CN117945951A - Preparation method of (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate - Google Patents
Preparation method of (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate Download PDFInfo
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 title claims abstract description 73
- -1 (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl Chemical group 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 122
- 239000003054 catalyst Substances 0.000 claims abstract description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 58
- 238000000034 method Methods 0.000 claims abstract description 54
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 46
- 239000002808 molecular sieve Substances 0.000 claims abstract description 37
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 37
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 claims abstract description 26
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 23
- RDULEYWUGKOCMR-UHFFFAOYSA-N ethyl 2-chloro-3-oxobutanoate Chemical compound CCOC(=O)C(Cl)C(C)=O RDULEYWUGKOCMR-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 8
- 238000004064 recycling Methods 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims description 49
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 38
- 239000000843 powder Substances 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000012295 chemical reaction liquid Substances 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 14
- 239000012265 solid product Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 13
- 239000005457 ice water Substances 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 7
- 238000001354 calcination Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 230000032683 aging Effects 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- NDBJTKNWAOXLHS-UHFFFAOYSA-N 4-methoxybenzenediazonium Chemical class COC1=CC=C([N+]#N)C=C1 NDBJTKNWAOXLHS-UHFFFAOYSA-N 0.000 claims description 4
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 4
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 238000003483 aging Methods 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 18
- 238000000926 separation method Methods 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 6
- SKDLVDOZQDGJDS-UHFFFAOYSA-N 1-(diazonioamino)-4-methoxybenzene Chemical class COC1=CC=C(N[N+]#N)C=C1 SKDLVDOZQDGJDS-UHFFFAOYSA-N 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 5
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 2
- 238000006193 diazotization reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 30
- 239000007788 liquid Substances 0.000 description 24
- 238000001228 spectrum Methods 0.000 description 23
- 239000011521 glass Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 15
- 238000002844 melting Methods 0.000 description 13
- 230000008018 melting Effects 0.000 description 13
- 230000002194 synthesizing effect Effects 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 6
- 239000001632 sodium acetate Substances 0.000 description 6
- 235000017281 sodium acetate Nutrition 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 239000003444 phase transfer catalyst Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RCCVPFXUUXGOLG-UHFFFAOYSA-L 4-methoxybenzenediazonium;sulfate Chemical compound [O-]S([O-])(=O)=O.COC1=CC=C([N+]#N)C=C1.COC1=CC=C([N+]#N)C=C1 RCCVPFXUUXGOLG-UHFFFAOYSA-L 0.000 description 1
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229940125895 MET kinase inhibitor Drugs 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 229960003886 apixaban Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- HJUFTIJOISQSKQ-UHFFFAOYSA-N fenoxycarb Chemical compound C1=CC(OCCNC(=O)OCC)=CC=C1OC1=CC=CC=C1 HJUFTIJOISQSKQ-UHFFFAOYSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, which comprises the steps of firstly taking p-methoxyaniline and sodium nitrite as raw materials, taking inorganic acid as a reaction solvent, preparing an intermediate p-methoxyaniline diazonium salt through diazotization reaction, directly carrying out addition decarboxylation reaction with 2-chloroacetoacetic acid ethyl ester in a reaction system without additional separation, and preparing (Z) -2-chloro-2- [2- (4-methoxyphenyl) -hydrazono ] ethyl acetate under the condition of supporting an alkaline catalyst by a molecular sieve. The method has the advantages of high reaction chemical selectivity, less catalyst consumption, recycling, higher yield, high product quality, simple and efficient separation and purification method, no need of adding extra alkali and organic solvent, mild reaction condition by taking water as a reaction solvent, environment friendliness, simple process and equipment, suitability for large-scale industrial production and provision of a novel synthesis method for (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate and similar compounds.
Description
Technical Field
The invention relates to the field of medicine synthesis, in particular to a preparation method of (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate.
Background
The (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate is an important organic intermediate in the field of drug synthesis, and is mainly used as an intermediate of novel oral Xa factor inhibitor apixaban and an intermediate of c-Met kinase inhibitor 1,2, 4-triazolone 4-phenoxyquinoline derivative in the field of medicine.
The synthesis method of the (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate mainly comprises the following three types:
(1) In 2013 Tao Haiyan et al report that p-methoxyaniline, concentrated hydrochloric acid and sodium nitrite are used as raw materials to prepare p-methoxybenzene diazonium hydrochloride, and the p-methoxybenzene diazonium hydrochloride is reacted with ethyl 2-chloroacetoacetate, sodium acetate and ethanol aqueous solution to prepare (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate by a one-pot method, wherein the reaction yield is 87.4 percent (HPLC: purity is 97.3 percent). The synthetic reaction formula is as follows:
the raw materials of sodium nitrite, hydrochloric acid and sodium acetate used in the synthesis method have large dosage, high acetic acid content and more reaction wastewater, and are not easy to treat; in addition, the quality of the product prepared by the synthetic method is poor, and the reaction yield is only 87.4%.
