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WO2009088025A1 - Procédé de fabrication de phényltriazolinone - Google Patents

Procédé de fabrication de phényltriazolinone Download PDF

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Publication number
WO2009088025A1
WO2009088025A1 PCT/JP2009/050091 JP2009050091W WO2009088025A1 WO 2009088025 A1 WO2009088025 A1 WO 2009088025A1 JP 2009050091 W JP2009050091 W JP 2009050091W WO 2009088025 A1 WO2009088025 A1 WO 2009088025A1
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Prior art keywords
formula
mixture
formaldehyde
reaction
phenyltriazolinones
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PCT/JP2009/050091
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English (en)
Japanese (ja)
Inventor
Tsunehiro Kido
Hiroyuki Okita
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Hokko Chemical Industry Co Ltd
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Hokko Chemical Industry Co Ltd
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Priority to CN2009801020866A priority Critical patent/CN101910139B/zh
Priority to JP2009548939A priority patent/JP5167283B2/ja
Publication of WO2009088025A1 publication Critical patent/WO2009088025A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms

Definitions

  • the present invention relates to a process for producing phenyl-1,2,4-triazolin-5-ones, and more specifically, phenyl-1,2,4 which is a compound useful as a raw material or intermediate for the synthesis of pharmaceuticals and agricultural chemicals. -Relates to a process for the preparation of triazolin-5-ones.
  • Phenyl-1,2,4-triazolin-5-ones are useful compounds as synthetic raw materials or intermediates for pharmaceuticals and agricultural chemicals, and various production methods have been proposed in the past. .
  • Patent Document 1 describes that phenyltriazolinones are produced by the following reaction.
  • n is 0 or an integer of 1 to 5, and X may be the same or different, and represents a halogen atom, a lower alkyl group, a lower haloalkyl group, etc.
  • phenylhydrazone (A-3) must be isolated in the reaction step, and expensive diphenylphosphoryl azide (A-4) is used during production.
  • the production cost of triazolinone (A-5) increases.
  • Patent Document 1 is an industrially advantageous production method.
  • Patent Document 2 PCT International Publication No. WO02 / 12203 (Patent Document 2) Formula (B-1):
  • X represents a halogen atom or a lower alkyl group having 1 to 6 carbon atoms
  • n represents an integer of 0 to 5.
  • X may be the same as or different from each other.
  • the aryl hydrazone (B-3) is reacted with an alkali metal cyanate and an acid to produce an aryl triazolidinone ( A process for the production of aryltriazolinones having the step of forming B-2) and then reacting with an oxidizing agent is disclosed.
  • the formaldehyde-aryl hydrazone represented by the general formula (B-3) can be converted into a tetrazine derivative by coupling the hydrazone to each other by an acid, as described in “Liebigs Ann..Chem. -91pp "(Non-Patent Document 1).
  • the formaldehyde-aryl hydrazone represented by the general formula (B-3) is unstable in the presence of an acid.
  • Patent Document 3 corresponding to PCT International Publication WO91 / 3470 Formula (C-1):
  • n is an integer of 1 to 3
  • R represents a halogen atom, an alkyl group, a haloalkyl group or the like
  • X is independently a hydrogen atom or a halogen atom (Cl, Br, I).
  • An aryl triazolidinone represented by a lower alkyl group, etc. is treated with hypohalous acid or hypohalite.
  • n is an integer of 1 to 3
  • R represents a halogen atom, an alkyl group, a haloalkyl group or the like
  • X independently represents a hydrogen atom, a halogen atom, a lower alkyl group or the like.
  • JP 7-503253 A (Patent Document 4) corresponding to PCT International Publication WO 93/23382 discloses: Formula (D):
  • R is a lower alkyl group
  • X is independently halogen, lower alkyl, nitro, hydroxy, NHSO 2 R ′, —N (SO 2 R ′) 2 , —N (R ′)
  • R ′ is a lower alkyl
  • n is an integer of 0 to 3
  • An aryl hydrazine represented by -Ph-NH.NH 2 (Ph: phenyl, X, n is the same as in Patent Document 3) is converted into (i) a C1-C3 aldehyde, (ii) a cyanate and a weak organic acid, and (iii)
  • a process for the production of aryltriazolinones by sequential treatment with hypochlorous acid, its salts or halogens is disclosed.
  • Patent Documents 3 and 4 do not describe or suggest any phenyltriazolinones in which R is hydrogen (H) in the formula (C) or (D) and the production method thereof. Absent. WO98 / 38176 WO02 / 12203 Japanese Patent Publication No. 6-78322 JP 7-503253 JP Liebigs Ann. Chem., 635 (1960), 82-91pp
  • the present invention seeks to solve the problems associated with the prior art as described above, and uses simpler, safer, lower cost and higher purity phenyl triazolinones by using cheaper raw materials. It aims at providing the novel manufacturing method of phenyl triazolinone which can be manufactured with a yield.
  • the present inventors formed formaldehyde-phenylhydrazones (also referred to as phenylhydrazones) under a specific pH range, and further obtained formaldehyde- It was found that phenyltriazolinones can be produced in high yield and high purity without causing the above side reaction by reacting phenylhydrazones with cyanic acid to form phenyltriazolidinones.
  • the present inventors (1) Formaldehyde-phenylhydrazone which is a coexisting acid by handling formaldehyde-phenylhydrazone in a specific pH range in the reaction step of forming phenyltriazolidinones from anilines via formaldehyde-phenylhydrazones Alleviate and reduce the adverse effects on the product (by-product of tetrazine derivatives), (2) Further, it was found that phenyl triazolinones, which are target substances, can be produced in high yield and high purity by cycloaddition of cyanic acid to formaldehyde-phenylhydrazones.
  • the present inventors have found that inexpensive and versatile anilines can be selected as raw materials in the production of phenyltriazolinones, and if necessary, the risk of fire, explosion, etc. and the harmfulness to health It is possible to avoid storing chemical substances such as phenylhydrazine, which are of concern.
  • the present inventors can produce high-purity phenyltriazolinones (5) in a high yield at a low cost, safely and efficiently, and complete the present invention. It came.
