CN117510426A - Synthesis method of anticoccidial veterinary drug triazine ring - Google Patents
Synthesis method of anticoccidial veterinary drug triazine ring Download PDFInfo
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- CN117510426A CN117510426A CN202410008597.8A CN202410008597A CN117510426A CN 117510426 A CN117510426 A CN 117510426A CN 202410008597 A CN202410008597 A CN 202410008597A CN 117510426 A CN117510426 A CN 117510426A
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- reaction
- triazine ring
- cyclization
- compound
- coupling reaction
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- 230000001165 anti-coccidial effect Effects 0.000 title claims abstract description 17
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 239000000273 veterinary drug Substances 0.000 title claims abstract description 16
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- -1 triazine ring compound Chemical class 0.000 claims abstract description 54
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 46
- 238000005859 coupling reaction Methods 0.000 claims abstract description 39
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 15
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 33
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 239000012954 diazonium Substances 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 claims description 21
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 20
- 235000010288 sodium nitrite Nutrition 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 239000004280 Sodium formate Substances 0.000 claims description 14
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 14
- 235000019254 sodium formate Nutrition 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- VIANBEAUACIOKY-UHFFFAOYSA-M sodium;3-ethoxy-3-oxopropanoate Chemical compound [Na+].CCOC(=O)CC([O-])=O VIANBEAUACIOKY-UHFFFAOYSA-M 0.000 claims description 12
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 10
- 235000019253 formic acid Nutrition 0.000 claims description 10
- ZSZFUDFOPOMEET-UHFFFAOYSA-N 2-(4-chlorophenyl)-2-[2,6-dichloro-4-(3,5-dioxo-1,2,4-triazin-2-yl)phenyl]acetonitrile Chemical compound C1=CC(Cl)=CC=C1C(C#N)C1=C(Cl)C=C(N2C(NC(=O)C=N2)=O)C=C1Cl ZSZFUDFOPOMEET-UHFFFAOYSA-N 0.000 claims description 8
- 235000011054 acetic acid Nutrition 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 229960000248 diclazuril Drugs 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 4
- IVYMIRMKXZAHRV-UHFFFAOYSA-N 4-chlorophenylacetonitrile Chemical group ClC1=CC=C(CC#N)C=C1 IVYMIRMKXZAHRV-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 claims description 2
- 229960001380 cimetidine Drugs 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 208000003495 Coccidiosis Diseases 0.000 claims 2
- 206010023076 Isosporiasis Diseases 0.000 claims 2
- 239000011541 reaction mixture Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 description 27
- 239000000047 product Substances 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 8
- 230000008878 coupling Effects 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- FTYAFGJLOIZOPD-UHFFFAOYSA-N N-[4-(4-amino-2-methylphenoxy)phenyl]acetamide Chemical compound CC1=C(C=CC(=C1)N)OC2=CC=C(C=C2)NC(=O)C FTYAFGJLOIZOPD-UHFFFAOYSA-N 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000006149 azo coupling reaction Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical group C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 239000002920 hazardous waste Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- WVUCPRGADMCTBN-UHFFFAOYSA-M potassium;3-ethoxy-3-oxopropanoate Chemical compound [K+].CCOC(=O)CC([O-])=O WVUCPRGADMCTBN-UHFFFAOYSA-M 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- OCINXEZVIIVXFU-UHFFFAOYSA-N 1-methyl-3-[3-methyl-4-[4-(trifluoromethylthio)phenoxy]phenyl]-1,3,5-triazinane-2,4,6-trione Chemical compound CC1=CC(N2C(N(C)C(=O)NC2=O)=O)=CC=C1OC1=CC=C(SC(F)(F)F)C=C1 OCINXEZVIIVXFU-UHFFFAOYSA-N 0.000 description 1
- QMNWYGTWTXOQTP-UHFFFAOYSA-N 1h-triazin-6-one Chemical group O=C1C=CN=NN1 QMNWYGTWTXOQTP-UHFFFAOYSA-N 0.000 description 1
- YVPUHAUYKMGZAY-UHFFFAOYSA-N 2-(4-amino-2,6-dichlorophenyl)-2-(4-chlorophenyl)acetonitrile Chemical compound ClC1=CC(N)=CC(Cl)=C1C(C#N)C1=CC=C(Cl)C=C1 YVPUHAUYKMGZAY-UHFFFAOYSA-N 0.000 description 1
- HGINADPHJQTSKN-UHFFFAOYSA-M 3-ethoxy-3-oxopropanoate Chemical compound CCOC(=O)CC([O-])=O HGINADPHJQTSKN-UHFFFAOYSA-M 0.000 description 1
- PHCWHZOOVBIOKL-UHFFFAOYSA-N C(CC(=O)O)(=O)O.C(C)[Na] Chemical compound C(CC(=O)O)(=O)O.C(C)[Na] PHCWHZOOVBIOKL-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 1
- 229960000898 toltrazuril Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
- Y02A40/70—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in livestock or poultry
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of an anticoccidial veterinary drug triazine ring, which belongs to the technical field of veterinary drugs, and comprises the following steps of: diazo reaction, coupling reaction and cyclization reaction; the cyclization reaction is carried out by adding cyclization agent and carbamic acid ethyl ester into coupling reaction product, carrying out cyclization reaction at 70-90 deg.C, tracking concentration of coupling reaction product in reaction system in cyclization reaction until concentration of coupling reaction product is less than 0.1%, finishing reaction, and post-treating to obtain triazine ring compound; the method has the advantages of cheap and easily obtained raw materials, mild conditions, high atom utilization rate and yield, shortened integral reaction steps, improved economic benefit, reduced total amount of three wastes and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of veterinary medicines, in particular to a synthesis method of an anticoccidial veterinary medicine triazine ring.
