CN110105349A - The synthetic method and its application of topramezone impurity - Google Patents
The synthetic method and its application of topramezone impurity Download PDFInfo
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- CN110105349A CN110105349A CN201910355436.5A CN201910355436A CN110105349A CN 110105349 A CN110105349 A CN 110105349A CN 201910355436 A CN201910355436 A CN 201910355436A CN 110105349 A CN110105349 A CN 110105349A
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- isoxazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention discloses a kind of synthetic methods of topramezone impurity; with 2; 3- dimethylaniline is starting material; by first vulcanization, bromo, oxidation, at oxime, chloro cyclization synthesis 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4; 5- dihydro-isoxazole; it is condensed under alkaline condition with 1- methyl -5- hydroxypyrazoles, and synthesis 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole；The invention also discloses a kind of applications of corresponding product.Synthetic method provided by the present invention is easy to operate, and process is easily controllable, and the yield of products obtained therefrom is 40%~80%, and obtained product can be used as standard items, for detecting and monitoring the synthesis of topramezone.
Description
Technical field
The invention belongs to pharmaceutical fields, are related to a kind of synthetic method of pesticide topramezone impurity, i.e. 3- [2- methyl -3-
(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole synthetic method and corresponding close
At the application of product.
Background technique
In the production process of drug, it is frequently accompanied by the generation of impurity, not only will affect product yield, but also will affect medicine
The quality of product, and then influence the use of drug.Effective monitoring is carried out for guaranteeing product matter to the impurity during synthesis
The influence of amount, yield and reduction impurity to drug effectiveness plays a key role.
Topramezone (Topramezone), chemical name are as follows: [3-(4,5- dihydro -3- isoxazolyl) -2- methyl -4-(first
Base sulfonyl) phenyl]-(5- hydroxyl -1- methyl-1 H- pyrazoles -4- base) ketone, sterling is white powder solid, molecular formula:
C16H17N3O5S, molecular weight: 363.39.Structural formula is as follows:
Topramezone is the novel 4- medical midbodies of para (ortho)-hydroxybenzoic acetone acid esters dual oxide enzyme of the newest research and development listing of BASF Aktiengesellschaft
(HPPD) inhibitor corn field herbicide after seedling.It can hinder synthesis and the photosynthesis of chloroplaset of carotenoid, finally
Cause the weeds albefaction containing HPPD enzyme dead.Most of corn is had good selectivity, including ordinary maize,
Sweety and waxy corn, it is best to the safety of corn at present.
And topramezone can be synthesized using following synthetic route in industrial production at present:
The synthetic route of topramezone
During being synthesized with said synthesis route, the 1- methyl -5- hydroxypyrazoles in polar aprotic solvent are found
Easily occur on phenyl ring under alkaline condition with 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole
Substitution reaction, to generate 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,
5- dihydro-isoxazole.Above-mentioned generation 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) benzene
Base] -4,5- dihydro-isoxazole directly affects the synthesis yield of topramezone, and there is no about this miscellaneous in document before
The relevant report of matter, therefore it is not provided with controlling measurement reaction condition in the prior art, it avoids generating 3- [2- methyl -3-(1-
Methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of topramezone impurity, i.e. 3- [2- methyl -3-(1- methyl -
1H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] and -4,5- dihydro-isoxazole synthetic method, with 3- [the bromo- 2- first of 3-
Base -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole is condensed with 1- methyl -5- hydroxypyrazoles under alkaline condition,
Synthesis 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole.It should
Synthetic method process is simple, easily controllable, and yield is 40~80%.
Another object of the present invention is to provide 3- obtained above [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygen
Base) -6-(methyl sulphonyl) phenyl] and -4,5- dihydro-isoxazole a kind of application.It as standard items, can be used for detecting and
Monitor the synthesis of topramezone.