  • Examples of the method for producing phenyltriazolinones according to the present invention include the following first production method, second production method, third production method, fourth production method, and fifth production method. Is preferred.
  • the first production method according to the present invention includes: General formula (1)
  • X represents a halogen atom or a lower alkyl group having 1 to 6 carbon atoms
  • n represents an integer of 0 to 5.
  • a plurality of X May be the same as or different from each other.
  • phenylhydrazines (2) may be separated from the reaction mixture containing phenylhydrazines by removing the aqueous layer as necessary by filtration, decantation or the like.
  • the crude product of formaldehyde-phenylhydrazone (3) may be separated from the reaction mixture containing formaldehyde-phenylhydrazone shown in the above by removing the aqueous layer by filtration, decantation or the like, if necessary.
  • X represents a halogen atom or a lower alkyl group having 1 to 6 carbon atoms
  • n represents an integer of 0 to 5.
  • n represents an integer of 2 or more
  • a plurality of X May be the same or different from each other.
  • the reaction is completed in a short time at a relatively low temperature, and high-purity phenyltriazolinones (5) can be obtained in a high yield.
  • the method for producing phenyltriazolinones (5) according to the present invention can be carried out continuously without isolating or purifying the intermediate produced in each step, so that it is efficient and safe with a small amount of energy.
  • the phenyl triazolinones (5) can be provided at low cost. Therefore, the method for producing phenyltriazolinones of the present invention is also suitable for large-scale industrial implementation.
  • phenyltriazolinones represented by the following formula (5) are produced through a series of reaction steps represented by the following ⁇ formula A>.
  • phenyltriazolinones represented by the following formula (5) are produced from the anilines (1) as a raw material through the following first to fourth steps.
  • anilines (1) are reacted with nitrites to form diazonium salts, and then reduced using sulfites or bisulfites. And then hydrolyzing to form phenylhydrazines (2).
  • This phenylhydrazines (2) is a crude product of the phenylhydrazines (2) obtained by removing the aqueous layer from the reaction mixture by filtration, decantation, etc. without isolation from the standpoint of improving yield purity.
  • the product or aqueous suspension may be used for the next step.
  • the anilines (1) are reacted with nitrites in the presence of an organic solvent to form a diazonium salt, and then reduced using sulfites or bisulfites,
  • the phenylhydrazines (2) may be formed by hydrolysis.
  • the obtained phenylhydrazines (2) and formaldehyde are reacted in the presence of a catalyst, preferably at a specific pH (pH 5 to 10) to form formaldehyde-phenylhydrazones (3).
  • a catalyst preferably at a specific pH (pH 5 to 10) to form formaldehyde-phenylhydrazones (3).
  • This formaldehyde-phenylhydrazone (3) is obtained by removing the aqueous layer from the reaction mixture by filtration, decantation, etc. without isolation from the viewpoint of improving the yield and purity.
  • the crude product or aqueous suspension of 3) may be used in the next step.
  • the phenyl triazolidinones (4) are reacted with an oxidizing agent selected from hypohalite and oxygen in the absence of a catalyst or in the presence of an oxidation catalyst, to give phenyl.
  • Triazolinones (5) are produced.
  • the phenyltriazolinones (5) may be purified by treating with alkali after completion of the reaction from the viewpoint of improving the purity.
  • the phenylhydrazines (2) may be isolated if necessary, and the formaldehyde-phenylhydrazones (3) (also referred to as phenylhydrazones) may be isolated if necessary. Also good.
  • the water layer may be removed at any of the first stage and the second stage.
  • X represents a halogen atom or a lower alkyl group having 1 to 6 carbon atoms
  • n represents an integer of 0 to 5.
  • n shows an integer greater than or equal to 2
  • several X may mutually be same or different.
  • halogen atom examples include chlorine, bromine, fluorine, and iodine atoms.
  • examples of the lower alkyl group include alkyl groups having 1 to 6 carbon atoms, which may be linear or branched.
  • alkyl groups having 1 to 6 carbon atoms which may be linear or branched.
  • the phenylhydrazines (2) may or may not be a salt.
  • ⁇ Synthesis of phenylhydrazine (2) (first stage)> First, in the “first stage”, the aniline represented by the general formula (1) is converted into a diazonium salt with nitrites, and the obtained diazonium salt is reduced with sulfites or hydrogen sulfites, It is preferable to obtain the corresponding phenylhydrazines represented by the general formula (2) by hydrolysis.
  • the raw material aniline (1) is reacted with hydrochloric acid to form a salt.
  • the starting aniline (1) is reacted with hydrochloric acid in the presence of an organic solvent to form a salt, then sodium nitrite is added to the hydrochloride to diazotize the diazotized product, and the pH of the diazotized product is 5.5.
  • Phenylhydrazines (2) can also be produced by adding to a solution of sodium sulfite adjusted to ⁇ 8.0, reducing, and further hydrolyzing.
  • the diazotization, reduction, and hydrolysis in the first stage can be carried out according to known methods.
  • preferred examples in the production method according to the present invention are as follows. Show.
  • the aniline (1) is first reacted with, for example, hydrochloric acid to form a salt, or the aniline (1) is reacted with hydrochloric acid in the presence of an organic solvent to form a salt.
  • hydrochloric acid is used excessively in this example.
  • sodium nitrite is added to diazotize.
  • the diazotized product is reduced by adding it to a solution of sodium sulfite whose pH is adjusted with, for example, sulfuric acid.
  • phenylhydrazine sulfonates are hydrolyzed to obtain phenylhydrazine salts.
  • the diazotization reaction for producing such a diazonium salt is usually carried out at a temperature range of ⁇ 25 ° C. to 25 ° C., preferably at a temperature of ⁇ 5 ° C. to 20 ° C., for 15 minutes to 2 hours, preferably 30 minutes to 1 Performed under normal pressure for hours.
  • Specific examples of the nitrites used as the diazotizing agent include sodium nitrite and potassium nitrite, and sodium nitrite is preferred.
  • the amount of nitrite used is usually 1.0 to 1.5 mol, preferably 1.0 to 1.2 mol, based on 1 mol of aniline (1). However, it is usually used as an aqueous solution.
