Process for preparation of 1, 2-disubstituted 1, 2-dihydro-3h-pyrazol-3-ones

Abstract

The invention provides a method for preparing 1, 2-disubstituted 1, 2-dihydro-3H-pyrazol-3-ketone, which comprises the following steps: by taking 1, 2-disubstituted pyrazol-3-ketone as an initial raw material, 1, 2-dichloroethane as a reaction solvent and pyridinium chlorochromate as an oxidizing agent, carrying out dehydroaromatization reaction on the 1, 2-disubstituted pyrazol-3-ketone to obtain the 1, 2-disubstituted 1, 2-dihydro-3H-pyrazol-3-ketone, and reacting the 1, 2-disubstituted 1, 2-dihydro-3H-pyrazol-3-ketone with 1, 2-dichloroethane to obtain the 1, 2-disubstituted 1, 2-dihydro-3H-pyrazol-3-ketone. The synthesis method comprises the following steps: preparing 1, 2-dihydro-3H-pyrazole-3-ketone. According to the present invention, the 1, 2-disubstituted 1, 2-dihydro-3H-pyrazole-3-ketone can be prepared, the reaction conditions are mild, the process is simple, the yield of the product 1, 2-disubstituted 1, 2-dihydro-3H-pyrazole-3-ketone is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] This disclosure relates to the field of organic synthesis technology, and in particular to a method for preparing 1,2-dihydro-3H-pyrazol-3-one. Background Technology

[0002] More than half of drug molecules belong to nitrogen-containing heterocyclic compounds. Pyrazole compounds, as an important class of nitrogen-containing heterocyclic structural units, are widely found in various natural products and drug molecules, serving as crucial building blocks for new drug development and the construction of bioactive compounds in pesticides. 1,2-Dihydro-3H-pyrazole-3-one, as an important component, has received increasing attention and has consistently been a research hotspot. For example, celecoxib (Celebrex) is used to relieve the symptoms and signs of osteoarthritis, relieve the symptoms and signs of rheumatoid arthritis in adults, and treat acute pain in adults; rimonaban (Acomplia) has insulin-sensitizing effects and improves lipid metabolism disorders.

[0003] Based on 1,2-dihydro-3H-pyrazole-3-one, exploring novel functional molecules and efficiently obtaining high-value compounds with specific uses is of great significance for improving physicochemical properties and drug-likeness, and expanding pharmacological applications. Summary of the Invention

[0004] The present disclosure aims to provide a method for preparing 1,2-disubstituted 1,2-dihydro-3H-pyrazole-3-one with mild reaction conditions, few reaction steps, and simple post-processing.

[0005] This disclosure provides a method for preparing 1,2-dihydro-3H-pyrazol-3-one, comprising: using 1,2-dihydro-3H-pyrazol-3-one as a starting material, 1,2-dichloroethane as a reaction solvent, and pyridinium chlorochromate as an oxidant, to cause a dehydrogenation aromatization reaction of 1,2-dihydro-3H-pyrazol-3-one to obtain 1,2-dihydro-3H-pyrazol-3-one.

[0006] In some embodiments, the reaction formula for preparing 1,2-dihydro-3H-pyrazol-3-one from 1,2-disubstituted pyrazolidine-3-one as a starting material is as follows: ; Wherein, substituents R1, R2, R3, R4, and R5 are selected from one or more of hydrogen, fluorine, chlorine, bromine, and iodine, and substituent R6 is selected from alkyl, phenylalkyl, arylalkyl, heterocyclic alkyl, and heteroarylalkyl.

[0007] In some embodiments, the substituent R6 has the following structural formula: ; Among them, substituents R7, R8, R9, R 10 Selected from one or more of hydrogen, fluorine, chlorine, bromine, and iodine, with substituent R 11 It is selected from hydrogen, C1-C6 alkyl, and 2-(N-methoxycarbonyl-N-methoxy)amino.

