CN108033944A - Rynaxypyr impurity preparation process - Google Patents
Rynaxypyr impurity preparation process Download PDFInfo
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- CN108033944A CN108033944A CN201711460497.5A CN201711460497A CN108033944A CN 108033944 A CN108033944 A CN 108033944A CN 201711460497 A CN201711460497 A CN 201711460497A CN 108033944 A CN108033944 A CN 108033944A
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Abstract
The invention discloses a kind of Rynaxypyr impurity preparation process, belong to technical field of organic synthesis.The technical problem to be solved in the present invention is to provide a series of technique that a kind of efficient, low cost prepares Rynaxypyr impurity.The technique comprises the following steps：Compound M2 first is made by raw material of M1, then one kettle way is carried out at the same time oxidation and S1 is prepared in bromination, and S2 is prepared through hydrolysis again in S1, and S3 is made through amidatioon in S2.This method eliminates isolating and purifying for intermediate M2, has saved the dosage of bromating agent and solvent, has shortened processing step, has reduced production cost, it is not necessary to uses the hazardous chemicals such as bromine, hydrogen peroxide；The method of the present invention can prepare a series of Rynaxypyr impurity, and effective guarantee is provided for the quality of production control of Rynaxypyr.
Description
Technical field
The invention belongs to technical field of organic synthesis, is related to a kind of Rynaxypyr impurity preparation process.
Background technology
Rynaxypyr is a kind of Green Chemistry insecticide, and the compound is in the effect Lepidoptera evil such as grain, cotton, fruit and vegetable
Have the characteristics that dosage is few, prevention is high, the lasting period is long, it is small that people and animals and environment are influenced in terms of worm prevention, its structural formula is as follows：
In the production process of Rynaxypyr, various impurity are inevitably resulted from, it is probably derived from activity
The side reaction that occurs in component building-up process comes from raw material, or there may be during production/storage of preparation.By
In all impurity can not be controlled by optimizing process, so change of some impurity between different batches may be compared with
Greatly.And the impurity in Rynaxypyr may have significant effect its pharmacological property/toxicity etc., there may be residual in food
Harm is produced to consumer, or causes environmental pollution.
Therefore, the impurity in Rynaxypyr, especially related impurities species and concentration, it is necessary to it is monitored from
And control the quality of Rynaxypyr.
The content of the invention
The technical problems to be solved by the invention be to provide it is a kind of efficiently, that low cost prepares a series of Rynaxypyrs is miscellaneous
The technique of matter, the quality control for Rynaxypyr.
To solve the above problems, inventor is had found by a large number of experiments, when using M1 as starting material, adding excessive bromating agent
When (such as tribromo oxygen phosphorus), it is only capable of obtaining single brominated product M2, rather than double brominated product M4；And then the step of oxidation can not be passed through again
Suddenly, Rynaxypyr impurity S1 is obtained：
Meanwhile using M1 be starting material by bromination-oxidation-brominated path, also M2' can not be efficiently converted into S1,
So as to be difficult to Rynaxypyr impurity S1 is prepared：
, but can expeditiously one when M2 is under the conditions of oxidant and bromating agent are simultaneous however, surprisingly
Step directly obtains the product through bromination and oxidation, i.e. Rynaxypyr impurity S1：
Meanwhile inventor further study show that, if appropriate solvent compatibility can be selected to prepare M2 and by M2 by M1
Prepare the reaction of S1, and a step feeds intake the bromating agent added needed for two-step reaction in the step of preparing M2, can not separate
Intermediate M2 and the step of removing solvent is saved at the same time, the chlorine worm of high-purity is directly prepared in high yield from the direct one kettle ways of M1
Benzamide impurity S1.
When preparing M2 with M1 raw materials, especially when organic solvent is acetonitrile, not only 3- is bromo- in reaction solution obtained by the step
The yield and content of 1- (3- chloropyridine -2- bases) -4,5- dihydro-1 h-pyrazole -5- Ethyl formates intermediates (M2) are all higher, together
When can ensure subsequently by M2 prepare S1 the step of in oxidation and bromination reaction be smoothed out, improve Rynaxypyr impurity S1
Yield and purity.