  • a mineral acid is usually used, and examples thereof include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, and hydrochloric acid and sulfuric acid are preferable.
  • the amount of the mineral acid used is usually 1.0 to 10.0 mol, preferably 2.0 to 6.0 mol, based on 1 mol of aniline (1), and usually used as an aqueous solution. It is done.
  • an organic solvent that is not miscible with water is usually used.
  • the organic solvent include aliphatic hydrocarbons such as pentane, hexane, heptane, and petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, diethylene, and the like. And halogenated hydrocarbons such as chlorobenzene.
  • the amount of the organic solvent used is usually 0.1 times or more, preferably about 0.5 to about 5 times the weight of the aniline.
  • the kind and usage-amount of the mineral acid used in this case are the same as those described above.
  • the subsequent reduction reaction of the diazonium salt obtained by diazotizing the anilines (1) is usually in the temperature range of 0 ° C. to 80 ° C., preferably 10 ° C. to 70 ° C. for 1 to 24 hours.
  • the reaction is preferably performed under normal pressure for 2 to 12 hours.
  • Examples of the sulfites that are reducing agents used in such a reduction reaction include ammonium sulfite, sodium sulfite, and potassium sulfite. Among these, sodium sulfite is preferable in view of high versatility.
  • Examples of the bisulfites that are reducing agents used in such a reduction reaction include ammonium bisulfite, sodium bisulfite, and potassium bisulfite.
  • ammonium bisulfite sodium bisulfite
  • potassium bisulfite potassium bisulfite.
  • sodium bisulfite is highly versatile. It is preferable in terms of the thickness.
  • These may be used as they are, but are usually used as an aqueous solution.
  • the amount of these sulfites or hydrogen sulfites to be used is usually 2.0 mol or more, preferably 2.5 to 4.0 mol, per 1 mol of anilines (1).
  • the reaction is usually carried out by adding a diazonium salt obtained by diazotizing anilines (1) to a solution in which the pH of an aqueous solution of sulfites or bisulfites is usually adjusted to 5.5 to 8.0. .
  • the pH in the reaction system is usually adjusted to be in the range of 5.5 to 8.0, preferably in the range of 6.0 to 7.5.
  • the pH can be adjusted with acids such as hydrochloric acid and sulfuric acid, or an alkaline aqueous solution such as sodium hydroxide, potassium hydroxide and ammonia.
  • the hydrolysis performed following such a reduction reaction is usually in the temperature range of ⁇ 5 ° C. to 90 ° C., preferably 0 ° C. to 80 ° C., for 1 to 24 hours, preferably 3 to 10 hours. Done under normal pressure.
  • a mineral acid is usually used, and examples thereof include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc. Among them, hydrochloric acid and sulfuric acid are preferable.
  • the amount of these mineral acids used is usually 2.0 mol or more, preferably 5.0 to 30.0 mol per mol of aniline (1) (moles of hydrogen chloride in hydrochloric acid). Number).
  • the phenylhydrazines (2) can be used in the next second stage reaction as they are as the reaction mixture obtained by such hydrolysis, but are preferably used after neutralization with an alkali.
  • alkali examples include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like.
  • sodium hydroxide is preferable in view of high versatility.
  • the obtained phenylhydrazines (2) may be used in the next step as a mixture at this stage, and at this stage, any one of purification, isolation, and separation by removing the aqueous layer is performed. From the above, it may be used for the next step.
  • the phenylhydrazines (2) and formaldehyde are added in the presence of a catalyst.
  • the reaction is usually carried out in a solvent at pH 5 to 10, preferably pH 6 to 8, to produce the corresponding formaldehyde-phenylhydrazones (3).
  • the phenylhydrazines (2) obtained in the first step are purified and isolated, and formaldehyde is added to the reaction mixture without any treatment of separation by removing the aqueous layer.
  • the reaction can be carried out efficiently.
  • Such a second stage reaction is usually performed at a temperature ranging from ⁇ 10 ° C. to the “boiling point of the solvent used”, preferably at a temperature of 0 ° C. to + 40 ° C., usually for 10 minutes to 24 hours, preferably For 30 minutes to 5 hours under normal pressure.
  • phenylhydrazines (2) and formaldehyde can be theoretically used (reacted) in equimolar amounts.
  • 1 mol of phenylhydrazines (2) is 1. It is used in an amount of 0 to 2.0 mol, preferably 1.0 to 1.2 mol, and usually an aqueous formaldehyde solution containing such an amount of formaldehyde is used.
  • a catalyst used when making the said phenylhydrazine (2) and formaldehyde react specifically, it is organic, such as ammonium formate, sodium formate, potassium formate, ammonium acetate, sodium acetate, potassium acetate, etc.
  • Acid salts Organic acids such as formic acid and acetic acid; sulfonic acids such as p-toluenesulfonic acid; Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate; And amines such as triethylamine, pyridine, 1,8-diazabicyclo [5,4,0] unde-7-ene; and the like.
  • These catalysts are usually used in an amount of 0.01 to 20.0 mol%, preferably 0.1 to 10.0 mol%, based on the phenylhydrazines (2).
  • the phenylhydrazines (2) contained in the mixture The amount can be determined by analysis using high performance liquid chromatography or the like.
  • the pH in the reaction system is desirable to be in the range of usually 5 to 10, preferably 6 to 8.
  • the pH can be adjusted with, for example, acids such as formic acid, acetic acid, hydrochloric acid and sulfuric acid, or an alkaline aqueous solution such as sodium hydroxide and potassium hydroxide.
  • phenylhydrazines (2) and formaldehyde are reacted in the above pH range from the viewpoint that side reactions can be suppressed.
  • examples of the solvent include water; alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, methoxyethyl alcohol, n-butyl alcohol, sec-butyl alcohol, isobutyl alcohol, and t-butyl alcohol.
  • Ethers such as tetrahydrofuran and dioxane
  • nitriles such as acetonitrile and propionitrile
  • a mixed solvent of these and water can be used.
  • a mixed solvent of t-butyl alcohol and water is used. used.
  • the mixed solvent may be a two-type mixed system or more.
  • the organic solvent and water are usually in an amount of 1 to 500 parts by weight, preferably 10 to 200 parts by weight with respect to 100 parts by weight of the organic solvent. Used in parts.
