CN109232441A - preparation method of 4-amino-2, 6-dimethoxypyrimidine - Google Patents
preparation method of 4-amino-2, 6-dimethoxypyrimidine Download PDFInfo
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- CN109232441A CN109232441A CN201810999839.9A CN201810999839A CN109232441A CN 109232441 A CN109232441 A CN 109232441A CN 201810999839 A CN201810999839 A CN 201810999839A CN 109232441 A CN109232441 A CN 109232441A
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- Prior art keywords
- methyl
- isourea
- added
- preparation
- cyanoacetate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- LNTJJKHTAZFVJJ-UHFFFAOYSA-N 2,6-dimethoxypyrimidin-4-amine Chemical compound COC1=CC(N)=NC(OC)=N1 LNTJJKHTAZFVJJ-UHFFFAOYSA-N 0.000 title abstract 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- MLIREBYILWEBDM-UHFFFAOYSA-M 2-cyanoacetate Chemical compound [O-]C(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-M 0.000 claims abstract description 10
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 102
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 43
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 32
- 238000004321 preservation Methods 0.000 claims description 30
- 238000005292 vacuum distillation Methods 0.000 claims description 30
- -1 cyano carbonyl-O- methyl-isourea Chemical compound 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- AJSGJCSWZUHDJB-UHFFFAOYSA-N 2,6-dimethoxypyridin-4-amine Chemical compound COC1=CC(N)=CC(OC)=N1 AJSGJCSWZUHDJB-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 238000004821 distillation Methods 0.000 claims description 14
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 claims description 14
- 229920002554 vinyl polymer Polymers 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 239000002904 solvent Chemical group 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methyl urea Chemical group CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 claims description 9
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- LHHACTKLABTCQF-UHFFFAOYSA-N [amino(hydroxy)methylidene]-methylazanium;chloride Chemical group Cl.CNC(O)=N LHHACTKLABTCQF-UHFFFAOYSA-N 0.000 claims description 6
- YOCUVKWMCBVIAF-UHFFFAOYSA-N acetic acid;methylurea Chemical group CC(O)=O.CNC(N)=O YOCUVKWMCBVIAF-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- 230000001035 methylating effect Effects 0.000 claims description 5
- OYPQRMVCANVXGY-UHFFFAOYSA-N methylurea;nitric acid Chemical group O[N+]([O-])=O.CNC(N)=O OYPQRMVCANVXGY-UHFFFAOYSA-N 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- ODJZWVFLHZHURI-UHFFFAOYSA-M [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] Chemical group [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] ODJZWVFLHZHURI-UHFFFAOYSA-M 0.000 claims 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 claims 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 18
- 238000004519 manufacturing process Methods 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 7
- 239000002351 wastewater Substances 0.000 abstract description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 4
- 239000011574 phosphorus Substances 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- RMAHPRNLQIRHIJ-UHFFFAOYSA-N methyl carbamimidate Chemical class COC(N)=N RMAHPRNLQIRHIJ-UHFFFAOYSA-N 0.000 abstract 1
- 230000011987 methylation Effects 0.000 abstract 1
- 238000007069 methylation reaction Methods 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 35
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 150000004703 alkoxides Chemical class 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 4
- 238000013019 agitation Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical group CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- SXGBREZGMJVYRL-UHFFFAOYSA-N butan-1-amine;hydrobromide Chemical compound [Br-].CCCC[NH3+] SXGBREZGMJVYRL-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000006198 methoxylation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UPVBKNZVOJNQKE-UHFFFAOYSA-N 2,6-dichloropyrimidin-4-amine Chemical compound NC1=CC(Cl)=NC(Cl)=N1 UPVBKNZVOJNQKE-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- OKUSWAGOKUGEDX-UHFFFAOYSA-N C(CCC)Br(CCCC)(CCCC)CCCC Chemical compound C(CCC)Br(CCCC)(CCCC)CCCC OKUSWAGOKUGEDX-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- AYTGUZPQPXGYFS-UHFFFAOYSA-N urea nitrate Chemical compound NC(N)=O.O[N+]([O-])=O AYTGUZPQPXGYFS-UHFFFAOYSA-N 0.000 description 1
- 210000003708 urethra Anatomy 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
- C07D239/52—Two oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to a preparation method of 4-amino-2, 6-dimethoxypyrimidine. The method takes o-methyl isourea salt and cyanoacetate as raw materials, and generates 4-amino-2, 6-dimethoxy pyrimidine through condensation, methylation and self cyclization. The invention not only simplifies the production process flow, optimizes the reaction conditions, improves the yield and the selectivity of the reaction, but also solves the problem that the original process can generate a large amount of colored phosphorus-containing wastewater, and provides a green and feasible path for the industrial production of the 4-amino-2, 6-dimethoxy pyrimidine. The structural formula of the 4-amino-2, 6-dimethoxypyrimidine is as follows:
Description
Technical field
The present invention relates to a kind of methodology of organic synthesis more particularly to a kind of preparations of 4- amino -2,6- dimethoxypyridin
Method.