On the basis of by a large number of experiments, technical solution there is provided one used by the present invention solves above-mentioned technical problem
Kind Rynaxypyr impurity preparation process, the technique include：
Step a：Prepare compound M2；
Step b：In the case of oxidant and bromating agent are simultaneous, chlorine worm benzene is prepared by raw material of compound M2
Formamide impurity S1：
Wherein, in Rynaxypyr impurity preparation process described above, in step b, the bromating agent is tribromo oxygen
At least one of phosphorus, phosphorus pentabromide, phosphorus tribromide, two bromo trialkyl phosphines, two bromodiphenyl-phosphines；It is preferred that tribromo oxygen phosphorus or
Phosphorus pentabromide.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, when bromating agent is tribromo oxygen phosphorus
When, the molar ratio of tribromo oxygen phosphorus and compound M2 are 0.33~2.5：1；When bromating agent is phosphorus pentabromide, phosphorus pentabromide is with changing
The molar ratio of compound M2 is 0.2~2：1.
Optimization, above-mentioned Rynaxypyr impurity preparation process specifically includes following steps：
Step a, compound M2 is prepared；
Step b, the mixture of compound M2, oxidant and bromating agent is heated to being reacted under 0 DEG C~solvent boiling point,
After completion of the reaction, through column chromatography for separation, Rynaxypyr impurity S1 is obtained.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, the step for adding acid is further included.
Wherein, in Rynaxypyr impurity preparation process described above, the acid is the concentrated sulfuric acid.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, the dosage of the concentrated sulfuric acid with
The molar ratio of compound M2 is 0.1~5：1；Preferably, the dosage of the concentrated sulfuric acid and the molar ratio of compound M2 are 1~5：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, the oxidant is persulfuric acid
At least one of potassium, persulfuric acid acid sodium, ammonium persulfate.
Wherein, in Rynaxypyr impurity preparation process described above, dosage and the compound M2 of the oxidant
Molar ratio be 1~2：1.
Wherein, in Rynaxypyr impurity preparation process described above, the reaction of step b be using acetonitrile as solvent into
Capable.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, organic solvent and compound M2
Volume mass ratio be 5~15mL：1g.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, the organic solvent is acetonitrile.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, the behaviour of the column chromatography for separation
As：System after completion of the reaction is filtered, takes filtrate, the filter cake organic solvent washing identical with step a, merges organic
Phase, be concentrated under reduced pressure organic phase, with ethyl acetate：N-hexane=1：10~20 solvent carries out column chromatography for separation.
Wherein, it is described to prepare compound M2's in step a in Rynaxypyr impurity preparation process described above
Operate and be：Compound M1 and bromating agent are reacted to obtain compound M2：
Wherein, in Rynaxypyr impurity preparation process described above, the bromating agent is tribromo oxygen phosphorus, five brominations
At least one of phosphorus, phosphorus tribromide, two bromo trialkyl phosphines, two bromodiphenyl-phosphines；It is preferred that tribromo oxygen phosphorus or phosphorus pentabromide.
Wherein, in Rynaxypyr impurity preparation process described above, wherein step a and step b use one kettle way
Carry out.
Wherein, in Rynaxypyr impurity preparation process described above, the bromating agent in step a and step b is phase
Same bromating agent, and the bromating agent needed for step a and step b reactions once feeds intake in step a.
Preferably, in Rynaxypyr impurity preparation process described above,
Step a is：By the mixture of compound M1, bromating agent and organic solvent in 20 DEG C of temperature to organic solvent boiling point
Under reacted, reaction finishes, and obtains reaction solution A；
Step b is：Reaction solution A obtained by step a and oxidant reaction, reaction are finished, obtain Rynaxypyr impurity
S1。
Wherein, in Rynaxypyr impurity preparation process described above, when step a and step b use one kettle way, when
When bromating agent is tribromo oxygen phosphorus, the molar ratio of tribromo oxygen phosphorus and compound M1 in step a are 0.67~2.5：1；When bromating agent is
During phosphorus pentabromide, the molar ratio of phosphorus pentabromide and compound M1 in step a are 0.4~2：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, the step for adding acid is further included.