  • solvents are used in an amount of, for example, 100 g to 4000 g per mole of phenylhydrazines (2).
  • the amount of the solvent is the third stage, which is the reaction stage of formaldehyde-phenylhydrazones (3) and cyanic acid, or the fourth stage, which is the reaction stage of the following phenyltriazolidinones (4) and an oxidizing agent. It can be appropriately changed according to the reactants and reaction conditions at each stage, and is not generally determined.
  • the obtained formaldehyde-phenylhydrazone (3) may be used in the next step as a mixture.
  • the next step after any treatment of purification, isolation, and separation by removing the aqueous layer is performed. You may use for the following process.
  • the formaldehyde-phenylhydrazone (3) and cyanic acid are reacted in a solvent, Phenyltriazolidinones (4) are formed.
  • Such a third stage reaction is carried out by subjecting the formaldehyde-phenylhydrazone (3) obtained in the second stage to cyanide without any purification, isolation or separation by aqueous layer removal. It can be carried out efficiently by reacting an acid.
  • the formaldehyde-phenylhydrazones (3) from the reaction mixture containing the formaldehyde-phenylhydrazones (3) from the reaction mixture obtained in the second step can be purified, isolated or separated by removing the aqueous layer. After such treatment, the reaction after the third stage can be performed.
  • the formaldehyde-phenylhydrazone (3) contained in the mixture is used.
  • the amount of can be determined by analysis using high performance liquid chromatography or the like.
  • This third stage reaction is usually carried out at a temperature of ⁇ 10 ° C. to + 60 ° C., preferably 0 ° C. to + 30 ° C., usually 1 to 24 hours, preferably 1 to 5 hours, under normal pressure.
  • the formaldehyde-phenylhydrazones (3) and cyanic acid may theoretically be used in equimolar amounts. Usually, however, cyanate is 1 mol per 1 mol of formaldehyde-phenylhydrazones (3). It is used in an amount of 0.0 to 3.0 mol, preferably 1.0 to 2.0 mol.
  • the same solvent as used in the second step is used from the viewpoint of handling efficiency.
  • the organic solvent and water are mixed with an organic solvent and water.
  • the organic solvent and water are mixed with 100 parts by weight of the organic solvent. Usually, it is used in an amount of 1 to 500 parts by weight, preferably 10 to 200 parts by weight.
  • the phenyltriazolidinones (4) obtained in the third stage may be purified and isolated as necessary, but are usually used in the fourth stage as a mixture.
  • an oxidizing agent selected from hypohalite and oxygen, and the above-mentioned phenyltriazolidinones (4) is reacted in a solvent in the absence of a catalyst or in the presence of an oxidation catalyst to form the desired phenyltriazolinones (5).
  • the phenyltriazolidinones (4) obtained in the third stage are usually used in the fourth stage as they are in a mixture containing the phenyltriazolidinones (4) without being isolated and purified. Is done. For this reason, such a reaction can be efficiently performed by adding an oxidizing agent to the reaction mixture containing the phenyltriazolidinones (4) obtained in the third stage.
  • the fourth stage reaction is usually carried out at a temperature of ⁇ 20 to 60 ° C., preferably 0 ° C. to 30 ° C., usually 1 to 24 hours, preferably 2 to 8 hours, under normal pressure.
  • hypohalite that is the oxidizing agent examples include sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, potassium hypobromite, and the like.
  • sodium hypochlorite is preferable from the viewpoint of versatility.
  • hypohalite can be used in the presence of an oxidation catalyst, if necessary.
  • oxidation catalyst examples include ferrous chloride, ferric chloride, ferrous bromide, ferric bromide, ferrous sulfate, ferric sulfate, cobalt chloride, cobalt bromide, Iron group salts such as cobalt sulfate, cobalt nitrate, cobalt acetate, nickel chloride; Iron group complexes such as iron (III) acetylacetonate, cobalt (II) acetylacetonate, cobalt (II) bis (salicylidene) ethylenediamine, hexaamminenickel (II) chloride; Platinum group such as platinum and palladium; Platinum group salts such as palladium chloride, palladium acetate, platinum oxide; Platinum group complexes such as chloro (triphenylphosphine) rhodium, dichlorobis (triphenylphosphine) ruthenium; Copper salts such as copper (I) chloride,
  • These catalysts may be used alone or in combination of two or more.
  • the above phenyltriazolidinones (4) and the oxidizing agent may theoretically be used in equimolar amounts, but usually the amount is 1 mol of phenyltriazolidinones (4).
  • the oxidizing agent is usually used in an amount of 1.0 to 1.4 mol, preferably 1.0 to 1.1 mol.
  • an aqueous solution of sodium hypochlorite having a concentration of 5 to 25% (weight / weight), preferably 5 to 15% can be used.
  • the oxidation catalyst used as necessary is usually 0.01 to 10.0 mol%, preferably 0.1 to 1.0 mol%, relative to the phenyltriazolidinone (4). used.
  • the amount of the phenyltriazolidinones (4) in the mixture is It can be determined by analysis using high performance liquid chromatography or the like.
  • the same solvents as those used in the second and third stages are used, and even in the case of a mixed solvent of an organic solvent and water, they are used at the same mixing ratio.
  • a solvent is used in an amount of 100 to 6000 g per 1 mol of phenyltriazolidinones (4).
  • reaction solution is preferably stirred at least gently in each of the first to fourth steps.
  • the organic solvent in the mixed solvent used (a mixed solvent of an organic solvent and water) can be reused by being distilled off from the reaction mixture and recovered using a distillation apparatus or the like.
  • the target phenyltriazolinones (5) can be isolated by ordinary extraction / separation, or after the organic solvent is distilled off, the target (5) is precipitated in water and filtered. Is done.
  • the target phenyltriazolinones (5) are dissolved in an aqueous solution of a base such as sodium hydroxide to form a salt, which is washed with the organic solvent. .
  • a mineral acid such as hydrochloric acid is added to the washed solution of the phenyltriazolinone (5) salt to neutralize the phenyltriazolinone (5) salt-containing solution. Phenyltriazolinones (5) are precipitated.