Background technique
4- amino -2,6- dimethoxypyridin is a kind of important medicine intermediate, can be used for synthesizing sulfamethoxyplridazine
Medicine --- suladimethoxydiazine.This medicine is especially effective to the infection in terms of the upper respiratory tract and urethra, and to the stimulation pole of kidney
To be slight, side effect is low.As a kind of long-acting sulfonamide haveing excellent performance, the concentration of suladimethoxydiazine in blood can be tieed up
Longer time is held, thus the number and dosage that are administered can be greatly reduced.
There are mainly two types of the synthesis technologies of existing 4- amino -2,6- dimethoxypyridin maturation.The first is barbital
Acid system, using barbiturates as raw material, phosphorus oxychloride is chlorinating agent, and through chlorination, ammonification, methoxylation obtains 4- amino -2,6- diformazan
Oxygroup pyrimidine.Phosphorus oxychloride toxicity is big in the method, and by-product 4- amino -2,6- dichloro pyrimidine phosphinylidyne dichloro that it is generated is met
Water is explosive, brings security risk.A large amount of isomeric by-products can be generated in synthesis process, are not readily separated purification, and yield is low.And
And a large amount of coloured phosphorus-containing wastewater can be generated in production process, water body is polluted.Second is ethyl cyanoacetate method, with cyanogen
Ethyl acetate, urea, sodium ethoxide are raw material, phonetic through cyclization, acidification, chlorination, obtained 4- amino -2, the 6- dimethoxy of methoxylation
Pyridine, this is domestic mainstream production technology.On the one hand the intermediate product of this method easily hydrolysis reduces yield.On the other hand, this
Method also uses toxic chlorinated dose of phosphorus oxychloride, can generate and meet explosive by-product 4- amino -2, the 6- dichloro pyrimidine phosphinylidyne of water
Dichloro.And a large amount of coloured phosphorus-containing wastewater can be generated in the synthesis process, therefore develop an environmentally protective new process
Path is significantly.
We devise a new processing route in order to solve the above problem.It is original with adjacent methyl-isourea salt and cyanoacetate
Material, is condensed, then methylate, then self loop symphysis is at 4- amino -2,6- dimethoxypyridin.This process simplify technique roads
Diameter has skipped chlorinating step, avoids using phosphorus oxychloride, is not only improved yield and also greatly reduces waste water, has
Great social benefit, economic interests and environmentally friendly interests.
Summary of the invention
The object of the present invention is to provide a kind of 4- amino -2,6- dimethoxypyridin preparation sides of new green environment protection
Method.
The technical solution of the present invention is as follows: a kind of preparation method of 4- amino -2,6- dimethoxypyridin, specific steps
Are as follows:
(1) adjacent methyl-isourea salt, solvent dissolution are added in the reaction vessel, then heating stirring is added cyanoacetate, returns
Flow held for some time；
(2) heat preservation is finished, and first normal pressure steams methanol, then vacuum distillation obtains product N '-second cyano carbonyl-O- methyl-isourea to doing,
Structure such as Formulas I；
(3) in the N '-second cyano carbonyl-O- methyl-isourea that step (2) obtains be added solid base, phase transfer catalyst and
Methylating reagent, solvent dissolution, reflux heat preservation；
(4) cooling filtering；
(5) first normal pressure steams solvent, then vacuum distillation obtains product N '-(1- methoxyl group -2- vinyl)-O- first to doing
Base isourea, structure such as Formula II；
(6) methanolic sodium methoxide is added in N '-(1- methoxyl group -2- the vinyl)-O- methyl-isourea obtained step (5)
Solution keeps the temperature cyclization；
(7) heat preservation is finished, and first normal pressure steams methanol, then vacuum distillation is to dry；
(8) distillation is finished, and the water with quality such as solvents in step (3) is added, and alkali is added and adjusts pH；
(9) it through cooling, filters, washes, it is dry, obtain 4- amino -2,6- dimethoxypyridin；
Adjacent methyl-isourea salt is adjacent methyl-isourea disulfate, adjacent methyl-isourea hydrochloride, adjacent methyl in preferred steps (1)
One of isourea nitrate or adjacent methyl-isourea acetate；Cyanoacetate is methyl cyanoacetate or ethyl cyanoacetate.
