CN118660877A - Preparation method of diphenylpyrazole compounds - Google Patents
Preparation method of diphenylpyrazole compounds Download PDFInfo
- Publication number
- CN118660877A CN118660877A CN202380017535.7A CN202380017535A CN118660877A CN 118660877 A CN118660877 A CN 118660877A CN 202380017535 A CN202380017535 A CN 202380017535A CN 118660877 A CN118660877 A CN 118660877A
- Authority
- CN
- China
- Prior art keywords
- compound
- synthesis
- reaction
- solvent
- hours
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供二苯基吡唑类化合物新的制备方法。本发明的制备方法成本低、安全性高，非常适合工业化生产。The invention provides a new preparation method of diphenylpyrazole compounds. The preparation method of the invention has low cost and high safety and is very suitable for industrial production.
Description
The invention relates to the technical field of pesticides, in particular to a preparation method of a diphenylpyrazole compound.
N' - (1, 3-diphenyl-1H-pyrazole-5-carbonyl) -2-oxo-1, 2-dihydroquinoline-4-carbohydrazide (PXG 22 in the application) belongs to diphenyl pyrazole compounds, and is a novel inhibitor for targeting insect GSTs. The inhibitor has wide inhibition activity on GSTs in various pests, and can effectively delay the in-vivo metabolism of the pests GSTs on pesticides, thereby reducing the metabolic resistance of the pests on the pesticides. The chemical structure of PXG22 is as follows:
In Chinese patent application CN202110760647.4 and PCT International patent application PCT/CN2021/105643, the synthetic route of PXG22 is mainly as follows:
The synthesis of the key intermediate compound B1 requires that the compound A1 is obtained firstly, and the synthetic route reference (J.org.chem.2010, 75,3,984-987) of the compound A1 is obtained, wherein the specific synthetic route is as follows:
Synthesis of Compound 2: to a 250ml three-necked flask, compound 1 (N-phenylglycine), 10g, 50ml of water, 5g of sodium nitrite and 30ml of water are added dropwise at room temperature, after about 20 minutes, the mixture is reacted overnight, 2g of active carbon is added into the system, the mixture is stirred for 10 minutes, suction filtration is carried out, the pH of the water phase is regulated by concentrated hydrochloric acid=2-3, a large amount of solids are separated out and dried, and then compound 2,9.7g is obtained, and the yield is 81.4%.
Synthesis of Compound 3: to a 250ml three-necked flask, compound 2,9.7g and acetic anhydride are added, 50ml of acetic anhydride is heated to 90 ℃ to react for 10 hours, the reaction is completed, a large amount of solids are separated out after the system is added into 150ml of water, and the compound 3,5.74g and the yield of 65.6% are obtained through suction filtration.
Synthesis of Compound 4: to 250ml three-mouth bottle, compound 3,4.74g, glacial acetic acid 100ml, NIS,9.9g are added in batches under stirring at room temperature, the reaction is carried out overnight, the system is completely added into water, solid is separated out, and the compound 4,7.9g is obtained through suction filtration, and the yield is 93.4%.
Synthesis of Compound 5: to a 250ml three-necked flask, compound 4,7.9g, phenylacetylene 5.6g, m-xylene 60ml were added and heated to 145℃for 24 hours, and the reaction was completely purified by passing through a column to obtain compound 5,8.74g, yield 92%.
Synthesis of compound A1: to a 250ml three-port flask, 5,8.74g of the compound, 100ml of anhydrous tetrahydrofuran, cooling to-78 ℃, dropwise adding 22.2ml of 2.5 m-n-butyllithium for about 30 minutes, reacting for 1 hour, adding 9.5g of methyl chloroformate to the system, reacting for 3 hours, adding 20ml of sodium bicarbonate solution to the system, quenching the reaction, extracting by EA, drying and concentrating, and obtaining the compound A1,4g and the yield 57.1% by column chromatography EA, wherein PE=1:5.
The synthetic route of PXG22 described above has several problems:
(1) Sodium nitrite is required to be added in the synthesis step of the compound 2, wherein sodium nitrite is a high carcinogen, and the compound 2 is also a high carcinogen, so that the synthesis operators and the environment are very unsafe.
(2) In the synthesis step of the compound A1, the compound A1 needs to be cooled to-78 ℃, and the flammable and explosive chemical substance of n-butyllithium is added, so that the cost is high and the industrial production is not facilitated.
(3) The key intermediate G22 is purchased directly, has high cost and is not beneficial to industrial production.
The present application is a continuation of the chinese patent application CN2021107606474 and PCT international application PCT/CN/2021/105643, the contents of both of which are incorporated herein by reference.
Therefore, a low-cost and high-safety preparation method of diphenylpyrazole compounds needs to be studied.
Disclosure of Invention
In order to solve the technical problems, the invention provides a novel preparation method of a diphenylpyrazole compound, in particular to a novel preparation method of N' - (1, 3-diphenyl-1H-pyrazole-5-carbonyl) -2-oxo-1, 2-dihydroquinoline-4-carbohydrazide (compound PXG 22).