  • High-purity phenyltriazolinones (5) can be obtained by filtering and washing the precipitated crystals.
  • alkali is added to the reaction mixture to form an alkali salt of the target phenyltriazolinones (5) and to perform an alkali treatment to decompose the reaction by-product.
  • a mixed solvent of an organic solvent and water is used as a reaction solvent, the organic solvent is distilled off, and then an aqueous mixture containing an alkali salt of the target phenyltriazolinones (5) and impurities. Is washed with an organic solvent to remove impurities from the aqueous mixture without loss of the desired product.
  • a mineral acid such as hydrochloric acid is added to an alkali salt-containing aqueous solution of phenyltriazolinones (5) washed with an organic solvent to neutralize the alkali salt-containing aqueous solution of phenyltriazolinones (5).
  • the target phenyltriazolinones (5) are precipitated.
  • High-purity phenyltriazolinones (5) can be obtained by filtering and washing the precipitated crystals.
  • Such an alkali treatment is usually carried out at a temperature of 0 ° C. to 100 ° C., preferably 20 ° C. to 90 ° C., usually for 1 to 24 hours, preferably 1 to 12 hours under normal pressure.
  • alkali used examples include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like.
  • sodium hydroxide is preferable in view of high versatility.
  • Such an alkali is usually used in an amount of 1.2 to 4.0 mol, preferably 2.0 to 2.5 mol, per mol of phenyltriazolinones (5).
  • organic solvent used for the washing examples include aliphatic hydrocarbons such as pentane, hexane, heptane and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, diisopropyl ether, t- And ethers such as butyl methyl ether; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, and the like.
  • aliphatic hydrocarbons such as pentane, hexane, heptane and petroleum ether
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • diethyl ether diisopropyl ether
  • t- And ethers such as butyl methyl ether
  • halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloro
  • the reaction by-product is decomposed by alkali. Therefore, the target mixture is lost by washing the aqueous mixture after the alkali treatment with an organic solvent. Impurities can be removed without accompanying, and high-purity phenyltriazolinones can be obtained in high yield.
  • the obtained target product may be further purified using means such as washing with an organic solvent, column chromatography, recrystallization and the like, if necessary.
  • the phenyltriazolinones (5) thus obtained are suitably used as agricultural chemicals, raw materials for producing pharmaceuticals, and the like.
  • the intermediate product is a phenylhydrazine represented by the above general formula (2), or the intermediate product is a formaldehyde-phenylhydrazone represented by the above general formula (3), and an intermediate product.
  • the whole process can be carried out without treating the phenyltriazolidinones represented by the above general formula (4), which are body products, by any of purification, isolation, and separation by aqueous layer removal.
  • the intermediate product is a phenylhydrazine represented by the general formula (2)
  • the intermediate product is a formaldehyde-phenylhydrazone represented by the general formula (3), or an intermediate product.
  • phenylhydrazines the formaldehyde-phenylhydrazones, and the phenyltriazolidinones may be treated by any of the above methods, and two kinds may be treated by any of the above methods.
  • all three types may be processed by any one of the methods described above.
  • the solvent does not adversely influence the reaction, and preferably anilines (1), phenylhydrazines (2), formaldehyde-phenylhydrazones (3) and phenyltriazolidinones (4) Solvents that can be satisfactorily dissolved in any of the above are preferable in the reaction operation, but the above-mentioned solvents that can dissolve or mix at least partly any of these are used.
  • a high purity target compound in a short time under a reaction condition as described above and in a short time by passing through a series of reactions consisting of the first to fourth stages.
  • Phenyltriazolinones (5) can be obtained in high yield.
  • Example 1 ⁇ Production of 1- (2,4-dichlorophenyl) -1,2,4-triazol-5-one> A 1 L 4-neck flask equipped with a stirrer, thermometer, and Dimroth condenser is used as a reaction vessel. Add 330 g of 10% hydrochloric acid and 48.6 g of 2,4-dichloroaniline (purity> 99%), and stir at 30 ° C. for 15 minutes. did.
  • the resulting mixture was cooled to ⁇ 5 ° C., and 63 g of 35% sodium nitrite aqueous solution was added dropwise over 30 minutes, followed by stirring at ⁇ 3 to 0 ° C. for 1 hour to obtain a diazonium salt solution.
  • a reaction vessel was prepared by attaching a stirrer, a thermometer, and a Dimroth condenser to a 2 L four-necked flask separate from the above vessel.
  • 97.4 g of sodium sulfite (purity 97%) was dissolved in 350 g of water, and 95% sulfuric acid was added to adjust the pH to 7.2.
  • the solution was cooled to 10 ° C., and the diazonium salt solution prepared earlier was quickly added.
  • the obtained mixture was heated to 20 ° C. over 30 minutes, then heated to 65 ° C. and stirred at the same temperature for 2 hours to reduce the diazonium salt, and a mixture containing 2,4-dichlorophenylhydrazine sulfonate was obtained. Obtained.
  • the separated aqueous layer was placed in a reaction vessel equipped with a stirrer, a thermometer, and a Dimroth condenser in a 3 L four-necked flask. Next, 313 g of 35% hydrochloric acid was added dropwise at 20 ° C. over 20 minutes. The mixture was stirred at 0 ° C. for 3 hours to hydrolyze 2,4-dichlorophenylhydrazine sulfonate to obtain a mixture containing hydrochloride of 2,4-dichlorophenylhydrazine.
  • reaction mixture was cooled to 10 ° C., 19.4 g of cyanic acid was added, and the mixture was stirred at the same temperature for 4 hours to obtain a mixture containing 2,4-dichlorophenyltriazolidinone.
  • the resulting organic layer (tertiary butanol layer) is subjected to 11% 162.5 g of sodium chlorite aqueous solution was added dropwise over 30 minutes.
  • Sodium hydroxide 24g was added to the aqueous layer after the tertiary butanol was distilled off to form the salt of the title target substance and dissolved in the aqueous layer, and then 100g of toluene was added and stirred to wash the aqueous layer. The reaction by-product was removed from the aqueous layer, and the mixture was allowed to stand for liquid separation.