Wherein, in Rynaxypyr impurity preparation process described above, the acid is the concentrated sulfuric acid.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, the dosage of the concentrated sulfuric acid with
The molar ratio of compound M1 is 0.1~5 in step a：1.
Preferably, in Rynaxypyr impurity preparation process described above, in step b, the dosage of the concentrated sulfuric acid
Molar ratio with compound M1 in step a is 1~5：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, the oxidant is persulfuric acid
At least one of potassium, persulfuric acid acid sodium, ammonium persulfate.
Wherein, in Rynaxypyr impurity preparation process described above, dosage and the M1 in step a of the oxidant
Molar ratio be 1~2：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step a, the organic solvent and chemical combination
The volume mass ratio of thing M1 is 5~15mL：1g.
Wherein, in Rynaxypyr impurity preparation process described above, in step a, the organic solvent is acetonitrile.
More optimize, above-mentioned Rynaxypyr impurity preparation process specifically includes following steps：
Step a, the mixture of compound M1, bromating agent and organic solvent is reacted under 20 DEG C to solvent boiling point,
0~50 DEG C is cooled to after completion of the reaction, and filtering, obtains reaction solution A；
Step b, the mixture of reaction solution A, oxidant and the concentrated sulfuric acid is heated to being reacted under 0 DEG C~solvent boiling point,
After completion of the reaction, through column chromatography for separation, Rynaxypyr impurity S1 is obtained.
Wherein, in Rynaxypyr impurity preparation process described above, in step a, time of the reaction for 2~
8h。
Wherein, in Rynaxypyr impurity preparation process described above, in step a, the operation of the filtering is：To
Diatomite is added in system after completion of the reaction, stirs 5~20min, filtering, filter cake is with identical with step a organic molten in right amount
Agent is washed 2~4 times.
Wherein, in Rynaxypyr impurity preparation process described above, in step b, the behaviour of the column chromatography for separation
As：System after completion of the reaction is filtered, takes filtrate, the filter cake organic solvent washing identical with step a, merges organic
Phase, be concentrated under reduced pressure organic phase, with ethyl acetate：N-hexane=1：10~20 solvent carries out column chromatography for separation.
On the above-mentioned Process ba- sis for preparing S1, invention still further provides second of Rynaxypyr impurity S2
Preparation process, it comprises the following steps：
Step c, the Rynaxypyr impurity S1 that step b is obtained is converted to obtain Rynaxypyr impurity S2：
In the preparation process of Rynaxypyr impurity S2, acid catalysis or alkali catalyzed hydrolysis can be used.It is preferred that base catalysis,
Available alkali includes the hydroxide of alkali metal, such as NaOH, KOH.Reaction can carry out in the mixed system of water and alcohol.
More specifically embodiment is：On the above-mentioned Process ba- sis for preparing S1, step c is further included：
Step c, Jiang Shui, methanol and sodium hydroxide are uniformly mixed, and are cooled to 15~25 DEG C, add step b institutes thereto
Rynaxypyr impurity S1, remove methanol after completion of the reaction, add water, water is mutually extracted with ethyl acetate, then by water phase pH
2~3 are adjusted to, is stirred, is filtered, drying, obtains Rynaxypyr impurity S2.
Wherein, in Rynaxypyr impurity preparation process described above, in step c, the dosage of the sodium hydroxide
Molar ratio with the addition of Rynaxypyr impurity S1 is 1~3：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step c, the methanol and chlorine worm benzene first
The mass ratio of the addition of amide impurities S1 is 1~4：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step c, Rynaxypyr is being added
Before impurity S1, the mass ratio of water and the addition of Rynaxypyr impurity S1 is 1~4：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step c, time of the reaction for 2~
10h。
Wherein, in Rynaxypyr impurity preparation process described above, in step c, water phase pH is adjusted using hydrochloric acid,
The concentration of hydrochloric acid is 10~38%.