The invention provides a novel preparation method of a diphenylpyrazole compound N' - (1, 3-diphenyl-1H-pyrazole-5-carbonyl) -2-oxo-1, 2-dihydroquinoline-4-carbohydrazide (compound PXG 22), which comprises the following steps:
Synthesis of compound PXG 22: the compound B1 and the compound G22 are subjected to condensation reaction to obtain a compound PXG22;
wherein compound B1 is prepared by the following method:
The method comprises the following steps:
Wherein: r2 may be C 1～4 alkoxycarbonyl or cyano; preferably, R2 may be methoxycarbonyl, ethoxycarbonyl or cyano;
synthesis of compound b: reacting the compound a with phenylhydrazine to obtain a compound b;
Synthesis of compound d: (1) Reacting the compound b with chloramine T (CAT), and then adding a compound c to react to obtain a compound d; or (2) in the presence of a catalyst, reacting the compound b with halogenated succinimide (preferably chlorosuccinimide (NCS)), then adding the compound c for reaction, and then adding Triethylamine (TEA) for reaction to obtain a compound d;
Synthesis of compound e: reacting the compound d with 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) to obtain a compound e;
synthesis of compound B1: reacting the compound e with alkali to obtain a compound B1; or alternatively
The second method is as follows:
Wherein: r3 may be C 1～4 alkoxycarbonyl; preferably, R3 may be methoxycarbonyl or ethoxycarbonyl;
Synthesis of Compound g: adding sodium hydride or metal alkoxide into a solvent, firstly reacting with a compound f, and then adding oxalic acid dibasic ester for condensation to obtain a compound g;
Synthesis of compound h: after methoxy amine hydrochloride reacts with the compound g, phenylhydrazine (or phenylhydrazine hydrochloride) is added for reaction to obtain a compound h;
synthesis of compound B1: the same as in method one; or alternatively
And a third method:
synthesis of compound B1: and after the compound 5 reacts with n-butyllithium, adding dry ice to react to obtain a compound B1.
Preferably, the method comprises the steps of,
Synthesis of compound PXG 22: the compound B1 and the compound G22 react in a solvent in the presence of a condensing agent and inorganic base to obtain a compound PXG22;
in the first method:
Synthesis of compound b: and (3) dissolving the compound a in a solvent, adding phenylhydrazine to react, carrying out suction filtration and drying to obtain the compound b. Alternatively, compound b was used directly as crude without purification in the next step;
Synthesis of compound d: (1) Dissolving a compound b in a solvent, adding chloramine T (CAT) for reaction, and then adding a compound c for reaction to obtain a compound d; or (2) dissolving the compound b in a solvent, adding a catalyst, then adding halogenated succinimide (preferably chlorosuccinimide (NCS)) for reaction, then adding the compound c for reaction, then adding Triethylamine (TEA) for reaction, then evaporating the reaction mixture to dryness, and purifying by column chromatography to obtain a compound d;
Synthesis of compound e: dissolving the compound d in a solvent, adding 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ) for reaction, and purifying by column chromatography to obtain a compound e;
Synthesis of compound B1: dissolving a compound e in a solvent, adding alkali for reaction, evaporating the reaction mixture to dryness, adding water, adjusting the pH value to 1-5 by using concentrated hydrochloric acid, and purifying to obtain a compound B1;
in the second method:
Synthesis of Compound g: cooling a solvent, slowly adding sodium hydride or metal alkoxide, releasing heat, controlling the feeding speed, performing a first heat-preserving reaction, then dropwise adding a compound f, performing a second heat-preserving reaction, then adding oxalic acid dibasic ester into a reaction system in batches, stirring until the reaction is completed after the addition, performing suction filtration, adding a filter cake into ice water, regulating the pH value by concentrated hydrochloric acid, stirring, and performing suction filtration to obtain a compound g; optionally, drying the compound g without purification, and directly using as a crude product in the next step;
Synthesis of compound h: dissolving methoxyamine hydrochloride in a solvent, cooling, dropwise adding a solution of a compound g, reacting after dropwise adding, adding phenylhydrazine (or phenylhydrazine hydrochloride) into a reaction system for reacting, heating and refluxing for reacting, and purifying to obtain a compound h;
In the third method:
Synthesis of compound B1: adding a compound 5 into a container, adding a solvent for cooling, dropwise adding n-butyllithium for reaction, adding dry ice into a reaction system for reaction, adding ammonium chloride into the reaction system for quenching reaction, concentrating, adding water and dilute hydrochloric acid for regulating the pH of the system to 2-3, and separating out solids to obtain a compound B1.
Preferably, in the synthesis of compound b of method one: the solvents include, but are not limited to: methanol (preferably absolute methanol), ethanol (preferably absolute ethanol), dichloromethane, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, isopropyl ether; the temperature of the reaction is 0-100 ℃; the reaction time is 1-24 hours; the molar ratio of the compound a to the phenylhydrazine is 1:1-1:2.
In one embodiment, in the synthesis of compound b of method one: the solvent is absolute ethyl alcohol; the temperature of the reaction is 50 ℃; the reaction time was 16 hours; the molar ratio of the compound a to the phenylhydrazine is 1:1.
Preferably, in the synthesis of compound d of method one: the solvents include, but are not limited to: methanol (preferably absolute methanol), ethanol (preferably absolute ethanol), dichloromethane, acetonitrile, tetrahydrofuran, methyl tert-butyl ether, isopropyl ether; the catalysts include, but are not limited to: pyridine.