In order to solve the above technical problems, the technical scheme adopted by the invention is that:
A kind of synthetic method of topramezone impurity, the impurity be 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -
6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole, synthetic method includes the following steps successively carried out:
1) prepared by raw material, including preparation 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole and 1-
Methyl -5- hydroxypyrazoles, the system of [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole wherein the 3-
Preparation Method is, with 2,3- dimethylaniline for starting material, by first vulcanization, bromo, oxidation, at oxime, chloro cyclization synthesis 3-
[the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole；
The synthetic method of the 1- methyl -5- hydroxypyrazoles is to synthesize 1- first with methyl hydrazine reaction with 3- methoxy-methyl acrylate
Base -5- hydroxypyrazoles；
2) condensation reaction
By the 3- of preparation [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole and 1- methyl -5- hydroxyl
Condensation reaction occurs under alkaline condition for pyrazoles, be finally prepared 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -
6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole.
The synthetic line of 3- in above-mentioned reaction [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole
Are as follows:
。
The synthetic route of 1- methyl -5- hydroxypyrazoles is as follows:
。
And then synthetic route of the invention are as follows:
。
As the restriction to step 2 in the present invention: the step 2 sequentially carries out in accordance with the following steps:
1. catalyst alkali and 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole is added to solvent A
Middle dissolution obtains solution B, and by solution B, is warming up to 80~150 DEG C；
2. being added dropwise in reaction flask after 1- methyl -5- hydroxypyrazoles are dissolved with solvent A, mixed with solution B, and 1. in step
At a temperature of fully reacting, after the reaction was completed reaction liquid C；
3. reaction liquid C is down to room temperature and is poured onto ice water, is extracted, be washed with water organic with ethyl acetate or methylene chloride
Phase is concentrated later up to 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- bis-
Hydrogen isoxazole.
As the limiting 1. to step in the present invention: the step 1. in catalyst alkali as sodium carbonate, potassium carbonate, hydrogen-oxygen
Change any one in sodium or potassium hydroxide, the dosage and 3- of the alkali [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -
The molar equivalent ratio of 4,5- dihydro-isoxazole dosage is 0.5~5:1.
Limited as to solvent A in the present invention: the step 1. with step 2. used in solvent A as DMF, DMAC,
Any one in NMP.
It is limited as to another kind of the invention: the 1- methyl -5- hydroxypyrazoles and 3- [the bromo- 2- methyl -6-(first of 3-
Base sulfonyl) phenyl] -4,5- dihydro-isoxazole dosage molar equivalent ratio be 1~1.5:1.
The present invention also provides a kind of 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl)
Phenyl] -4,5- dihydro-isoxazole application, the 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphur
Acyl group) phenyl] -4,5- dihydro-isoxazole is as standard items, to detect and monitor the synthesis of topramezone.
Compared with prior art, the present invention acquired progress is: the present invention provides in topramezone production process
The impurity of generation: 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro is different
The reaction process and reaction condition of oxazole can be known according to above-mentioned reaction and generate 3-
Needed for [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole
Condition, and then can be during generating topramezone according to the present invention to 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -
5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole is monitored, and then realizes detection and monitoring topramezone
The purpose of synthesis generates beneficial effect to the income of topramezone.
The present invention is described in further detail below in conjunction with specific embodiment.
Detailed description of the invention
Fig. 1 be 1-7 of the embodiment of the present invention in synthesize 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(first
Base sulfonyl) phenyl] -4,5- dihydro-isoxazole LCMS figure；
Fig. 2 be inventive embodiments 1-7 in synthesize 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(sulfonyloxy methyl
Base) phenyl] -4,5- dihydro-isoxazole1HNMR figure；
Fig. 3 is 1- methyl -5- hydroxypyrazoles in 1-7 of the embodiment of the present invention1HNMR figure；
Fig. 4 is 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole in 1-7 of the embodiment of the present invention1HNMR figure；
Fig. 5 is 2,3- dimethyl benzene thiomethane in 1-7 of the embodiment of the present invention1HNMR figure
Fig. 6 is 2,3- dimethyl -4- methyl sulphonyl bromobenzene in 1-7 of the embodiment of the present invention1HNMR figure；
Fig. 7 is the bromo- 2- methyl -6- methyl sulphonyl benzaldoxime of 3- in 1-7 of the embodiment of the present invention1HNMR figure；
Fig. 8 a is that 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro is different
Oxazole liquid phase figure；
Fig. 8 b is topramezone standard items liquid phase figure；
Fig. 8 c is the liquid phase figure of topramezone in production.