  • the aqueous layer obtained by the liquid separation was cooled to 15 ° C., and 94 g of 35% hydrochloric acid was added dropwise over 15 minutes to neutralize the aqueous layer to release the title target substance and to precipitate crystals was collected by filtration and washed with 200 g of water.
  • the resulting mixture was cooled to ⁇ 5 ° C., and 63 g of 35% sodium nitrite aqueous solution was added dropwise over 30 minutes, followed by stirring at ⁇ 3 to 0 ° C. for 1 hour to obtain a diazonium salt solution.
  • a reaction vessel was prepared by attaching a stirrer, a thermometer, and a Dimroth condenser to a 2 L four-necked flask separate from the above vessel.
  • 97.4 g of sodium sulfite (purity 97%) was dissolved in 350 g of water, and 95% sulfuric acid was added to adjust the pH to 7.2.
  • the solution was cooled to 10 ° C., and the diazonium salt solution prepared earlier was quickly added.
  • the obtained mixture was heated to 20 ° C. over 30 minutes, then heated to 65 ° C. and stirred at the same temperature for 2 hours to reduce the diazonium salt, and a mixture containing 2,4-dichlorophenylhydrazine sulfonate was obtained. Obtained.
  • the aqueous layer recovered by liquid separation was placed in a reaction vessel equipped with a stirrer, thermometer, and Dimroth condenser in a 3 L four-necked flask, and 313 g of 35% hydrochloric acid was added dropwise at 20 ° C. over 20 minutes.
  • 2,4-dichlorophenylhydrazine sulfonate was hydrolyzed to obtain a mixture containing hydrochloride of 2,4-dichlorophenylhydrazine.
  • reaction mixture was cooled to 10 ° C., 19.4 g of cyanic acid was added, stirred at the same temperature for 4 hours, and the aqueous layer was removed from the separated two layers (organic layer and aqueous layer). The formaldehyde and salts of the reaction were removed.
  • the separated aqueous layer was cooled to 15 ° C., and 94 g of 35% hydrochloric acid was added dropwise over 15 minutes to neutralize the aqueous layer to release the title target substance, and the precipitated crystals were collected by filtration. Washed with water.
  • the resulting mixture was cooled to ⁇ 5 ° C., and 63 g of 35% sodium nitrite aqueous solution was added dropwise over 30 minutes, followed by stirring at ⁇ 3 to 0 ° C. for 1 hour to obtain a diazonium salt solution.
  • a reaction vessel was prepared by attaching a stirrer, a thermometer, and a Dimroth condenser to a 2 L four-necked flask separate from the above vessel.
  • 97.4 g of sodium sulfite (purity 97%) was dissolved in 350 g of water, and 95% sulfuric acid was added to adjust the pH to 7.2.
  • the solution was cooled to 10 ° C., and the diazonium salt solution prepared earlier was quickly added.
  • the obtained mixture was heated to 20 ° C. over 30 minutes, then heated to 65 ° C. and stirred at the same temperature for 2 hours to reduce the diazonium salt, and a mixture containing 2,4-dichlorophenylhydrazine sulfonate was obtained. Obtained.
  • 200 g of toluene was added, and the mixture was stirred at 65 ° C. for 15 minutes to wash the aqueous layer. Unreacted raw materials and reaction byproducts were removed from the aqueous layer, and then the mixture was allowed to stand for separation.
  • the separated aqueous layer was placed in a 3 L four-necked flask in a reaction vessel equipped with a stirrer, thermometer and Dimroth condenser, and 313 g of 35% hydrochloric acid was added dropwise at 20 ° C. over 20 minutes.
  • the mixture was stirred for a period of time to hydrolyze the 2,4-dichlorophenylhydrazine sulfonate obtained previously to obtain a mixture containing hydrochloride of 2,4-dichlorophenylhydrazine.
  • the mixture was cooled to 10 ° C., and 300 g of a 50% aqueous sodium hydroxide solution was slowly added to precipitate 2,4-dichlorophenylhydrazine to obtain an aqueous 2,4-dichlorophenylhydrazine suspension.
  • the aqueous layer recovered by liquid separation is cooled to 15 ° C., and 94 g of 35% hydrochloric acid is added dropwise over 15 minutes to neutralize the aqueous layer to release the title target substance, and the precipitated crystals are filtered. Collected and washed with 200 g of water.
  • the resulting mixture was cooled to ⁇ 5 ° C., and 63 g of 35% sodium nitrite aqueous solution was added dropwise over 30 minutes, followed by stirring at ⁇ 3 to 0 ° C. for 1 hour to obtain a diazonium salt solution.
  • a reaction vessel was prepared by attaching a stirrer, a thermometer, and a Dimroth condenser to a 2 L four-necked flask separate from the above vessel.
  • 97.4 g of sodium sulfite (purity 97%) was dissolved in 350 g of water, and 95% sulfuric acid was added to adjust the pH to 7.2.
  • the solution was cooled to 10 ° C., and the diazonium salt solution prepared earlier was quickly added.
  • the obtained mixture was heated to 20 ° C. over 30 minutes and then heated to 65 ° C. and stirred at the same temperature for 2 hours to reduce the diazonium salt to obtain a mixture containing phenylhydrazine sulfonate.
  • the separated aqueous layer was placed in a reaction vessel equipped with a stirrer, a thermometer, and a Dimroth condenser in a 3 L four-necked flask. Next, 313 g of 35% hydrochloric acid was added dropwise at 20 ° C. over 20 minutes. The mixture was stirred at 0 ° C. for 3 hours to hydrolyze the previously obtained phenylhydrazine sulfonate to obtain a mixture containing phenylhydrazine hydrochloride.
  • the mixture was cooled to 10 ° C., 300 g of 50% aqueous sodium hydroxide was slowly added to precipitate phenylhydrazine, and then the aqueous layer was removed by filtration to recover the crude phenylhydrazine product. It was.
  • the obtained phenylhydrazine crude product was 34 g (purity 90%).
  • reaction mixture was cooled to 10 ° C., 19.4 g of cyanic acid was added, and the mixture was stirred at the same temperature for 4 hours to obtain a mixture containing phenyltriazolidinone.
