CN105646356A - Preparation method of sulfophenyl pyrazolone and intermediate thereof - Google Patents
Preparation method of sulfophenyl pyrazolone and intermediate thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of sulfophenyl pyrazolone. The method consists of: taking a compound (I) as the raw material, in the presence of alkali, subjecting the compound (I) and a compound (II) to substitution reaction, then conducting oxidation by an oxidizing agent to obtain a compound (III), esterfying the compound (III) to obtain a compound (IV), subjecting the compound (IV) to thionation to obtain a compound (VI), conducting oxidation and hydrolysis (or hydrolysis, oxidation) on the compound (VI) to obtain a compound (VII), subjecting the compound (VII) to acyl chlorination, subjecting the obtained acyl chloride (VIII) and 1, 3-dimethyl-5-hydroxypyrazole to esterification reaction so as to obtain a compound (IX), and finally carrying out rearrangement on the compound (IX) to obtain a compound (X). The method provided by the invention has the advantages of cheap and easily available raw materials, high reaction conversion rate, few three wastes, and is beneficial to industrial production.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to the preparation of a kind of sulfophenyl pyrazolone and intermediate thereofMethod.
Background technology
Sulfophenyl pyrazolone is the important organic compound of a class, is widely used in medicine and pesticide field.For example sulphonyl grass pyrazoles is a kind of novel benzoylpyrazole class herbicide that Beyer Co., Ltd developed in 1999,Went on the market in the U.S., Canada and Australia in 2008. This herbicide broad weed-killing spectrum, can separate wellCertainly the problem of wheatland resistant weed, safe, is with a wide range of applications and market prospects.
At present, the method for preparing sulphonyl grass pyrazoles adopts taking 4-trifluoromethyl-2-thiamphenicol benzoic acid as raw material,Through chloride, the acyl chlorides obtaining carries out base catalyzed reactions with 1,3-dimethyl-5-hydroxypyrazoles or pyrazolone againObtain (US4261729 and CN1187335). Its raw material 4-trifluoromethyl-2-thiamphenicol benzoic acid is to pass through oxygenChange 4-trifluoromethyl-2-methylthio-benzoic acid and obtain (US5804532 and EP0487357). Compound 4-trifluoroThe preparation of methyl-2-methylthio-benzoic acid mainly contains following 3 kinds of methods:
Method one: CN1143846 discloses taking the bromo-3-nitro-trifluoromethyl toluene of 4-as raw material, through cyano group and first sulphurBase replaces, then hydrolysis obtains 4-trifluoromethyl-2-methylthio-benzoic acid, is expressed as follows with reaction equation:
The method need to be used highly toxic cyano group reagent, and technological operation security is low, and generation contains in a large numberCyanogen waste water, is not suitable for suitability for industrialized production.
Method two: EP780371 discloses with 3,4-, bis-chlorobenzotrifluorides for raw material, first at CO2For electrolysisUnder the condition of matter, carry out electrode reaction, obtain 4-trifluoromethyl-2-chlorobenzoic acid, then carry out methyl mercapto replacement,Obtain 4-trifluoromethyl-2-methylthio-benzoic acid, be expressed as follows with reaction equation:
The organic electrolysis reaction of the method must have certain device and equipment, and scale effect is less, andProduct is often not easily separated, and energy consumption is high, reacts unstable, is unfavorable for industrial production.
Method three: CN1149582 discloses taking the bromo-3-5 amido benzotrifluoride of 4-as raw material, through diazotising, firstSulfenyl replaces, and the bromo-3-methyl mercapto of the 4-benzotrifluoride obtaining is again under the effect of n-BuLi, with carbon dioxideReaction obtains 4-trifluoromethyl-2-methylthio-benzoic acid, is expressed as follows with reaction equation:
High and the difficult acquisition of the method cost of material, and use organometallic reagent, severe reaction conditions, noSuitability for industrialized is produced.
Summary of the invention
Object of the present invention aims to provide that a kind of productive rate is high, cost is low, the sulfophenyl pyrazolone of green safety andThe preparation method of its intermediate.
A preparation method for sulfophenyl pyrazolone, comprises the steps:
Step 1, in solvent and under alkali existence, compound (I) is anti-at a certain temperature with compound (II)After should completing, continue and oxidant reaction, obtain compound (III);
Step 2, after compound (III) reacts with chloride reagent, then reacts and obtains with alcohol at a certain temperatureCompound (IV), or compound (III) reacts and obtains under alkali effect with alkylating reagent at a certain temperatureCompound (IV);
Step 3, under solvent neutralization bases exists, compound (IV) and sulfide (V) are at a certain temperatureReaction, obtains compound (VI);
Step 4, basic hydrolysis for compound (VI), then becomes compound (VII) with hydrogen peroxide oxidation, or usesHydrogen peroxide oxidation, then becomes compound (VII) with basic hydrolysis;
Step 5, compound (VII) reacts with chloride reagent, makes compound (VIII);
Step 6, under the effect of acid binding agent, compound (VIII) and 1,3-dimethyl-5-hydroxypyrazoles occursEsterification, obtains compound (IX);
Step 7, under the effect of alkali and catalyst, compound (IX) is reset, and obtains target product sulphurPhenylpyrazolone (X);
Be expressed as follows with reaction equation:
Wherein, L is halogen, sulfonyl or sulfinyl, R be alkoxyl, amino, alkylamino radical, alkyl,Aryl or hydrogen, the fluoro-alkyl that Rf is C1-C6, R1For methyl or ethyl, R2For the alkyl of C1-C6 orThe aryl of C6-C10, M is alkali metal.