(2) In 2017 Zhu Jiang et al, p-methoxyaniline diazonium salt is prepared by diazotizing p-methoxyaniline serving as a raw material, sulfuric acid or hydrochloric acid, sodium bromide and sodium nitrite. The reaction condition of the diazo salt of the p-methoxyaniline and 2-ethyl chloroacetate, sodium acetate and ethanol/diethyl ether solvent prepares (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, and the reaction yield is 92.3 percent (HPLC: purity is 98.1 percent). The synthetic reaction formula is as follows:
The sodium nitrite reaction has the advantages of large feeding amount of sodium acetate, large concentration of organic solvents and inorganic salts in reaction liquid, difficult waste liquid treatment, difficult transfer and storage in the using process, and the synthesis process is only suitable for theoretical research in a laboratory.
(3) In 2014 Ma Shutao et al report that the first step of the method is to prepare p-methoxy aniline diazonium hydrochloride by diazotizing p-methoxy aniline, hydrochloric acid and sodium nitrite as raw materials. In the second step, the p-methoxyaniline diazonium salt and 2-ethyl chloroacetate are prepared into (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate under the catalysis of a phase transfer catalyst, and the yield is 97% (HPLC: 96%). The synthetic reaction formula is as follows:
the synthesis method uses a phase transfer catalyst triethylbenzyl ammonium bromide to accelerate the reaction rate and shorten the reaction time; the wastewater discharge amount is large, the post treatment is troublesome, the large-scale production is not facilitated, and the product purity is poor.
Disclosure of Invention
The invention aims to provide a green and efficient preparation method of (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate. The method has the advantages of good chemical selectivity, less catalyst consumption, recycling, higher yield, high product quality, simple and efficient separation and purification method, no need of adding extra alkali and organic solvent, mild reaction condition by using water as a reaction solvent, environmental protection, and simple and convenient reaction wastewater treatment, and provides a novel synthesis method for the (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate.
In order to solve the technical problems, the invention adopts the following technical scheme:
Provides a preparation method of (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, which comprises the following steps:
1) Dropwise adding an inorganic acid and sodium nitrite aqueous solution into the p-methoxyaniline aqueous solution in sequence at the temperature of-10 ℃, and continuing to react until the reaction is complete after the dropwise addition is completed to obtain p-methoxybenzene diazonium salt;
2) Directly adding a molecular sieve supported alkaline catalyst and a solvent into the reaction liquid in the step 1), dropwise adding 2-chloroacetoacetic acid ethyl ester at the temperature of-10-20 ℃, continuing to react after the dropwise adding is finished, and performing post-treatment to obtain (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate; wherein:
The molecular sieve supported alkaline catalyst comprises a mesoporous molecular sieve SBA-15 carrier and KOH supported on the carrier;
The dosage of the molecular sieve supported alkaline catalyst is 0.1-1% of the feeding mass of the ethyl 2-chloroacetate.
According to the scheme, in the step 1), the reaction time is 0.5-1 h after the dripping is finished.
According to the scheme, in the step 1), the molar ratio of the p-methoxyaniline to the inorganic acid is 1:1.0 to 3.0; the molar ratio of the p-methoxyaniline to the sodium nitrite is 1:1.0 to 2.0.
According to the above scheme, in the step 1), the inorganic acid is hydrochloric acid, dilute sulfuric acid, concentrated sulfuric acid or hydrobromic acid.
According to the above scheme, in the step 2), the solvent for the reaction is water, methanol, ethanol, acetonitrile or ethyl acetate.
According to the scheme, the molar ratio of the p-methoxyaniline in the step 1) to the ethyl 2-chloroacetoacetate in the step 2) is 1:1.0 to 1.4.
According to the scheme, in the step 2), the reaction time is 4-6 h.
According to the scheme, in the step 2), in the molecular sieve supported alkaline catalyst, the mass ratio of KOH to SBA-15 is 1:7.5 to 12.
According to the scheme, in the step 2), the molecular sieve supported alkaline catalyst is prepared by mixing KOH and mesoporous molecular sieve SBA-15 powder for reaction and roasting.
Preferably, the mass ratio of KOH to SBA-15 is 1:7.5 to 12.
Preferably, the roasting is carried out at 500-600 ℃ for 10-16h.
Preferably, the reaction is carried out at 60-80 ℃ with stirring for 8-15 h.
Preferably, the preparation of the molecular sieve supported basic catalyst comprises the steps of:
Mixing KOH and anhydrous isopropanol, heating, stirring and dissolving, adding mesoporous molecular sieve SBA-15, stirring at 60-80 ℃ for reaction for 8-15 h, drying after the reaction is finished, and roasting at 500-600 ℃ for 10-16h to obtain the KOH/SBA-15 catalyst.
More preferably, the dissolution temperature by heating and stirring is 60 to 70 ℃.
More preferably, the drying process is 10-16 hours of drying in an oven at 100-110 ℃.