On the above-mentioned Process ba- sis for preparing S2, invention still further provides the third Rynaxypyr impurity S3
Preparation process, it comprises the following steps：
Step d, in the presence of sulfonic acid chloride class compound, by the obtained Rynaxypyr impurity S2 of step c and chemical combination
Thing M3 reacts, and reaction finishes, and obtains Rynaxypyr impurity S3：
Wherein, in Rynaxypyr impurity preparation process described above, in step d, the sulfonic acid chloride class compound
For mesyl chloride or paratoluensulfonyl chloride.
Wherein, in Rynaxypyr impurity preparation process described above, in step d, the sulfonic acid chloride class compound
The molar ratio of addition of dosage and Rynaxypyr impurity S2 be 1~1.5：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step d, dosage and the chlorine worm of the M3
The molar ratio of the addition of benzamide impurity S2 is 1~1.5：1.
More specifically embodiment is：On the above-mentioned Process ba- sis for preparing S2, step d is further included：
Step d, Rynaxypyr impurity S2 obtained by step c is uniformly mixed with M3, acetonitrile, pyridine, -5 DEG C~0 DEG C,
The mixture of acetonitrile and mesyl chloride is added dropwise, drop finishes, and after 2~4h of insulation reaction, warms naturally to 15~25 DEG C, adds water, after
After 1~2h of continuous stirring, filtered, washing, drying, obtain Rynaxypyr impurity S3.
Wherein, in Rynaxypyr impurity preparation process described above, in step d, the acetonitrile and chlorine worm benzene first
The volume mass ratio of amide impurities S2 is 5~15mL：1g.
Wherein, in Rynaxypyr impurity preparation process described above, in step d, the dosage chlorine worm of the pyridine
The molar ratio of the addition of benzamide impurity S2 is 1~5：1.
The beneficial effects of the invention are as follows：
First, by single step reaction chlorine worm can be prepared in compound M2, simultaneous oxidation and bromination by the method for the present invention
Benzamide impurity S1.
Then, the present invention on this basis, additionally provide using compound M1 for starting material by adjusting aoxidize, bromination bar
Part, Rynaxypyr impurity S1 can be prepared in high yield using two-step reaction one kettle way, eliminate intermediate M2's
Isolate and purify, saved the dosage of bromating agent and solvent, shortened processing step, reduced production cost, it is not necessary to used bromine
The hazardous chemicals such as element, hydrogen peroxide, it is safe, it is advantageously implemented industrialized production.
Finally, present invention also offers by Rynaxypyr impurity S1 be prepared Rynaxypyr impurity S2 and
Rynaxypyr impurity S3.
Therefore, the method for the present invention can prepare a series of Rynaxypyr impurity, be the quality of production of Rynaxypyr
Control provides effective guarantee.
Brief description of the drawings
Fig. 1 is the reaction equation that the present invention prepares Rynaxypyr impurity S1, S2 and S3.