In one embodiment, in the synthesis of compound d of method one: the solvent is absolute ethyl alcohol or acetonitrile; the catalyst is pyridine.
In the synthesis of compound d of method one:
In (1), the solvent includes, but is not limited to, absolute ethanol; the reaction temperature of the compound b and CAT is 0-100 ℃; the reaction time after CAT is added is 10 to 60 minutes; the reaction time after the compound c is added is 1 to 24 hours; the molar ratio of the compound b to the compound CAT is 1:1-1:3; the molar ratio of the compound b to the compound c is 1:1-1:5; the reaction temperature after the addition of the compound c is 0 to 100 ℃.
In one embodiment, in (1), the solvent is absolute ethanol; the reaction temperature of the compound b and CAT is 25 ℃; the reaction time after CAT addition was 30 minutes; the reaction time after addition of compound c was 12 hours; the molar ratio of the compound b to CAT is 1:1.5; the molar ratio of the compound b to the compound c is 1:3; the reaction temperature after addition of compound c was 75 ℃.
In (2), the solvent includes, but is not limited to, acetonitrile; the reaction temperature of the compound b and the halogenated succinimide is 0-100 ℃; the reaction time of the compound b and the halogenated succinimide is 1-3 hours; the reaction temperature after TEA is added is 0-100 ℃; the reaction time after TEA is added is 1 to 24 hours; the molar ratio of the compound b to the halogenated succinimide is 1:1-1:2; the molar ratio of the compound b to the compound c is 1:1-1:5; the molar ratio of the compound c to TEA is 3:1-3:5; the reaction time after addition of compound c is 10 to 60 minutes.
In one embodiment, in (2), the solvent is acetonitrile; the reaction temperature of the compound b and the halogenated succinimide is 5 ℃; the reaction time of the compound b and the halogenated succinimide is 1 hour; the reaction temperature of the added TEA is 20 ℃; the reaction time after TEA addition was 6 hours; the molar ratio of the compound b to the halogenated succinimide is 1:1.1; the molar ratio of the compound b to the compound c is 1:3; the molar ratio of the compound c to TEA is 3:1.4; the reaction time after addition of compound c was 30 minutes.
Preferably, in the synthesis of compound e of method one: the solvents include, but are not limited to: dichloromethane, tetrahydrofuran, toluene, dioxane, acetic acid; the temperature of the reaction is 0-200 ℃; the reaction time is 1-24 hours; the molar ratio of the compound d to the DDQ is 1:1-1:5.
In one embodiment, in the synthesis of compound e of method one: the solvent is toluene; the temperature of the reaction is 100 ℃; the reaction time is 12 hours; the molar ratio of the compound d to the DDQ is 1:3.
Preferably, in the synthesis of compound B1 of method one: the solvents include, but are not limited to: methanol (preferably absolute methanol), ethanol (preferably absolute ethanol), isopropanol, tetrahydrofuran; the bases include, but are not limited to: potassium hydroxide, sodium hydroxide, lithium hydroxide; the temperature of the reaction is 0-100 ℃; the reaction time is 1-24 hours; the molar ratio of the compound e to the alkali is 1:1-1:5.
In one embodiment, in the synthesis of compound B1 of method one: the solvent is absolute ethyl alcohol; the alkali is potassium hydroxide; the temperature of the reaction is 20 ℃; the reaction time is 12 hours; the molar ratio of the compound e to the base is 1:2.
Preferably, in the synthesis of compound g of method two: the solvents include, but are not limited to: methanol (preferably absolute methanol), ethanol (preferably absolute ethanol), isopropanol, tetrahydrofuran; the metal alkoxides include, but are not limited to: sodium methoxide and sodium ethoxide; the oxalic acid dibasic esters include, but are not limited to: dimethyl oxalate and diethyl oxalate; the temperature of the cooled solvent is 0-20 ℃; the time of the first heat preservation reaction is 10-60 minutes; the time of the second heat preservation reaction is 10-60 minutes; the reaction temperature after adding oxalic acid dibasic ester is 0-100 ℃; the reaction time after adding oxalic acid dibasic ester is 1-24 hours; the pH value is regulated to 1-5 by concentrated hydrochloric acid; the stirring time after adding the concentrated hydrochloric acid is 10 to 60 minutes.
In one embodiment, in the synthesis of compound g of method two: the solvent is absolute ethyl alcohol; the metal alkoxide is sodium ethoxide; the oxalic acid dibasic ester is diethyl oxalate; the temperature of the solvent after cooling is 10 ℃; the time of the first heat preservation reaction is 30 minutes; the time of the second heat preservation reaction is 30 minutes; the reaction temperature after adding oxalic acid dibasic ester is 15 ℃; the reaction time after adding oxalic acid dibasic ester is 2 hours; regulating the pH value to 2-3 by concentrated hydrochloric acid; the stirring time after the addition of concentrated hydrochloric acid was 30 minutes.
