CN110240601A - Synthesis method of penoxsulam intermediate - Google Patents
Synthesis method of penoxsulam intermediate Download PDFInfo
- Publication number
- CN110240601A CN110240601A CN201910660002.6A CN201910660002A CN110240601A CN 110240601 A CN110240601 A CN 110240601A CN 201910660002 A CN201910660002 A CN 201910660002A CN 110240601 A CN110240601 A CN 110240601A
- Authority
- CN
- China
- Prior art keywords
- reaction
- methoxy
- pyrimidine
- penoxsuam
- synthetic method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000005592 Penoxsulam Substances 0.000 title abstract description 3
- SYJGKVOENHZYMQ-UHFFFAOYSA-N Penoxsulam Chemical compound N1=C2C(OC)=CN=C(OC)N2N=C1NS(=O)(=O)C1=C(OCC(F)F)C=CC=C1C(F)(F)F SYJGKVOENHZYMQ-UHFFFAOYSA-N 0.000 title abstract description 3
- 238000001308 synthesis method Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 81
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 30
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims abstract description 30
- KELXHQACBIUYSE-UHFFFAOYSA-N 5-methoxy-1h-pyrimidine-2,4-dione Chemical compound COC1=CNC(=O)NC1=O KELXHQACBIUYSE-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000010189 synthetic method Methods 0.000 claims abstract description 19
- 239000004202 carbamide Substances 0.000 claims abstract description 17
- SSMSXWXZJUCBMA-UHFFFAOYSA-N (2-chloro-5-methoxypyrimidin-4-yl)hydrazine Chemical compound COC1=CN=C(Cl)N=C1NN SSMSXWXZJUCBMA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 11
- ZTHHRSBDBPCCMZ-UHFFFAOYSA-N 2,4-dichloro-5-methoxypyrimidine Chemical compound COC1=CN=C(Cl)N=C1Cl ZTHHRSBDBPCCMZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 7
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methylthiourea Natural products CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 claims abstract description 4
- -1 methoxy menthyl acetate Chemical compound 0.000 claims description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 38
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 28
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 24
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 22
- 239000001605 (5-methyl-2-propan-2-ylcyclohexyl) acetate Substances 0.000 claims description 21
- XHXUANMFYXWVNG-UHFFFAOYSA-N D-menthyl acetate Natural products CC(C)C1CCC(C)CC1OC(C)=O XHXUANMFYXWVNG-UHFFFAOYSA-N 0.000 claims description 21
- XHXUANMFYXWVNG-ADEWGFFLSA-N Menthyl acetate Natural products CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(C)=O XHXUANMFYXWVNG-ADEWGFFLSA-N 0.000 claims description 21
- 238000010792 warming Methods 0.000 claims description 17
- 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 claims description 16
- 238000001035 drying Methods 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 14
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 238000001556 precipitation Methods 0.000 claims description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 10
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 10
- 230000003213 activating effect Effects 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 7
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 claims description 7
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 7
- 238000000926 separation method Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 3
- YLZYSVYZMDJYOT-UHFFFAOYSA-N 2-methoxypyrimidine Chemical compound COC1=NC=CC=N1 YLZYSVYZMDJYOT-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 150000004992 toluidines Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 4
- DBJPBHJHAPAUQU-UHFFFAOYSA-N 5,8-dimethoxy-[1,2,4]triazolo[1,5-c]pyrimidin-2-amine Chemical compound COC1=CN=C(OC)N2N=C(N)N=C12 DBJPBHJHAPAUQU-UHFFFAOYSA-N 0.000 abstract 2
- ICPWFHKNYYRBSZ-UHFFFAOYSA-M 2-methoxypropanoate Chemical compound COC(C)C([O-])=O ICPWFHKNYYRBSZ-UHFFFAOYSA-M 0.000 abstract 1
- 239000013543 active substance Substances 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000000376 reactant Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 230000001376 precipitating effect Effects 0.000 description 6
- IJQIGKLDBGKSNT-UHFFFAOYSA-N 4,6-dichloro-5-methoxypyrimidine Chemical compound COC1=C(Cl)N=CN=C1Cl IJQIGKLDBGKSNT-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229960000935 dehydrated alcohol Drugs 0.000 description 5
- 230000001934 delay Effects 0.000 description 5
- 230000005311 nuclear magnetism Effects 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- PRXQQZUWYABUCX-UHFFFAOYSA-N 2-(ethylamino)butanoic acid Chemical compound CCNC(CC)C(O)=O PRXQQZUWYABUCX-UHFFFAOYSA-N 0.000 description 3
