting point is 159-160°C. MS (m/z): 268 (M ⁺ ).

Example 3 Synthesis of 4-bromo-5-fluoro-3(2H)-pyridazinone

0.25 g (1 mmol) of 4,5-dibromo-3 (2H)-pyridazinone, 0.29 g (5 mmol) of potassium fluoride, 1-butyl-3-methylimidazolium tetrafluoroborate 2 ml, placed in a 50 ml three-necked flask, stirred and heated, and reacted at 100°C for 5 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.15 g of a white powdery solid product with a yield of 79%. The melting point is 212-213°C. MS (m/z): 192 (M ⁺ ).

Example 4 Preparation of 4-bromo-5-fluoro-3(2H)-pyridazinone by recycling ionic liquid

The ionic liquid was recovered from Example 1, and the other reactants and their amounts and steps were the same as in Example 1 to obtain 0.23 g of the product with a yield of 84%.

Example 5 Synthesis of 4-chloro-5-fluoro-2-benzyl-3(2H)-pyridazinone

0.26 g (1 mmol) of 4,5-dichloro-2-benzyl-3 (2H)-pyridazinone, 0.29 g (5 mmol) of potassium fluoride, 1-butyl-3-methylimidazole Put 2 milliliters of tetrafluoroborate in a 50 milliliter three-neck flask, stir and heat, and react at 100° C. for 5 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.22 g of a white powdery solid product with a yield of 85%. The melting point is 71-73°C. MS (m/z): 238 (M ⁺ ).

Example 6 Synthesis of 4-chloro-5-fluoro-2-(2'-naphthyl)-3(2H)-pyridazinone

0.29 g (1 mmol) of 4,5-dichloro-2-(2′-naphthyl)-3(2H)-pyridazinone, 0.21 g (5 mmol) of sodium fluoride, 1-butyl- 2 ml of 3-methylimidazolium tetrafluoroborate was placed in a 50 ml three-necked flask, stirred and heated, and reacted at 100° C. for 5 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.25 g of a white powdery solid product with a yield of 85%. MS (m/z): 274 (M ⁺ ).

Example 7 Synthesis of 4-chloro-5-fluoro-2-tert-butyl-3(2H)-pyridazinone

0.2 g (1 mmol) of 4,5-dichloro-2-tert-butyl-3 (2H)-pyridazinone, 0.21 g (5 mmol) of sodium fluoride, 1-butyl-3-methyl Put 2 ml of imidazolium tetrafluoroborate into a 50 ml three-neck flask, stir and heat, and react at 100° C. for 5 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.17 g of a white powdery solid product with a yield of 85%. The melting point is 52-54°C. MS (m/z): 204 (M ⁺ ).

Example 8 Synthesis of 4-chloro-5-fluoro-2-(3'-bromo-benzyl)-3(2H)-pyridazinone

0.33 g (1 mmol) of 4,5-dichloro-2-(3′-bromo-benzyl)-3(2H)-pyridazinone, 0.29 g (5 mmol) of potassium fluoride, 1-butanol 2 ml of base-3-methylimidazolium tetrafluoroborate was placed in a 50 ml three-necked flask, stirred and heated, and reacted at 100° C. for 5 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.27 g of a white powdery solid product with a yield of 90%. The melting point is 94-96°C. MS (m/z): 318 (M ⁺ ).

Example 9 Synthesis of 4-chloro-5-fluoro-2-(2'-naphthyl)-3(2H)-pyridazinone

0.29 g (1 mmol) of 4,5-dichloro-2-(2′-naphthyl)-3(2H)-pyridazinone, 0.13 g (3 mmol) of sodium fluoride, 1-ethyl- 4 ml of 3-methylimidazolium tetrafluoroborate was placed in a 50 ml three-necked flask, stirred and heated, and reacted at 50° C. for 20 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.25 g of a white powdery solid product with a yield of 85%.

Example 10 Synthesis of 4-chloro-5-fluoro-2-tert-butyl-3(2H)-pyridazinone

0.2 g (1 mmol) of 4,5-dichloro-2-tert-butyl-3 (2H)-pyridazinone, 0.25 g (6 mmol) of sodium fluoride, 1-ethyl-3-methyl Put 2 ml of imidazolium tetrafluoroborate into a 50 ml three-necked flask, stir and heat, and react at 120° C. for 4.5 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.17 g of a white powdery solid product with a yield of 85%. The melting point is 52-54°C.