Preferably, in the synthesis of compound h of method two: the solvents include, but are not limited to: methanol (preferably absolute methanol), ethanol (preferably absolute ethanol), isopropanol, tetrahydrofuran; the cooling temperature is-5 ℃; the dropping time of the solution of the compound g is 1-3 hours; solvents for the compound g solution include, but are not limited to: methanol (preferably absolute methanol), ethanol (preferably absolute ethanol), isopropanol, tetrahydrofuran; the reaction temperature after the compound g is dropped is 0-100 ℃; the reaction time after the compound g is added is 0 to 24 hours; the reaction temperature after phenylhydrazine or phenylhydrazine hydrochloride is 0-100 ℃; the reaction time after phenylhydrazine or phenylhydrazine hydrochloride is 1 to 24 hours; adding phenylhydrazine or phenylhydrazine hydrochloride to react, and then heating and refluxing for 0-24 hours; the molar ratio of the methoxyamine hydrochloride to the compound g is 1:1-1:5.
In one embodiment, in the synthesis of compound h of method two: the solvent is absolute ethyl alcohol; the temperature of the cooling is 0 ℃; the dropping time of the solution of the compound g is 1 hour; the solvent of the solution of the compound g is absolute ethyl alcohol; the reaction temperature after the compound g is dropped is 15 ℃; the reaction time after the compound g is added is 12 hours; the reaction temperature after phenylhydrazine or phenylhydrazine hydrochloride is 15 ℃; the reaction time after adding phenylhydrazine or phenylhydrazine hydrochloride is 4 hours; adding phenylhydrazine or phenylhydrazine hydrochloride to react, and then heating and refluxing for 6 hours; the molar ratio of the methoxyamine hydrochloride to the compound g is 1:1.
Preferably, in the synthesis of compound B1 of method three: the solvents include, but are not limited to: methyl tetrahydrofuran, tetrahydrofuran; the dosage of the compound 5 is 1 equivalent to 5 equivalents; the dosage of the n-butyl lithium is 1-3 equivalents; the dosage of the dry ice is 1-20 equivalents; the cooling temperature after adding the solvent is-100-5 ℃; the reaction time after Bi Zheng butyl lithium is dripped is 1 to 6 hours; the reaction time after adding dry ice is 10 to 60 minutes.
In one embodiment, in the synthesis of compound B1 of method three: the solvent is anhydrous tetrahydrofuran; the dosage of the compound 5 is 1 equivalent; the dosage of the n-butyl lithium is 1.2-1.3 equivalent; the dry ice is used in an amount of 10 equivalents; the cooling temperature after adding the solvent is-78 ℃; the reaction time after the Bi Zheng butyllithium drop was 1 hour; the reaction time after addition of dry ice was 30 minutes.
Preferably, in the synthesis of compound PXG 22: the condensing agent includes, but is not limited to: active esters, carbodiimide, onium salts, organic phosphorus, and other condensing agents; the inorganic bases include, but are not limited to: sodium carbonate, potassium carbonate, sodium hydroxide, sodium bicarbonate; the solvents include, but are not limited to: n, N-Dimethylformamide (DMF), dichloromethane, acetonitrile, tetrahydrofuran; the temperature of the reaction is 0-100 ℃; the reaction time is 1-48 hours; the molar ratio of the compound B1 to the compound G22 is 1:1-1:2.
In one embodiment, the compound PXG22 is synthesized by: the condensing agent is HBTU; the inorganic base is potassium carbonate; the solvent is DMF; the temperature of the reaction is 20 ℃; the reaction time was 24 hours; the molar ratio of compound B1 to compound G22 was 1:1.
Preferably, the preparation method of the compound G22 comprises the following steps:
Wherein: r4 is methoxycarbonyl or ethoxycarbonyl.
Synthesis of compound F: dissolving the compound E in methanol or ethanol, dropwise adding raw materials, heating for reaction, evaporating the reaction mixture to dryness, adding water, adjusting the pH of a reaction system to 8-9 by using alkali, carrying out suction filtration, and washing a filter cake by using water to obtain the compound F. Alternatively, compound F was used directly in the next step as crude without purification.
Synthesis of compound G22: and (3) dissolving the compound F in a solvent, adding hydrazine hydrate, heating for reaction, and carrying out suction filtration to obtain the compound G22.
Preferably, in the synthesis of compound F: the raw materials include, but are not limited to: thionyl chloride, oxalyl chloride and concentrated sulfuric acid; the bases include, but are not limited to: sodium carbonate, sodium hydroxide, potassium hydroxide; the reaction temperature after the raw materials are dropped is 0-100 ℃; the reaction time after the raw materials are dropped is 1 to 48 hours; the dosage of the compound E is 1 to 5 equivalents; the amount of the raw materials is 1 equivalent to 10 equivalents.
In one embodiment, in the synthesis of compound F: the raw material is thionyl chloride; the alkali is sodium carbonate; the reaction temperature after the raw materials are dropped is 65 ℃; the reaction time after the raw materials are dripped is 24 hours; the dosage of the compound E is 1 equivalent; the amount of the raw material was 5 equivalents.
Preferably, in the synthesis of compound G22: the solvents include, but are not limited to: methanol (preferably absolute methanol), ethanol (preferably absolute ethanol), isopropanol, tetrahydrofuran; the temperature of the reaction is 0-100 ℃; the reaction time is 1-48 hours; the molar ratio of the compound F to the hydrazine hydrate is 1:1-1:5.