Described L is preferably fluorine, chlorine or bromine; Described R is preferably methoxyl group, ethyoxyl or amino; InstituteThe Rf stating is preferably trifluoromethyl; Described R2Be preferably methyl; M is preferably sodium or potassium; Step 1The oxidant of stating is preferably oxygen, ozone, peroxy acid, clorox, chlorine, bromine or hydrogen peroxide; Step 1Described alkali is preferably alkali carbonate, alkali metal hydroxide, alkaline earth metal carbonate, alkaline-earth metalHydroxide, alkali metal acetate, alkali metal formate, alkali metal organic alkoxide, quaternary ammonium base, season phosphine alkaliOr organic amine.
Solvent described in step 1 be preferably DMF, NMP, DMSO, THF, ethanol, methyl alcohol, acetonitrile,One or more of water, the alkali described in step 1 more preferably sodium carbonate, potash, NaOH,Potassium hydroxide, caustic alcohol, sodium methoxide, triethylamine or pyridine, the alkali described in step 1 and compound (I)Mol ratio is preferably 1-3:1, and described compound (II) is preferably 1-2:1 with the mol ratio of compound (I),Be preferably-10-60 DEG C of reaction temperature described in step 1, the more preferably dioxygen of oxidant described in step 1Water, the oxidant described in step 1 and the mol ratio of compound (I) are preferably 2-8:1; Acyl described in step 2Chlorination reagent is preferably phosgene, triphosgene, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or threeChlorethoxyfos, the mol ratio of chloride reagent and compound (III) is preferably 1-5:1, and the alcohol described in step 2 is excellentElect methyl alcohol or ethanol as, the acyl chlorides described in step 2 and the reaction temperature of alcohol are preferably 0-80 DEG C, step 2The alkylating reagent of stating is preferably dimethyl suflfate, dithyl sulfate, iodomethane or iodoethane, described alkaneThe mol ratio of base reagent and compound (III) is preferably 1-3:1, the alkali described in step 2 be preferably sodium carbonate,Potash, NaOH, potassium hydroxide or triethylamine, the alkylated reaction temperature described in step 2 is preferably10-50 DEG C; Solvent described in step 3 is preferably DMF, DMSO or NMP, the sulfuration described in step 3The mol ratio of thing (V) and compound (IV) is preferably 1-3:1, and the reaction temperature described in step 3 is preferably0-50 DEG C; The concentration of the hydrogen peroxide described in step 4 is preferably 20-50%, hydrogen peroxide and compound (VI)Mol ratio is 2-8:1, and the alkali described in step 4 is preferably alkali metal hydroxide, alkali and change described in step 4The mol ratio of compound (VI) is preferably 1-3:1, and the reaction temperature described in step 4 is preferably 30-60 DEG C; StepChloride reagent described in rapid 5 be preferably thionyl chloride, oxalyl chloride, phosgene, triphosgene, POCl3,Phosphorus trichloride or phosphorus pentachloride, the mol ratio of chloride reagent and compound (VII) is preferably 1-5:1, stepSolvent described in 5 be preferably thionyl chloride, carrene, dichloroethanes, chloroform, carbon tetrachloride, toluene orDimethylbenzene, the reaction temperature described in step 5 is preferably 30-100 DEG C; Acid binding agent described in step 6 is preferablyOrganic base, the mol ratio of organic base and compound (VIII) is preferably 1-2:1, and the solvent described in step 6 is excellentElect carrene, dichloroethanes, chloroform, carbon tetrachloride, toluene or dimethylbenzene as, anti-described in step 6Answer temperature to be preferably 0-50 DEG C; Catalyst described in step 7 be preferably sodium carbonate, potash, acetone cyanohydrin,Azide, nitrine quaternary ammonium salt, DMAP or cyanide, the mol ratio of catalyst and compound (IX) is excellentElect 0.01-0.1:1 as, the alkali described in step 7 is preferably sodium carbonate, potash or triethylamine, alkali and compound(IX) mol ratio is preferably 1-2:1, the solvent described in step 7 be preferably carrene, dichloroethanes,One or more in chloroform, acetonitrile, carbon tetrachloride, DMF, DMSO or aromatic hydrocarbon, described in step 7Reaction temperature be preferably 10-70 DEG C.
A preparation method for sulfosalicylic acid, comprises the steps:
Step 1, in solvent and under alkali existence, compound (I) is anti-at a certain temperature with compound (II)Ying Hou, continues and oxidant reaction, obtains compound (III);
Step 2, after compound (III) reacts with chloride reagent, then reacts and obtains with alcohol at a certain temperatureCompound (IV), or compound (III) reacts and obtains under alkali effect with alkylating reagent at a certain temperatureCompound (IV);
Step 3, in solvent, compound (IV) reacts at a certain temperature with sulfide (V), obtainsCompound (VI);
Step 4, basic hydrolysis for compound (VI), then becomes compound (VII) with hydrogen peroxide oxidation, or usesHydrogen peroxide oxidation, then becomes compound (VII) with basic hydrolysis;
Be expressed as follows with reaction equation:
Wherein, L is halogen, sulfonyl or sulfinyl, R be alkoxyl, amino, alkylamino radical, alkyl,Aryl or hydrogen, the fluoro-alkyl that Rf is C1-C6, R1For methyl or ethyl, R2For the alkyl of C1-C6 orThe aryl of C6-C10, M is alkali metal.