Specific embodiment
Embodiment 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- two
The synthetic method of hydrogen isoxazole
The present embodiment includes the following steps successively carried out:
1) prepared by raw material, including preparation 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole and 1-
Methyl -5- hydroxypyrazoles, the system of [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole wherein the 3-
Preparation Method are as follows: with 2,3- dimethylaniline be starting material, by first vulcanization, bromo, oxidation, at oxime, chloro cyclization synthesis 3-
[the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole, specific synthetic route are shown in route 1.
Route 1
The synthesis of 2,3- dimethyl benzene thiomethane, the conjunction of 2,3- dimethyl -4- methyl thio bromobenzene are contained in the route 1
At, the synthesis of 2,3- dimethyl -4- methyl sulphonyl bromobenzene, the synthesis of the bromo- 2- methyl -6- methyl sulphonyl benzaldoxime of 3-,
The synthesis of 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole, the present embodiment will be to above-mentioned five kinds
The synthesis of substance is illustrated respectively.
A dimethyl disulfide 500g, 2,3-) the synthesis of 2,3- dimethyl benzene thiomethane: are added in 1000 mL flasks
Dimethylaniline 100g, copper powder 52.55g are warming up to 50 DEG C, and in nitrite tert-butyl 135g is added dropwise in 3 hours, lye absorbs
Tail gas.Drop finishes, and continuation is reacted one hour at 50 DEG C.After the reaction was completed, copper powder is filtered, sodium bicarbonate solution washs filtrate, subtracts
Pressure distillation separation dimethyl disulfide and product 2,3- dimethyl benzene thiomethane.The synthetic1HNMR schemes such as Fig. 5 institute
Show.
B) the synthesis of 2,3- dimethyl -4- methyl thio bromobenzene: at room temperature, 2,3- are added in 1000 mL four-hole bottles
Dimethyl benzene thiomethane 109g, 400 mL of acetic acid.N2The lower mixed liquor that 114g bromine and 100 mL acetic acid is added dropwise of protection, alkali
Liquid absorbs exhaust gas, and the reaction was continued 1 hour after drop finishes.Filter solid is crossed after the reaction was completed, and filtrate is added sodium acetate stirring, steams vinegar
Methylene chloride, water stirring is added in acid, and concentration dichloro is mutually up to 2,3- dimethyl -4- methyl thio bromobenzene.
C) the synthesis of 2,3- dimethyl -4- methyl sulphonyl bromobenzene: at 100 DEG C, to 182g 2,3- dimethyl -4- first
266 g (30%) aqueous hydrogen peroxide solution is added dropwise in 600 mL acetums of the thio bromobenzene of base and 5.24g tungstic acid hydrate sodium,
It is added dropwise, continues to react 1 hour at this temperature.Reaction solution is cooled to 70 DEG C, and elutriation is added into reaction solution and produces
Object, filtering, 2,3- dimethyl -4- methyl sulphonyl bromobenzene obtained by drying.The synthetic1HNMR figure is as shown in Figure 6.
D) the synthesis of the bromo- 2- methyl -6- methyl sulphonyl benzaldoxime of 3-: 276 g sodium methoxides are dissolved in 0.4 L's
In DMF, and 400g 2,3- dimethyl -4- methyl sulphonyl bromobenzene and 216.4g nitrous are added thereto in -20 DEG C~-15 DEG C
The 0.8L DMF solution of acid butyl ester then adds 100g sodium methoxide, the total stirring of reaction mixture 5.5 hours again.
Mixture is poured in 4L ice water and 0.4L acetic acid, and with the tertiary ether extraction of 4L first in total, is washed with sodium bicarbonate solution
Organic phase is washed, organic phase is concentrated, obtains the bromo- 2- methyl -6- methyl sulphonyl benzaldoxime of 3-.The synthetic1HNMR figure
As shown in Figure 7.
E) the synthesis of 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole: at 60 DEG C,
A small amount of N- chloro succinyl is added into 200 mL DMF solutions of the bromo- 2- methyl -6- methyl sulphonyl benzaldoxime of 50g 3-
Imines.Reaction measures the N- chlorosuccinimide of total amount of adding 23.3g in 40 DEG C~50 DEG C once rear.Reaction solution is again
Stirring 30 minutes, until fully reacting, reaction mixture is poured in ice water, crosses filter solid, and wash twice.Solid is directly used
In the next step.