In one embodiment, in the synthesis of compound G22: the solvent is absolute ethyl alcohol; the temperature of the reaction is 80 ℃; the reaction time was 24 hours; the ratio of the compound F to the hydrazine hydrate is 1:3.
The present application is a continuation of the chinese patent application CN2021107606474 and PCT international application PCT/CN/2021/105643, the contents of both of which are incorporated herein by reference.
Compared with the prior art, the method has the following beneficial effects:
1. The present invention improves the synthesis of compound B1 in the previous applications (China patent application CN2021107606474 and PCT International application PCT/CN/2021/105643). Compared to the process for obtaining compound B1 with reference to the prior art (j.org.chem.2010, 75,3,984-987): after the compound A1 is synthesized by the compound 5, the compound B1 is obtained by hydrolyzing the compound A1, and the invention provides a new route which can lead the compound 5 to be directly synthesized to obtain the compound B1, shortens the route for synthesizing the PXG22 by one step and saves the synthetic cost of the PXG 22.
2. The invention provides two brand-new synthetic methods of a compound B1. Compared with the synthesis method of the compound B1 in the prior application, the preparation method of the invention has the advantages that the raw materials used by the preparation method do not have high carcinogen and flammable and explosive products, do not need harsh reaction conditions such as ultralow temperature cooling and the like, are very friendly to synthesis personnel and environment, are simple to purify, have high yield, greatly reduce the synthesis cost of the PXG22, and are suitable for industrial production.
3. The invention provides a brand new synthesis method of a compound G22. The prior application requires direct purchase of compound G22 as a starting material, which is very expensive. The synthesis method of the compound G22 provided by the invention has low price of initial raw materials, and the whole synthesis method only needs two steps, so that the synthesis cost of the PXG22 is further reduced, and the method is suitable for industrial production.
FIG. 1 is a mass spectrum of compound d 1.
FIG. 2 is a mass spectrum of compound e 1.
Fig. 3 is a mass spectrum of compound B1.
FIG. 4 is a 1 H-NMR spectrum of compound B1 dissolved in deuterated DMSO.
Fig. 5 is a mass spectrum of compound G22.
FIG. 6 is a 1 H-NMR spectrum of compound G22 dissolved in deuterated DMSO.
Fig. 7 is a mass spectrum of compound PXG 22.
FIG. 8 is a 1 H-NMR spectrum of compound PXG22 dissolved in deuterated DMSO.
Fig. 9 is a mass spectrum of compound e 2.
FIG. 10 is a 1 H-NMR spectrum of compound e2 dissolved in deuterated chloroform.
FIG. 11 is a mass spectrum of compound h 1.
FIG. 12 is a 1 H-NMR spectrum of compound H1 dissolved in deuterated DMSO.
FIG. 13 is a 1 H-NMR spectrum of compound 5 dissolved in deuterated chloroform.
The present invention will be described below by way of examples, but the present invention is not limited thereto. The experimental methods shown in the following examples are conventional methods unless otherwise specified. The reagents and materials shown are all commercially available products.
Preparation example 1
Synthesis of compound b: compound a (100 g,1 eq) was dissolved in absolute ethanol (1000 mL) and phenylhydrazine (102 g,1 eq) was added and reacted at 50℃for 16 hours. The reaction was monitored by TLC for completion. The reaction system was suction-filtered to give an off-white solid compound b, which was dried to about 170g (yield 91.8%) and used directly as a crude product in the next step without purification.
Synthesis of compound d1:
To a solution of compound b (20 g,1 eq) in absolute ethanol (200 mL), CAT (34.8 g,1.5 eq) was added, and the reaction was stirred at about 20 ℃ for 30 minutes, then compound c1 acrylonitrile (16.2 g,3 eq) was added, the reaction mixture was warmed to an internal temperature of 75 ℃ and reacted for 12 hours, and the completion of the reaction was monitored by TLC. The reaction system was distilled to dryness by rotary evaporation, and the obtained white solid was purified by column chromatography to obtain about 6.5g of compound d1 (yield 25.7%).
MS (ES-API) cacld.for C 16H13N3 found 248[ M+1] + (FIG. 1).
Alternatively, pyridine (1 g,0.1 eq) was added to a solution of compound b (25 g,1 eq) in acetonitrile (100 mL), cooled to about 5℃at an internal temperature, NCS (18.7 g,1.1 eq) was added, the reaction was continued at about 5℃for 1 hour, compound c1 acrylonitrile (20.25 g,3 eq) was added to the reaction system, the reaction was stirred for 30 minutes, TEA (18 g,1.4 eq) was added, and the reaction was monitored by TLC at 20℃for 6 hours. The reaction system was distilled to dryness by rotary evaporation, and the white solid compound d1 was obtained by column chromatography in an amount of about 20g (yield 63%).
MS (ES-API) cacld.for C 16H13N3 found 248[ M+1] + (FIG. 1)
Synthesis of compound e 1: to a solution of compound d1 (20 g,1 eq) in toluene (200 mL) was added DDQ (55 g,3 eq), and the reaction was reacted at an internal temperature of 100 ℃ for 12 hours, and the completion of the reaction was monitored by TLC. Purification by column chromatography gave compound e1 as a white solid (yield 49.3%) in an amount of about 10.5 g.