- 238000007259 addition reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229940124277 aminobutyric acid Drugs 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- VFPXCQBCUAPMEC-UHFFFAOYSA-N 1-(2,2-difluoroethoxy)-3-(trifluoromethyl)benzene sulfuryl dichloride Chemical compound S(=O)(=O)(Cl)Cl.FC(COC1=CC(=CC=C1)C(F)(F)F)F VFPXCQBCUAPMEC-UHFFFAOYSA-N 0.000 description 1
- VOGSDFLJZPNWHY-UHFFFAOYSA-N 2,2-difluoroethanol Chemical compound OCC(F)F VOGSDFLJZPNWHY-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- NAJLGLKRLKMZKX-UHFFFAOYSA-N S(=O)(=O)(Cl)Cl.FC1=C(C=CC=C1)C(F)(F)F Chemical compound S(=O)(=O)(Cl)Cl.FC1=C(C=CC=C1)C(F)(F)F NAJLGLKRLKMZKX-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000006198 methoxylation reaction Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthesis method of a penoxsulam intermediate, which comprises the following four steps of reaction: (1) the first step of reaction: reacting methyl methoxyacetate, methyl formate and urea under the action of an active agent to generate 2, 4-dihydroxy-5-methoxypyrimidine; (2) the second step of reaction: 2, 4-dihydroxy-5-methoxyl pyrimidine is subjected to hydroxyl chlorination reaction to synthesize 2, 4-dichloro-5-methoxyl pyrimidine; (3) the third step of reaction: carrying out a hydrazidation reaction on the 2, 4-dichloro-5-methoxypyrimidine to generate 2-chloro-4-hydrazino-5-methoxypyrimidine; (4) and a fourth step of reaction: cyclizing and methoxylating to obtain 2-amino-5, 8-dimethoxy [1, 2, 4] triazolo [1, 5-c ] pyrimidine. The invention is a synthetic method of intermediate 2-amino-5, 8-dimethoxy [1, 2, 4] triazolo [1, 5-c ] pyrimidine, which has the advantages of simple process, low cost, green and environment-friendly synthetic process, highest yield reaching 62 percent, and good economic prospect of industrial production.
Description
Technical field
The present invention relates to pesticide synthesis technical field, in particular to a kind of synthetic method of penoxsuam intermediate.
Background technique
The seedling that penoxsuam (penoxsulam) system is developed by The Dow Agrosciences, LLC. (DowAgroSciences)
Translocated herbicide afterwards, blade, stem and root through weeds are absorbed, are conducted by xylem and bast to separate living tissue,
Inhibit plant strain growth, the removing activity with wide spectrum.
Penoxsuam is by key intermediate 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine and 2-
Substitution -6- (trifluoromethyl) benzene sulfonyl chloride is reacted to obtain, and mainly has two synthetic routes:
Route 1: using the fluoro- 6- 5-trifluoromethylaniline of 2- as starting material, by diazo-reaction, the fluoro- 6- tri- of 2- is made
Methyl fluoride benzene sulfonyl chloride.Then the fluoro- 6- trifluoromethyl benzene sulfonyl chloride of the 2- and 2- amino -5,8- dimethoxy [1,2,4] triazole
[1,5-c] pyrimidine carries out condensation reaction, obtains the target compound of 2- fluoro, finally reacts, obtains with 2,2- difluoroethanol
It is as follows to be finally synthesizing penoxsuam route for penoxsuam:
Route 2: being used as starting material with 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine (DAT), with
The reaction of 2- (2,2- difluoroethoxy) -6- (trifluoromethyl) benzene sulfonyl chloride, it is as follows to be finally synthesizing penoxsuam route:
For synthesizing the two lines of penoxsuam, it is necessary to synthetic intermediate 2- amino -5,8- dimethoxy first
[1,2,4] triazole [1,5-c] pyrimidine, it is seen that this intermediate has served critical in the synthesis of penoxsuam, is one
The critically important pharmaceutical intermediate of kind.
The common system of intermediate 2-amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine is prepared in the prior art
Preparation Method reacts under the conditions of mostly using high temperature and expensive starting material.Such reaction would generally there are many side reactions to produce
Raw, not only separating-purifying is difficult, but also complex procedures, production cost are higher.Therefore with the development of modern industry, exploration is gone to work
Simple, easy to operate, the environmentally protective synthetic route of skill also become it is current there is an urgent need to.
Summary of the invention
The present invention to realize the above-mentioned technical purpose, provides that a kind of simple process, at low cost, synthesis process is environmentally protective, produces
The synthetic method of high intermediate 2-amino -5,8- dimethoxy [1,2,4] triazole [1, the 5-c] pyrimidine of rate, industrialized production
Economic prospect is good.
Above-mentioned technical purpose of the invention has the technical scheme that a kind of penoxsuam intermediate
Synthetic method, by following four-step reaction, obtain target product 2- amino-using methoxy menthyl acetate as starting material
5,8- dimethoxys [1,2,4] triazole [1,5-c] pyrimidine:
(1) first step is reacted: being occurred under the action of activating agent with methoxy menthyl acetate, methyl formate and urea anti-
It answers, generates 2,4- dihydroxy -5- methoxy pyrimidine；
(2) second step reacts: 2,4- dihydroxy -5- methoxy pyrimidines react under the action of chlorination reaction component, synthesis
2,4- dichloro-5-methoxy pyrimidine out；
(3) third step is reacted: 2,4- dichloro-5-methoxy pyrimidines and hydrazine hydrate occur substitution reaction and generate the chloro- 4- hydrazine of 2-
Base -5- methoxy pyrimidine；
(4) four-step reactions: the chloro- 4- diazanyl -5- methoxy pyrimidine of 2- cyclization under the action of cyanogen bromide, using
Methoxylation obtains 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine.
By using above-mentioned technical proposal: using methoxy menthyl acetate as starting material, being synthesized using four-step reaction intermediate
Body 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine, yield can reach 53~62%.
As the further setting of the present invention: the quality of methoxy menthyl acetate, methyl formate, urea in first step reaction
Than for 1:1~2:0.5~2.
As the further setting of the present invention: activating agent is carboxyethylamino group butyric acid in first step reaction: 4,4'- different sub- third
Base biphenol mass ratio is the composition of 2:3~5.
As the further setting of the present invention: second step reaction in chlorination reaction component include: hydroxyethyl methyl toluidines,
Phosphorus oxychloride, dichloroethanes.
As the further setting of the present invention: hydroxyethyl methyl toluidines, phosphorus oxychloride, dichloroethanes mass ratio are as follows:
1:0.5:1.2~1.5.
As the further setting of the present invention: the mass ratio of methoxy menthyl acetate and chlorination reaction component is 1:5~10.
As the further setting of the present invention: the first step is reacted the following steps are included: by methoxy menthyl acetate, formic acid first
Ester, sodium methoxide, activating agent put into 20~30min of heating stirring in organic solvent, then put into urea, first react at 20~30 DEG C
Then 30min~60min is gradually warming up to reaction temperature, react 5~8h, sloughs organic solvent, adjusts pH to 4~5, obtains
White solid Precipitation after filtration drying, obtains 2,4- dihydroxy -5- methoxy pyrimidine.
By using above-mentioned technical proposal: methoxy menthyl acetate, methyl formate generate 2,4- bis- with urea single step reaction
Hydroxy-5-methyl oxygroup pyrimidine, activating agent carboxyethylamino group butyric acid and 4,4'- isopropylidenediphenol and methoxy menthyl acetate,
Addition reaction, activating agent carboxyethylamino group butyric acid and 4,4'- isopropylidene hexichol occurs with urea after methyl formate mixing
Phenol collaboration reduces the reaction activity barrier that addition reaction occurs for methoxy menthyl acetate, methyl formate and urea, improves 2,
The yield of 4- dihydroxy -5- methoxy pyrimidine.
As the further setting of the present invention: second step reacts the following steps are included: by 2, and 4- dihydroxy -5- methoxyl group is phonetic
Pyridine, phosphorus oxychloride and dichloroethanes are mixed to form mixed liquor, hydroxyethyl methyl toluidines are added in mixed liquor, 100
Reaction is completely disappeared to 2,4- dihydroxy -5- methoxy pyrimidine at~120 DEG C, and the chloro- 5- of 2,4- bis- is obtained after separation process
Methoxy pyrimidine.
By using above-mentioned technical proposal: hydroxy chloride occurs by 2,4- dihydroxy -5- methoxy pyrimidine and phosphorus oxychloride
Change reaction and generate 2,4- dichloro-5-methoxy pyrimidine, is added to hydroxyethyl methyl toluidines, one side energy in chlorination reaction component
The byproduct hydrogen chloride generated is removed, the hydroxy chloride extent of reaction is improved, on the other hand can improve the reactivity of phosphorus oxychloride,
Increase and the chlorination reaction of 2,4- dihydroxy -5- methoxy pyrimidine is selective, to further mention the yield of product.
As the further setting of the present invention: reaction temperature is 100~120 DEG C.
As the further setting of the present invention: organic solvent is toluene, dimethylbenzene or toluene and chlorobenzene volume ratio is 1:1 mixed
Bonding solvent.
The beneficial effects of the present invention are:
1, the present invention develops a kind of synthetic method of penoxsuam intermediate, is that starting is former with methoxy menthyl acetate
Material, using four-step reaction synthetic intermediate 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine, yield can reach
53~62%, it is industrialized good in economic efficiency.
2, activating agent carboxyethyl is used in the first step reaction in the synthetic method of penoxsuam intermediate of the invention
Aminobutyric acid and 4,4'- isopropylidenediphenol and methoxy menthyl acetate, methyl formate occur to add after being mixed with urea
At reaction, activating agent carboxyethylamino group butyric acid and 4, the collaboration of 4'- isopropylidenediphenol reduces methoxy menthyl acetate, formic acid
The reaction activity barrier of addition reaction occurs for methyl esters and urea, improves the yield of 2,4- dihydroxy -5- methoxy pyrimidine.
3, add in chlorination reaction component in the second step reaction in the synthetic method of penoxsuam intermediate of the invention
Add hydroxyethyl methyl toluidines, on the one hand can remove the byproduct hydrogen chloride generated, improves the hydroxy chloride extent of reaction, it is another
Aspect can improve the reactivity of phosphorus oxychloride, increase and the chlorination reaction of 2,4- dihydroxy -5- methoxy pyrimidine is selective, from
And further mention the yield of product.
Specific embodiment
Below in conjunction with specific embodiment, technical solution of the present invention is clearly and completely described.Obviously, it is retouched
The embodiment stated is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiment of the present invention, originally
Field those of ordinary skill every other embodiment obtained without making creative work, belongs to the present invention
The range of protection.
A kind of synthetic method of penoxsuam intermediate, each embodiment specific as follows:
Embodiment 1
The first step is reacted the following steps are included: by methoxy menthyl acetate 10g, methyl formate 10g, sodium methoxide 0.5g, carboxylic
Ethylamino butyric acid 2g, 4,4'- isopropylidenediphenol 3g put into heating stirring 20min in organic solvent, then put into urea 5g,
30min is first reacted at 20 DEG C, is then gradually warming up to 100 DEG C of reaction temperature, reacts 5h, sloughs toluene, is adjusted pH to 4, is obtained
To white solid Precipitation, after filtration drying, 2,4- dihydroxy -5- methoxy pyrimidine is obtained.
Second step reaction is the following steps are included: by 2, the 4- dihydroxy -5- methoxy pyrimidine of reaction generation, phosphorus oxychloride
9.3g and dichloroethanes 22.2g are mixed to form mixed liquor, and hydroxyethyl methyl toluidines 18.5g is added in mixed liquor,
Reaction is completely disappeared to 2,4- dihydroxy -5- methoxy pyrimidine at 100 DEG C, and the chloro- 5- first of 2,4- bis- is obtained after separation process
Oxygroup pyrimidine.
Third step reaction: 80% hydrazine hydrate 10g, natrium carbonicum calcinatum 10g being put into dehydrated alcohol and form blended liquid, and 2,4-
Toluene, dimethylbenzene or toluene is added in dichloro-5-methoxy pyrimidine and chlorobenzene volume ratio is that 1:1 in the mixed solvent forms mixed liquor,
Mixed liquor is added dropwise in blended liquid, is gradually warming up to 40 DEG C, until reactant disappears, has solid precipitation after adding water, by solid mistake
Be filtered dry it is dry after obtain the chloro- 4- diazanyl -5- methoxy pyrimidine of 2-；
Four-step reaction: by the chloro- 4- diazanyl -5- methoxy pyrimidine of 2- and tert-butyl alcohol 50ml, adding cyanogen bromide 10g, delays
Slowly 50 DEG C are warming up to, reaction to reactant disappears, and cooling reaction solution to room temperature is added the methanol solution of 25% sodium methoxide, rises
High-temperature is cooled to room temperature to the reaction was continued at 50 DEG C, obtains solid precipitating after adding water, obtains amino -5 2- after filtration drying,
8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine, product 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] are phonetic
The total recovery of pyridine is 53%, and product passes through nuclear-magnetism Structural Identification, is confirmed as target product.
Embodiment 2
The first step is reacted the following steps are included: by methoxy menthyl acetate 10g, methyl formate 20g, sodium methoxide 1g, carboxylic second
Base aminobutyric acid 2g, 4,4'- isopropylidenediphenol, 3~5g put into heating stirring 30min in organic solvent, then put into urea
20g first reacts 60min at 30 DEG C, is then gradually warming up to 120 DEG C of reaction temperature, reacts 8h, sloughs dimethylbenzene, adjusts pH
To 5, white solid Precipitation is obtained, after filtration drying, obtain 2,4- dihydroxy -5- methoxy pyrimidine.
Second step reaction is the following steps are included: by 2, the 4- dihydroxy -5- methoxy pyrimidine of reaction generation, phosphorus oxychloride
8.3g and dichloroethanes 25g are mixed to form mixed liquor, hydroxyethyl methyl toluidines 16.6g are added in mixed liquor, 120
Reaction is completely disappeared to 2,4- dihydroxy -5- methoxy pyrimidine at DEG C, and 2,4-, bis- chloro-5-methoxyl is obtained after separation process
Pyrimidine.
Third step reaction: 80% hydrazine hydrate 20g, natrium carbonicum calcinatum 15g being put into dehydrated alcohol and form blended liquid, and 2,4-
Toluene, dimethylbenzene or toluene is added in dichloro-5-methoxy pyrimidine and chlorobenzene volume ratio is that 1:1 in the mixed solvent forms mixed liquor,
Mixed liquor is added dropwise in blended liquid, is gradually warming up to 50 DEG C, until reactant disappears, has solid precipitation after adding water, by solid mistake
Be filtered dry it is dry after obtain the chloro- 4- diazanyl -5- methoxy pyrimidine of 2-；
Four-step reaction: by the chloro- 4- diazanyl -5- methoxy pyrimidine of 2- and tert-butyl alcohol 80ml, adding cyanogen bromide 20g, delays
Slowly 60 DEG C are warming up to, reaction to reactant disappears, and cooling reaction solution to room temperature is added the methanol solution of 25% sodium methoxide, rises
High-temperature is cooled to room temperature to the reaction was continued at 50~60 DEG C, obtains solid precipitating after adding water, obtains 2- ammonia after filtration drying
Base -5,8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine, product 2- amino -5,8- dimethoxy [1,2,4] triazole [1,
5-c] pyrimidine total recovery be 62%, product pass through nuclear-magnetism Structural Identification, be confirmed as target product.
Embodiment 3
The first step is reacted the following steps are included: by methoxy menthyl acetate 10g, methyl formate 15g, sodium methoxide 0.8g, carboxylic
Ethylamino butyric acid 2g, 4,4'- isopropylidenediphenol 4g put into heating stirring 25min in organic solvent, then put into urea
10g first reacts 40min at 25 DEG C, is then gradually warming up to 110 DEG C of reaction temperature, reacts 6h, sloughs toluene and chlorobenzene volume
Than adjusting pH to 5 for 1:1 mixed solvent, white solid Precipitation is obtained, after filtration drying, obtain 2,4- dihydroxy -5-
Methoxy pyrimidine.
Second step reaction is the following steps are included: by 2, the 4- dihydroxy -5- methoxy pyrimidine of reaction generation, phosphorus oxychloride
8.6g and dichloroethanes 24.1g are mixed to form mixed liquor, and hydroxyethyl methyl toluidines 17.2g is added in mixed liquor,
Reaction is completely disappeared to 2,4- dihydroxy -5- methoxy pyrimidine at 110 DEG C, and the chloro- 5- first of 2,4- bis- is obtained after separation process
Oxygroup pyrimidine.
Third step reaction: 80% hydrazine hydrate 15g, natrium carbonicum calcinatum 13g being put into dehydrated alcohol and form blended liquid, and 2,4-
Toluene is added in dichloro-5-methoxy pyrimidine, and mixed liquor is added dropwise in blended liquid, is gradually warming up to 45 DEG C, until reactant disappears,
There is solid precipitation after adding water, the chloro- 4- diazanyl -5- methoxy pyrimidine of 2- will be obtained after solid filtration drying；
Four-step reaction: by the chloro- 4- diazanyl -5- methoxy pyrimidine of 2- and tert-butyl alcohol 60ml, adding cyanogen bromide 15g, delays
Slowly 50 DEG C are warming up to, reaction to reactant disappears, and cooling reaction solution to room temperature is added the methanol solution of 25% sodium methoxide, rises
High-temperature is cooled to room temperature to the reaction was continued at 50 DEG C, obtains solid precipitating after adding water, obtains amino -5 2- after filtration drying,
8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine, product 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] are phonetic
The total recovery of pyridine is 58%, and product passes through nuclear-magnetism Structural Identification, is confirmed as target product.
Embodiment 4
First step reaction is the following steps are included: methoxy menthyl acetate 10g, methyl formate 15g, sodium methoxide 0.8g are put into
Heating stirring 25min in organic solvent, then urea 10g is put into, 40min is first reacted at 25 DEG C, is then gradually warming up to reaction
110 DEG C of temperature, 6h is reacted, toluene is sloughed and chlorobenzene volume ratio is 1:1 mixed solvent, adjust pH to 5, obtain white solid precipitating
It is precipitated, after filtration drying, obtains 2,4- dihydroxy -5- methoxy pyrimidine.
Second step reaction is the following steps are included: by 2, the 4- dihydroxy -5- methoxy pyrimidine of reaction generation, phosphorus oxychloride
8.6g and dichloroethanes 24.1g are mixed to form mixed liquor, and hydroxyethyl methyl toluidines 17.2g is added in mixed liquor,
Reaction is completely disappeared to 2,4- dihydroxy -5- methoxy pyrimidine at 110 DEG C, and the chloro- 5- first of 2,4- bis- is obtained after separation process
Oxygroup pyrimidine.
Third step reaction: 80% hydrazine hydrate 15g, natrium carbonicum calcinatum 13g being put into dehydrated alcohol and form blended liquid, and 2,4-
Toluene is added in dichloro-5-methoxy pyrimidine, and mixed liquor is added dropwise in blended liquid, is gradually warming up to 45 DEG C, until reactant disappears,
There is solid precipitation after adding water, the chloro- 4- diazanyl -5- methoxy pyrimidine of 2- will be obtained after solid filtration drying；
Four-step reaction: by the chloro- 4- diazanyl -5- methoxy pyrimidine of 2- and tert-butyl alcohol 60ml, adding cyanogen bromide 15g, delays
Slowly 50 DEG C are warming up to, reaction to reactant disappears, and cooling reaction solution to room temperature is added the methanol solution of 25% sodium methoxide, rises
High-temperature is cooled to room temperature to the reaction was continued at 50 DEG C, obtains solid precipitating after adding water, obtains amino -5 2- after filtration drying,
8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine, product 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] are phonetic
The total recovery of pyridine is 41%, and product passes through nuclear-magnetism Structural Identification, is confirmed as target product.
Embodiment 5
The first step is reacted the following steps are included: by methoxy menthyl acetate 10g, methyl formate 15g, sodium methoxide 0.8g, carboxylic
Ethylamino butyric acid 2g, 4,4'- isopropylidenediphenol 4g put into heating stirring 25min in organic solvent, then put into urea
10g first reacts 40min at 25 DEG C, is then gradually warming up to 110 DEG C of reaction temperature, reacts 6h, sloughs toluene and chlorobenzene volume
Than adjusting pH to 5 for 1:1 mixed solvent, white solid Precipitation is obtained, after filtration drying, obtain 2,4- dihydroxy -5-
Methoxy pyrimidine.
Second step reaction is the following steps are included: by 2, the 4- dihydroxy -5- methoxy pyrimidine of reaction generation, phosphorus oxychloride
8.6g and dichloroethanes 24.1g are mixed to form mixed liquor, react at 110 DEG C to 2,4- dihydroxy -5- methoxy pyrimidine
It completely disappears, 2,4- dichloro-5-methoxy pyrimidine is obtained after separation process.
Third step reaction: 80% hydrazine hydrate 15g, natrium carbonicum calcinatum 13g being put into dehydrated alcohol and form blended liquid, and 2,4-
Toluene is added in dichloro-5-methoxy pyrimidine, and mixed liquor is added dropwise in blended liquid, is gradually warming up to 45 DEG C, until reactant disappears,
There is solid precipitation after adding water, the chloro- 4- diazanyl -5- methoxy pyrimidine of 2- will be obtained after solid filtration drying；
Four-step reaction: by the chloro- 4- diazanyl -5- methoxy pyrimidine of 2- and tert-butyl alcohol 60ml, adding cyanogen bromide 15g, delays
Slowly 50 DEG C are warming up to, reaction to reactant disappears, and cooling reaction solution to room temperature is added the methanol solution of 25% sodium methoxide, rises
High-temperature is cooled to room temperature to the reaction was continued at 50 DEG C, obtains solid precipitating after adding water, obtains amino -5 2- after filtration drying,
8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine, product 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] are phonetic
The total recovery of pyridine is 44%, and product passes through nuclear-magnetism Structural Identification, is confirmed as target product.
Claims (10)
1. a kind of synthetic method of penoxsuam intermediate, it is characterised in that: using methoxy menthyl acetate as starting material,
By following four-step reaction, target product 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine is obtained:
(1) first step is reacted: it is reacted under the action of activating agent with methoxy menthyl acetate, methyl formate and urea, it is raw
At 2,4- dihydroxy -5- methoxy pyrimidine；
(2) second step reacts: 2,4- dihydroxy -5- methoxy pyrimidines react under the action of chlorination reaction component, synthesize 2,
4- dichloro-5-methoxy pyrimidine；
(3) third step is reacted: 2,4- dichloro-5-methoxy pyrimidines and hydrazine hydrate occur substitution reaction and generate the chloro- 4- diazanyl -5- of 2-
Methoxy pyrimidine；
(4) four-step reactions: the chloro- 4- diazanyl -5- methoxy pyrimidine of 2- cyclization under the action of cyanogen bromide, using methoxy
Base obtains 2- amino -5,8- dimethoxy [1,2,4] triazole [1,5-c] pyrimidine.
2. a kind of synthetic method of penoxsuam intermediate according to claim 1, which is characterized in that the first step
Methoxy menthyl acetate in reaction, methyl formate, urea mass ratio be 1:1~2:0.5~2.
3. a kind of synthetic method of penoxsuam intermediate according to claim 1, which is characterized in that the first step
Activating agent is carboxyethylamino group butyric acid in reaction: 4,4'- isopropylidenediphenol mass ratioes are the composition of 2:3~5.
4. a kind of synthetic method of penoxsuam intermediate according to claim 1, which is characterized in that the second step
Chlorination reaction component includes: hydroxyethyl methyl toluidines, phosphorus oxychloride, dichloroethanes in reaction.
5. a kind of synthetic method of penoxsuam intermediate according to claim 4, which is characterized in that the ethoxy
Methyl toluene amine, phosphorus oxychloride, dichloroethanes mass ratio are as follows: 1:0.5:1.2~1.5.
6. a kind of synthetic method of penoxsuam intermediate according to claim 4, which is characterized in that the methoxyl group
Methyl acetate and the mass ratio of chlorination reaction component are 1:5~10.
7. a kind of synthetic method of penoxsuam intermediate according to claim 1, which is characterized in that the first step
Reaction by heating in methoxy menthyl acetate, methyl formate, sodium methoxide, activating agent investment organic solvent the following steps are included: stir
20~30min is mixed, then puts into urea, 30min~60min is first reacted at 20~30 DEG C, is then gradually warming up to reaction temperature,
5~8h is reacted, sloughs organic solvent, adjusts pH to 4~5, obtains white solid Precipitation, after filtration drying, obtains 2,4-
Dihydroxy -5- methoxy pyrimidine.
8. a kind of synthetic method of penoxsuam intermediate according to claim 1, which is characterized in that the second step
Reaction is the following steps are included: 4- dihydroxy -5- methoxy pyrimidine, phosphorus oxychloride and dichloroethanes are mixed to form mixing by 2
Hydroxyethyl methyl toluidines is added in liquid in mixed liquor, reacts at 100~120 DEG C to 2,4- dihydroxy -5- methoxy pyrimidine
It completely disappears, 2,4- dichloro-5-methoxy pyrimidine is obtained after separation process.
9. a kind of synthetic method of penoxsuam intermediate according to claim 7, which is characterized in that the reaction temperature
Degree is 100~120 DEG C.
10. a kind of synthetic method of penoxsuam intermediate according to claim 7, which is characterized in that described organic
Solvent is toluene, dimethylbenzene or toluene and chlorobenzene volume ratio is 1:1 mixed solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910660002.6A CN110240601A (en) | 2019-07-22 | 2019-07-22 | Synthesis method of penoxsulam intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910660002.6A CN110240601A (en) | 2019-07-22 | 2019-07-22 | Synthesis method of penoxsulam intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110240601A true CN110240601A (en) | 2019-09-17 |
Family
ID=67892971
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910660002.6A Pending CN110240601A (en) | 2019-07-22 | 2019-07-22 | Synthesis method of penoxsulam intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110240601A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101486684A (en) * | 2009-02-20 | 2009-07-22 | 常熟华益化工有限公司 | Preparation of 2,4-dichloro-5-methoxy pyrimidine |
| WO2011144577A1 (en) * | 2010-05-17 | 2011-11-24 | Senexis Limited | Compounds |
| WO2011144578A1 (en) * | 2010-05-17 | 2011-11-24 | Senexis Limited | Compounds |
| WO2011149861A1 (en) * | 2010-05-25 | 2011-12-01 | Dow Agrosciences Llc | Process for the preparation of 5-substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amines |
| CN104326988A (en) * | 2014-09-30 | 2015-02-04 | 大连九信生物化工科技有限公司 | Synthesis method for 2, 4-dichloro-5-methoxy pyrimidine |
| CN106243045A (en) * | 2016-07-27 | 2016-12-21 | 常州大学 | A kind of preparation method of 2,5 dimethoxy 4 aminopyrimidines |
-
2019
- 2019-07-22 CN CN201910660002.6A patent/CN110240601A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101486684A (en) * | 2009-02-20 | 2009-07-22 | 常熟华益化工有限公司 | Preparation of 2,4-dichloro-5-methoxy pyrimidine |
| WO2011144577A1 (en) * | 2010-05-17 | 2011-11-24 | Senexis Limited | Compounds |
| WO2011144578A1 (en) * | 2010-05-17 | 2011-11-24 | Senexis Limited | Compounds |
| WO2011149861A1 (en) * | 2010-05-25 | 2011-12-01 | Dow Agrosciences Llc | Process for the preparation of 5-substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amines |
| CN104326988A (en) * | 2014-09-30 | 2015-02-04 | 大连九信生物化工科技有限公司 | Synthesis method for 2, 4-dichloro-5-methoxy pyrimidine |
| CN106243045A (en) * | 2016-07-27 | 2016-12-21 | 常州大学 | A kind of preparation method of 2,5 dimethoxy 4 aminopyrimidines |
Non-Patent Citations (4)
| Title |
|---|
| ZHIHUA SUN ET AL.: "Solvent-Free or Low-Solvent Large-Scale Preparation of Chloropyrimidine and Analogues", 《J.ORG.CHEM.》 * |
| 何凤元: "五氟磺草胺中间体2-氨基-5,8-二甲氧基[1,2,4]三唑[1,5-c]嘧啶的合成研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
| 曹燕蕾: "五氟磺草胺的合成简介", 《现代农药》 * |
| 顾林玲: "三唑并嘧啶磺酰胺类除草剂--五氟磺草胺", 《现代农药》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103121999A (en) | Method for synthesizing tyrosine kinase inhibitor PCI-32765 | |
| CN109721545B (en) | Preparation method of azoxystrobin intermediate | |
| CN108440301B (en) | Preparation method of o-nitrobenzyl bromide | |
| CN111518154B (en) | Preparation method of 24-epibrassinol intermediate (22E, 24R) -3 alpha, 5-ring-5 alpha-ergosta-7, 22-diene-6-ketone | |
| CN103145568A (en) | Cardanol cationoid quaternary ammonium salt and preparation method thereof | |
| CN111470994A (en) | Preparation method of p-chlorobenzene glycine | |
| CN104961710A (en) | Synthesis method of dinotefuran | |
| CN104119243B (en) | A kind of energy-saving clean production method of iminodiethanoic acid | |
| CN110240601A (en) | Synthesis method of penoxsulam intermediate | |
| CN1834092B (en) | Preparation of pramipexole | |
| CN102199127B (en) | Method for preparing azoxystrobin | |
| CN105924328B (en) | A kind of highly selective green hydrolysis technique for preparing benzyl alcohol | |
| CN111995640A (en) | Method for synthesizing (3-amino-3-cyano) propyl methyl butyl phosphite based on microchannel reactor | |
| CN113845487B (en) | Preparation method of amicarbazone | |
| CN113388102B (en) | Preparation method and product of high-content tristyrylphenol polyoxyethylene ether ammonium sulfate | |
| CN114656406B (en) | Synthesis method of 2-fluoropyrimidine-4-carboxylic acid | |
| CN113651751B (en) | Preparation method of N-methoxycarbonyl-3-trifluoromethylpyridine-2-sulfonamide | |
| CN115322098B (en) | Method for synthesizing dimethyl carbonate by ionic liquid catalysis | |
| US5945556A (en) | Process for preparing N-carboxymethylene-4-chloro-anthranilic acid and its dialkyl esters | |
| CN110437092A (en) | A kind of preparation method of ticagrelor key intermediate aromatic cyclopropane amide | |
| JP2915515B2 (en) | Process for producing O-methylisourea sulfate | |
| CN112500446B (en) | Synthetic method of 2 '-fluoro-2' -deoxyuridine | |
| CN114292297B (en) | Method for preparing antiviral drug tenofovir alafenamide fumarate | |
| CN106946719A (en) | A kind of nonionic Gemini surface active and its synthetic method | |
| CN110003275B (en) | Synthesis method of 4, 6-di (diphenylphosphine) phenazine compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190917 |
|
| RJ01 | Rejection of invention patent application after publication |