According to the scheme, in the step 2), the preparation of the mesoporous molecular sieve SBA-15 comprises the following steps:
Mixing P123 with water and concentrated hydrochloric acid to obtain a clear solution, dropwise adding TEOS at the temperature of 40-60 ℃, stirring for reaction to obtain white sol, cooling after ageing, filtering, washing to be neutral, drying and calcining to obtain the mesoporous molecular sieve SBA-15.
Preferably, the aging conditions are: aging for 12-24 h at 115-125 ℃.
Preferably, the calcination process is: calcining at 500-600 deg.c for 6-12 hr.
Preferably, the drying conditions are: drying at 70-90 deg.c for 8-10 hr.
Preferably, after mixing the P123 with water and concentrated hydrochloric acid, stirring the mixture at a constant temperature of 40-60 ℃ until the solution is clear.
Preferably, the mass ratio of the P123 template agent to the hydrochloric acid is 1:4.5 to 5.9, the mass ratio of the P123 template agent to TEOS is 1:2.0 to 2.9.
According to the scheme, in the step 2), the post-treatment specific process comprises the following steps: adding ice water into the reaction solution, stirring for 0.5-2 h, heating to 40-60 ℃, filtering the molecular sieve to load the alkaline catalyst while the reaction solution is hot, and washing the recovered catalyst with water for recycling; the filtered reaction liquid is subjected to gradient cooling and stirring, then is filtered, the crude product is pulped for 1-2 hours at 20-30 ℃ by using clear water, and is filtered and dried, thus obtaining a pale yellow powder solid product.
Preferably, the gradient cooling and stirring process comprises the following steps: the reaction solution is cooled to 35-45 ℃ and stirred for 1-2 h, then cooled to 20-30 ℃ and stirred for 1-2 h, and finally cooled to 8-12 ℃ and stirred for 1-2 h.
The beneficial effects of the invention are as follows:
1. The invention provides a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate by a one-pot method, which comprises the steps of firstly taking p-methoxyaniline and sodium nitrite as raw materials, taking water as a reaction solvent, preparing an intermediate p-methoxyaniline diazonium salt through diazotization reaction, directly carrying out addition decarboxylation reaction with 2-chloroacetoacetic acid ethyl ester in a reaction system without additional separation, and preparing (Z) -2-chloro-2- [2- (4-methoxyphenyl) -hydrazono ] ethyl acetate under the condition that a molecular sieve is loaded with an alkaline catalyst (namely KOH/SBA-15); compared with the traditional alkali catalyst, the catalyst dosage in the invention is greatly reduced, only the catalyst dosage is needed, the reaction chemical selectivity is high, the reaction rate is fast, and the yield is high; the byproducts in the reaction process are few, the quality of the obtained product is high, no additional separation and purification are needed, and the purity of the product is high.
2. The synthesis method has safe reaction process, no additional organic solvent, simple and efficient separation and purification method, and is applicable to large-scale industrial production; meanwhile, the reaction process method has less three wastes, the reaction is environment-friendly, the reaction molecular sieve loaded alkaline catalyst can be recycled, the product yield and quality are not affected, and the method has important economic benefit and environment-friendly benefit.
Detailed Description
The invention is further described below in connection with examples which, of course, should not be construed as in any way limiting.
The embodiment of the invention provides a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate by a one-pot method, which comprises the steps of firstly preparing p-methoxy aniline diazonium salt by diazotizing p-methoxy aniline, sodium nitrite and inorganic acid serving as raw materials and water serving as a reaction solvent; the p-methoxybenzene diazonium salt and 2-chloroacetoacetic acid ethyl ester are subjected to addition reaction under the condition of a molecular sieve supported alkaline (KOH/SBA-15) catalyst, and are subjected to alpha carbon dehydrogenation and deprotonation, nucleophilic addition, internal electron migration bond breaking and deprotonation reaction to prepare the (Z) -2-chloro-2- [2- (4-methoxyphenyl) -hydrazone ] acetic acid ethyl ester. Wherein, the specific synthetic reaction formula is as follows:
Example 1
The preparation method of the self-made molecular sieve supported alkaline (KOH/SBA-15) catalyst comprises the following steps:
4.0g of P123 is weighed and put into a four-necked flask, 105mL of water and 20mL of concentrated hydrochloric acid are added, and the mixture is stirred at a constant temperature of 40 ℃ until the solution is clear; slowly dripping 8.00g of TEOS, and continuously stirring at the constant temperature of 60 ℃; filling the obtained white sol into a reaction bottle with a polytetrafluoroethylene lining, and aging for 24 hours at 120 ℃; taking out, cooling, filtering, washing to neutrality, and drying at 80deg.C in a forced air drying oven for 10 hr; calcining for 12 hours at 550 ℃ by using a muffle furnace to obtain mesoporous molecular sieve SBA-15 powder solid.