  • Sodium hydroxide 24g was added to the aqueous layer after the tertiary butanol was distilled off to form the salt of the title target substance and dissolved in the aqueous layer, and then 100g of toluene was added and stirred to wash the aqueous layer. Then, the reaction by-product was removed from the aqueous layer, and then allowed to stand for liquid separation.
  • the aqueous layer obtained by liquid separation was cooled to 15 ° C., and 94 g of 35% hydrochloric acid was added dropwise over 15 minutes to neutralize the aqueous layer to release the title target substance, and the precipitated crystals were filtered. And washed with 150 g of water.
  • the resulting mixture was cooled to ⁇ 5 ° C., and 63 g of 35% sodium nitrite aqueous solution was added dropwise over 30 minutes, followed by stirring at ⁇ 3 to 0 ° C. for 1 hour to obtain a diazonium salt solution.
  • a 5 L four-necked flask is equipped with a stirrer, thermometer and Dimroth condenser to make a reaction vessel.
  • the solution was cooled to 10 ° C., and the diazonium salt solution prepared earlier was quickly added.
  • the mixture was heated to 20 ° C. over 30 minutes and then heated to 65 ° C. and stirred at the same temperature for 2 hours to reduce the diazonium salt to obtain a reaction mixture containing 2,3-dimethylphenylhydrazine sulfonate. It was.
  • the obtained mixture was cooled to 10 ° C., and 300 g of 50% aqueous sodium hydroxide solution was slowly added to precipitate 2,3-dimethylphenylhydrazine to obtain an aqueous 2,3-dimethylphenylhydrazine suspension.
  • reaction mixture was cooled to 10 ° C., 19.4 g of cyanic acid was added, and the mixture was stirred at the same temperature for 4 hours to obtain a mixture containing 2,3-dimethylphenyltriazolidinone.
  • the resulting organic layer (tertiary butanol layer) is subjected to 11% 162.5 g of sodium chlorite aqueous solution was added dropwise over 30 minutes.
  • Sodium hydroxide 24g was added to the aqueous layer after the tertiary butanol was distilled off to form the salt of the title target substance and dissolved in the aqueous layer, and then 100g of toluene was added and stirred to wash the aqueous layer. And then left to separate.
  • the separated aqueous layer was cooled to 15 ° C., and 94 g of 35% hydrochloric acid was added dropwise over 15 minutes to neutralize the aqueous layer to release the title target substance.
  • the precipitated crystals were collected by filtration, and 150 g Washed with water.
  • the obtained mixture was cooled to ⁇ 5 ° C., 452 g of 35% aqueous sodium nitrite solution was added dropwise over 30 minutes, and then stirred at ⁇ 3 to 0 ° C. for 1 hour to obtain a diazonium salt solution.
  • a reaction vessel was prepared by attaching a stirrer, a thermometer, and a Dimroth condenser to a 10 L four-necked flask separate from the above vessel.
  • 698.9 g of sodium sulfite (purity 97%) was dissolved in 2796 g of water, and 22.2 g of 95% sulfuric acid was added to adjust the pH to 7.2.
  • the solution was cooled to 10 ° C., and the diazonium salt solution prepared above was added over 5 minutes.
  • the obtained mixture was heated to 20 ° C. over 30 minutes, then heated to 65 ° C. and stirred at the same temperature for 2 hours to reduce the diazonium salt, and a mixture containing 2,4-dichlorophenylhydrazine sulfonate was obtained. Obtained.
  • the obtained mixture was allowed to stand and the toluene layer and the aqueous layer were separated to remove unreacted raw materials and reaction byproducts contained in the toluene layer.
  • the separated aqueous layer was put into a reaction vessel equipped with a stirrer, a thermometer, and a Dimroth condenser in a 10 L capacity four-necked flask, and then 2241 g of 35% hydrochloric acid was added dropwise at 20 ° C. over 30 minutes.
  • the mixture was stirred at 0 ° C. for 3 hours to hydrolyze 2,4-dichlorophenylhydrazine sulfonate to obtain a mixture containing hydrochloride of 2,4-dichlorophenylhydrazine.
  • the obtained 2,4-dichlorophenylhydrazine crude product was 900 g. (Purity 98%).
  • reaction mixture was cooled to 10 ° C., 130.1 g of cyanic acid was added, and the mixture was stirred at the same temperature for 4 hours to obtain a mixture containing 2,4-dichlorophenyltriazolidinone.
  • the aqueous layer containing the sodium salt of the title target compound obtained by liquid separation was cooled to 20 ° C., and 1660 g of 18% hydrochloric acid was added dropwise over 60 minutes to neutralize the water layer and The compound was released and the precipitated crystals were collected by filtration and washed with 2000 g of water.
  • the obtained mixture was cooled to ⁇ 5 ° C., 452 g of 35% aqueous sodium nitrite solution was added dropwise over 30 minutes, and then stirred at ⁇ 3 to 0 ° C. for 1 hour to obtain a diazonium salt solution.
  • a reaction vessel was prepared by attaching a stirrer, a thermometer, and a Dimroth condenser to a 10 L four-necked flask separate from the above vessel.
  • 698.9 g of sodium sulfite (purity 97%) was dissolved in 2796 g of water, and 22.2 g of 95% sulfuric acid was added to adjust the pH to 7.2.
  • the solution was cooled to 10 ° C., and the diazonium salt solution prepared above was added over 5 minutes.
  • the obtained mixture was heated to 20 ° C. over 30 minutes, then heated to 65 ° C. and stirred at the same temperature for 2 hours to reduce the diazonium salt, and a mixture containing 2,4-dichlorophenylhydrazine sulfonate was obtained. Obtained.
  • the obtained mixture was allowed to stand and the toluene layer and the aqueous layer were separated to remove unreacted raw materials and reaction byproducts contained in the toluene layer.
  • the separated aqueous layer was put into a reaction vessel equipped with a stirrer, a thermometer, and a Dimroth condenser in a 10 L capacity four-necked flask, and then 2241 g of 35% hydrochloric acid was added dropwise at 20 ° C. over 30 minutes.
  • the mixture was stirred at 0 ° C. for 3 hours to hydrolyze 2,4-dichlorophenylhydrazine sulfonate to obtain a mixture containing hydrochloride of 2,4-dichlorophenylhydrazine.