MS (ES-API) cacld.for C 16H11N3 found 246[ M+1] + (FIG. 2)
Synthesis of compound B1: to a solution of compound e1 (10 g,1 eq) in absolute ethanol (100 mL) and water (100 mL) was added potassium hydroxide (4.5 g,2 eq), and the reaction was reacted at an internal temperature of 20 ℃ for 12 hours, followed by TLC monitoring the completion of the reaction. Concentrating the system, adding 100ml of water, adjusting pH to 1-2 with hydrochloric acid, extracting with ethyl acetate, and directly stirring. Purification by column chromatography gave compound B1 as a white solid (yield 32.5%) in an amount of about 3.5 g.
MS (ES-API) cacld.for C 16H12N2O2 found 265.05[ M+1] + (FIG. 3);
1H NMR(400MHz,DMSO)δ13.45(s,1H),7.96–7.88(m,2H),7.55(s,1H),7.55–7.42(m,7H),7.42–7.33(m,1H).( FIG. 4
Synthesis of compound F1: to a solution of compound E (100 g,1 eq) in anhydrous methanol (500 mL) was added thionyl chloride dropwise, and after completion of the addition, the reaction system was reacted at 65 ℃ for 24 hours, and the completion of the reaction was monitored by TLC. The reaction system was distilled to dryness by spin evaporation, water (500 mL) was added, pH8-9 was adjusted with saturated sodium carbonate, suction filtration was performed, and the cake was washed with water 2 times to obtain an off-white solid compound F1, about 80g (yield 74.5%) after drying, without purification, and was directly used as a crude product for the next step.
Synthesis of compound G22: to a solution of compound F1 (50 g,1 eq) in absolute ethanol (500 mL) was added 80% hydrazine hydrate (31.4 g,3 eq), and the reaction system was reacted at 80 ℃ for 24 hours, and the completion of the reaction was monitored by TLC. Suction filtration gave compound G22 as an off-white solid (yield 74%).
MS (ES-API) cacld.for C 10H9N3O2 found 204.2[ M+1] + (FIG. 5);
1H NMR(400MHz,DMSO)δ11.96(s,1H),9.89(s,1H),7.74(dd,J＝8.2,1.4Hz,1H),7.54(ddd,J＝8.4,7.1,1.4Hz,1H),7.34(dd,J＝8.3,1.1Hz,1H),7.20(ddd,J＝8.2,7.1,1.2Hz,1H),6.45(s,1H),4.63(s,2H).( FIG. 6
Synthesis of compound PXG 22: to a solution of compound B1 (1G, 1 eq) in DMF (5 mL) was added potassium carbonate (1.3G, 2.5 eq) and HBTU (1.56G, 1.1 eq), followed by compound G22 (0.769G, 1 eq) and the reaction was monitored by TLC for completion at 20 ℃ for 24 hours. 50mL of water was added to the reaction system, followed by suction filtration, to obtain about 0.8g (yield 47%) of an off-white solid compound PXG 22.
MS (ES-API) cacld.for C 26H19N5O3 found 450.2[ M+1] + (FIG. 7);
1H NMR(400MHz,DMSO):δ12.03(s,1H),10.92(s,2H),7.92(d,J＝7.5Hz,2H),7.86(d,J＝8.1Hz,1H),7.66–7.34(m,10H),7.22(t,J＝7.5Hz,1H),6.57(s,1H).( FIG. 8)
Preparation example 2
Synthesis of compound b: the same as in preparation example 1.
Synthesis of compound d 2: pyridine (0.8 g,0.1 eq) was added to a solution of compound b (20 g,1 eq) in acetonitrile (100 mL), cooled to about 5℃at an internal temperature, NCS (15 g,1.1 eq) was added, the reaction was continued at about 5℃for 1 hour, methyl acrylate (26.33 g,3 eq) was added to the reaction system, the reaction was stirred for 30 minutes, TEA (14.4 g,1.4 eq) was added, and the reaction was monitored by TLC for completion at 20℃for 6 hours. The reaction system was distilled to dryness by rotary evaporation, and the white solid compound d2 was obtained by column chromatography in an amount of about 16.4g (yield 57%).
Synthesis of compound e 2: to a solution of compound d2 (20 g,1 eq) in toluene (200 mL) was added DDQ (46.27 g,3 eq), and the reaction was reacted at an internal temperature of 100 ℃ for 12 hours, and the completion of the reaction was monitored by TLC. Purification by column chromatography gave compound e2 as a white solid (yield 53%) in an amount of about 10.5 g.
MS (ES-API) cacld.for C 17H14N2O2 found 279.2[ M+1] + (FIG. 9);
1HNMR(400MHz,CDCl3 ) Delta 3.83 (s, 3H), 7.33-7.36 (m, 2H), 7.41-7.50 (m, 7H), 7.87 (m, 2H) (FIG. 10)
Synthesis of compound B1: to a solution of compound e2 (10 g,1 eq) in absolute ethanol (250 mL) and water (50 mL) was added potassium hydroxide (3 g,1.5 eq), and the reaction was reacted at an internal temperature of 20 ℃ for 12 hours, and the completion of the reaction was monitored by TLC. The reaction system was distilled to dryness by rotary evaporation, water (1000 mL) was added, pH2-3 was adjusted with concentrated hydrochloric acid, a white solid was precipitated, suction filtration was performed, and the cake was washed with water 2 times to obtain about 6.5g of a white solid compound B1 (yield 68%).