Background
Triazine ring veterinary drugs, such as Sha Mizhu and diclazuril, are high-efficiency low-toxicity broad-spectrum anticoccidial drugs. The composition can be clinically used for preventing and controlling poultry coccidium. The existing anticoccidial medicines such as toltrazuril, diclazuril, sha Mizhu and the like generally have better anticoccidial performance, wherein, the diclazuril has extremely low dosage, and the Sha Mizhu has lower drug resistance, so that the anticoccidial medicines have wide application in the prevention and treatment of poultry coccidium.
The synthesis process of the existing triazine ring veterinary drug diclazuril and Sha Mizhu comprises the steps of taking acetic acid as a solvent, adding aniline compound and diethyl oxycarbonyl malonamide into the solvent, then dropwise adding aqueous solution of sodium nitrite for diazotization, and then carrying out heat preservation for coupling,
Carrying out cyclization under the condition of sodium acetate, adding hydrochloric acid for hydrolysis, and finally decarboxylating, and adding a cyclization agent for preparing the total six steps of reactions; however, the cyclizing agent diethyl oxycarbonyl malonamide used in the conventional synthesis process of the 1,2, 4-triazine ring of diclazuril and Sha Mizhu is extremely easy to hydrolyze, so that the raw material unit consumption is high, a large amount of intermediates are generated in the diazo, coupling and cyclization processes, and finally, the purity of the product is low and the yield is low.
Chinese patent CN101050202 discloses a novel triazine compound with anticoccidial activity, a preparation method and application thereof, and the triazine compound obtained by the preparation method has low yield, and the qualified product can be obtained only by complicated refining means, which is not suitable for industrial production.
Chinese patent CN113248453B discloses a preparation method of triazinone ring, in which aniline and potassium monoethylmalonate are subjected to diazonium condensation reaction, then are subjected to amidation reaction with sodium cyanate under acidic condition, and finally acetic acid and sodium acetate are added, and the temperature is raised for cyclization reaction, thus obtaining triazinone compound; however, the method uses potassium monoethyl malonate, the cost of the potassium salt is higher, acetic acid and sodium nitrite are added in the diazotization step, a mixed system of potassium acetate, sodium acetate and acetic acid is obtained after the reaction is finished, the final byproducts can only be used as hazardous waste, and the amidation and cyclization reactions also generate byproducts of sodium chloride and sodium acetate, so that hazardous waste generated in the preparation is difficult to treat.
Chinese patent CN114890962B discloses a method for synthesizing anticoccidial veterinary medicine 1,2, 4-triazine ring, which uses malonic acid and carbamic acid ethyl ester as reaction raw materials, adds acetic anhydride, heats and carries out heat preservation reaction, and separates to obtain malonic acid monoamide carbamic acid ethyl ester; adding an aniline compound and malonic acid monoamide ethyl formate into acetic acid, and diazo-coupling by sodium nitrite to obtain a reaction solution containing a diazo-coupling product; taking a reaction solution containing a diazonium coupling product, adding a cyclization agent into the reaction solution, heating, refluxing and distilling to obtain the product; however, acetic anhydride is needed in the synthesis of the malonic acid monoamide ethyl formate, water is generated in the reaction in the step, the acetic anhydride is easy to hydrolyze, the loss of raw materials and auxiliary materials is large, and in the synthesis method, an aqueous solution of sodium nitrite is used, hydrolysis exists in the coupling process of the malonic acid monoamide ethyl formate due to the addition of a large amount of water, the consumption of the raw materials and the auxiliary materials, namely the malonic acid monoamide ethyl formate, is increased, and the cost is increased.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a synthesis method of the anticoccidial veterinary drug triazine ring, which has the advantages of cheap and easily obtained raw materials, mild conditions, high atom utilization rate and yield, shortened integral reaction steps, improved economic benefit and reduced total amount of three wastes, and is more suitable for industrial production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a synthesis method of an anticoccidial veterinary drug triazine ring comprises the following steps: diazo reaction, coupling reaction and cyclization reaction;
adding a solvent and an aniline compound into a reaction vessel, controlling the temperature of the reaction vessel to 5-20 ℃, stirring, slowly adding sodium nitrite, performing diazonium reaction at 5-20 ℃ after the addition, controlling the diazonium reaction time to be 1h, and obtaining a diazonium reaction product after the reaction is finished;
in the diazo reaction, the solvent is one of formic acid, acetic acid and propionic acid;
preferably, the solvent is formic acid;
the mass ratio of the solvent to the aniline compound is 2-3:1;
preferably, the mass ratio of the solvent to the aniline compound is 2.5:1;
preferably, the temperature of the diazonium reaction is 10-15 ℃;
the adding time of the sodium nitrite is 0.5h;
the molar ratio of the aniline compound to the sodium nitrite is 1:1.0-1.05;
preferably, the molar ratio of the aniline compound to sodium nitrite is 1:1;
the structural general formula of the aniline compound is as follows:
wherein R1 is acetaminophenoxy, R2 is hydrogen, and R3 is methyl; or R1 is 2- (4-chlorophenyl) acetonitrile group, R2 is chlorine, and R3 is chlorine;
adding sodium monoethylmalonate into the diazonium reaction product, performing coupling reaction at 20-30 ℃, controlling the coupling reaction time to be 2h, and obtaining the coupling reaction product after the reaction is finished;
the molar ratio of the aniline compound in the diazo reaction to the sodium monoethylmalonate in the coupling reaction is 1:1.0-1.05;
preferably, the molar ratio of the aniline compound in the diazonium reaction to the monoethyl malonate sodium in the coupling reaction is 1:1.025;
preferably, the temperature of the coupling reaction is 25 ℃;
the sodium monoethyl malonate is prepared by reacting diethyl malonate with sodium hydroxide according to a molar ratio of 1:1 at 120 ℃.
The structural general formula of the coupling reaction product is as follows:
the cyclization reaction is carried out by adding cyclization agent and carbamic acid ethyl ester into coupling reaction product, carrying out cyclization reaction at 70-90 deg.C, tracking concentration of coupling reaction product in reaction system in cyclization reaction until concentration of coupling reaction product is less than 0.1%, finishing reaction, and post-treating to obtain triazine ring compound;
the cyclic mixture is one of sodium formate, potassium formate and ammonium formate;
preferably, the cyclization agent is sodium formate;
the molar ratio of the aniline compound in the diazo reaction to the ethyl carbamate in the cyclization reaction is 1:1.0-1.05;
preferably, the molar ratio of the aniline compound in the diazonium reaction to the ethyl carbamate in the cyclization reaction is 1:1.025;
the molar ratio of the aniline compound in the diazonium reaction to the cyclization mixture in the cyclization reaction is 1:0-0.5;
preferably, the molar ratio of the aniline compound in the diazonium reaction to the cyclization mixture in the cyclization reaction is 1:0.5;
and (3) the post-treatment is carried out, and the filtering, the water washing and the separation are carried out after the solvent is recovered.
The structural general formula of the triazine ring compound is as follows:
when R1 in the structural general formulas of the aniline compound, the coupling reaction product and the triazine ring compound is acetaminophenoxy, R2 is hydrogen and R3 is methyl, the triazine ring compound is cimetidine;
when the aniline compound, the coupling reaction product and the triazine ring compound have the structural general formula, R1 is 2- (4-chlorophenyl) acetonitrile group, R2 is chlorine, R3 is chlorine, and the triazine ring compound is diclazuril.
Compared with the prior art, the invention has the beneficial effects that:
(1) According to the invention, the diethyl malonate and sodium hydroxide are used for synthesizing the monoethyl malonate sodium salt in equimolar quantity, then diazo coupling decarboxylation is synchronously carried out in the reaction process of the monoethyl malonate and the aniline compound, and then sodium formate is added for cyclization reaction to obtain the triazine ring veterinary drug, so that the raw materials are cheap and easy to obtain, the condition is mild, the atom utilization rate is high, the three wastes are few, the operation is simple and convenient, the cost is low, the industrial production is suitable, the step of decarboxylation of thioglycollic acid is saved, compared with the prior art, the mixed salt of sodium chloride and sodium acetate is not generated, and the cyclization agent in the cyclization reaction can be recycled;
(2) Under the condition of new raw materials, the invention obtains the product with higher yield by three steps of reactions, has extremely high economic value, less material conversion, simple operation, low-cost and easily obtained raw materials, less three wastes, low production cost, 96.1-98.5 percent of total reaction yield and 97.8-99.1 percent of product purity, and is suitable for industrial production;
(3) The method unifies the solvents, so that the reaction can be performed by a one-pot method, the investment is reduced, sodium formate generated by diazo coupling can be used as a cyclization reagent, the cost of raw materials and auxiliary materials is reduced, and only sodium formate in the product can be purified by a simple mode for recycling, so that compared with the prior art, the method has higher industrial value.
Drawings
FIG. 1 is a liquid chromatogram of the reaction system after the cyclization reaction was performed for 2 hours in example 2;
FIG. 2 is a liquid chromatogram of the reaction system after 4 hours of cyclization in example 2;
FIG. 3 is a liquid chromatogram of the reaction system after 7 hours of cyclization in example 2;
FIG. 4 is a liquid chromatogram of the reaction system after the cyclization reaction was performed for 8 hours in example 2.
Detailed Description
Specific embodiments of the present invention will now be described in order to provide a clearer understanding of the technical features, objects and effects of the present invention.
The reaction schemes of examples 2-24 are:
the reaction scheme for example 25 is:
example 1
Adding 2000g of diethyl malonate and 499.47g of sodium hydroxide into a 3000mL reaction kettle, carrying out reduced pressure reaction at 120 ℃ and rectifying to remove ethanol, finishing the reaction when the ethanol is not generated at the top of the kettle, cooling, and filtering and separating to obtain filter residues, wherein the weight of the filter residues is 949.55g of monoethyl sodium malonate, the yield is 98.3%, and the purity is 99.6%; and (5) applying the filtrate mechanically.
Example 2
150g of formic acid, 50g of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide and stirring at a stirring speed of 300rpm are added into a 500mL four-port bottle, the temperature is reduced to 10 ℃, 13.46g of sodium nitrite is added by using a solid powder screw feeder, the charging time is controlled to be 0.5h, the temperature is kept for 1h after charging, diazonium reaction is carried out, 31.57g of sodium monoethyl malonate is added, the temperature is increased to 25 ℃, the reaction is carried out for 2h, coupling products are obtained, 3.98g of sodium formate of cyclic agent and 17.81g of ethyl carbamate are added into the obtained coupling products, the reaction is carried out after heating to 80 ℃, the concentration of the coupling reaction products is controlled to be less than 0.1%, the reaction is finished, the liquid chromatogram obtained after the cyclization reaction is carried out for 2h, 4h, 7h and 8h is shown in figures 1,2, 3 and 4h, wherein the peak at 24min is the peak of the reaction products, the peak of the reaction products is recovered after the cyclization reaction is finished, the solvent is filtered, washed and separated to obtain Sha Mizhu%, the coupling products have a purity of 3779%, and the purity of the coupling products is 96.3.3%.
Example 3
The same preparation as in example 2 was used, except that: the addition amount of the sodium monoethylmalonate is changed to 30.81g, and finally Sha Mizhu:67.97 g is obtained, the yield is 97.6%, and the purity is 98.7%.
Example 4
The same preparation as in example 2 was used, except that: the addition amount of the sodium monoethylmalonate is changed to 30.06g, and Sha Mizhu g-67.55 g is finally obtained, the yield is 96.8%, and the purity is 98.5%.
From the results of examples 2-4, it can be seen that the optimum molar ratio of aniline to sodium monoethylmalonate is 1:1.025.
Example 5
The same preparation as in example 3 was used, except that: the coupling reaction temperature was 20℃to give Sha Mizhu to 67.90g in 96.9% yield and 98.1% purity.
Example 6
The same preparation as in example 3 was used, except that: the coupling reaction temperature was 30℃to give Sha Mizhu g/67.69 g in 96.7% yield and 98.2% purity.
As can be seen from the results of examples 3, 5 and 6, the optimal temperature for the coupling reaction was 25 ℃.
Example 7
The same preparation as in example 3 was used, except that: the adding amount of sodium nitrite is changed to 13.80g, and Sha Mizhu g-67.83 g is finally obtained, the yield is 97.2%, and the purity is 98.5%.
Example 8
The same preparation as in example 3 was used, except that: the addition amount of sodium nitrite is changed to 14.13g, and Sha Mizhu:67.76 g is finally obtained, the yield is 97%, and the purity is 98.4%.
From the results of examples 3, 7, 8, it can be seen that the optimum molar ratio of aniline to sodium nitrite is 1:1.
Example 9
The same preparation as in example 3 was used, except that: the temperature of the diazo reaction is changed to 5 ℃, and Sha Mizhu to 67.06g is finally obtained, the yield is 96.1 percent, and the purity is 98.5 percent.
Example 10
The same preparation as in example 3 was used, except that: the temperature of the diazo reaction is changed to 15 ℃, and Sha Mizhu g/67.83 g is finally obtained, the yield is 97.5%, and the purity is 98.8%.
Example 11
The same preparation as in example 3 was used, except that: the temperature of the diazo reaction is changed to 20 ℃, and Sha Mizhu g/67.55 g is finally obtained, the yield is 96.5%, and the purity is 98.2%.
As can be seen from the results of examples 3, 9-11, the optimum temperature for the diazonium reaction is 10-15 ℃.
Example 12
The same preparation as in example 3 was used, except that: the addition amount of formic acid is changed to 100g, and Sha Mizhu and 67.62g are finally obtained, the yield is 96.8%, and the purity is 98.4%.
Example 13
The same preparation as in example 3 was used, except that: the addition amount of formic acid is changed to 125g, and Sha Mizhu and 68.18g are finally obtained, the yield is 98.1%, and the purity is 98.9%.
From the results of examples 3, 12, 13, it can be seen that the optimum mass ratio of formic acid to N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide is 2.5:1.
Example 14
The same preparation as in example 13 was used, except that: equivalent amount of formic acid is replaced by acetic acid, and Sha Mizhu:67.90 g is finally obtained, the yield is 97.4%, and the purity is 98.6%.
Example 15
The same preparation as in example 13 was used, except that: equivalent amount of formic acid is replaced by propionic acid, sha Mizhu g, 67.96g and 96.7% yield and 97.8% purity are finally obtained.
From the results of examples 13-15, it can be seen that the most preferred solvent for the diazo reaction is formic acid.
Example 16
The same preparation as in example 13 was used, except that: the addition amount of methyl carbamate is changed to 17.38g, and Sha Mizhu, 68.25g, yield 97.7% and purity 98.4% are finally obtained.
Example 17
The same preparation as in example 13 was used, except that: the addition amount of methyl carbamate is changed to 18.25g, and Sha Mizhu to 67.90g is finally obtained, the yield is 97.5%, and the purity is 98.7%.
From the results of examples 13, 16, 17, it can be seen that the optimum molar ratio of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide to ethyl carbamate is 1:1.05;
example 18
The same preparation as in example 13 was used, except that: the addition amount of sodium formate is changed to 1.33g, and Sha Mizhu g/67.83 g is finally obtained, the yield is 97.3%, and the purity is 98.6%.
Example 19
The same preparation as in example 13 was used, except that: the addition amount of sodium formate is changed to 6.63g, and Sha Mizhu g/68.32 g is finally obtained, the yield is 98.5%, and the purity is 99.1%.
Example 20
The same preparation as in example 13 was used, except that: the addition of sodium formate was omitted, and Sha Mizhu to 66.66g was finally obtained in 93.1% yield and 96% purity.
From the results of examples 13, 18, 19, 20, it can be seen that the optimum molar ratio of N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide to sodium formate is 1:0.5;
example 21
The same preparation as in example 19 was used, except that: the temperature of the cyclization reaction is changed to 70 ℃, and Sha Mizhu g/68.39 g is finally obtained, the yield is 98.4%, and the purity is 98.9%.
Example 22
The same preparation as in example 19 was used, except that: the temperature of the cyclization reaction is changed to 90 ℃, and Sha Mizhu g/68.39 g is finally obtained, the yield is 98.3%, and the purity is 98.8%.
As can be seen from the results of examples 19, 21 and 22, the cyclization reaction temperature was 70-90℃and the yields were high.