Solvent is methanol or ethyl alcohol in preferred steps (1)；Cyanoacetate and adjacent methyl-isourea salt molar ratio be 1:(1.2~
2)。
Reflux temperature is 60~90 DEG C in preferred steps (1), and return time is 3~6h.
Vapo(u)rizing temperature is 40~80 DEG C in preferred steps (2), (5) and (7), and negative pressure is -0.09~-0.07MPa.
Solid base described in preferred steps (3) is potassium carbonate, sodium carbonate, sodium bicarbonate or saleratus；Solvent is third
Ketone, toluene or dimethylformamide；Phase transfer catalyst is tetrabutylammonium bromide, cetyl trimethylammonium bromide or the tetrabutyl
Ammonium hydrogen sulfate；Methylating reagent is dimethyl suflfate or dimethyl carbonate；N '-second cyano carbonyl-O- methyl-isourea is (with cyanoacetic acid
100% yield meter of ester) and the molar ratio of solid base, phase transfer catalyst and methylating reagent be respectively 1:(0.3~1), 1:
(0.08~0.12), 1:(1~2).
Reflux temperature is 50~80 DEG C in preferred steps (3), and return time is 5~8h；Temperature described in step (4) is 30
~50 DEG C.
The mass concentration of methanol solution of sodium methylate is 25%~60% in preferred steps (6)；N '-(1- methoxyl group -2- cyano
Vinyl) molar ratio of-O- methyl-isourea (in terms of 100% yield of cyanoacetate) and sodium methoxide is 1:(1.5~2).
Reflux temperature is 50~90 DEG C in preferred steps (6), and return time is 3~8h.
Alkali described in preferred steps (8) is sodium carbonate or sodium bicarbonate, and pH is 7~9.
Its synthetic route is as follows:
Wherein R1It can be HNO3, HCl, CH3COOH or H2SO4In any one；R2For any one in methyl or ethyl.
The utility model has the advantages that
The present invention is condensed using adjacent methyl-isourea salt and cyanoacetate as raw material, then is methylated, then self loop symphysis at
4- amino -2,6- dimethoxypyridin.This process simplify processing routes, have skipped chlorinating step, avoid using trichlorine oxygen
Phosphorus is not only improved yield and also greatly reduces waste water, has great social benefit, economic interests and environmentally friendly interests.
Invention not only simplifies the technological process of productions, optimize reaction condition, improve the yield and selectivity of reaction,
And solve the problems, such as that original technique can generate a large amount of coloured phosphorus-containing wastewaters, it is industrialized production 4- amino -2,6- dimethoxy
Yl pyrimidines provide the feasible path of green.
Specific embodiment
It is for a more detailed description to the present invention with embodiment below.These implement to be only to best mode for carrying out the invention
Description, do not have any restrictions to protection scope of the present invention.
Embodiment 1
Using adjacent methyl-isourea disulfate and methyl cyanoacetate as raw material
12mmol neighbour's methyl-isourea disulfate is added in the three-neck flask of 100mL in step 1., and dissolution 20mL methanol adds
10mmol methyl cyanoacetate is added when reaching 60 DEG C in thermal agitation, temperature, and 3h is kept the temperature at 60 DEG C, and heat preservation is finished, and controls vapo(u)rizing temperature
It is 40 DEG C, first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.08MPa, until no distillate, obtains 1.25g pale yellow powder
N '-second cyano carbonyl-O- methyl-isourea.
3mmol potassium carbonate, 0.8mmol is added in the pale yellow powder 10mmol (1.29g) that step 2. takes step (1) to obtain
Tetrabutylammonium bromide and 10mmol dimethyl suflfate, are dissolved in 20mL acetone.Then the back flow reaction 5h at 50 DEG C, heat preservation are finished,
30 DEG C are cooled to, filtering.Controlling vapo(u)rizing temperature is 80 DEG C, and first normal pressure steams acetone, then vacuum distillation to negative pressure is -0.09MPa, nothing
Until distillate, 1.41g pale yellow powder N '-(1- methoxyl group -2- vinyl)-O- methyl-isourea is obtained.
The first containing 15mmol sodium methoxide is added in the pale yellow powder 10mmol (1.55g) that step 3. takes step (2) to obtain
(methanol sodium content is 25wt%) to sodium alkoxide methanol solution, then the back flow reaction 3h at 60 DEG C.Heat preservation is finished, and control vapo(u)rizing temperature is
80 DEG C, first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.07MPa, and until without distillate, distillation is finished, addition and acetone
Etc. quality water, sodium carbonate is then added and adjusts pH to 9, cools to 10 DEG C, is filtered, washed, it is dry, obtain pale yellow powder 4-
Amino -2,6- dimethoxypyridin 1.33g, gross production rate are 86% (in terms of methyl cyanoacetate).
1H NMR(400MHz,DMSO-d6):δ6.60(s,2H,NH2),5.33(s,1H,CH),3.71(d,6H,OCH3)
ppm；
13C NMR(100MHz,DMSO-d6):δ172.5,172.3,170.8,84.7,56.8,56.8ppm。
Embodiment 2
Using adjacent methyl-isourea hydrochloride and methyl cyanoacetate as raw material
Step 1. is added 15mmol neighbour's methyl-isourea hydrochloride, is dissolved in 20mL methanol in the three-neck flask of 100mL,
10mmol methyl cyanoacetate is added when reaching 70 DEG C in heating stirring, temperature, and 5h is kept the temperature at 70 DEG C, and heat preservation is finished, control distillation temperature
Degree is 80 DEG C, and first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.08MPa, until no distillate, obtains the yellowish toner of 1.23g
Last N '-second cyano carbonyl-O- methyl-isourea.
5mmol potassium carbonate, 0.8mmol tetra- is added in the pale yellow powder 10mmol (1.29g) that step 2. takes step (1) to obtain
Butylammonium bromide and 12mmol dimethyl suflfate are dissolved in 20mL acetone, then the back flow reaction 6h at 60 DEG C, and heat preservation is complete, drop
Temperature is to 40 DEG C, filtering.Controlling vapo(u)rizing temperature is 40 DEG C, and first normal pressure steams acetone, then vacuum distillation to negative pressure is -0.09MPa, and nothing evaporates
Out until object, 1.36g pale yellow powder N '-(1- methoxyl group -2- vinyl)-O- methyl-isourea is obtained.
The first containing 17mmol sodium methoxide is added in the pale yellow powder 10mmol (1.55g) that step 3. takes step (2) to obtain
(methanol sodium content is 25wt%) to sodium alkoxide methanol solution, then the back flow reaction 3h at 60 DEG C.Heat preservation is finished, and control vapo(u)rizing temperature is
80 DEG C, first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.07MPa, and until no distillate, distillation is finished, be added with acetone etc.
Then the water of quality is added sodium bicarbonate and adjusts pH to 9, cools to 10 DEG C, filtered, washed, dry, obtains pale yellow powder 4-
Amino -2,6- dimethoxypyridin 1.29g, gross production rate are 83% (in terms of methyl cyanoacetate).
1H NMR(400MHz,DMSO-d6):δ6.60(s,2H,NH2),5.33(s,1H,CH),3.71(d,6H,OCH3)
ppm；
13C NMR(100MHz,DMSO-d6):δ172.5,172.3,170.8,84.7,56.8,56.8ppm。
Embodiment 3
Using adjacent methyl-isourea nitrate and methyl cyanoacetate as raw material
Step 1. is added 18mmol neighbour's methyl-isourea nitrate, is dissolved in 20mL methanol and adds in the three-neck flask of 100mL
10mmol methyl cyanoacetate is added when reaching 70 DEG C in thermal agitation, and 6h is kept the temperature at 70 DEG C, and heat preservation is finished, and control vapo(u)rizing temperature is 80
DEG C, first normal pressure steams methanol, then vacuum distillation to negative pressure is that -0.08MPa obtains 1.21g pale yellow powder until without distillate
N '-second cyano carbonyl-O- methyl-isourea.
8mmol potassium carbonate, 1mmol tetra- is added in the pale yellow powder 10mmol (1.29g) that step 2. takes step (1) to obtain
Butylammonium bromide and 16mmol dimethyl suflfate, are dissolved in 20mL acetone.Then the back flow reaction 6h at 70 DEG C, heat preservation are finished, drop
Temperature is to 50 DEG C, filtering.Controlling vapo(u)rizing temperature is 70 DEG C, and first normal pressure steams acetone, then vacuum distillation to negative pressure is -0.09MPa, until nothing
Until distillate, 1.32g pale yellow powder N '-(1- methoxyl group -2- vinyl)-O- methyl-isourea is obtained.