[0008] In some embodiments, the base R is replaced 11 The structural formula is as follows: ; Among them, substituent R 12 Selected from C1-C6 alkyl groups, with substituent R 13 Selected from C1-C6 alkyl groups.

[0009] In some embodiments, the structural formula of 1,2-disubstituted pyrazolidine-3-one is as follows: ; The structural formula of the 1,2-dihydro-3H-pyrazol-3-one with 1,2-disubstituted form is as follows: .

[0010] In some embodiments, the structural formula of 1,2-disubstituted pyrazolidine-3-one is as follows: ; The structural formula of the 1,2-dihydro-3H-pyrazol-3-one with 1,2-disubstituted form is as follows: .

[0011] In some embodiments, the structural formula of 1,2-disubstituted pyrazolidine-3-one is as follows: ; The structural formula of the 1,2-dihydro-3H-pyrazol-3-one with 1,2-disubstituted form is as follows: .

[0012] In some embodiments, the reaction is carried out at room temperature for 24 hours.

[0013] In some embodiments, the molar ratio of the 1,2-substituted pyrazolidine-3-one compound to the pyridine chlorochromate salt ranges from 1:5 to 1:10.

[0014] In some embodiments, the method further includes: extracting with saturated sodium sulfite solution and ethyl acetate to obtain an organic layer solution; drying the organic layer solution to obtain a crude product; and separating the crude product by column chromatography to obtain 1,2-disubstituted 1,2-dihydro-3H-pyrazole-3-one.

[0015] In this embodiment, 1,2-disubstituted pyrazolidine-3-one is used as the starting material to prepare 1,2-disubstituted 1,2-dihydro-3H-pyrazol-3-one. The reaction conditions are mild, the process is simple, and the yield of 1,2-disubstituted 1,2-dihydro-3H-pyrazol-3-one is high, making it suitable for industrial production. Attached Figure Description

[0016] Figure 1 This is a synthetic route diagram for 1,2-dihydro-3H-pyrazol-3-one in the embodiments of this disclosure.

[0017] Figure 2 This is a synthetic route diagram of 1-p-chlorophenyl-2-(2-(N-methoxycarbonyl-N-methoxy)amino)benzyl-1,2-dihydro-3H-pyrazole-3-one in the embodiments of this disclosure.

[0018] Figure 3 This is a synthetic route diagram of 1-p-chlorophenyl-2-benzyl-1,2-dihydro-3H-pyrazole-3-one in the embodiments of this disclosure.

[0019] Figure 4 This is a synthetic route diagram of 1-p-chlorophenyl-2-methyl-1,2-dihydro-3H-pyrazol-3-one in the embodiments of this disclosure.

[0020] Figure 5 As in Example 1 1 H NMR spectrum. Detailed Implementation

[0021] To enable those skilled in the art to better understand the technical solutions of this disclosure, the technical solutions of this disclosure will be described in detail below with reference to the accompanying drawings.

[0022] Exemplary embodiments will be described more fully below with reference to the accompanying drawings; however, these exemplary embodiments may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will enable those skilled in the art to fully understand the scope of this disclosure.

[0023] Where there is no conflict, the various embodiments of this disclosure and the features thereof in the embodiments may be combined with each other.

[0024] As used herein, the term “and / or” includes any and all combinations of one or more related enumerated entries.

[0025] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit this disclosure. As used herein, the singular forms “a” and “the” are also intended to include the plural forms unless the context clearly indicates otherwise. It will also be understood that when the terms “comprising” and / or “made of” are used in this specification, the presence of the stated feature, integral, step, operation, element, and / or component is specified, but the presence or addition of one or more other features, integrals, steps, operations, elements, components, and / or groups thereof is not excluded.

[0026] Unless otherwise specified, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art. It will also be understood that terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant art and this disclosure, and will not be interpreted as having an idealized or overly formal meaning, unless expressly so defined herein.