Adding 0.40g KOH and 30mL anhydrous isopropanol into a four-necked flask, heating to 60 ℃ and stirring to dissolve, taking 3g mesoporous molecular sieve SBA-15 prepared, stirring at 60-80 ℃ to react for 10 hours, then placing into a 100 ℃ oven to dry for 12 hours, placing into a muffle furnace to heat to 550 ℃ and roasting for 12 hours to obtain the KOH/SBA-15 catalyst, and using the catalyst for catalytic synthesis of (Z) -2-chloro-2- [2- (4-methoxyphenyl) -hydrazone ] ethyl acetate in the following examples.
Example 2
Provides a preparation method of (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, which comprises the following steps:
adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated hydrochloric acid (4.45 kg,44 mol) is added dropwise into the reaction liquid, and the temperature is controlled between-5 ℃ and 0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.52 kg,22 mol) was added dropwise to the reaction solution, and the reaction temperature was maintained at-5 to 0℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 5 ℃ to 0 ℃, and the liquid spectrum detection is carried out until the raw materials are completely reacted, thus preparing the p-methoxybenzene diazonium salt (HPLC: 99.60%). Without separating the product, 3.29g of the molecular sieve-supported alkaline catalyst (0.1% eq) prepared in example 1 was continuously added to a 50L glass reactor and dissolved in 12kg of water, and 2-chloroacetoacetic acid ethyl ester (3.29 kg,20 mol) was slowly added dropwise while maintaining the reaction temperature at 0℃and reacting at 0℃for 4 hours. Adding 4kg of ice water into the reaction solution, stirring for 1h, heating to 60 ℃, filtering the molecular sieve to load the alkaline catalyst while the catalyst is hot, and adding 400g of water into the recovered catalyst for washing, so that the catalyst can be recycled. The filtered reaction solution is cooled to 40 ℃ firstly, stirred for 1h, cooled to 25 ℃ again, stirred for 2h, cooled to 10 ℃ finally, stirred for 2h, filtered, and the crude product is pulped with 10kg of clear water at 25 ℃ for 1h, filtered and dried in vacuum at 80 ℃ to obtain 4.87kg of pale yellow powder solid product, the total yield is 94.9%, the liquid spectrum content is 99.3% (HPLC), the melting point is high performance liquid chromatography (DSC)：102.0～104.2℃.1H NMR(CDCl3,400MHZ)δ8.30(s,1H),7.12-7.15(q,J＝4.0Hz,4H),6.85-6.89(m,2H),4.34-4.39(q,J＝7.2Hz,2H),3.78(s,3H),1.37-1.40(t,J＝7.2Hz,3H).
The liquid chromatography (HPLC) test was performed in each example of the present invention: chromatographic column (high performance liquid chromatography AGLIENT ECLIPSE XDB-C 18, 5 μm, 4.6 x 150 mm), flow rate (1.0 mL/min), wavelength (230 nm), column temperature (25 ℃), elution time (15 min), mobile phase: acetonitrile (40%) with 0.01% phosphate buffer (60%).
Comparative example 1
There is provided a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, comprising the steps of:
1) Preparing a supported alkaline catalyst: the procedure is as in example 1 except that 0.40g KOH is replaced by 0.98g K 2CO3 and the resulting catalyst is a K 2CO3/SBA-15 catalyst.
2) Adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated hydrochloric acid (4.45 kg,44 mol) is added dropwise into the reaction liquid, and the temperature is controlled between-5 ℃ and 0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.52 kg,22 mol) was added dropwise to the reaction solution, and the reaction temperature was maintained at-5 to 0℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 5 ℃ to 0 ℃, and the p-methoxybenzene diazonium hydrochloride (HPLC: 99.60%) is prepared after the liquid spectrum detection is carried out and the raw materials are completely reacted. 3.29g of the molecular sieve supported alkaline catalyst (0.1% eq) prepared in the step 1 and 12kg of water are continuously added into a 50L glass reaction kettle to be dissolved, and 2-chloroacetoacetic acid ethyl ester (3.29 kg,20 mol) is slowly added dropwise, the reaction temperature is maintained at 0 ℃ in the dropwise adding process, and the reaction is carried out for 4 hours at 0 ℃. 4kg of ice water was added to the reaction mixture, followed by stirring for 1 hour. The reaction solution is firstly cooled to 40 ℃, stirred for 1h, then cooled to 25 ℃ and stirred for 2h, finally cooled to 10 ℃, stirred for 2h, filtered, and the crude product is pulped for 2h at 25 ℃ by using 10kg of clear water, filtered and dried in vacuum at 80 ℃ to obtain 4.36kg of pale yellow powder solid product, the total yield is 85.0%, the liquid spectrum content is 98.7% (HPLC), the melting point (DSC): 101.0-105.5 ℃.
Comparative example 2
There is provided a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, comprising the steps of:
1) Preparing a supported alkaline catalyst: the procedure is as in example 1 except that 0.40g KOH is replaced by 0.45g KF and the catalyst obtained is KF/SBA-15 catalyst.
2) Adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated hydrochloric acid (4.45 kg,44 mol) is added dropwise into the reaction liquid, and the temperature is controlled between-5 ℃ and 0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.52 kg,22 mol) was added dropwise to the reaction solution, and the reaction temperature was maintained at-5 to 0℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 5 ℃ to 0 ℃, and the p-methoxybenzene diazonium hydrochloride (HPLC: 99.60%) is prepared after the liquid spectrum detection is carried out and the raw materials are completely reacted. 3.29g of the molecular sieve supported alkaline catalyst (0.1% eq) prepared in the step 1 and 12kg of water are continuously added into a 50L glass reaction kettle to be dissolved, and 2-chloroacetoacetic acid ethyl ester (3.29 kg,20 mol) is slowly added dropwise, the reaction temperature is maintained at 0 ℃ in the dropwise adding process, and the reaction is carried out for 4 hours at 0 ℃. 4kg of ice water was added to the reaction mixture, followed by stirring for 1 hour. The reaction solution is firstly cooled to 40 ℃, stirred for 1h, then cooled to 25 ℃ and stirred for 2h, finally cooled to 10 ℃, stirred for 1h, filtered, and the crude product is pulped for 1h at 25 ℃ by using 10kg of clear water, filtered and dried in vacuum at 80 ℃ to obtain 4.60kg of pale yellow powder solid product, the total yield is 90.1%, the liquid spectrum content is 96.3% (HPLC), the melting point (DSC): 100.1-105.5 ℃.
Comparative example 3
There is provided a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, comprising the steps of:
Adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated hydrochloric acid (4.45 kg,44 mol) is added dropwise into the reaction liquid, and the temperature is controlled between-5 ℃ and 0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.52 kg,22 mol) was added dropwise to the reaction solution, and the reaction temperature was maintained at-5 to 0℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 5 ℃ to 0 ℃, and the p-methoxybenzene diazonium hydrochloride (HPLC: 99.60%) is prepared after the liquid spectrum detection is carried out and the raw materials are completely reacted. Sodium acetate (4.92 kg,60mol,3.0 eq) and 24kg water are continuously added into a 50L glass reaction kettle to be dissolved, and then 2-chloroacetoacetic acid ethyl ester (3.29 kg,20 mol) is slowly added dropwise, the reaction temperature is maintained at 0 ℃ in the dropwise adding process, and the reaction is carried out for 4 hours at 0 ℃. 4kg of ice water was added to the reaction mixture, followed by stirring for 1 hour. The reaction solution is firstly cooled to 40 ℃, stirred for 1h, then cooled to 25 ℃ and stirred for 2h, finally cooled to 10 ℃, stirred for 2h, filtered, and the crude product is pulped for 1h at 25 ℃ by using 10kg of clear water, filtered and dried in vacuum at 80 ℃ to obtain 4.36kg of pale yellow powder solid product with the liquid spectrum content of 95.4 percent (HPLC) and the melting point (DSC): 100.0-105.0 ℃. Adding 8.72kg of methanol into the solid crude product, heating, refluxing and stirring for 0.5h with 4.36kg of water, slowly cooling to 10 ℃, centrifuging, filtering, and drying to obtain 4.00kg of pale yellow powder solid product, wherein the liquid spectrum content is 98.4% (HPLC), and the melting point (DSC): 101.3-105.0 ℃.
Comparative example 4
There is provided a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, comprising the steps of:
Adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated hydrochloric acid (4.45 kg,44 mol) is added dropwise into the reaction liquid, and the temperature is controlled between-5 ℃ and 0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.52 kg,22 mol) was added dropwise to the reaction solution, and the reaction temperature was maintained at-5 to 0℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 5 ℃ to 0 ℃, and the p-methoxybenzene diazonium hydrochloride (HPLC: 99.60%) is prepared after the liquid spectrum detection is carried out and the raw materials are completely reacted. Without isolation of the product, sodium acetate (8.16 kg,60mol,3.0 eq) was continuously added to a 50L glass reactor, tetrabutylammonium bromide (3.23 g,0.1mol,0.5% eq) as a phase transfer catalyst was dissolved in 12kg of water, and 2-acetoacetate (3.29 kg,20 mol) was slowly added dropwise while maintaining a reaction temperature of 0℃and reacting at 0℃for 4 hours. 4kg of ice water was added to the reaction mixture, followed by stirring for 1 hour. The reaction solution is firstly cooled to 40 ℃, stirred for 1h, then cooled to 25 ℃ and stirred for 2h, finally cooled to 10 ℃, stirred for 2h, filtered, and the crude product is pulped for 1h at 25 ℃ by using 10kg of clear water, filtered and dried in vacuum at 80 ℃ to obtain 4.82kg of pale yellow powder solid product, the total yield is 93.9%, the liquid spectrum content is 99.2% (HPLC), the melting point (DSC): 101.8-104.0 ℃.