The first containing 18mmol sodium methoxide is added in the pale yellow powder 10mmol (1.55g) that step 3. takes step (2) to obtain
(methanol sodium content is 40wt%) to sodium alkoxide methanol solution, then the back flow reaction 5h at 70 DEG C.Heat preservation is finished, and control vapo(u)rizing temperature is
80 DEG C, first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.07MPa, and until no distillate, distillation is finished, be added with acetone etc.
Then the water of quality is added sodium carbonate and adjusts pH to 8, cools to 10 DEG C, filtered, washed, dry, obtains pale yellow powder 4- ammonia
Base -2,6- dimethoxypyridin 1.22g, gross production rate are 79% (in terms of methyl cyanoacetate).
1H NMR(400MHz,DMSO-d6):δ6.60(s,2H,NH2),5.33(s,1H,CH),3.71(d,6H,OCH3)
ppm；
13C NMR(100MHz,DMSO-d6):δ172.5,172.3,170.8,84.7,56.8,56.8ppm。
Embodiment 4
Using adjacent methyl-isourea acetate and methyl cyanoacetate as raw material
Step 1. is added 20mmol neighbour's methyl-isourea acetate, is dissolved in 20mL methanol in the three-neck flask of 100mL,
10mmol methyl cyanoacetate is added when reaching 80 DEG C in heating stirring, and 6h is kept the temperature at 80 DEG C, and heat preservation is finished, and control vapo(u)rizing temperature is
80 DEG C, first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.08MPa, until no distillate, obtains 1.21g pale yellow powder
N '-second cyano carbonyl-O- methyl-isourea.
10mmol potassium carbonate, 1.2mmol is added in the pale yellow powder 10mmol (1.29g) that step 2. takes step (1) to obtain
Tetrabutylammonium bromide and 20mmol dimethyl suflfate, are dissolved in 20mL acetone, then the back flow reaction 8h at 80 DEG C, and heat preservation is finished,
30 DEG C are cooled to, filtering.Controlling vapo(u)rizing temperature is 70 DEG C, and first normal pressure steams acetone, then vacuum distillation to negative pressure is -0.09MPa, nothing
Until distillate, 1.28g pale yellow powder N '-(1- methoxyl group -2- vinyl)-O- methyl-isourea is obtained.
The first containing 20mmol sodium methoxide is added in the pale yellow powder 10mmol (1.55g) that step 3. takes step (2) to obtain
(methanol sodium content is 60wt%) to sodium alkoxide methanol solution, then the back flow reaction 8h at 90 DEG C.Heat preservation is finished, and control vapo(u)rizing temperature is
80 DEG C, first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.09MPa, and until without distillate, distillation is finished, addition and acetone
Etc. quality water, sodium bicarbonate is then added and adjusts pH to 8, cools to 10 DEG C, is filtered, washed, it is dry, obtain pale yellow powder
4- amino -2,6- dimethoxypyridin 1.16g, gross production rate are 75% (in terms of methyl cyanoacetate).
1H NMR(400MHz,DMSO-d6):δ6.60(s,2H,NH2),5.33(s,1H,CH),3.71(d,6H,OCH3)
ppm；
13C NMR(100MHz,DMSO-d6):δ172.5,172.3,170.8,84.7,56.8,56.8ppm。
Embodiment 5
Using adjacent methyl-isourea disulfate and ethyl cyanoacetate as raw material
Step 1. is added 14mmol neighbour's methyl-isourea disulfate, is dissolved in 20mL second in the three-neck flask of 100mL
10mmol ethyl cyanoacetate is added when reaching 70 DEG C in alcohol, heating stirring, temperature, and 4h is kept the temperature at 70 DEG C, and heat preservation is finished, control distillation
Temperature is 80 DEG C, and first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.09MPa, and until no distillate, it is faint yellow to obtain 1.23g
Powder N '-second cyano carbonyl-O- methyl-isourea.
4mmol potassium carbonate, 0.8mmol is added in the pale yellow powder 10mmol (1.29g) that step 2. takes step (1) to obtain
4-butyl ammonium hydrogen sulfate and 11mmol dimethyl carbonate, are dissolved in 20mL toluene, then the back flow reaction 5h at 50 DEG C, heat preservation
Finish, is cooled to 50 DEG C, filtering.Controlling vapo(u)rizing temperature is 70 DEG C, and first normal pressure steams acetone, then vacuum distillation to negative pressure be-
It is different to obtain 1.39g pale yellow powder N '-(1- methoxyl group -2- vinyl)-O- methyl until without distillate by 0.07MPa
Urea.