MS (ES-API) cacld.for C 16H12N2O2 found 265.05[ M+1] + (FIG. 3);
1H NMR(400MHz,DMSO)δ13.45(s,1H),7.96–7.88(m,2H),7.55(s,1H),7.55–7.42(m,7H),7.42–7.33(m,1H).( FIG. 4
The synthesis of compound G22 and PXG22 was the same as that of preparation example 1.
Preparation example 3
The synthesis of compound B, compound e3, compound B1, compound G22 and PXG22 was the same as that of preparation example 2, except that ethyl acrylate (30.57G, 3 eq) was added to the reaction system instead of methyl acrylate in the synthesis step of compound d 3.
Preparation example 4
Synthesis of compound b: the same as in preparation example 1.
Synthesis of compound d 2: to a solution of compound b (50 g,1 eq) in absolute ethanol (500 mL) was added CAT (87 g,1.5 eq), and the reaction was stirred at about 25 ℃ for 30 minutes, methyl acrylate (65.8 g,3 eq) was added dropwise, the dropwise addition was completed for about 30 minutes, the temperature was raised to 80 ℃ and the reaction was monitored by TLC for completion of the reaction for 12 hours. The reaction system was distilled to dryness by rotary evaporation, and the white solid compound d2 was obtained by column chromatography in an amount of about 55g (yield 77%).
The synthesis of compound e2, compound B1, compound G22, and PXG22 was the same as in preparation example 2.
Preparation example 5
The synthesis of compound B, compound e3, compound B1, compound G22 and PXG22 was the same as that of preparation example 2, except that ethyl acrylate (76.5G, 3 eq) was added dropwise in place of methyl acrylate in the synthesis step of compound d 3.
Preparation example 6
Synthesis of compound g 1: anhydrous ethanol (1000 mL) was added to the reaction flask, cooled to an internal temperature of about 10 ℃, sodium ethoxide (32.6 g,1.15 eq) was slowly added, the feeding rate was controlled by a large amount of heat release, compound f (50 g,1 eq) was added dropwise after 30 minutes of reaction under heat preservation, no significant heat release was observed, reaction was carried out for 30 minutes under heat preservation after the completion of the addition, diethyl oxalate (63.9 g,1.05 eq) was added to the reaction system in portions, and after the completion of the addition, the reaction solution was stirred at 15℃for 2 hours. The reaction was monitored by TLC for completion. The reaction system is filtered by suction, the filter cake is added into 500mL of ice water, the pH is regulated to 2-3 by concentrated hydrochloric acid, the mixture is stirred for 30 minutes and then filtered by suction, the off-white solid compound g1 is obtained, about 64g (yield 70%) is obtained after drying, and the purification is not needed, and is directly used as a crude product for the next step.
Synthesis of compound h 1: methoxy amine hydrochloride (24.27 g,1 eq) was dissolved in absolute ethanol (200 mL), cooled to about 0 ℃, a solution of compound g1 (64 g,1 eq) in absolute ethanol (100 mL) was added dropwise, the reaction system was reacted at 15 ℃ for 12 hours after about 1 hour, and the reaction was completed by TLC monitoring. Phenylhydrazine or phenylhydrazine hydrochloride is added into the reaction system to react for 4 hours at 15 ℃, and the reaction is heated to reflux for 6 hours, and the completion of the reaction is monitored by TLC. The reaction mixture was purified by column chromatography to give compound h 1.20 g (yield 23.5%) as a pale yellow solid.
MS (ES-API) cacld.for C 18H16N2O2 found 293.1[ M+1] + (FIG. 11);
1H NMR(400MHz,DMSO):δ7.98–7.91(m,2H),7.61(s,1H),7.52(tt,J＝8.2,4.7Hz,5H),7.46(t,J＝7.5Hz,2H),7.39(d,J＝7.3Hz,1H),4.22(q,J＝7.1Hz,2H),1.19(t,J＝7.1Hz,3H).( FIG. 12
Synthesis of compound B1: to a solution of compound h1 (22.6 g,1 eq) in absolute ethanol (250 mL) and water (50 mL) was added potassium hydroxide (6.49 g,1.5 eq), and the reaction solution was reacted at an internal temperature of 20 ℃ for 12 hours, and the completion of the reaction was monitored by TLC. The reaction system was distilled to dryness by spin evaporation, water (1000 mL) was added, pH2-3 was adjusted with concentrated hydrochloric acid, a white solid was precipitated, suction filtration was performed, and the cake was washed with water 2 times to obtain about 15g of a white solid compound B1 (yield 73.5%).
MS (ES-API) cacld.for C 16H12N2O2 found 265.05[ M+1] + (FIG. 3);
1H NMR(400MHz,DMSO)δ13.45(s,1H),7.96–7.88(m,2H),7.55(s,1H),7.55–7.42(m,7H),7.42–7.33(m,1H).( FIG. 4
The synthesis of compound G22 and PXG22 was the same as in preparation example 1.
Preparation example 7
Synthesis of Compound 5: synthetic route reference for compound 5 (j. Org. Chem.2010,75,3,984-987).