Described L is preferably fluorine, chlorine or bromine; Described R is preferably methoxyl group, ethyoxyl or amino; InstituteThe Rf stating is preferably trifluoromethyl; Described R2Be preferably methyl; M is preferably sodium or potassium; Step 1The oxidant of stating is preferably oxygen, ozone, peroxy acid, clorox, chlorine, bromine or hydrogen peroxide; Step 1Described alkali is preferably alkali carbonate, alkali metal hydroxide, alkaline earth metal carbonate, alkaline-earth metalHydroxide, alkali metal acetate, alkali metal formate, alkali metal organic alkoxide, quaternary ammonium base, season phosphine alkaliOr organic amine.
Solvent described in step 1 be preferably DMF, NMP, DMSO, THF, ethanol, methyl alcohol, acetonitrile,One or more of water, the alkali described in step 1 more preferably sodium carbonate, potash, NaOH,Potassium hydroxide, caustic alcohol, sodium methoxide, triethylamine or pyridine, the alkali described in step 1 and compound (I)Mol ratio is preferably 1-3:1, and described compound (II) is preferably 1-2:1 with the mol ratio of compound (I),Be preferably-10-60 DEG C of reaction temperature described in step 1, the more preferably dioxygen of oxidant described in step 1Water, the oxidant described in step 1 and the mol ratio of compound (I) are preferably 2-8:1; Acyl described in step 2Chlorination reagent is preferably phosgene, triphosgene, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or threeChlorethoxyfos, the mol ratio of chloride reagent and compound (III) is preferably 1-5:1, and the alcohol described in step 2 is excellentElect methyl alcohol or ethanol as, the acyl chlorides described in step 2 and the reaction temperature of alcohol are preferably 0-80 DEG C, step 2The alkylating reagent of stating is preferably dimethyl suflfate, dithyl sulfate, iodomethane or iodoethane, described alkaneThe mol ratio of base reagent and compound (III) is preferably 1-3:1, the alkali described in step 2 be preferably sodium carbonate,Potash, NaOH, potassium hydroxide or triethylamine, the alkylated reaction temperature described in step 2 is preferably10-50 DEG C; Solvent described in step 3 is preferably DMF, DMSO or NMP, the sulfuration described in step 3The mol ratio of thing (V) and compound (IV) is preferably 1-3:1, and the reaction temperature described in step 3 is preferably0-50 DEG C; The concentration of the hydrogen peroxide described in step 3 is preferably 20-50%, hydrogen peroxide and compound (VI)Mol ratio is 2-8:1, and the alkali described in step 4 is preferably alkali metal hydroxide, alkali and change described in step 4The mol ratio of compound (VI) is preferably 1-3:1, and the reaction temperature described in step 4 is preferably 30-60 DEG C.
The preparation method of sulfophenyl pyrazolone provided by the invention and intermediate thereof, has the following advantages:
1, prepare sulfophenyl pyrazolone and intermediate thereof by the raw material being easy to get, reaction condition gentleness, safety,Green;
2, avoided the safety and the three wastes problem that use hypertoxic cyanide to bring;
3, total recovery is high, and product purity is high, and cost is low, is conducive to suitability for industrialized production.
Detailed description of the invention
A preparation method for sulfophenyl pyrazolone, comprises the steps:
Step 1, in solvent and under alkali existence, compound (I) is anti-at a certain temperature with compound (II)After should completing, continue and oxidant reaction, obtain compound (III);
Step 2, after compound (III) reacts with chloride reagent, then reacts and obtains with alcohol at a certain temperatureCompound (IV), or compound (III) reacts and obtains under alkali effect with alkylating reagent at a certain temperatureCompound (IV);
Step 3, under solvent neutralization bases exists, compound (IV) and sulfide (V) are at a certain temperatureReaction, obtains compound (VI);
Step 4, basic hydrolysis for compound (VI), then becomes compound (VII) with hydrogen peroxide oxidation, or usesHydrogen peroxide oxidation, then becomes compound (VII) with basic hydrolysis;
Step 5, compound (VII) reacts with chloride reagent, makes compound (VIII);
Step 6, under the effect of acid binding agent, compound (VIII) and 1,3-dimethyl-5-hydroxypyrazoles occursEsterification, obtains compound (IX);
Step 7, under the effect of alkali and catalyst, compound (IX) is reset, and obtains target product sulphurPhenylpyrazolone (X);
Be expressed as follows with reaction equation:
Wherein, L is halogen, sulfonyl or sulfinyl, R be alkoxyl, amino, alkylamino radical, alkyl,Aryl or hydrogen, the fluoro-alkyl that Rf is C1-C6, R1For methyl or ethyl, R2For the alkyl of C1-C6 orThe aryl of C6-C10, M is alkali metal.
Described L is preferably fluorine, chlorine or bromine; Described R is preferably methoxyl group, ethyoxyl or amino; InstituteThe Rf stating is preferably trifluoromethyl; Described R2Be preferably methyl; M is preferably sodium or potassium; Step 1The oxidant of stating is preferably oxygen, ozone, peroxy acid, clorox, chlorine, bromine or hydrogen peroxide; Step 1Described alkali is preferably alkali carbonate, alkali metal hydroxide, alkaline earth metal carbonate, alkaline-earth metalHydroxide, alkali metal acetate, alkali metal formate, alkali metal organic alkoxide, quaternary ammonium base, season phosphine alkaliOr organic amine.