The first containing 15mmol sodium methoxide is added in the pale yellow powder 10mmol (1.55g) that step 3. takes step (2) to obtain
(methanol sodium content is 25wt%) to sodium alkoxide methanol solution, then the back flow reaction 6h at 80 DEG C.Heat preservation is finished, and control vapo(u)rizing temperature is
50 DEG C, first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.09MPa, and until without distillate, distillation is finished, addition and toluene
Etc. quality water, sodium carbonate is then added and adjusts pH to 8, cools to 10 DEG C, is filtered, washed, it is dry, obtain pale yellow powder 4-
Amino -2,6- dimethoxypyridin 1.27g, gross production rate are 82% (in terms of ethyl cyanoacetate).
1H NMR(400MHz,DMSO-d6):δ6.60(s,2H,NH2),5.33(s,1H,CH),3.71(d,6H,OCH3)
ppm；
13C NMR(100MHz,DMSO-d6):δ172.5,172.3,170.8,84.7,56.8,56.8ppm。
Embodiment 6
Using adjacent methyl-isourea hydrochloride and ethyl cyanoacetate as raw material
Step 1. is added 16mmol neighbour's methyl-isourea hydrochloride, is dissolved in 20mL ethyl alcohol in the three-neck flask of 100mL,
10mmol ethyl cyanoacetate is added when reaching 70 DEG C in heating stirring, temperature, and 6h is kept the temperature at 70 DEG C, and heat preservation is finished, control distillation temperature
Degree is 80 DEG C, and first normal pressure steams methanol, then vacuum distillation to negative pressure is that it is faint yellow to obtain 1.2g until without distillate by -0.07MPa
Powder N '-second cyano carbonyl-O- methyl-isourea.
The pale yellow powder 10mmol (1.29g) that step 2. takes step (1) to obtain, addition 7mmol saleratus,
0.9mmol cetyl trimethylammonium bromide and 14mmol dimethyl suflfate, are dissolved in 20ml acetone, then flow back at 70 DEG C
7h is reacted, heat preservation is finished, and is cooled to 50 DEG C, filtering.Controlling vapo(u)rizing temperature is 70 DEG C, and first normal pressure steams acetone, then vacuum distillation is to negative
Pressure is that -0.09MPa obtains 1.35g pale yellow powder N '-(1- methoxyl group -2- vinyl)-O- first until without distillate
Base isourea.
The first containing 16mmol sodium methoxide is added in the pale yellow powder 10mmol (1.55g) that step 3. takes step (2) to obtain
(methanol sodium content is 30wt%) to sodium alkoxide methanol solution, then the back flow reaction 3h at 60 DEG C.Heat preservation is finished, and control vapo(u)rizing temperature is
80 DEG C, first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.08MPa, and until without distillate, distillation is finished, addition and acetone
Etc. quality water, sodium carbonate is then added and adjusts pH to 7, cools to 10 DEG C, is filtered, washed, it is dry, obtain pale yellow powder 4-
Amino -2,6- dimethoxypyridin 1.24g, gross production rate are 80% (in terms of ethyl cyanoacetate).
1H NMR(400MHz,DMSO-d6):δ6.60(s,2H,NH2),5.33(s,1H,CH),3.71(d,6H,OCH3)
ppm；
13C NMR(100MHz,DMSO-d6):δ172.5,172.3,170.8,84.7,56.8,56.8ppm。
Embodiment 7
Using adjacent methyl-isourea nitrate and ethyl cyanoacetate as raw material
Step 1. is added 19mmol neighbour's methyl-isourea nitrate, is dissolved in 20mL ethyl alcohol in the three-neck flask of 100mL,
10mmol ethyl cyanoacetate is added when reaching 80 DEG C in heating stirring, temperature, and 6h is kept the temperature at 80 DEG C, and heat preservation is finished, control distillation temperature
Degree is 80 DEG C, and first normal pressure steams methanol, then vacuum distillation to negative pressure is -0.09MPa, until no distillate, obtains the yellowish toner of 1.17g
Last N '-second cyano carbonyl-O- methyl-isourea.
9mmol potassium carbonate, 60ml third is added in the pale yellow powder 10mmol (1.29g) that step 2. takes step (1) to obtain
Ketone, 0.1mmol tetrabutylammonium bromide and 16mmol dimethyl suflfate, then the back flow reaction 8h at 80 DEG C, heat preservation are finished, are cooled to
40 DEG C, filtering.Controlling vapo(u)rizing temperature is 70 DEG C, and first normal pressure steams acetone, then vacuum distillation to negative pressure is -0.09MPa, until without distillating
Until object, 1.32g pale yellow powder N '-(1- methoxyl group -2- vinyl)-O- methyl-isourea is obtained.
It is molten that the methanolic sodium methoxide containing 9mmol sodium methoxide is added in the pale yellow powder 1.55g that step 3. takes step (2) to obtain
(methanol sodium content is 40wt%) to liquid, then the back flow reaction 5h at 90 DEG C.Heat preservation is finished, and control vapo(u)rizing temperature is 80 DEG C, often first
Pressure steams methanol, then vacuum distillation to negative pressure is -0.09MPa, and until without distillate, distillation is finished, and is added and the quality such as acetone
Then water is added sodium carbonate and adjusts pH to 7, cools to 10 DEG C, filtered, washed, dry, obtains amino -2 pale yellow powder 4-,
6- dimethoxypyridin 1.19g, gross production rate are 77% (in terms of ethyl cyanoacetate).
1H NMR(400MHz,DMSO-d6):δ6.60(s,2H,NH2),5.33(s,1H,CH),3.71(d,6H,OCH3)
ppm；
13C NMR(100MHz,DMSO-d6):δ172.5,172.3,170.8,84.7,56.8,56.8ppm。
Embodiment 8 is using adjacent methyl-isourea acetate and ethyl cyanoacetate as raw material
Step 1. is added 20mmol neighbour's methyl-isourea acetate, is dissolved in 20mL ethyl alcohol and adds in the three-neck flask of 100mL
10mmol ethyl cyanoacetate is added when reaching 80 DEG C in thermal agitation, temperature, and 6h is kept the temperature at 80 DEG C, and heat preservation is finished, and controls vapo(u)rizing temperature
It is 80 DEG C, first normal pressure steams methanol, then vacuum distillation to negative pressure is that -0.09MPa obtains the yellowish toner of 1.14g until without distillate
Last N '-second cyano carbonyl-O- methyl-isourea.
10mmol potassium carbonate, 1.2mmol tetrabutyl bromine is added in the pale yellow powder 1.29g that step 2. obtains step (1)
Change ammonium and 20mmol dimethyl suflfate, be dissolved in 20ml acetone, then the back flow reaction 8h at 80 DEG C, heat preservation is finished, and is cooled to 50
DEG C, filtering.Controlling vapo(u)rizing temperature is 70 DEG C, and first normal pressure steams acetone, then vacuum distillation to negative pressure is -0.09MPa, and no distillate is
Only, 1.27g pale yellow powder N '-(1- methoxyl group -2- vinyl)-O- methyl-isourea is obtained.
The methanolic sodium methoxide containing 20mmol sodium methoxide is added in the pale yellow powder 1.55g that step 3. obtains step (2)
(methanol sodium content is 50wt%) to solution, then the back flow reaction 8h at 90 DEG C.Heat preservation is finished, and control vapo(u)rizing temperature is 80 DEG C, first
Normal pressure steams methanol, then vacuum distillation to negative pressure is -0.09MPa, and until without distillate, distillation is finished, and is added and the quality such as acetone
Water, sodium bicarbonate is then added and adjusts pH to 7, cools to 10 DEG C, is filtered, washed, it is dry, obtain pale yellow powder 4- ammonia
Base -2,6- dimethoxypyridin 1.15g, gross production rate are 75% (in terms of ethyl cyanoacetate).
1H NMR(400MHz,DMSO-d6):δ6.60(s,2H,NH2),5.33(s,1H,CH),3.71(d,6H,OCH3)
ppm；
13C NMR(100MHz,DMSO-d6):δ172.5,172.3,170.8,84.7,56.8,56.8ppm。
Claims (10)
1. a kind of preparation method of 4- amino -2,6- dimethoxypyridin, the specific steps are that:
(1) adjacent methyl-isourea salt, solvent dissolution are added in the reaction vessel, then cyanoacetate is added in heating stirring, reflux is protected
Warm certain time；
(2) heat preservation is finished, and first normal pressure steams methanol, then vacuum distillation obtains product N '-second cyano carbonyl-O- methyl-isourea, structure to doing
Such as Formulas I；
(3) solid base, phase transfer catalyst and methyl are added in the N '-second cyano carbonyl-O- methyl-isourea that step (2) obtains
Change reagent, solvent dissolution, reflux heat preservation；
(4) cooling filtering；
(5) first normal pressure steams solvent, then it is different to obtain product N '-(1- methoxyl group -2- vinyl)-O- methyl to doing for vacuum distillation
Urea, structure such as Formula II；
(6) it is molten that methanolic sodium methoxide is added in N '-(1- methoxyl group -2- the vinyl)-O- methyl-isourea obtained step (5)
Liquid keeps the temperature cyclization；
(7) heat preservation is finished, and first normal pressure steams methanol, then vacuum distillation is to dry；
(8) distillation is finished, and the water with quality such as solvents in step (3) is added, and alkali is added and adjusts pH；
(9) it through cooling, filters, washes, it is dry, obtain 4- amino -2,6- dimethoxypyridin；
2. preparation method as described in claim 1, it is characterised in that: adjacent methyl-isourea salt is adjacent methyl-isourea in step (1)
One of disulfate, adjacent methyl-isourea hydrochloride, adjacent methyl-isourea nitrate or adjacent methyl-isourea acetate；Cyanoacetate
For methyl cyanoacetate or ethyl cyanoacetate.
3. preparation method as described in claim 1, it is characterised in that: solvent is methanol or ethyl alcohol in step (1)；Cyanoacetate
It is 1:(1.2~2 with adjacent methyl-isourea salt molar ratio).
4. preparation method as described in claim 1, it is characterised in that: reflux temperature is 60~90 DEG C, when reflux in step (1)
Between be 3~6h.
5. preparation method as described in claim 1, it is characterised in that: in step (2), (5) and (7) vapo(u)rizing temperature be 40~
80 DEG C, negative pressure is -0.09~-0.07MPa.
6. preparation method as described in claim 1, it is characterised in that: solid base described in step (3) is potassium carbonate, carbonic acid
Sodium, sodium bicarbonate or saleratus；Solvent is acetone, toluene or dimethylformamide；Phase transfer catalyst is tetrabutyl phosphonium bromide
Ammonium, cetyl trimethylammonium bromide or 4-butyl ammonium hydrogen sulfate；Methylating reagent is dimethyl suflfate or dimethyl carbonate；
The molar ratio of N '-second cyano carbonyl-O- methyl-isourea and solid base, phase transfer catalyst and methylating reagent is respectively 1:(0.3
~1), 1:(0.08~0.12), 1:(1~2).
7. preparation method as described in claim 1, it is characterised in that: reflux temperature is 50~80 DEG C, when reflux in step (3)
Between be 5~8h；Temperature described in step (4) is 30~50 DEG C.
8. preparation method as described in claim 1, it is characterised in that: the mass concentration of methanol solution of sodium methylate in step (6)
It is 25%~60%；The molar ratio of N '-(1- methoxyl group -2- vinyl)-O- methyl-isourea and sodium methoxide be 1:(1.5~
2)。
9. preparation method as described in claim 1, it is characterised in that: reflux temperature is 50~90 DEG C, when reflux in step (6)
Between be 3~8h.
10. preparation method as described in claim 1, it is characterised in that: alkali described in step (8) is sodium carbonate or bicarbonate
Sodium, pH are 7~9.
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| CN102491948A (en) * | 2011-12-12 | 2012-06-13 | 湖北志诚化工科技有限公司 | Preparation method for 2-amino-4, 6-dimethoxy pyrimidine |
| CN105646373A (en) * | 2016-02-18 | 2016-06-08 | 滨海新东方医化有限公司 | Preparation method of 4-amino-2,6-dimethoxypyrimidine |
| CN107721938A (en) * | 2017-11-12 | 2018-02-23 | 王微 | A kind of method that dry stir-fry method prepares the dihydroxy-pyrimidine of 4 amino 2,6 |
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2018
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| CN102491948A (en) * | 2011-12-12 | 2012-06-13 | 湖北志诚化工科技有限公司 | Preparation method for 2-amino-4, 6-dimethoxy pyrimidine |
| CN105646373A (en) * | 2016-02-18 | 2016-06-08 | 滨海新东方医化有限公司 | Preparation method of 4-amino-2,6-dimethoxypyrimidine |
| CN107721938A (en) * | 2017-11-12 | 2018-02-23 | 王微 | A kind of method that dry stir-fry method prepares the dihydroxy-pyrimidine of 4 amino 2,6 |
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