Example 11 Synthesis of 4-chloro-5-fluoro-2-(3'-bromo-benzyl)-3(2H)-pyridazinone

0.33 g (1 mmol) of 4,5-dichloro-2-(3′-bromo-benzyl)-3(2H)-pyridazinone, 0.29 g (5 mmol) of potassium fluoride, 1-butanol 8 ml of 3-methylimidazolium tetrafluoroborate was placed in a 50 ml three-neck flask, stirred and heated, and reacted at 30° C. for 25 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.27 g of a white powdery solid product with a yield of 90%. The melting point is 94-96°C.

Example 12 Synthesis of 4-chloro-5-fluoro-2-phenyl-3(2H)-pyridazinone

0.24 g (1 mmol) of 4,5-dichloro-2-phenyl-3 (2H)-pyridazinone, 0.21 g (5 mmol) of sodium fluoride, 1-ethyl-3-methylimidazole 6 milliliters of tetrafluoroborate was placed in a 50 milliliter three-necked flask, stirred and heated, and reacted at 100° C. for 6 hours. After the reaction is finished, cool, and the reaction solution is extracted with dichloromethane to extract the product, reclaim the ionic liquid, distill the extraction solvent under reduced pressure, use a chromatographic column with silica gel GF ₂₅₄ as the stationary phase, and a 1:1 mixture of ethyl acetate and petroleum ether as the washing agent. The liquid was removed for separation and purification to obtain 0.2 g of a white powdery solid product with a yield of 89%. The melting point is 145-146°C.

Claims (10)

1. A method for preparing a 5-fluoro-3(2H)-pyridazinone compound represented by formula (I), characterized in that it proceeds as follows: the halogenated pyridazinone compound shown in formula (II) React with alkali metal fluoride in ionic liquid, stirring and reacting at 20°C-150°C for 1-30 hours, and post-treatment to obtain 5-fluoro-3(2H)-pyridazinone compound; Wherein, R ¹ in formulas (I) and (II) is one of the following: hydrogen atom, C ₁ -C ₆ alkyl, phenyl, benzyl, substituted phenyl, substituted benzyl, substituted naphthyl; R ² is one of the following: a hydrogen atom or a halogen atom; X is chlorine, bromine or iodine; The ionic liquid is 3-methylimidazole inorganic acid salt or 1-alkyl-3-methylimidazole inorganic acid salt [Bmim] ⁺ L ^- as shown in formula (III), and R in formula (III) represents H or an alkyl group containing n=1-18 carbon atoms, L is one of the following: BF ₄ , PF ₆ , OAC, CF ₃ SO ₃ , N(SO ₂ CF ₃ ) ₂ . 2. The preparation method of 5-fluoro-3(2H)-pyridazinone compound according to claim 1, characterized in that the alkali metal fluoride is potassium fluoride, sodium fluoride or cesium fluoride. 3. The preparation method of 5-fluoro-3(2H)-pyridazinone compound according to claim 1, characterized in that said R ¹ is one of the following: hydrogen atom, phenyl, benzyl, halogenated benzyl or naphthyl. 4. The preparation method of 5-fluoro-3(2H)-pyridazinone compound according to claim 1, characterized in that said R ¹ is tert-butyl. 5. The preparation method of 5-fluoro-3(2H)-pyridazinone compound according to claim 1, characterized in that the ionic liquid is 1-butyl-3-methylimidazolium tetrafluoroborate Or 1-ethyl-3-methylimidazolium tetrafluoroborate. 6. The preparation method of 5-fluoro-3(2H)-pyridazinone compound according to claim 5, characterized in that the ionic liquid is 1-butyl-3-methylimidazolium tetrafluoroborate or -1 ethyl-3-methylimidazolium tetrafluoroborate. 7. The preparation method of 5-fluoro-3(2H)-pyridazinone compound according to claim 2, characterized in that said R ² is chlorine or bromine. 8. The preparation method of 5-fluoro-3(2H)-pyridazinone compound according to any one of claims 1 to 7, characterized in that the post-treatment is: after extracting the reaction solution with an organic solvent, followed by The product 5-fluoro-3(2H)-pyridazinone compound was purified. 9. The preparation method of 5-fluoro-3(2H)-pyridazinone compound according to claim 8, characterized in that the reaction temperature is 50°C-120°C, and the reaction time is preferably 2-10 hours. 10. The preparation method of 5-fluoro-3(2H)-pyridazinone compound according to claim 8, characterized in that the molar ratio of said halogenated pyridazinone to alkali metal fluoride is 1:2～ 8. The amount of the ionic liquid used is 1 to 20 times the mass of the halogenated pyridazinone compound.