[0027] This disclosure provides a method for preparing 1,2-dihydro-3H-pyrazole-3-one. Figure 1 The synthetic route for preparing 1,2-dihydro-3H-pyrazol-3-one from 1,2-disubstituted pyrazolidine-3-one as a starting material includes: using 1,2-disubstituted pyrazolidine-3-one as a starting material, 1,2-dichloroethane as a reaction solvent, and pyridinium chlorochromate (PCC) as an oxidant, the 1,2-disubstituted pyrazolidine-3-one undergoes a dehydrogenation aromatization reaction to obtain 1,2-dihydro-3H-pyrazol-3-one.

[0028] In the embodiments disclosed herein, using pyridinium chlorochromate as an oxidant ensures the preparation of the target product, 1,2-disubstituted 1,2-dihydro-3H-pyrazol-3-one.

[0029] In some embodiments, the reaction formula for preparing 1,2-dihydro-3H-pyrazol-3-one from 1,2-disubstituted pyrazolidine-3-one as a starting material is as follows: ; Wherein, substituents R1, R2, R3, R4, and R5 are selected from one or more of hydrogen, fluorine, chlorine, bromine, and iodine, and substituent R6 is selected from alkyl, phenylalkyl, arylalkyl, heterocyclic alkyl, and heteroarylalkyl.

[0030] In some embodiments, the substituent R6 is selected from alkyl, phenylalkyl, arylalkyl, heterocyclic alkyl, and heteroarylalkyl, and its alkyl structural portion is each a saturated straight-chain or branched hydrocarbon group having 1-6 or 1-4 carbon atoms. For example, substituent R6 is selected from methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethyl, 1-ethyl, hexyl, 1,1-dimethyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and their isomers, and benzyl. This disclosure does not specifically limit the specific substituents in this regard.

[0031] In some embodiments, the substituent R6 has the following structural formula: ; Among them, substituents R7, R8, R9, R 10 Selected from one or more of hydrogen, fluorine, chlorine, bromine, and iodine, with substituent R 11 It is selected from hydrogen, C1-C6 alkyl, and 2-(N-methoxycarbonyl-N-methoxy)amino.

[0032] In some embodiments, the base R is replaced 11 The structural formula is as follows: ; Among them, substituent R 12 Selected from C1-C6 alkyl groups, with substituent R 13 Selected from C1-C6 alkyl groups.

[0033] In some embodiments, the base R is replaced 12 It is methyl or methyl, for example, R 12 It is a methyl group.

[0034] In some embodiments, the base R is replaced 13 It is methyl or methyl, for example, R 13 It is a methyl group.

[0035] In some embodiments, the structural formula of 1,2-disubstituted pyrazolidine-3-one is as follows: ; The structural formula of the 1,2-dihydro-3H-pyrazol-3-one with 1,2-disubstituted form is as follows: .

[0036] In some embodiments, the structural formula of 1,2-disubstituted pyrazolidine-3-one is as follows: ; The structural formula of the 1,2-dihydro-3H-pyrazol-3-one with 1,2-disubstituted form is as follows: .

[0037] In some embodiments, the structural formula of 1,2-disubstituted pyrazolidine-3-one is as follows: ; The structural formula of the 1,2-dihydro-3H-pyrazol-3-one with 1,2-disubstituted form is as follows: .

[0038] The embodiments disclosed herein do not impose any special limitation on the reaction temperature; for example, the reaction temperature range is 15 to 50°C.

[0039] The inventors discovered that as the reaction temperature increases, the substrate may disintegrate, leading to a decrease in reaction stability.

[0040] In some embodiments, the reaction is carried out at room temperature for 24 hours.

[0041] In the embodiments disclosed herein, the dehydrogenation aromatization reaction can occur stably at room temperature.

[0042] In some embodiments, the molar ratio of the 1,2-substituted pyrazolidine-3-one compound to the pyridine chlorochromate salt ranges from 1:5 to 1:10.