Solvent described in step 1 be preferably DMF, NMP, DMSO, THF, ethanol, methyl alcohol, acetonitrile,One or more of water, the alkali described in step 1 more preferably sodium carbonate, potash, NaOH,Potassium hydroxide, caustic alcohol, sodium methoxide, triethylamine or pyridine, the alkali described in step 1 and compound (I)Mol ratio is preferably 1-3:1, and described compound (II) is preferably 1-2:1 with the mol ratio of compound (I),Be preferably-10-60 DEG C of reaction temperature described in step 1, the more preferably dioxygen of oxidant described in step 1Water, the oxidant described in step 1 and the mol ratio of compound (I) are preferably 2-8:1; Acyl described in step 2Chlorination reagent is preferably phosgene, triphosgene, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or threeChlorethoxyfos, the mol ratio of chloride reagent and compound (III) is preferably 1-5:1, and the alcohol described in step 2 is excellentElect methyl alcohol or ethanol as, the acyl chlorides described in step 2 and the reaction temperature of alcohol are preferably 0-80 DEG C, step 2The alkylating reagent of stating is preferably dimethyl suflfate, dithyl sulfate, iodomethane or iodoethane, described alkaneThe mol ratio of base reagent and compound (III) is preferably 1-3:1, the alkali described in step 2 be preferably sodium carbonate,Potash, NaOH, potassium hydroxide or triethylamine, the alkylated reaction temperature described in step 2 is preferably10-50 DEG C; Solvent described in step 3 is preferably DMF, DMSO or NMP, the sulfuration described in step 3The mol ratio of thing (V) and compound (IV) is preferably 1-3:1, and the reaction temperature described in step 3 is preferably0-50 DEG C; The concentration of the hydrogen peroxide described in step 4 is preferably 20-50%, hydrogen peroxide and compound (VI)Mol ratio is 2-8:1, and the alkali described in step 4 is preferably alkali metal hydroxide, alkali and change described in step 4The mol ratio of compound (VI) is preferably 1-3:1, and the reaction temperature described in step 4 is preferably 30-60 DEG C; StepChloride reagent described in rapid 5 be preferably thionyl chloride, oxalyl chloride, phosgene, triphosgene, POCl3,Phosphorus trichloride or phosphorus pentachloride, the mol ratio of chloride reagent and compound (VII) is preferably 1-5:1, stepSolvent described in 5 be preferably thionyl chloride, carrene, dichloroethanes, chloroform, carbon tetrachloride, toluene orDimethylbenzene, the reaction temperature described in step 5 is preferably 30-100 DEG C; Acid binding agent described in step 6 is preferablyOrganic base, the mol ratio of organic base and compound (VIII) is preferably 1-2:1, and the solvent described in step 6 is excellentElect carrene, dichloroethanes, chloroform, carbon tetrachloride, toluene or dimethylbenzene as, anti-described in step 6Answer temperature to be preferably 0-50 DEG C; Catalyst described in step 7 be preferably sodium carbonate, potash, acetone cyanohydrin,Azide, nitrine quaternary ammonium salt, DMAP or cyanide, the mol ratio of catalyst and compound (IX) is excellentElect 0.01-0.1:1 as, the alkali described in step 7 is preferably sodium carbonate, potash or triethylamine, alkali and compound(IX) mol ratio is preferably 1-2:1, the solvent described in step 7 be preferably carrene, dichloroethanes,One or more in chloroform, acetonitrile, carbon tetrachloride, DMF, DMSO or aromatic hydrocarbon, described in step 7Reaction temperature be preferably 10-70 DEG C.
A preparation method for sulfosalicylic acid, comprises the steps:
Step 1, in solvent and under alkali existence, compound (I) is anti-at a certain temperature with compound (II)Ying Hou, continues and oxidant reaction, obtains compound (III);
Step 2, after compound (III) reacts with chloride reagent, then reacts and obtains with alcohol at a certain temperatureCompound (IV), or compound (III) reacts and obtains under alkali effect with alkylating reagent at a certain temperatureCompound (IV);
Step 3, in solvent, compound (IV) reacts at a certain temperature with sulfide (V), obtainsCompound (VI);
Step 4, basic hydrolysis for compound (VI), then becomes compound (VII) with hydrogen peroxide oxidation, or usesHydrogen peroxide oxidation, then becomes compound (VII) with basic hydrolysis;
Be expressed as follows with reaction equation:
Wherein, L is halogen, sulfonyl or sulfinyl, R be alkoxyl, amino, alkylamino radical, alkyl,Aryl or hydrogen, the fluoro-alkyl that Rf is C1-C6, R1For methyl or ethyl, R2For the alkyl of C1-C6 orThe aryl of C6-C10, M is alkali metal.
Described L is preferably fluorine, chlorine or bromine; Described R is preferably methoxyl group, ethyoxyl or amino; InstituteThe Rf stating is preferably trifluoromethyl; Described R2Be preferably methyl; M is preferably sodium or potassium; Step 1The oxidant of stating is preferably oxygen, ozone, peroxy acid, clorox, chlorine, bromine or hydrogen peroxide; Step 1Described alkali is preferably alkali carbonate, alkali metal hydroxide, alkaline earth metal carbonate, alkaline-earth metalHydroxide, alkali metal acetate, alkali metal formate, alkali metal organic alkoxide, quaternary ammonium base, season phosphine alkaliOr organic amine.