1H NMR(400MHz,CDCl3):δ7.95–7.88(m,1H),7.92–7.72(m,9H),7.58(dd,J＝4.6,2.6Hz,4H),7.57(d,J＝1.1Hz,3H),7.50(s,1H),7.49(s,1H),7.48(s,4H),7.47–7.22(m,21H),6.91(s,4H).( FIG. 13
Synthesis of compound B1: 5,8.74g of anhydrous tetrahydrofuran (100 ml) is added into a 250ml three-port bottle, the mixture is cooled to 78 ℃ below zero, 22.2ml of n-butyllithium (2.5 m) is added dropwise for about 30 minutes, after the mixture is reacted for 1 hour, 6g of dry ice is added into the system for 30 minutes, the ammonium chloride is added into the system for quenching reaction, the mixture is directly concentrated, 20ml of water is added, and the pH=2-3 of dilute hydrochloric acid is adjusted to separate out solid, thus obtaining the compound B1,4.5g and the yield is 67.5%.
The synthesis of compound G22 and PXG22 was the same as in preparation example 1.
Based on the above description of the invention, one skilled in the art could fully apply the invention, and all such modifications as are intended to be included within the scope of the present invention.
Claims (10)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210512409 | 2022-05-12 | ||
| CN2022105124096 | 2022-05-12 | ||
| PCT/CN2023/093367 WO2023217203A2 (en) | 2022-05-12 | 2023-05-11 | Preparation method for diphenyl pyrazole compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118660877A true CN118660877A (en) | 2024-09-17 |
Family
ID=88729732
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202380017535.7A Pending CN118660877A (en) | 2022-05-12 | 2023-05-11 | Preparation method of diphenylpyrazole compounds |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN118660877A (en) |
| WO (1) | WO2023217203A2 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2011002899A (en) * | 2008-09-18 | 2011-04-11 | Pfizer Ltd | Amide compounds useful in therapy. |
| CN103483313A (en) * | 2013-09-03 | 2014-01-01 | 南开大学 | Novel hydrazide derivatives as well as preparation method and application thereof |
| CN109721539B (en) * | 2017-10-27 | 2021-07-09 | 天津药物研究院有限公司 | Pyrazole amide derivative and preparation method and application thereof |
| CN114716409B (en) * | 2021-01-05 | 2024-01-12 | 西北农林科技大学 | Diphenyl pyrazole compounds and their preparation methods and uses |
-
2023
- 2023-05-11 CN CN202380017535.7A patent/CN118660877A/en active Pending
- 2023-05-11 WO PCT/CN2023/093367 patent/WO2023217203A2/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023217203A2 (en) | 2023-11-16 |
| WO2023217203A3 (en) | 2024-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101440257B1 (en) | Process for the manufacture of intermediates for preparing pharmaceutically active compounds | |
| CN103058993B (en) | Chlorantraniliprole preparation method | |
| CN103880830B (en) | Synthesis method of azilsartan | |
| WO2023174449A1 (en) | Method for preparing n-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide | |
| CN110305018B (en) | Preparation method of 3-bromo-2-fluoronitrobenzene | |
| CN118660877A (en) | Preparation method of diphenylpyrazole compounds | |
| CN115197261B (en) | Synthesis method of oxadiazine boron derivative | |
| CN107098902B (en) | A kind of synthetic method of pyrrolo[1,2-a]quinoline derivative | |
| CN110483387A (en) | A kind of method of one pot process nicotimine amide derivatives | |
| EP4121416A1 (en) | Improved synthesis of 6-aryl-4-aminopicolinates | |
| CN110483391B (en) | Five-component synthesis method of nicotinamide amide derivative | |
| CN112125843B (en) | A kind of preparation method of 3-hydroxymethyl-4-phenyl-3,4-dihydroquinolinone compound | |
| CN106188049B (en) | Dibenzo naphthyridones compound and its preparation method and application | |
| WO2021242807A1 (en) | Methods for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionate and hydrochloric acid salts thereof | |
| CN106316885B (en) | A kind of preparation method of 3- [5- (2- fluorophenyl) -1,2,4- oxadiazoles -3- base] benzoic acid | |
| CN117069711A (en) | Preparation method of benzoxazine-4-one derivative | |
| CN104558014B (en) | Chiral N-heterocyclic carbene precursor salt with 3,4-dihydroisoquinoline skeleton, synthetic method and application | |
| Li et al. | Synthesis of telmisartan via oxidative cyclization | |
| TW202214624A (en) | Process for preparing (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide enabled by a catalytic asymmetric hantzsch ester reduction | |
| CN100402508C (en) | Alkoxytetrazol-1-ylbenzaldehyde compound and process for producing the same | |
| CN112824379B (en) | A kind of (E)-3-aryl-3-(2-methylhydrazino) propionate compound and its preparation method and application | |
| WO2010000197A1 (en) | A method for preparing 5h-cyano-imido stilbene | |
| CN114436890B (en) | A kind of synthetic method of 3-amino-2-indenecarbonitrile compound | |
| CA2523190C (en) | Process for the preparation of nicotinaldehydes | |
| CN108794387B (en) | Synthesis method of N- [1- (5-bromopyridine-2-yl) -vinyl ] -acetamide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |