CN116789606A - Synthesis and refining method of 2, 4-diamino-5, 6-dichloropyrimidine - Google Patents
Synthesis and refining method of 2, 4-diamino-5, 6-dichloropyrimidine Download PDFInfo
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- CN116789606A CN116789606A CN202310734850.3A CN202310734850A CN116789606A CN 116789606 A CN116789606 A CN 116789606A CN 202310734850 A CN202310734850 A CN 202310734850A CN 116789606 A CN116789606 A CN 116789606A
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- diamino
- dichloropyrimidine
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- LQNTZVJAJKGYMB-UHFFFAOYSA-N 5,6-dichloropyrimidine-2,4-diamine Chemical compound NC1=NC(N)=C(Cl)C(Cl)=N1 LQNTZVJAJKGYMB-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 238000007670 refining Methods 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 27
- 230000015572 biosynthetic process Effects 0.000 title abstract description 11
- 238000003786 synthesis reaction Methods 0.000 title abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 26
- QJIUMVUZDYPQRT-UHFFFAOYSA-N 6-chloro-2,4-pyrimidinediamine Chemical compound NC1=CC(Cl)=NC(N)=N1 QJIUMVUZDYPQRT-UHFFFAOYSA-N 0.000 claims abstract description 25
- 150000004965 peroxy acids Chemical class 0.000 claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 15
- 239000012065 filter cake Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 3
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 239000000575 pesticide Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- KOZORTLKFZNFEZ-UHFFFAOYSA-N 3-chlorobenzenecarboperoxoic acid;hydrochloride Chemical compound Cl.OOC(=O)C1=CC=CC(Cl)=C1 KOZORTLKFZNFEZ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- ULQQGOGMQRGFFR-UHFFFAOYSA-N 2-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=CC=C1Cl ULQQGOGMQRGFFR-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000000864 peroxy group Chemical group O(O*)* 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- -1 pyrimidine compound Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960002135 sulfadimidine Drugs 0.000 description 1
- ASWVTGNCAZCNNR-UHFFFAOYSA-N sulfamethazine Chemical compound CC1=CC(C)=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ASWVTGNCAZCNNR-UHFFFAOYSA-N 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical chemical industry, in particular to a method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine, which takes 2, 4-diamino-6-chloropyrimidine as a raw material and reacts in dilute hydrochloric acid solution in the presence of peroxyacid to obtain the 2, 4-diamino-5, 6-dichloropyrimidine. Compared with the traditional method, the synthesis and refining method of the 2, 4-diamino-5, 6-dichloropyrimidine has the advantages of easily available raw materials, low cost, easy control of reaction, simple post-treatment, high yield, suitability for industrial production and the like.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical industry, in particular to a method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine.
Background
2, 4-diamino-5, 6-dichloropyrimidine having formula C 4 H 4 C l2 N 4 Is pink crystalline powder. Pyrimidine compounds have active molecular structures, are intermediates of many medicines and pesticides, and have important roles in the pesticides and medicines. PyrimidineThe derivatives have various forms in human body, organism and natural world, and play important roles in physiological activities. Cytosine (C) and thymine (T) in DNA and cytosine (C) and uracil (U) in RNA, and a small number of modified bases, all contain pyrimidine rings. The special structure of the pyrimidine compound determines the special property of the compound, has the functions of resisting bacteria, killing insects and promoting plant regulation, and is widely used for preparing various pesticide products, such as pesticides, bactericides, herbicides and the like. The pyrimidine compounds can also form metal complexes with metal ions through intermolecular acting force, so that the pharmacological activity and the persistence are improved, the half life of the medicine is prolonged, and the toxicity and the side effects are effectively reduced. When used as a medical intermediate, the composition is mainly used for producing sulfonamides, such as sulfadimidine, sulfamethoxazole, sulfa Mo Tuoxin, sulfa-6-methoxypyrimidine and the like. Meanwhile, 2, 4-diamino-5, 6-dichloropyrimidine is also a raw material for synthesizing minoxidil impurities. Therefore, the synthesis research of the 2, 4-diamino-5, 6-dichloropyrimidine has important significance.
At present, few reports about the synthesis of 2, 4-diamino-5, 6-dichloropyrimidine are provided, and products can be synthesized through the reaction, but the raw materials are expensive, or the post-treatment is complex, so that the method is not suitable for industrial production.
Overseas patent KR2016002318 takes 2, 4-diamino-6-chloropyrimidine as a starting material and takes N, N' -Dimethylformamide (DMF) as a solvent to carry out substitution reaction with N-chlorosuccinimide (NCS) to obtain 2, 4-diamino-5, 6-dichloropyrimidine. The method needs NCS and simultaneously needs DMF as an organic solvent to allow the reaction to proceed, and the reaction time is 48 hours, so that the purity and the yield of the obtained 2, 4-diamino-5, 6-dichloropyrimidine are required to be improved.
Chinese patent CN115572265 uses 2, 4-diamino-6-chloropyrimidine as initial material and N, N' -Dimethylformamide (DMF) as solvent to produce substitution reaction with N-chlorosuccinimide (NCS) to obtain 2, 4-diamino-5, 6-dichloropyrimidine. The method requires Ethyl Acetate (EA) to be used for multiple times of extraction after the reaction is finished, and meanwhile, the purity and the yield of the obtained 2, 4-diamino-5, 6-dichloropyrimidine are required to be improved.
Disclosure of Invention
The invention aims to solve the technical problems that: in order to solve the technical problems of less synthesis of 2, 4-diamino-5, 6-dichloropyrimidine and lower purity and yield of the only synthesis method in the prior art. The invention provides a method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine, which has the advantages of easily available raw materials, low cost, high reaction efficiency, high yield, suitability for industrial production and the like. The technical scheme adopted for solving the technical problems is as follows: a method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine takes 2, 4-diamino-6-chloropyrimidine as raw material and reacts in dilute hydrochloric acid solution in the presence of peroxyacid to obtain 2, 4-diamino-5, 6-dichloropyrimidine.
The specific synthetic route is as follows:
further, the synthesis and refining method of the 2, 4-diamino-5, 6-dichloropyrimidine comprises the following steps:
dissolving 2, 4-diamino-6-chloropyrimidine in hydrochloric acid with preset concentration, slowly dropwise adding peroxy acid at preset temperature, and after the reaction is completed, performing post-treatment to obtain an intermediate 2, 4-diamino-5, 6-dichloropyrimidine.
Further, in the step, the molar ratio of the raw material 2, 4-diamino-6-chloropyrimidine to the peroxyacid is 1:1.1-1.3.
further, the peroxyacid includes chloroperoxybenzoic acid (m-CPBA), peroxyacetic acid (CH) 3 CO 3 H) And peroxyformic acid (HCO) 3 H) One or more of the following.
Further, the concentration of the preset hydrochloric acid is in the range of 2.0% -8.0%.
Further, the mass ratio of the 2, 4-diamino-6-chloropyrimidine to the total solvent is 1:6-10.
further, the reaction temperature is preset to be 15-30 ℃ and the reaction time is 4-12 h.
Further, the post-processing includes: mixing the crude 2, 4-diamino-5, 6-dichloropyrimidine obtained by the reaction with a refining solvent, refining to obtain a refining system, sequentially crystallizing and suction-filtering the refining system to obtain a filter cake, and finally sequentially washing and drying the filter cake to obtain the 2, 4-diamino-5, 6-dichloropyrimidine.
Further, the refining solvent includes one or more of methanol, ethanol, and water.
Further, the refining temperature is 75-85 ℃, and the crystallization temperature is 0-5 ℃.