Solvent described in step 1 be preferably DMF, NMP, DMSO, THF, ethanol, methyl alcohol, acetonitrile,One or more of water, the alkali described in step 1 more preferably sodium carbonate, potash, NaOH,Potassium hydroxide, caustic alcohol, sodium methoxide, triethylamine or pyridine, the alkali described in step 1 and compound (I)Mol ratio is preferably 1-3:1, and described compound (II) is preferably 1-2:1 with the mol ratio of compound (I),Be preferably-10-60 DEG C of reaction temperature described in step 1, the more preferably dioxygen of oxidant described in step 1Water, the oxidant described in step 1 and the mol ratio of compound (I) are preferably 2-8:1; Acyl described in step 2Chlorination reagent is preferably phosgene, triphosgene, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or threeChlorethoxyfos, the mol ratio of chloride reagent and compound (III) is preferably 1-5:1, and the alcohol described in step 2 is excellentElect methyl alcohol or ethanol as, the acyl chlorides described in step 2 and the reaction temperature of alcohol are preferably 0-80 DEG C, step 2The alkylating reagent of stating is preferably dimethyl suflfate, dithyl sulfate, iodomethane or iodoethane, described alkaneThe mol ratio of base reagent and compound (III) is preferably 1-3:1, the alkali described in step 2 be preferably sodium carbonate,Potash, NaOH, potassium hydroxide or triethylamine, the alkylated reaction temperature described in step 2 is preferably10-50 DEG C; Solvent described in step 3 is preferably DMF, DMSO or NMP, the sulfuration described in step 3The mol ratio of thing (V) and compound (IV) is preferably 1-3:1, and the reaction temperature described in step 3 is preferably0-50 DEG C; The concentration of the hydrogen peroxide described in step 3 is preferably 20-50%, hydrogen peroxide and compound (VI)Mol ratio is 2-8:1, and the alkali described in step 4 is preferably alkali metal hydroxide, alkali and change described in step 4The mol ratio of compound (VI) is preferably 1-3:1, and the reaction temperature described in step 4 is preferably 30-60 DEG C.
The following examples further for example understand features more of the present invention, but the present invention applies for protectionContent and scope be not subject to the restriction of following embodiment.
The preparation of the chloro-3-nitro-trifluoromethyl toluene of embodiment 1:4-
In 1000mL three-neck flask, add 400g p-chloro benzo trifluoride-99, at 30 DEG C, drip 273g98%The nitration mixture of sulfuric acid and 190g98% nitric acid, dropwises rear continuation reaction 4 hours, separates organic layer, organicLayer washing twice, obtains the chloro-3-nitro-trifluoromethyl toluene of 480g4-, yield 96%.
The preparation of embodiment 2:2-nitro-4-trifluoromethylbenzoic acid
In 1000mL three-neck flask, add 500gDMF, 180g potash, 78g cyan-acetic esterWith the chloro-3-nitro-trifluoromethyl toluene of 150g4-, control temperature of charge in 50 DEG C, stirring reaction 1 hour.Add again 230g35%H2O2, react 2 hours, cancellation hydrogen peroxide, Distillation recovery DMF, adds water, saltAcid acidifying, solid is separated out, and filters, and filter cake washing, dry, obtains 149g2-nitro-4-trifluoromethylbenzene firstAcid.1H-NMRδppm(DMSO-d6)14.39(br,1H),8.46(s,1H),8.21(d,J＝8.0Hz,1H),8.09(d,J＝8.0Hz,1H)。
The preparation of embodiment 3:2-nitro-4-trifluoromethylbenzoic acid
In 1000mL three-neck flask, add 400mLNMP, 128g triethylamine, 55g cyanoacetamideWith the chloro-3-nitro-trifluoromethyl toluene of 143g4-, control temperature of charge at 30 DEG C, stirring reaction 2 hours. Add againEnter 162g40%H2O2, react 2 hours, cancellation hydrogen peroxide, Distillation recovery NMP, adds water, hydrochloric acid acidChange, solid is separated out, and filters, and filter cake washing, dry, obtains 145g2-nitro-4-trifluoromethylbenzoic acid.The preparation of embodiment 4:2-nitro-4-trifluoromethylbenzoic acid
In 1000mL three-neck flask, add 500mLDMSO, 40g NaOH, 41g cyano group acetylThe fluoro-3-nitro-trifluoromethyl toluene of amine and 100g4-, controls temperature of charge at 10 DEG C, reacts 3 hours. Add again122g40％H2O2, after reaction finishes, cancellation hydrogen peroxide, Distillation recovery DMSO, adds water, hcl acidifying,Solid is separated out, and filters, and filter cake washing, dry, obtains 106g2-nitro-4-trifluoromethylbenzoic acid.
The preparation of embodiment 5:4-trifluoromethyl-2-nitrobenzene methyl
In 250mL round-bottomed flask, add 30g4-trifluoromethyl-2-nitrobenzoic acid, then drip 100gThionyl chloride. At 80 DEG C, insulation reaction 4 hours, is cooled to room temperature, steams except unnecessary thionyl chloride. SlowlyAdd 16.4g methyl alcohol, stirring at room temperature 3-5 hour, after reaction finishes, precipitation, obtains 31g4-trifluoromethyl-2-nitrobenzene methyl.1H-NMRδppm(CDCl3)8.23(d,J＝10Hz,1H),7.50(s,1H), 7.43(d,J＝10Hz,1H),2.52(s,3H)。
The preparation of embodiment 6:4-trifluoromethyl-2-nitrobenzene methyl
In 500mL round-bottomed flask, add 50g4-trifluoromethyl-2-nitrobenzoic acid, add 200g toluene,Under room temperature, drip 27g dimethyl suflfate, be warming up to 50 DEG C of reactions 4 hours, be down to room temperature, use unsaturated carbonateThe washing of hydrogen sodium solution, water washing, precipitation, obtains 49g4-trifluoromethyl-2-nitrobenzene methyl.