[0043] In some embodiments, the molar ratio of the 1,2-substituted pyrazolidine-3-one compound to the pyridine chlorochromate salt is 1:5.

[0044] In some embodiments, the method for preparing 1,2-dihydro-3H-pyrazole-3-one further includes: extracting with saturated sodium sulfite solution and ethyl acetate, and taking the organic layer solution; drying the organic layer solution to obtain a crude product; and separating the crude product by column chromatography to obtain 1,2-dihydro-3H-pyrazole-3-one.

[0045] In this embodiment, 1,2-disubstituted pyrazolidine-3-one is used as the starting material to prepare 1,2-disubstituted 1,2-dihydro-3H-pyrazol-3-one. The reaction conditions are mild, the process is simple, and the yield of 1,2-disubstituted 1,2-dihydro-3H-pyrazol-3-one is high, making it suitable for industrial production.

[0046] Example 1 In this embodiment, the 1,2-dihydro-3H-pyrazole-3-one specifically is 1-p-chlorophenyl-2-(2-(N-methoxycarbonyl-N-methoxy)amino)benzyl-1,2-dihydro-3H-pyrazole-3-one, with the following structural formula: ; The 1,2-disubstituted pyrazolidine-3-one is specifically 1-p-chlorophenyl-2-(2-(N-methoxycarbonyl-N-methoxy)amino)benzylpyrazolidine-3-one, with the following structural formula: ; The synthetic route for preparing 1-p-chlorophenyl-2-(2-(N-methoxycarbonyl-N-methoxy)amino)benzylpyrazolidine-3-one from 1-p-chlorophenyl-2-(2-(N-methoxycarbonyl-N-methoxy)amino)benzyl-1,2-dihydro-3H-pyrazolidine-3-one is as follows: Figure 2 As shown, it includes: In a 500 mL reaction flask, a magnetic stir bar and 1-p-chlorophenyl-2-(2-(N-methoxycarbonyl-N-methoxy)amino)benzylpyrazolidine-3-one (51.4 mmol, 20 g) were added, followed by dissolution in dichloroethane (200 mL). Then, pyridine chlorochromate (0.26 mol, 44.3 g) was weighed and added. The reaction was carried out at room temperature for 24 hours, and monitored by thin-layer chromatography (LC-MS) during the reaction. The reaction system was extracted three times at room temperature by adding saturated sodium sulfite solution (200 mL) and ethyl acetate (200 mL). The organic layer solution was dried with anhydrous sodium sulfate, the solvent was evaporated, and then the crude product was separated by column chromatography (the volume ratio of dichloromethane to methanol was 20:1) to obtain 1-p-chlorophenyl-2-(2-(N-methoxycarbonyl-N-methoxy)amino)benzyl-1,2-dihydro-3H-pyrazole-3-one (13.9 g, purity 97.2%, yield 67.8%).

[0047] The obtained 1-p-chlorophenyl-2-(2-(N-methoxycarbonyl-N-methoxy)amino)benzyl-1,2-dihydro-3H-pyrazole-3-one was characterized. Figure 5 It is the obtained 1-p-chlorophenyl-2-(2-(N-methoxycarbonyl-N-methoxy)amino)benzyl-1,2-dihydro-3H-pyrazole-3-one 1 HNMR spectrum, in which: 1 HNMR (400MHz, DMSO) d6):δ8.12(s,1H),7.44-7.47(m,2H),7.21 7.32 (m, 5H), 6.69 6.71(m,1H), 5.69(s,1H), 4.86(s,2H), 3.61(s,3H), 3.31(s,3H).

[0048] As can be seen, the target product 1-p-chlorophenyl-2-(2-(N-methoxycarbonyl-N-methoxy)amino)benzyl-1,2-dihydro-3H-pyrazole-3-one was successfully prepared by the preparation method of Example 1. Chromatographic analysis confirmed that its purity reached 97.2% and the yield reached 67.8%.