The invention provides a method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine, which comprises the following steps: mixing 2, 4-diamino-6-chloropyrimidine, peroxy acid and dilute hydrochloric acid solution, and reacting at room temperature to obtain the 2, 4-diamino-5, 6-dichloropyrimidine crude product. The invention can improve the purity and the yield of the 2, 4-diamino-5, 6-dichloropyrimidine. The results of the examples show that the purity of the 2, 4-diamino-5, 6-dichloropyrimidine prepared by the invention is 98.76-99.52% and the yield is 90.71-96.12%.
Drawings
The invention will be further described with reference to the drawings and examples.
FIG. 1 is a schematic diagram of 2, 4-diamino-5, 6-dichloropyrimidine 1 H-NMR spectrum;
FIG. 2 is an LC-MS spectrum of 2, 4-diamino-5, 6-dichloropyrimidine.
Detailed Description
The invention provides a method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine, which comprises the following steps:
mixing 2, 4-diamino-6-chloropyrimidine, peroxy acid and dilute hydrochloric acid, and reacting at room temperature to obtain the 2, 4-diamino-5, 6-dichloropyrimidine crude product.
In the present invention, all raw material components are commercially available products well known to those skilled in the art unless specified otherwise.
The invention mixes 2, 4-diamino-6-chloropyrimidine, peroxy acid and dilute hydrochloric acid, and reacts at room temperature to obtain a crude product of 2, 4-diamino-5, 6-dichloropyrimidine. In the present invention, the molar ratio of 2, 4-diamino-6-chloropyrimidine to peroxyacid is preferably 1:1.1-1.3. in the present invention, the concentration of the dilute hydrochloric acid is 2.0% -8.0%. In the present invention, the peroxyacid includes m-chloroperoxybenzoic acid (m-CPBA), peroxyacetic acid (CH) 3 CO 3 H) And peroxyformic acid (HCO) 3 H) One or more of the following.
In the present invention, the mixing of 2, 4-diamino-6-chloropyrimidine, peroxy acid and dilute hydrochloric acid preferably comprises: dissolving 2, 4-diamino-6-chloropyrimidine in partial diluted hydrochloric acid to obtain 2, 4-diamino-6-chloropyrimidine solution, dissolving peroxyacid in the residual diluted hydrochloric acid to obtain peroxyacid-diluted hydrochloric acid solution, and dropwise adding the peroxyacid-diluted hydrochloric acid solution into the 2, 4-diamino-6-chloropyrimidine solution.
In the present invention, the mass ratio of 2, 4-diamino-6-chloropyrimidine to dilute hydrochloric acid is preferably 1:6-10, more preferably 1:8. in the present invention, the concentration of the diluted hydrochloric acid is 2.0% to 8.0%, more preferably 5%. In the present invention, the dissolution process of 2, 4-diamino-6-chloropyrimidine is preferably performed under stirring, and the dissolution temperature is preferably 10-20 ℃. In the invention, the 2, 4-diamino-6-chloropyrimidine solution is preferably kept at 15-30 ℃ and then the dilute acid solution of the peroxy acid-salt is added.
In the present invention, the mass ratio of the peroxyacid to the remaining acid solvent is preferably 1:3-6, more preferably 1:4.95. in the present invention, the dropping rate of the dilute peroxyacid-salt acid solution is preferably 0.1L/min. The invention adopts a dripping mode to avoid explosion risk caused by adding a large amount of peroxyacid at one time; meanwhile, the impurity generation can be avoided, and the purity of the product is improved.
In the present invention, the temperature of the reaction is preferably 15 to 30 ℃; the reaction time is preferably 4 to 12 hours, more preferably 6 to 8 hours, and the present invention preferably uses TLC to monitor the end of the reaction.
In the invention, proper post-treatment is carried out, preferably, the obtained reaction system is cooled and stirred, crystallization is carried out overnight, suction filtration is carried out, the obtained filter cake is washed by ethanol, and the crude product of 2, 4-diamino-5, 6-dichloropyrimidine is obtained after drying. In the present invention, the crystallization temperature is preferably 0 to 10 ℃, more preferably 2 to 5 ℃. In the invention, the crude product of the 2, 4-diamino-5, 6-dichloropyrimidine is a pink solid.
In a specific embodiment of the invention, the purity of the crude 2, 4-diamino-5, 6-dichloropyrimidine product is 93.66-97.66%, and the yield is 84.28-98.01%.
After obtaining a 2, 4-diamino-5, 6-dichloropyrimidine crude product, the invention preferably mixes the 2, 4-diamino-5, 6-dichloropyrimidine crude product with a refining solvent to refine to obtain a refining system, sequentially performs crystallization and suction filtration on the refining system to obtain a filter cake, and sequentially washes and dries the filter cake to obtain the 2, 4-diamino-5, 6-dichloropyrimidine. In the present invention, the refining solvent preferably includes one or more of methanol, ethanol, and water, more preferably a mixed solution of ethanol and water. In the present invention, the water is preferably purified water. In the invention, the mass ratio of ethanol to water in the mixed solution of methanol and water is preferably 1.2-1.3:1. in the invention, the mass ratio of the refining solvent to the crude product of 2, 4-diamino-5, 6-dichloropyrimidine is preferably 7-9:1. in the present invention, the refining is preferably carried out under reflux conditions, and the refining temperature is preferably 75-85 ℃; the time for the refining is preferably 1h. In the present invention, the crystallization temperature is preferably 0 to 5 ℃. In the present invention, the washing solvent is preferably ethanol.
In the present invention, 2, 4-diamino-5, 6-dichloropyrimidine is a pink solid.
The solvent used in the invention is environment-friendly, low in cost and easy to obtain, can be recycled, reduces the production cost, and is suitable for industrial production. In a specific embodiment of the present invention, the purity of the obtained 2, 4-diamino-5, 6-dichloropyrimidine is 98.76-99.52% and the yield is 90.71-96.12%.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Synthesis of crude 2, 4-diamino-5, 6-dichloropyrimidine
2mol of 2, 4-diamino-6-chloropyrimidine and 2.3kg of 5% diluted hydrochloric acid are added into a reaction kettle, the system is dissolved by stirring, the temperature is reduced to 15 ℃, a solution of m-chloroperoxybenzoic acid-hydrochloric acid prepared from 2.4mol of m-chloroperoxybenzoic acid and 2.1kg of diluted hydrochloric acid is added into the reaction kettle in a dropwise manner, the dropwise speed is 0.1L/min, the reaction is completed, and the reaction is carried out for 6 hours at 15 ℃, and the TLC chromatographic plate monitors the reaction end point. Stirring and cooling to 5 ℃, crystallizing overnight, filtering, washing a filter cake with methanol for one time, and drying to obtain 0.300kg of pink solid 2, 4-diamino-5, 6-dichloropyrimidine, wherein the purity of the product is 93.66%, and the yield is 84.28%.
Refining of 2, 4-diamino-5, 6-dichloropyrimidine
Adding 0.300kg of crude 2, 4-diamino-5, 6-dichloropyrimidine, 1.4kg of ethanol and 1.0kg of purified water into a reaction kettle, stirring and heating to 80 ℃, and carrying out reflux reaction for 1 hour to dissolve a system; stirring and cooling to 5 ℃, crystallizing overnight, filtering, washing a filter cake with ethanol once, and drying to obtain 0.271kg of pink solid 2, 4-diamino-5, 6-dichloropyrimidine, wherein the purity of the product is 99.24%, and the yield is 90.33%.