The preparation of embodiment 7:4-trifluoromethyl-2-methylthio-benzoic acid methyl esters
In 250mL round-bottomed flask, add 16g4-trifluoromethyl-2-nitrobenzene methyl, 11g carbonic acidSodium, 9g sodium methyl mercaptide and 80mLDMF, room temperature reaction 2 hours, filters, and steams except DMF solid firstBenzene-water-soluble solution, organic phase is water, saturated NaHCO successively3The aqueous solution is washed 2 times, and dry, precipitation, obtains15g product. 1H-NMR δ ppm (CDCl3)8.09(d,J＝8.0Hz,1H),7.48(s,1H),7.39(d,J＝8.0Hz,1H),3.95(s,3H),2.50(s,3H)。
The preparation of embodiment 8:4-trifluoromethyl-2-thiamphenicol benzoic acid
In 500mL round-bottomed flask, add 40g4-trifluoromethyl-2-methylthio-benzoic acid methyl esters, 200mL firstAlcohol and 12.8g NaOH, be heated to 60 DEG C, reacts 2 hours, steams except organic solvent, adjusts pH with hydrochloric acidTo 1-2, filter, filter cake is dissolved in 100mL acetic acid, then splashes into the hydrogen peroxide of 54g40%, is heated to 60 DEG C,After reaction finishes, reactant liquor is extracted with ethyl acetate, and organic phase is dry, concentrated, obtains 38.6g4-fluoroformBase-2-thiamphenicol benzoic acid. MS-ESI (m/e): 267[m-1].
The preparation of embodiment 9:4-trifluoromethyl-2-thiamphenicol benzoic acid
In 500mL round-bottomed flask, add 45g4-trifluoromethyl-2-methylthio-benzoic acid methyl esters, 100mL secondAcid, then splash into the hydrogen peroxide of 82g30%, be heated to 60 DEG C, after reaction finishes, remove unnecessary hydrogen peroxide,Organic solvent is removed in distillation, then adds 21g NaOH, after hydrolysis finishes, adjusts pH extremely with hydrochloric acid1-2, filters, and filter cake washing, dry, obtains 44g4-trifluoromethyl-2-thiamphenicol benzoic acid.
The preparation of embodiment 10:4-trifluoromethyl-2-methylsulfonyl chlorobenzoyl chloride
In 500mL round-bottomed flask, add 27g4-trifluoromethyl-2-thiamphenicol benzoic acid, 100mL protochlorideSulfone, is heated to reflux, and reaction, to completely, is steamed except unnecessary thionyl chloride, obtains 25g4-trifluoromethyl-2-Methylsulfonyl chlorobenzoyl chloride.
Embodiment 11:1, the preparation of 3-dimethyl-2-(4 '-trifluoromethyl-2 '-methylsulfonyl benzoyloxy) pyrazoles
In 1000mL round-bottomed flask, add 50g4-trifluoromethyl-2-methylsulfonyl chlorobenzoyl chloride, 300mL bis-Chloromethanes, ice bath is cooling, adds 24.7g1,3-dimethyl-5-hydroxypyrazoles and 24.2g triethylamine. Room temperature is anti-Answer 2 hours, add 50mL water, separatory, water dichloromethane extraction, merges organic phase, dry, denseContracting, recrystallization, obtains 61g1,3-dimethyl-2-(4 '-trifluoromethyl-2 '-methylsulfonyl benzoyloxy) pyrazoles.1H-NMRδppm(CDCl3)8.45(s,1H),8.03(m,2H),6.05(s,1H),3.71(s,3H),3.38(s, 3H),2.26(s,3H)。
Embodiment 12: the preparation of sulphonyl grass pyrazoles
In 500mL round-bottomed flask, add 22g1,3-dimethyl-2-(4 '-trifluoromethyl-2 '-methylsulfonyl benzoylOxygen base) pyrazoles, 12g Anhydrous potassium carbonate and 250mL toluene, be heated to reflux, and reacts 1 hour. Reaction knotShu Hou, adds 100mL water, separatory, and water is used after 2MHCl acidifying, then is extracted with ethyl acetate, and hasMachine is dry mutually, concentrated, and recrystallization obtains 20g sulphonyl grass pyrazoles.1H-NMRδppm(CDCl3)8.40(s,1H),7.99(d,J＝7.8Hz,1H),7.58(d,J＝7.8Hz,1H),3.62(s,3H),3.30(s,3H)。
Embodiment 13: the preparation of sulphonyl grass pyrazoles
In 500mL round-bottomed flask, add 36.3g1,3-dimethyl-2-(4 '-trifluoromethyl-2 '-methylsulfonyl benzene firstAcyloxy) pyrazoles, 15g triethylamine, 0.5mL acetone cyanohydrin and 170mL toluene. Reaction system is warming up to40 DEG C, react 8 hours. After reaction finishes, be cooled to room temperature, add the 50g10%NaOH aqueous solution,Layering, water is used after 2MHCl acidifying, then is extracted with ethyl acetate, and organic phase is dry, concentrated, recrystallization,Obtain 32.7g sulphonyl grass pyrazoles.
Embodiment 14: the preparation of sulphonyl grass pyrazoles
In the four-hole bottle of 250mL, add 34g1,3-dimethyl-2-(4 '-trifluoromethyl-2 '-methylsulfonyl benzene firstAcyloxy) pyrazoles, 11.5g triethylamine and 1.2g benzyl triethyl ammonium ammonium azide. At 40 DEG C, be stirred to reactionCompletely, lower the temperature, add the mixed liquor of 150mL chloroform and water, with 2MHCl tune pH to 1, separatory, hasMachine phase precipitation, obtains 32g sulphonyl grass pyrazoles.