[0049] Example 2 In this embodiment, the 1,2-dihydro-3H-pyrazole-3-one specifically is 1-p-chlorophenyl-2-benzyl-1,2-dihydro-3H-pyrazole-3-one, whose structural formula is as follows: ; The 1,2-disubstituted pyrazolidine-3-one is specifically 1-p-chlorophenyl-2-benzylpyrazolidine-3-one, and its structural formula is as follows: ; The synthetic route for preparing 1-p-chlorophenyl-2-benzyl-1,2-dihydro-3H-pyrazole-3-one from 1-p-chlorophenyl-2-benzylpyrazolidine-3-one is as follows: Figure 3 As shown, it includes: In a 500 mL reaction flask, a magnetic stir bar and 1-p-chlorophenyl-2-benzylpyrazolidine-3-one (69.9 mmol, 20 g) were added, followed by dissolution in dichloroethane (300 mL). Then, pyridine chlorochromate (0.35 mol, 59.6 g) was weighed and added. The reaction was carried out at room temperature for 24 hours, monitored by thin-layer chromatography (LC-MS). The reaction system was extracted three times at room temperature with saturated sodium sulfite solution (300 mL) and ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: dichloromethane to methanol, volume ratio 20:1) to obtain 1-p-chlorophenyl-2-benzyl-1,2-dihydro-3H-pyrazolidine-3-one (13.1 g, purity 98.5%, yield 65.3%).

[0050] As can be seen, the target product 1-p-chlorophenyl-2-benzyl-1,2-dihydro-3H-pyrazole-3-one was successfully prepared by the preparation method in Example 2. Chromatographic analysis confirmed that its purity reached 98.5% and the yield reached 65.3%.

[0051] Example 3 In this embodiment, the 1,2-dihydro-3H-pyrazole-3-one specifically is 1-p-chlorophenyl-2-methyl-1,2-dihydro-3H-pyrazole-3-one, whose structural formula is as follows: ; The 1,2-disubstituted pyrazolidine-3-one is specifically 1-p-chlorophenyl-2-methylpyrazolidine-3-one, and its structural formula is as follows: ; The synthetic route for preparing 1-p-chlorophenyl-2-methyl-1,2-dihydro-3H-pyrazol-3-one from 1-p-chlorophenyl-2-methylpyrazolidine-3-one is as follows: Figure 4 As shown, it includes: In a 500 mL reaction flask, a magnetic stir bar and 1-p-chlorophenyl-2-methylpyrazolidine-3-one (95.2 mmol, 20 g) were added, followed by dissolution in dichloroethane (300 mL). Then, pyridine chlorochromate (0.48 mol, 81.1 g) was weighed and added. The reaction was carried out at room temperature for 24 hours, monitored by thin-layer chromatography (LC-MS). The reaction system was extracted three times at room temperature with saturated sodium sulfite solution (300 mL) and ethyl acetate (200 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was then separated by column chromatography (eluent: dichloromethane to methanol, volume ratio 20:1) to obtain 1-p-chlorophenyl-2-benzyl-1,2-dihydro-3H-pyrazolidine-3-one (14.6 g, purity 98.2%, yield 72.5%).

[0052] As can be seen, the target product 1-p-chlorophenyl-2-benzyl-1,2-dihydro-3H-pyrazole-3-one was successfully prepared by the preparation method in Example 3. Chromatographic analysis confirmed that its purity reached 98.2% and the yield reached 72.5%.

[0053] The results of Examples 1 to 3 fully demonstrate that the process route for preparing 1,2-dihydro-3H-pyrazole-3-one provided in this disclosure is feasible, with mild reaction conditions, few reaction steps, simple post-processing, and high yield of 1,2-dihydro-3H-pyrazole-3-one, making it suitable for industrial application.