Solid is dissolved in 250mL methylene chloride, ethylene gas displacement, it is not open close enter ethylene gas, be added dropwise simultaneously
20.3g triethylamine reacts at room temperature 72 hours in the case where being constantly passed through ethylene.After the reaction was completed, it washes, and solvent is evaporated off to get 3-
[the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole.The synthetic1HNMR schemes such as Fig. 4 institute
Show.
And the synthetic method of the 1- methyl -5- hydroxypyrazoles in the present embodiment is: under ice-water bath, burning to tetra- mouthfuls of 1000mL
Methanol 170g is added in bottle.116g 3- methoxy-methyl acrylate, 262.8g (35%) methyl hydrazine water is added dropwise into flask simultaneously
Solution.It is added dropwise, the reaction was continued 2 hours.After the reaction was completed, decompression steams methanol, water and methyl hydrazine.Up to product 1- first
Base -5- hydroxypyrazoles.Specific synthetic route is shown in route 2.The synthetic1HNMR figure is as shown in Figure 3.
Route 2
2) condensation reaction
By the 3- of preparation [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole and 1- methyl -5- hydroxyl
Condensation reaction occurs under alkaline condition for pyrazoles, be finally prepared 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -
6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole.
It is specifically included in this step:
1. 200mL solvent A is added in 500mL flask, the solvent A in the present embodiment uses DMF, and 14.9g 3- is then added
(the bromo- 2- methyl -6- methylsulfonyl phenyl of 3-) -4,5- dihydro isoxazole, 16.18g potassium carbonate, obtains solution B, stirring
Under be gradually heated to 140 DEG C.
2. 4.6g 1- methyl -5- hydroxypyrazoles are dissolved by 50mL solvent A, dissolved in the present embodiment using DFM,
Then it is all added drop-wise in the solution B of flask, after being added dropwise, at a temperature of continuing after 1. step heats up (at i.e. 140 DEG C)
It reacts to complete, obtained solution C.
3. solution C after the reaction was completed, is cooled to room temperature, down in cold water, ethyl acetate extraction, water are then successively carried out
It washes, dry concentration to get 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5-
Dihydro-isoxazole solid.
Above-mentioned 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro
The synthetic route of isoxazole is specifically shown in route 3.The LCMS figure of the synthetic is as shown in Figure 1；The synthetic1HNMR
Figure is as shown in Figure 2.
Route 3
Embodiment 2-7 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- two
The synthetic method of hydrogen isoxazole
Embodiment 2-7 be respectively a kind of 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) benzene
Base] -4,5- dihydro-isoxazole synthetic method, the synthetic method of synthetic method and synthetic route and embodiment 1 is essentially identical,
The difference is that each step 2. in solvent for use type and add the variation of each parameter of materials, be specifically shown in Table 1
Table 1
8 3- of embodiment [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro
The application of isoxazole
This implementation is the 3- [2- methyl -3-(1- methyl-1 H- pyrrole using any one synthetic method preparation in embodiment 1-7
Azoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] and -4,5- dihydro-isoxazole application, i.e., prepared 3- [2- methyl -3-(1-
Methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] and -4,5- dihydro-isoxazole can be used as standard reference material detection
Topramezone is with the presence or absence of 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5-
How much are dihydro-isoxazole and its content.
Furthermore during synthesizing topramezone in aforementioned manners, it may be used as standard items detection and monitor this impurity
Situation is generated, this is significant to the improvement of reaction condition.As shown in Fig. 8 a to Fig. 8 c, by comparing topramezone standard items
With the liquid phase figure and 3- of the topramezone in production [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphur
Acyl group) phenyl] -4,5- dihydro-isoxazole liquid phase figure, it is known that in the topramezone product of production contain 3- [2- methyl -3-(1-
Methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole impurity, further illustrate 3- [2-
Methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole is as standard items
Application value.
Claims (7)
1. a kind of synthetic method of topramezone impurity, it is characterised in that: the impurity is 3- [2- methyl -3-(1- methyl-1 H-
Pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole, synthetic method include successively carry out it is following
Step:
1) prepared by raw material, including preparation 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole and 1-
Methyl -5- hydroxypyrazoles, the system of [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole wherein the 3-
Preparation Method is, with 2,3- dimethylaniline for starting material, by first vulcanization, bromo, oxidation, at oxime, chloro cyclization synthesis 3-
[the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole；
The synthetic method of the 1- methyl -5- hydroxypyrazoles is to synthesize 1- first with methyl hydrazine reaction with 3- methoxy-methyl acrylate
Base -5- hydroxypyrazoles；
2) condensation reaction
By the 3- of preparation [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole and 1- methyl -5- hydroxyl
Condensation reaction occurs under alkaline condition for pyrazoles, be finally prepared 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -
6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole.
2. the synthetic method of topramezone impurity according to claim 1, it is characterised in that:
The 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] the different evil of -4,5- dihydro
The synthetic line of azoles are as follows:
。
3. the synthetic method of topramezone impurity according to claim 1 or 2, it is characterised in that the step 2 is according to such as
Lower sequence of steps carries out:
1. catalyst alkali and 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole is added to solvent A
Middle dissolution obtains solution B, and solution B is warming up to 80~150 DEG C；
2. being added dropwise in reaction flask after 1- methyl -5- hydroxypyrazoles are dissolved with solvent A, mixed with solution B, and 1. in step
At a temperature of fully reacting, after the reaction was completed reaction liquid C；
3. reaction liquid C is down to room temperature and is poured onto ice water, is extracted, be washed with water organic with ethyl acetate or methylene chloride
Phase is concentrated later up to 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- bis-
Hydrogen isoxazole.
4. the synthetic method of topramezone impurity according to claim 3, it is characterised in that: the step 1. in catalysis
Agent alkali is any one in sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, the dosage and 3- [the bromo- 2- first of 3- of the alkali
Base -6-(methyl sulphonyl) phenyl] -4,5- dihydro-isoxazole dosage molar equivalent ratio be 0.5~5:1.
5. the synthetic method of topramezone impurity according to claim 3, it is characterised in that: the step 1. with step 2.
Used in solvent A be DMF, DMAC, NMP in any one.
6. the synthetic method of topramezone impurity according to claim 3, it is characterised in that: 1- methyl -5- hydroxyl used
The molar equivalent ratio of pyrazoles and 3- [the bromo- 2- methyl -6-(methyl sulphonyl of 3-) phenyl] -4,5- dihydro-isoxazole dosage is 1~
1.5:1。
7. 3- [2- obtained by a kind of synthetic method of topramezone impurity described in any one of -6 according to claim 1
Methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] and -4,5- dihydro-isoxazole application, it is special
Sign is: the 3- [2- methyl -3-(1- methyl-1 H- pyrazoles -5- oxygroup) -6-(methyl sulphonyl) phenyl] -4,5- dihydro is different
Oxazole is used as standard items, to detect and monitor the synthesis of topramezone.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111848536A (en) * | 2020-07-17 | 2020-10-30 | 山东京博生物科技有限公司 | Preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole |
| CN112094211A (en) * | 2020-09-25 | 2020-12-18 | 江苏七洲绿色化工股份有限公司 | Preparation method of topramezone intermediate |
| CN112694425A (en) * | 2020-12-29 | 2021-04-23 | 利民化学有限责任公司 | Method for preparing topramezone intermediate by using supergravity reaction |
| CN115385832A (en) * | 2022-09-13 | 2022-11-25 | 江苏七洲绿色科技研究院有限公司 | Preparation method of 2, 3-dimethyl 4-methylsulfonyl bromobenzene |
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| CN111848536A (en) * | 2020-07-17 | 2020-10-30 | 山东京博生物科技有限公司 | Preparation method of 3- [ 3-bromo-2-methyl-6- (methylsulfonyl) phenyl ] -4, 5-dihydroisoxazole |
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| CN112694425A (en) * | 2020-12-29 | 2021-04-23 | 利民化学有限责任公司 | Method for preparing topramezone intermediate by using supergravity reaction |
| CN112694425B (en) * | 2020-12-29 | 2022-04-26 | 利民化学有限责任公司 | Method for preparing topramezone intermediate by using supergravity reaction |
| CN115385832A (en) * | 2022-09-13 | 2022-11-25 | 江苏七洲绿色科技研究院有限公司 | Preparation method of 2, 3-dimethyl 4-methylsulfonyl bromobenzene |
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