Example 3
There is provided a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, comprising the steps of:
Adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated hydrochloric acid (4.45 kg,44 mol) is added dropwise into the reaction liquid, and the temperature is controlled between-5 ℃ and 0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.38 kg,20 mol) was added dropwise to the reaction solution, and the reaction temperature was maintained at-5 to 0℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 5 ℃ to 0 ℃, and the p-methoxybenzene diazonium hydrochloride (HPLC: 99.80%) is prepared after the liquid spectrum detection is carried out for the raw materials to react completely. Without separating the product, 3.29g of the molecular sieve-supported alkaline catalyst (0.1% eq) prepared in example 1 was continuously added to a 50L glass reactor and dissolved in 12kg of water, and 2-chloroacetoacetic acid ethyl ester (3.29 kg,20 mol) was slowly added dropwise while maintaining the reaction temperature at 0℃and reacting at 0℃for 2 hours. Adding 4kg of ice water into the reaction solution, stirring for 1h, heating to 60 ℃, filtering the molecular sieve to load the alkaline catalyst while the catalyst is hot, and adding 400g of water into the recovered catalyst for washing, so that the catalyst can be recycled. The filtered reaction solution is firstly cooled to 40 ℃, stirred for 1h, then cooled to 25 ℃ and stirred for 2h, finally cooled to 10 ℃ and stirred for 2h, filtered, and crude product is pulped for 1h at 25 ℃ by using 10kg of clear water, filtered and dried in vacuum at 80 ℃ to obtain 4.73kg of pale yellow powder solid product, the total yield is 94.9%, the liquid spectrum content is 99.4% (HPLC), and the melting point (DSC): 102.6-104.0 ℃.
Example 4
There is provided a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, comprising the steps of:
Adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated sulfuric acid (2.15 kg,22 mol) is added dropwise into the reaction liquid, and the temperature is controlled at-5-0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.52 kg,22 mol) was added dropwise to the reaction solution, and the reaction temperature was maintained at-5 to 0℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 5 ℃ to 0 ℃, and the p-methoxybenzene diazonium sulfate (HPLC: 99.10%) is prepared after the liquid spectrum detection is carried out and the raw materials are completely reacted. Without separating the product, 3.29g of the molecular sieve-supported alkaline catalyst (0.1% eq) prepared in example 1 was continuously added to a 50L glass reactor and dissolved in 12kg of water, and 2-chloroacetoacetic acid ethyl ester (3.29 kg,20 mol) was slowly added dropwise while maintaining the reaction temperature at 0℃and reacting at 0℃for 4 hours. Adding 4kg of ice water into the reaction solution, stirring for 1h, heating to 60 ℃, filtering the molecular sieve to load the alkaline catalyst while the catalyst is hot, and adding 400g of water into the recovered catalyst for washing, so that the catalyst can be recycled. The filtered reaction solution is firstly cooled to 40 ℃, stirred for 1h, then cooled to 25 ℃ and stirred for 2h, finally cooled to 10 ℃ and stirred for 2h, filtered, and crude product is pulped for 1h at 25 ℃ by using 10kg of clear water, filtered and dried in vacuum at 80 ℃ to obtain 4.62kg of pale yellow powder solid product, the total yield is 90.2%, the liquid spectrum content is 99.0% (HPLC), and the melting point (DSC): 101.3-104.2 ℃.
Example 5
There is provided a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, comprising the steps of:
Adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated hydrochloric acid (4.45 kg,44 mol) is added dropwise into the reaction liquid, and the temperature is controlled between-5 ℃ and 0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.65 kg,24 mol) was dissolved in 3.75kg of water) was added dropwise to the reaction solution, and the reaction temperature was maintained at 0 to 5℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 1 hour at the temperature of 0 to 5 ℃, and the p-methoxybenzene diazonium hydrochloride (HPLC: 99.40%) is prepared after the raw materials are completely reacted by liquid spectrum detection. Without separating the product, 3.29g of the molecular sieve-supported alkaline catalyst (0.1% eq) prepared in example 1 was continuously added to a 50L glass reactor and dissolved in 12kg of water, and 2-chloroacetoacetic acid ethyl ester (3.29 kg,20 mol) was slowly added dropwise while maintaining the reaction temperature at 0℃and reacting at 0℃for 4 hours. Adding 4kg of ice water into the reaction solution, stirring for 1h, heating to 60 ℃, filtering the molecular sieve to load the alkaline catalyst while the catalyst is hot, and adding 400g of water into the recovered catalyst for washing, so that the catalyst can be recycled. The filtered reaction solution is firstly cooled to 40 ℃, stirred for 1h, then cooled to 25 ℃ and stirred for 2h, finally cooled to 10 ℃ and stirred for 2h, filtered, and crude product is pulped for 1h at 25 ℃ by using 10kg of clear water, filtered and dried in vacuum at 80 ℃ to obtain 4.82kg of pale yellow powder solid product, the total yield is 94.0%, the liquid spectrum content is 99.2% (HPLC), and the melting point (DSC): 102.0-104.1 ℃.
Example 6
There is provided a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, comprising the steps of:
Adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated hydrochloric acid (4.45 kg,44 mol) is added dropwise into the reaction liquid, and the temperature is controlled between-5 ℃ and 0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.37 kg,20 mol) was dissolved in 3.75kg of water) was added dropwise to the reaction solution, and the reaction temperature was maintained at-5 to 0℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 5 ℃ to 0 ℃, and the p-methoxybenzene diazonium hydrochloride (HPLC: 99.80%) is prepared after the liquid spectrum detection is carried out for the raw materials to react completely. Without separating the product, 16.45g of the molecular sieve-supported alkaline catalyst (0.5% eq) prepared in example 1 was continuously added to a 50L glass reactor and dissolved in 12kg of water, and 2-chloroacetoacetic acid ethyl ester (3.29 kg,20 mol) was slowly added dropwise while maintaining the reaction temperature at 0℃and reacting at 0℃for 1 hour. Adding 4kg of ice water into the reaction solution, stirring for 1h, heating to 60 ℃, filtering the molecular sieve to load the alkaline catalyst while the catalyst is hot, and adding 400g of water into the recovered catalyst for washing, so that the catalyst can be recycled. The filtered reaction solution is firstly cooled to 40 ℃, stirred for 1h, then cooled to 25 ℃ and stirred for 2h, finally cooled to 10 ℃ and stirred for 2h, filtered, and crude product is pulped for 1h at 25 ℃ by using 10kg of clear water, filtered and dried in vacuum at 80 ℃ to obtain 4.97kg of pale yellow powder solid product, the total yield is 96.9%, the liquid spectrum content is 99.7% (HPLC), and the melting point (DSC): 102.9-104.0 ℃.
Example 7
There is provided a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, comprising the steps of:
Adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated hydrochloric acid (4.45 kg,44 mol) is added dropwise into the reaction liquid, and the temperature is controlled between-5 ℃ and 0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.38 kg,20 mol) was added dropwise to the reaction solution, and the reaction temperature was maintained at-5 to 0℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 5 ℃ to 0 ℃, and the p-methoxybenzene diazonium hydrochloride (HPLC: 99.80%) is prepared after the liquid spectrum detection is carried out for the raw materials to react completely. Without separating the product, 3.94g of the molecular sieve-supported alkaline catalyst (0.1% eq) prepared in example 1 was continuously added to a 50L glass reactor and dissolved in 12kg of water, and 2-chloroacetoacetic acid ethyl ester (3.95 kg,24 mol) was slowly added dropwise while maintaining the reaction temperature at 0℃and reacting at 0℃for 2 hours. Adding 4kg of ice water into the reaction solution, stirring for 1h, heating to 60 ℃, filtering the molecular sieve to load the alkaline catalyst while the catalyst is hot, and adding 400g of water into the recovered catalyst for washing, so that the catalyst can be recycled. The filtered reaction solution is firstly cooled to 40 ℃, stirred for 1h, then cooled to 25 ℃ and stirred for 2h, finally cooled to 10 ℃ and stirred for 2h, filtered, and crude product is pulped for 1h at 25 ℃ by using 10kg of clear water, filtered and dried in vacuum at 80 ℃ to obtain 4.98kg of pale yellow powder solid product, the total yield is 97.2%, the liquid spectrum content is 99.6% (HPLC), and the melting point (DSC): 102.7-104.0 ℃.
Example 8
There is provided a method for synthesizing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, comprising the steps of:
Adding p-methoxyaniline (2.46 kg,20 mol) and water (10 kg) into a 50L glass reaction kettle provided with a stirring device, a thermometer and a constant pressure dropping funnel, stirring and dissolving, and controlling the temperature to be-5-0 ℃; concentrated hydrochloric acid (4.45 kg,44 mol) is added dropwise into the reaction liquid, and the temperature is controlled between-5 ℃ and 0 ℃ in the dropping process; an aqueous solution of sodium nitrite (1.44 kg,20 mol) was dissolved in 3.75kg of water) was added dropwise to the reaction solution, and the reaction temperature was maintained at-5 to 0℃during the dropwise addition. After the dripping is finished, the reaction is carried out for 0.5h at the temperature of minus 5 ℃ to 0 ℃, and the p-methoxybenzene diazonium hydrochloride (HPLC: 99.80%) is prepared after the liquid spectrum detection is carried out for the raw materials to react completely. Without separating the product, 3.29g of the molecular sieve-supported alkaline catalyst (0.1% eq) prepared in example 1 was continuously added to a 50L glass reactor and dissolved in 12kg of water, and 2-chloroacetoacetic acid ethyl ester (3.29 kg,20 mol) was slowly added dropwise while maintaining the reaction temperature at 10℃and reacting at 10℃for 2 hours. Adding 4kg of ice water into the reaction solution, stirring for 1h, heating to 60 ℃, filtering the molecular sieve to load the alkaline catalyst while the catalyst is hot, and adding 400g of water into the recovered catalyst for washing, so that the catalyst can be recycled. The filtered reaction solution is firstly cooled to 40 ℃, stirred for 1h, then cooled to 25 ℃ and stirred for 2h, finally cooled to 10 ℃ and stirred for 2h, filtered, and crude product is pulped for 1h at 25 ℃ by using 10kg of clear water, filtered and dried in vacuum at 80 ℃ to obtain 4.87kg of pale yellow powder solid product, the total yield is 95.0%, the liquid spectrum content is 99.4% (HPLC), and the melting point (DSC): 102.8-104.2 ℃.
Example 9
The other steps were the same as in example 2, except that the catalyst was continuously used three times, and the results of three times of application of the molecular sieve-supported basic catalyst are shown in the following table 1:
TABLE 1
As can be seen from comparison of the example data, the catalyst is repeatedly used for three times, the reaction yield is maintained to be more than 90%, the main content (HPLC) of the product is more than 99%, the melting range is 101-105 ℃, and the reaction effect is not affected by repeated use of the catalyst.
While the present invention has been described in detail with reference to specific examples thereof, those skilled in the art will recognize that various changes and modifications can be made therein without departing from the scope and spirit of the invention, and it is intended to claim the invention as defined by the appended claims.
Claims (10)
1. A method for preparing (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate, which is characterized by comprising the following steps:
1) Dropwise adding an inorganic acid and sodium nitrite aqueous solution into the p-methoxyaniline aqueous solution in sequence at the temperature of-10 ℃, and continuing to react until the reaction is complete after the dropwise addition is completed to obtain p-methoxybenzene diazonium salt;
2) Directly adding a molecular sieve supported alkaline catalyst and a solvent into the reaction liquid in the step 1), dropwise adding 2-chloroacetoacetic acid ethyl ester at the temperature of-10-20 ℃, continuing to react after the dropwise adding is finished, and performing post-treatment to obtain (Z) -2-chloro [ (4-methoxyphenyl) hydrazono ] ethyl acetate; wherein:
The molecular sieve supported alkaline catalyst comprises a mesoporous molecular sieve SBA-15 carrier and KOH supported on the carrier;
The dosage of the molecular sieve supported alkaline catalyst is 0.1-1% of the feeding mass of the ethyl 2-chloroacetate.
2. The method according to claim 1, wherein in the step 1), the reaction time is 0.5 to 1h; in the step 2), the reaction time is 4-6 h.
3. The method according to claim 1, wherein in the step 1), the molar ratio of p-methoxyaniline to inorganic acid is 1:1.0 to 3.0; the molar ratio of the p-methoxyaniline to the sodium nitrite is 1:1.0 to 2.0.
4. The method according to claim 1, wherein in the step 1), the inorganic acid is hydrochloric acid, dilute sulfuric acid, concentrated sulfuric acid or hydrobromic acid; in the step 2), the solvent for the reaction is water, methanol, ethanol, acetonitrile or ethyl acetate.
5. The method according to claim 1, wherein the molar ratio of the p-methoxyaniline in step 1) to the ethyl 2-chloroacetoacetate in step 2) is 1:1.0 to 1.4.
6. The method according to claim 1, wherein in the step 2), the mass ratio of KOH to SBA-15 in the molecular sieve-supported alkaline catalyst is 1:7.5 to 12.
7. The method according to claim 1, wherein in the step 2), the molecular sieve supported alkaline catalyst is prepared by mixing KOH and mesoporous molecular sieve SBA-15 powder, reacting and then calcining.
8. The preparation method according to claim 7, wherein the reaction is carried out at 60-80 ℃ for 8-15 hours; roasting for 10-16h at 500-600 ℃.
9. The method according to any one of claims 1 or 7, wherein the mesoporous molecular sieve SBA-15 is prepared by: mixing P123 with water and concentrated hydrochloric acid to obtain a clear solution, dropwise adding TEOS at the temperature of 40-60 ℃, stirring for reaction to obtain white sol, cooling after ageing, filtering, washing to be neutral, drying and calcining to obtain the mesoporous molecular sieve SBA-15.
10. The preparation method according to claim 1, wherein in the step 2), the specific post-treatment process is as follows: adding ice water into the reaction solution, stirring for 0.5-2 h, heating to 40-60 ℃, filtering the molecular sieve to load the alkaline catalyst while the reaction solution is hot, and washing the recovered catalyst with water for recycling; the filtered reaction liquid is subjected to gradient cooling and stirring, then is filtered, the crude product is pulped for 1-2 hours at 20-30 ℃ by using clear water, and is filtered and dried, thus obtaining a pale yellow powder solid product.
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