[0054] Example embodiments have been disclosed herein, and while specific terminology has been used, it is for illustrative purposes only and should be construed as such, and is not intended to be limiting. In some instances, it will be apparent to those skilled in the art that features, characteristics, and / or elements described in connection with particular embodiments may be used alone, or in combination with features, characteristics, and / or elements described in connection with other embodiments, unless otherwise expressly indicated. Therefore, those skilled in the art will understand that various changes in form and detail may be made without departing from the scope of this disclosure as set forth by the appended claims.

Claims

1. A method for preparing 1,2-dihydro-3H-pyrazole-3-one, characterized in that, include: Using 1,2-disubstituted pyrazolidine-3-one as the starting material, 1,2-dichloroethane as the reaction solvent, and pyridinium chlorochromate as the oxidant, the 1,2-disubstituted pyrazolidine-3-one underwent a dehydrogenation aromatization reaction to obtain 1,2-disubstituted 1,2-dihydro-3H-pyrazolidine-3-one.

2. The method for preparing 1,2-dihydro-3H-pyrazole-3-one according to claim 1, characterized in that, The reaction formula is as follows: ； Wherein, substituents R1, R2, R3, R4, and R5 are selected from one or more of hydrogen, fluorine, chlorine, bromine, and iodine, and substituent R6 is selected from alkyl, phenylalkyl, arylalkyl, heterocyclic alkyl, and heteroarylalkyl.

3. The method for preparing 1,2-dihydro-3H-pyrazole-3-one according to claim 2, characterized in that, The structural formula of substituent R6 is as follows: ； Among them, substituents R7, R8, R9, R 10 Selected from one or more of hydrogen, fluorine, chlorine, bromine, and iodine, with substituent R 11 It is selected from hydrogen, C1-C6 alkyl, and 2-(N-methoxycarbonyl-N-methoxy)amino.

4. The method for preparing 1,2-dihydro-3H-pyrazole-3-one according to claim 3, characterized in that, Substituent R 11 The structural formula is as follows: ； Among them, substituent R 12 Selected from C1-C6 alkyl groups, with substituent R 13 Selected from C1-C6 alkyl groups.

5. The method for preparing 1,2-dihydro-3H-pyrazole-3-one according to claim 2, characterized in that, The structural formula of the 1,2-disubstituted pyrazolidine-3-one is as follows: ； The structural formula of the 1,2-dihydro-3H-pyrazol-3-one with 1,2-disubstituted form is as follows: 。 6. The method for preparing 1,2-dihydro-3H-pyrazole-3-one according to claim 3, characterized in that, The structural formula of the 1,2-disubstituted pyrazolidine-3-one is as follows: ； The structural formula of the 1,2-dihydro-3H-pyrazol-3-one with 1,2-disubstituted form is as follows: 。 7. The method for preparing 1,2-dihydro-3H-pyrazole-3-one according to claim 4, characterized in that, The structural formula of the 1,2-disubstituted pyrazolidine-3-one is as follows: ； The structural formula of the 1,2-dihydro-3H-pyrazol-3-one with 1,2-disubstituted form is as follows: 。 8. The method for preparing 1,2-disubstituted 1,2-dihydro-3H-pyrazole-3-one according to any one of claims 1 to 7, characterized in that, React at room temperature for 24 hours.

9. The method for preparing 1,2-dihydro-3H-pyrazole-3-one according to any one of claims 1 to 7, characterized in that, The molar ratio of 1,2-substituted pyrazolidine-3-one compounds to pyridine chloride salts ranges from 1:5 to 1:

10.

10. The method for preparing 1,2-disubstituted 1,2-dihydro-3H-pyrazole-3-one according to any one of claims 1 to 7, characterized in that, Also includes: Extract with saturated sodium sulfite solution and ethyl acetate, and collect the organic layer solution. The organic layer solution was dried to obtain a crude product; The crude product was separated by column chromatography to obtain 1,2-disubstituted 1,2-dihydro-3H-pyrazol-3-one.

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