Claims (8)
1. a preparation method for sulfophenyl pyrazolone, is characterized in that, comprises the steps:
Step 1, in solvent and under alkali existence, after compound (I) reacts at a certain temperature with compound (II),Continue and oxidant reaction, obtain compound (III);
Step 2, after compound (III) reacts with chloride reagent, then reacts and obtains chemical combination with alcohol at a certain temperatureThing (IV), or compound (III) reacts and obtains chemical combination under alkali effect with alkylating reagent at a certain temperatureThing (IV);
Step 3, in solvent, compound (IV) reacts at a certain temperature with sulfide (V), obtains chemical combinationThing (VI);
Step 4, basic hydrolysis for compound (VI), then becomes compound (VII) with hydrogen peroxide oxidation, or uses dioxygenWater oxidation, then becomes compound (VII) with basic hydrolysis;
Step 5, compound (VII) reacts with chloride reagent, makes compound (VIII);
Step 6, under the effect of acid binding agent, compound (VIII) and 1,3-dimethyl-5-hydroxypyrazoles generation esterificationReaction, obtains compound (IX);
Step 7, under the effect of alkali and catalyst, compound (IX) is reset, and obtains target product sulfophenylPyrazolone (X);
Be expressed as follows with reaction equation:
Wherein, L is halogen, sulfonyl or sulfinyl, R be alkoxyl, amino, alkylamino radical, alkyl,Aryl or hydrogen, the fluoro-alkyl that Rf is C1-C6, R1For methyl or ethyl, R2For the alkyl of C1-C6 orThe aryl of C6-C10, M is alkali metal.
2. preparation method according to claim 1, is characterized in that, described L be preferably fluorine, chlorine orBromine; Described R is preferably methoxyl group, ethyoxyl or amino; Described Rf is preferably trifluoromethyl; DescribedR2Be preferably methyl; The preferred sodium of M or potassium; Oxidant described in step 1 is preferably oxygen, ozone, mistakeOxygen acid, clorox, chlorine, bromine or hydrogen peroxide; Alkali described in step 1 be preferably alkali carbonate,Alkali metal hydroxide, alkaline earth metal carbonate, alkaline earth metal hydroxide, alkali metal acetate, alkali goldBelong to formates, alkali metal organic alkoxide, quaternary ammonium base, season phosphine alkali or organic amine.
3. preparation method according to claim 1, is characterized in that, the solvent described in step 1 is preferablyOne or more of DMF, NMP, DMSO, THF, ethanol, methyl alcohol, acetonitrile, water, step 1The alkali of stating more preferably sodium carbonate, potash, NaOH, potassium hydroxide, caustic alcohol, sodium methoxide,Triethylamine or pyridine, the alkali described in step 1 and the mol ratio of compound (I) are preferably 1-3:1, described changeThe mol ratio of compound (II) and compound (I) is preferably 1-2:1, and the reaction temperature described in step 1 is preferably-10-60 DEG C, the more preferably hydrogen peroxide of oxidant described in step 1, oxidant and change described in step 1The mol ratio of compound (I) is preferably 2-8:1.
4. preparation method according to claim 1, is characterized in that, the chloride reagent described in step 2Be preferably phosgene, triphosgene, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or POCl3,The mol ratio of chloride reagent and compound (III) is preferably 1-5:1, and the alcohol described in step 2 is preferably methyl alcoholOr ethanol, the acyl chlorides described in step 2 and the reaction temperature of alcohol are preferably 0-80 DEG C, the alkyl described in step 2Change reagent and be preferably dimethyl suflfate, dithyl sulfate, iodomethane or iodoethane, described alkylating reagentBe preferably 1-3:1 with the mol ratio of compound (III), the alkali described in step 2 be preferably sodium carbonate, potash,NaOH, potassium hydroxide or triethylamine, the alkylated reaction temperature described in step 2 is preferably 10-50 DEG C;Solvent described in step 3 is preferably DMF, DMSO or NMP, the sulfide (V) described in step 3 withThe mol ratio of compound (IV) is preferably 1-3:1, and the reaction temperature described in step 3 is preferably 0-50 DEG C; StepThe concentration of the hydrogen peroxide described in rapid 4 is preferably 20-50%, and the mol ratio of hydrogen peroxide and compound (VI) is 2-8:1,Alkali described in step 4 is preferably alkali metal hydroxide, and the alkali described in step 4 and compound (VI) rubYou are than being preferably 1-3:1, and the reaction temperature described in step 4 is preferably 30-60 DEG C; Acyl chlorides described in step 5Change reagent and be preferably thionyl chloride, oxalyl chloride, phosgene, triphosgene, POCl3, phosphorus trichloride or pentachloro-Change phosphorus, the mol ratio of chloride reagent and compound (VII) is preferably 1-5:1, and the solvent described in step 5 is excellentElect thionyl chloride, carrene, dichloroethanes, chloroform, carbon tetrachloride, toluene or dimethylbenzene as, step 5Described reaction temperature is preferably 30-100 DEG C; Acid binding agent described in step 6 is preferably organic base, organic baseBe preferably 1-2:1 with the mol ratio of compound (VIII), the solvent described in step 6 be preferably carrene,Dichloroethanes, chloroform, carbon tetrachloride, toluene or dimethylbenzene, the reaction temperature described in step 6 is preferably 0-50 DEG C;Catalyst described in step 7 is preferably sodium carbonate, potash, acetone cyanohydrin, azide, nitrine quaternary ammoniumSalt, DMAP or metal cyanides, the mol ratio of catalyst and compound (IX) is preferably 0.01-0.1:1,Alkali described in step 7 is preferably sodium carbonate, potash or triethylamine, the mol ratio of alkali and compound (IX)Be preferably 1-2:1, the solvent described in step 7 is preferably carrene, dichloroethanes, chloroform, acetonitrile, fourOne or more in chlorination carbon, DMF, DMSO or aromatic hydrocarbon, the reaction temperature described in step 7 is preferredFor 10-70 DEG C.