Example 23
The same preparation as in example 19 was used, except that: equal amount of sodium formate is replaced by potassium formate, and Sha Mizhu g with 68.25g, yield 98% and purity 98.7% are finally obtained.
Example 24
The same preparation as in example 19 was used, except that: equivalent substitution of sodium formate with ammonium formate finally gives Sha Mizhu to 67.90g, 97.1% yield and 98.3% purity.
From the results of examples 19, 23, 24, it can be seen that the most preferred choice of ring-forming agent in the cyclization reaction is sodium formate.
Example 25
The same preparation as in example 19 was used, except that: 50. 50g N- (4- (4-amino-2-methylphenoxy) phenyl) acetamide was replaced with 60.79g of 2- (4-amino-2, 6-dichlorophenyl) -2- (4-chlorophenyl) acetonitrile to give 80.37g of diclazuril in 97.5% yield and 98.9% purity.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. The synthesis method of the anticoccidial veterinary drug triazine ring is characterized by comprising the following steps of: diazo reaction, coupling reaction and cyclization reaction;
adding a solvent and an aniline compound into a reaction vessel, controlling the temperature of the reaction vessel to 5-20 ℃, stirring, slowly adding sodium nitrite, performing diazonium reaction at 5-20 ℃ after the addition, controlling the diazonium reaction time to be 1h, and obtaining a diazonium reaction product after the reaction is finished;
the structural general formula of the aniline compound is as follows:
；
in the structural general formula of the aniline compound, R1 is acetaminophenoxy, R2 is hydrogen, and R3 is methyl; or R1 is 2- (4-chlorophenyl) acetonitrile group, R2 is chlorine, and R3 is chlorine;
adding sodium monoethylmalonate into the diazonium reaction product, performing coupling reaction at 20-30 ℃, controlling the coupling reaction time to be 2h, and obtaining the coupling reaction product after the reaction is finished;
and (3) adding a cyclization reaction mixture and ethyl carbamate into the coupling reaction product, performing the cyclization reaction at 70-90 ℃, and tracking the concentration of the coupling reaction product in a reaction system in the cyclization reaction until the concentration of the coupling reaction product is less than 0.1%, and performing post-treatment to obtain the triazine ring compound.
2. The method for synthesizing the anticoccidial veterinary drug triazine ring according to claim 1, wherein in the diazonium reaction, the solvent is one of formic acid, acetic acid and propionic acid;
the mass ratio of the solvent to the aniline compound is 2-3:1;
the adding time of the sodium nitrite is 0.5h;
the molar ratio of the aniline compound to the sodium nitrite is 1:1.0-1.05.
3. The method for synthesizing the triazine ring of the anticoccidial veterinary drug according to claim 1, wherein the molar ratio of the aniline compound in the diazonium reaction to the sodium monoethylmalonate in the coupling reaction is 1:1.0-1.05.
4. The method for synthesizing the anticoccidial veterinary drug triazine ring according to claim 1, wherein the sodium monoethylmalonate is prepared by reacting diethyl malonate with sodium hydroxide according to a molar ratio of 1:1 at 120 ℃.
5. The method for synthesizing the triazine ring of the anti-coccidiosis veterinary drug according to claim 1, wherein in the cyclization reaction, the cyclization agent is one of sodium formate, potassium formate and ammonium formate.
6. The method for synthesizing the triazine ring of the anti-coccidiosis veterinary drug according to claim 1, wherein the molar ratio of the aniline compound in the diazonium reaction to the ethyl carbamate in the cyclization reaction is 1:1.0-1.05;
the molar ratio of the aniline compound in the diazonium reaction to the cyclization mixture in the cyclization reaction is 1:0-0.5;
and (3) the post-treatment is carried out, and the filtering, the water washing and the separation are carried out after the solvent is recovered.
7. The method for synthesizing the anticoccidial veterinary drug triazine ring according to claim 1, wherein the coupling reaction product has a structural formula as follows:
；
the structural general formula of the triazine ring compound is as follows:
；
when R1 in the structural general formulas of the aniline compound, the coupling reaction product and the triazine ring compound is acetaminophenoxy, R2 is hydrogen and R3 is methyl, the triazine ring compound is cimetidine;
when the aniline compound, the coupling reaction product and the triazine ring compound have the structural general formula, R1 is 2- (4-chlorophenyl) acetonitrile group, R2 is chlorine, R3 is chlorine, and the triazine ring compound is diclazuril.
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