  • the mixture was cooled to 10 ° C., and 2241 g of 48% aqueous sodium hydroxide solution was added dropwise over 30 minutes to precipitate 2,4-dichlorophenylhydrazine to obtain an aqueous 2,4-dichlorophenylhydrazine suspension.
  • the aqueous layer containing the sodium salt of the title target compound obtained by liquid separation was cooled to 20 ° C., and 1660 g of 18% hydrochloric acid was added dropwise over 60 minutes to neutralize the water layer and The compound was released and the precipitated crystals were collected by filtration and washed with 2000 g of water.
  • reaction mixture is brought to 10 ° C. in an ice-water bath, 127 g of 90% sodium cyanate suspended in 500 g of water is added at once, and 80 g of water is used to wash away sodium cyanate adhering to the container, and washing is performed.
  • the liquid was poured into the flask.
  • the addition of sodium cyanate increased the temperature of the reaction mixture by 15 ° C.
  • the precipitated solid was collected by filtration and washed with 500 g of water.
  • the method for producing phenyl triazolinones according to the present invention it is possible to produce high-purity phenyl triazolinones in a simpler, safer, lower cost and higher purity by using cheaper raw materials. . Therefore, the method for producing phenyltriazolinone of the present invention is also suitable for large-scale industrial implementation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention porte sur un nouveau procédé de fabrication de phényltriazolinone qui permet de produire une phényltriazolinone extrêmement pure avec un rendement élevé d'une manière plus simple et plus sûre et à un plus faible coût à l'aide d'une matière première meilleur marché. De façon précise, l'invention porte sur un procédé de fabrication d'une phényltriazolinone, qui consiste : à faire réagir une aniline avec un sel nitrite pour produire un sel de diazonium ; à réduire le sel de diazonium par un sel sulfite ou un sel bisulfite ; à hydrolyser le produit réduit pour produire une phénylhydrazine ; à faire réagir la phénylhydrazine avec du formaldéhyde en présence d'un catalyseur à pH de 5 à 10 pour produire une formaldéhyde-phénylhydrazone ; à faire réagir la formaldéhyde-phénylhydrazone (3) avec de l'acide cyanique pour produire une phényltriazolidinone, et à faire réagir la phényltriazolidinone (4) avec un agent oxydant choisi parmi un sel d'acide hypohalogéneux et de l'oxygène en l'absence de tout catalyseur ou en présence d'un catalyseur d'oxydation.
PCT/JP2009/050091 2008-01-10 2009-01-07 Procédé de fabrication de phényltriazolinone Ceased WO2009088025A1 (fr)

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JP2012246274A (ja) * 2011-05-31 2012-12-13 Sumitomo Chemical Co Ltd フェニルヒドラジン類の製造方法
JP2013502387A (ja) * 2009-08-20 2013-01-24 バイエル・クロップサイエンス・アーゲー 殺ダニ剤および殺虫剤としての３−トリアゾリルフェニル置換スルフィド誘導体
JP2013502386A (ja) * 2009-08-20 2013-01-24 バイエル・クロップサイエンス・アーゲー 殺ダニ剤及び殺虫剤として使用するための３−［１−（３−ハロアルキル）−トリアゾリル］−フェニル−スルフィド誘導体
WO2014202510A1 (fr) 2013-06-20 2014-12-24 Bayer Cropscience Ag Dérivés d'arylsulfure et d'arylsulfoxyde utilisés comme acaricides et insecticides
CN113402472A (zh) * 2021-06-16 2021-09-17 山东潍坊润丰化工股份有限公司 一种甲磺草胺中间体的合成方法
JP2022502415A (ja) * 2018-09-26 2022-01-11 メレオ バイオファーマ １ リミテッド ヒドラジン化合物の調製のための合成方法
US11649213B2 (en) 2018-09-26 2023-05-16 Mereo Biopharma 1 Limited Synthetic method for the preparation of a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol compound

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JP2012246276A (ja) * 2011-05-31 2012-12-13 Sumitomo Chemical Co Ltd フェニルヒドラジン類の製造方法
CN104672157B (zh) * 2015-02-12 2017-06-27 山东潍坊润丰化工股份有限公司 一种芳基三唑啉酮的制备方法
CN105348140A (zh) * 2015-12-18 2016-02-24 武汉武药制药有限公司 一种盐酸苯肼的合成方法
CN115850123B (zh) * 2022-11-16 2024-04-19 山东潍坊润丰化工股份有限公司 一种2,4-二氯苯胺/肼的制备方法

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Publication number Priority date Publication date Assignee Title
JP2013502387A (ja) * 2009-08-20 2013-01-24 バイエル・クロップサイエンス・アーゲー 殺ダニ剤および殺虫剤としての３−トリアゾリルフェニル置換スルフィド誘導体
JP2013502386A (ja) * 2009-08-20 2013-01-24 バイエル・クロップサイエンス・アーゲー 殺ダニ剤及び殺虫剤として使用するための３−［１−（３−ハロアルキル）−トリアゾリル］−フェニル−スルフィド誘導体
JP2012246274A (ja) * 2011-05-31 2012-12-13 Sumitomo Chemical Co Ltd フェニルヒドラジン類の製造方法
WO2014202510A1 (fr) 2013-06-20 2014-12-24 Bayer Cropscience Ag Dérivés d'arylsulfure et d'arylsulfoxyde utilisés comme acaricides et insecticides
JP2022502415A (ja) * 2018-09-26 2022-01-11 メレオ バイオファーマ １ リミテッド ヒドラジン化合物の調製のための合成方法
US11649213B2 (en) 2018-09-26 2023-05-16 Mereo Biopharma 1 Limited Synthetic method for the preparation of a 3-[5-amino-4-(3-cyanobenzoyl)-pyrazol compound
CN113402472A (zh) * 2021-06-16 2021-09-17 山东潍坊润丰化工股份有限公司 一种甲磺草胺中间体的合成方法
CN113402472B (zh) * 2021-06-16 2022-09-13 山东潍坊润丰化工股份有限公司 一种甲磺草胺中间体的合成方法

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