5. a preparation method for sulfosalicylic acid, is characterized in that, comprises the steps:
Step 1, in solvent and under alkali existence, after compound (I) reacts at a certain temperature with compound (II),Continue and oxidant reaction, obtain compound (III);
Step 2, after compound (III) reacts with chloride reagent, then reacts and obtains chemical combination with alcohol at a certain temperatureThing (IV), or compound (III) reacts and obtains chemical combination under alkali effect with alkylating reagent at a certain temperatureThing (IV);
Step 3, in solvent, compound (IV) reacts at a certain temperature with sulfide (V), obtains chemical combinationThing (VI);
Step 4, basic hydrolysis for compound (VI), then becomes compound (VII) with hydrogen peroxide oxidation, or uses dioxygenWater oxidation, then becomes compound (VII) with basic hydrolysis;
Be expressed as follows with reaction equation:
Wherein, L is halogen, sulfonyl or sulfinyl, R be alkoxyl, amino, alkylamino radical, alkyl,Aryl or hydrogen, the fluoro-alkyl that Rf is C1-C6, R1For methyl or ethyl, R2For the alkyl of C1-C6 orThe aryl of C6-C10, M is alkali metal.
6. preparation method according to claim 5, is characterized in that, described L be preferably fluorine, chlorine orBromine; Described R is preferably methoxyl group, ethyoxyl or amino; Described Rf is preferably trifluoromethyl; DescribedR2Be preferably methyl; M is preferably sodium or potassium; Oxidant described in step 1 be preferably oxygen, ozone,Peroxy acid, clorox, chlorine, bromine or hydrogen peroxide; Alkali described in step 1 be preferably alkali carbonate,Alkali metal hydroxide, alkaline earth metal carbonate, alkaline earth metal hydroxide, alkali metal acetate, alkali goldBelong to formates, alkali metal organic alkoxide, quaternary ammonium base, season phosphine alkali or organic amine.
7. preparation method according to claim 5, is characterized in that, the solvent described in step 1 is preferablyOne or more of DMF, NMP, DMSO, THF, ethanol, methyl alcohol, acetonitrile, water, step 1The alkali of stating more preferably sodium carbonate, potash, NaOH, potassium hydroxide, caustic alcohol, sodium methoxide,Triethylamine or pyridine, the alkali described in step 1 and the mol ratio of compound (I) are preferably 1-3:1, described changeThe mol ratio of compound (II) and compound (I) is preferably 1-2:1, and the reaction temperature described in step 1 is preferably-10-60 DEG C, the more preferably hydrogen peroxide of oxidant described in step 1, oxidant and change described in step 1The mol ratio of compound (I) is preferably 2-8:1.
8. preparation method according to claim 5, is characterized in that, the chloride reagent described in step 2Be preferably phosgene, triphosgene, oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride or POCl3,The mol ratio of chloride reagent and compound (III) is preferably 1-5:1, and the alcohol described in step 2 is preferably methyl alcoholOr ethanol, the acyl chlorides described in step 2 and the reaction temperature of alcohol are preferably 0-80 DEG C, the alkyl described in step 2Change reagent and be preferably dimethyl suflfate, dithyl sulfate, iodomethane or iodoethane, described alkylating reagentBe preferably 1-3:1 with the mol ratio of compound (III), the alkali described in step 2 be preferably sodium carbonate, potash,NaOH, potassium hydroxide or triethylamine, the alkylated reaction temperature described in step 2 is preferably 10-50 DEG C;Solvent described in step 3 is preferably DMF, DMSO or NMP, the sulfide (V) described in step 3 withThe mol ratio of compound (IV) is preferably 1-3:1, and the reaction temperature described in step 3 is preferably 0-50 DEG C; StepThe concentration of the hydrogen peroxide described in rapid 3 is preferably 20-50%, and the mol ratio of hydrogen peroxide and compound (VI) is 2-8:1,Alkali described in step 4 is preferably alkali metal hydroxide, and the alkali described in step 4 and compound (VI) rubYou are than being preferably 1-3:1, and the reaction temperature described in step 4 is preferably 30-60 DEG C.
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| CN112010793A (en) * | 2019-05-30 | 2020-12-01 | 帕潘纳(北京)科技有限公司 | Synthetic method of 2-methylsulfonyl-4-trifluoromethylbenzoic acid |
| CN114163316A (en) * | 2021-11-19 | 2022-03-11 | 爱斯特（成都）生物制药股份有限公司 | Method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde |
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| CN112010793B (en) * | 2019-05-30 | 2021-04-06 | 帕潘纳(北京)科技有限公司 | Synthetic method of 2-methylsulfonyl-4-trifluoromethylbenzoic acid |
| CN114163316A (en) * | 2021-11-19 | 2022-03-11 | 爱斯特（成都）生物制药股份有限公司 | Method for preparing 4-bromo-2-methoxy-5-trifluoromethylbenzaldehyde |
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