The chemical reaction formula for preparing the 2, 4-diamino-5, 6-dichloropyrimidine in the embodiment is as follows:
example 2
Synthesis of crude 2, 4-diamino-5, 6-dichloropyrimidine
2mol of 2, 4-diamino-6-chloropyrimidine and 2.3kg of 5% diluted hydrochloric acid are added into a reaction kettle, the system is dissolved by stirring, the temperature is reduced to 15 ℃ by stirring, a m-chloroperoxybenzoic acid-hydrochloric acid solution prepared from 2.4mol of peroxyacetic acid and 0.9kg of diluted hydrochloric acid is added into the reaction kettle in a dropwise manner, the dropwise speed is 0.1L/min, the reaction is completed after the dropwise addition, the reaction is carried out for 5 hours at 15 ℃, and a TLC chromatographic plate monitors the reaction end point. Stirring and cooling to 5 ℃, crystallizing overnight, filtering, washing a filter cake with methanol for one time, and drying to obtain 0.349kg of pink solid 2, 4-diamino-5, 6-dichloropyrimidine, wherein the purity of the product is 97.66%, and the yield is 98.01%.
Refining of 2, 4-diamino-5, 6-dichloropyrimidine
Adding 0.349kg of crude 2, 4-diamino-5, 6-dichloropyrimidine, 1.6kg of ethanol and 1.2kg of purified water into a reaction kettle, stirring and heating to 80 ℃, carrying out reflux reaction for 1 hour, dissolving the system, stirring and cooling to 5 ℃, crystallizing overnight, carrying out suction filtration, washing a filter cake with ethanol once, and drying to obtain 0.342kg of pink solid 2, 4-diamino-5, 6-dichloropyrimidine, wherein the purity of the product is 99.52%, and the yield is 98.07%.
The chemical reaction formula for preparing the 2, 4-diamino-5, 6-dichloropyrimidine in the embodiment is as follows:
example 3
Synthesis of crude 2, 4-diamino-5, 6-dichloropyrimidine
2mol of 2, 4-diamino-6-chloropyrimidine and 2.3kg of 5% dilute hydrochloric acid are added into a reaction kettle, the mixture is stirred to dissolve the system, and the mixture is stirred and cooled to 15 ℃; the reaction kettle is dripped with a solution of m-chloroperoxybenzoic acid-hydrochloric acid prepared from 2.4mol of m-chloroperoxybenzoic acid and 0.737kg of dilute hydrochloric acid, the dripping speed is 0.1L/min, the reaction is carried out for 6 hours at 15 ℃ after the dripping is finished, and the TLC chromatographic plate monitors the reaction end point. Stirring and cooling to 5 ℃, crystallizing overnight, filtering, washing a filter cake with methanol for one time, and drying to obtain 0.331kg of pink solid 2, 4-diamino-5, 6-dichloropyrimidine, wherein the purity of the product is 95.66%, and the yield is 93.01%.
Refining of 2, 4-diamino-5, 6-dichloropyrimidine
Adding 0.331kg of crude 2, 4-diamino-5, 6-dichloropyrimidine, 1.5kg of ethanol and 1.1kg of purified water into a reaction kettle, stirring and heating to 80 ℃, and carrying out reflux reaction for 1 hour to dissolve the system; stirring and cooling to 5 ℃, crystallizing overnight, filtering, washing a filter cake with ethanol once, and drying to obtain 0.314kg of pink solid 2, 4-diamino-5, 6-dichloropyrimidine, wherein the purity of the product is 98.54%, and the yield is 94.86%.
The chemical reaction formula for preparing the 2, 4-diamino-5, 6-dichloropyrimidine in the embodiment is as follows:
comparative example 1
Taking the example in overseas patent KR2016002318 as a comparative example, the reaction time was found to be too long, unfavorable for reaction monitoring, and more side reactions.
Comparative example 2
Using reference example 3 in Chinese patent CN115572265 as a comparative example, it was found that it was difficult to extract the product from water.
As shown in FIG. 1, the picture is 2, 4-diamino-5, 6-dichloropyrimidine 1 H-NMR spectra, in which 4 groups of peaks are visible, wherein δ=2.5 is the peak of solvent DMSO, δ=3.33 is the water peak, δ=6.49 is a single group of peaks for two hydrogens on the 2-amino group, and δ=6.97 is a single group of broad peaks for two hydrogens on the 4-amino group; therefore, the nuclear magnetic data is 1 H NMR(400MHz，DMSO－d 6 ): delta 6.97 (brs, 2H), 6.49 (s, 2H), demonstrating that 2, 4-diamino-5, 6-dichloropyrimidine was prepared;
as shown in FIG. 2, the pictures are 2, 4-diamino-5, 6-dichloropyrimidine and 2, 4-diamino-6-chloropyrimidineThe LG-MS spectra after mixing, in which 2 sets of peaks are visible, where time=1.27 is the peak of 2, 4-diamino-6-chloropyrimidine in the liquid phase, detected in mass spectrometry [ m+h] + =145.1 corresponds to reality; time=2.39 is the peak of 2, 4-diamino-5, 6-dichloropyrimidine in the liquid phase, detected in mass spectrometry [ m+h ]] + =179.0 corresponds to reality; the mass spectrum data of 2, 4-diamino-5, 6-dichloropyrimidine was therefore HRMS (ESI) m/z: [ M+H ]] + calcd for，C 4 H 5 Cl 2 N 4 179.0,found 179.0 it was further demonstrated that the synthesized compound was 2, 4-diamino-5, 6-dichloropyrimidine.
In summary, the synthesis and refining method of 2, 4-diamino-5, 6-dichloropyrimidine can improve the purity and yield of 2, 4-diamino-5, 6-dichloropyrimidine, and has the advantages of easily available raw materials, low cost, high efficiency of reaction, high yield, suitability for industrial production and the like.
With the above-described preferred embodiments according to the present invention as an illustration, the above-described descriptions can be used by persons skilled in the relevant art to make various changes and modifications without departing from the scope of the technical idea of the present invention. The technical scope of the present invention is not limited to the description, but must be determined as the scope of the claims.
Claims (10)
1. A method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine is characterized in that: 2, 4-diamino-6-chloropyrimidine is taken as a raw material, and reacts in a dilute hydrochloric acid solution in the presence of peroxyacid to obtain 2, 4-diamino-5, 6-dichloropyrimidine.
The specific synthetic route is as follows:
2. the method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine according to claim 1, wherein: the method comprises the following steps:
dissolving 2, 4-diamino-6-chloropyrimidine in hydrochloric acid with preset concentration, slowly dropwise adding peroxy acid at preset temperature, and after the reaction is completed, performing post-treatment to obtain an intermediate 2, 4-diamino-5, 6-dichloropyrimidine.
3. The method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine according to claim 2, wherein: the molar ratio of the raw materials of the step (A) to the peroxy acid is 1:1.1-1.3.
4. the method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine as claimed in claim 2, wherein: the peroxyacid includes one or more of m-chloroperoxybenzoic acid, peroxyacetic acid and peroxyformic acid.
5. The method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine as claimed in claim 2, wherein: the concentration range of the preset hydrochloric acid is 2.0% -8.0%.
6. The method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine as claimed in claim 2, wherein: the mass ratio of the 2, 4-diamino-6-chloropyrimidine to the total solvent is 1:6-10.
7. The method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine as claimed in claim 2, wherein: the reaction temperature is preset to be 15-30 ℃ and the reaction time is 4-12 h.
8. The method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine as claimed in claim 2, wherein: the post-treatment comprises the following steps: mixing the crude 2, 4-diamino-5, 6-dichloropyrimidine obtained by the reaction with a refining solvent, refining to obtain a refining system, sequentially crystallizing and suction-filtering the refining system to obtain a filter cake, and finally sequentially washing and drying the filter cake to obtain the 2, 4-diamino-5, 6-dichloropyrimidine.
9. The method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine as claimed in claim 8, wherein: the refining solvent includes one or more of methanol, ethanol, and water.
10. The method for synthesizing and refining 2, 4-diamino-5, 6-dichloropyrimidine as claimed in claim 8, wherein: the refining temperature is 75-85 ℃, and the crystallization temperature is 0-5 ℃.
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