Embodiment
A kind of Rynaxypyr impurity preparation process, the technique include：
Step a：Prepare compound M2；
Step b：In the case of oxidant and bromating agent are simultaneous, chlorine worm benzene is prepared by raw material of compound M2
Formamide impurity S1：
Wherein, it is described to prepare compound M2's in step a in Rynaxypyr impurity preparation process described above
Operate and be：Compound M1 and bromating agent are reacted to obtain compound M2：
Inventor is had found by a large number of experiments, when using M1 as starting material, adding excess bromating agent (such as tribromo oxygen phosphorus),
It is only capable of obtaining single brominated product M2, rather than double brominated product M4；And then the step of oxidation can not be passed through again, obtain chlorine worm benzene first
Amide impurities S1：
Meanwhile using M1 be starting material by bromination-oxidation-brominated path, also M2' can not be efficiently converted into S1,
So as to be difficult to Rynaxypyr impurity S1 is prepared：
, but can expeditiously one when M2 is under the conditions of oxidant and bromating agent are simultaneous however, surprisingly
Step directly obtains the product through bromination and oxidation, i.e. Rynaxypyr impurity S1：
Meanwhile inventor further study show that, if can select, appropriate solvent compatibility step a's and step b is anti-
Should, and a step feeds intake the bromating agent added needed for two-step reaction in step a, can not the product M2 of separating step a and same
Shi Sheng removes the step of solvent, and the Rynaxypyr impurity of high-purity is directly prepared in high yield from the direct one kettle ways of M1
S1。
In step a, especially when organic solvent is acetonitrile, the not only bromo- 1- of 3- (3- chlorine pyrroles in reaction solution A obtained by step a
Pyridine -2- bases) -4,5- dihydro-1 h-pyrazole -5- Ethyl formates intermediates (M2) yield and content it is all higher, while can ensure to walk
Oxidation and bromination reaction are smoothed out in rapid b, improve the yield and purity of Rynaxypyr impurity S1.
Wherein, in Rynaxypyr impurity preparation process described above, the bromating agent is tribromo oxygen phosphorus, five brominations
At least one of phosphorus, phosphorus tribromide, two bromo trialkyl phosphines, two bromodiphenyl-phosphines；It is preferred that tribromo oxygen phosphorus or phosphorus pentabromide.
When the method for the present invention prepares S1 with raw material M1, oxidation and bromination two-step reaction can one pot be carried out at the same time, obtained by step a
In reaction solution A main component for the bromo- 1- of 3- (3- chloropyridine -2- bases) -4,5- dihydro-1 h-pyrazoles -5- Ethyl formates intermediates and
Bromating agent, it can purify directly series connection without isolation and prepare the reaction of S1, it is therefore desirable to in step a and step b it is a variety of because
Element is investigated, to ensure the effect of one kettle way.
When preparing S1 using one kettle way, the bromating agent in step a and step b is identical bromating agent, and in step a
Bromating agent needed for step a and step b reactions is once fed intake.
More particularly, when preparing S1 with raw material M1 one kettle ways, step a is：By compound M1, bromating agent and organic solvent
Mixture reacted at a temperature of 20 DEG C to organic solvent boiling point, reaction finishes, and obtains reaction solution A；
Step b is：Reaction solution A obtained by step a and oxidant reaction, reaction are finished, obtain Rynaxypyr impurity
S1。
Step a of the present invention is bromination reaction, and the bromating agent is tribromo oxygen phosphorus, phosphorus pentabromide, phosphorus tribromide, two bromos three
Alkylphosphines, two bromodiphenyl-phosphines；It is excellent in order to improve the yield of S1, it is necessary to carry out two step brominations when preparing S1 due to the present invention
Select the stronger bromating agent of bromination ability；It is preferred, therefore, that the bromating agent is tribromo oxygen phosphorus or phosphorus pentabromide；Using one kettle way
When, when bromating agent is tribromo oxygen phosphorus, the molar ratio of tribromo oxygen phosphorus and compound M1 in step a are 0.67~2.5：1；Work as bromination
When agent is phosphorus pentabromide, the molar ratio of phosphorus pentabromide and compound M1 in step a are 0.4~2：1；It is furthermore preferred that the bromination
Agent is tribromo oxygen phosphorus.
When the method for the present invention one kettle way prepares S1, in step a and step b, oxidation and bromination use two-step reaction one kettle way
Carry out, therefore the organic solution selected should compatible two-step reaction；Inventor attempts by a large amount of, in step a, when organic solvent is
During acetonitrile, the not only bromo- 1- of 3- (3- chloropyridine -2- bases) -4,5- dihydro-1 h-pyrazole -5- formic acid second in reaction solution A obtained by step a
The yield and content of ester intermediate are all higher, while can ensure that oxidation and bromination reaction are smoothed out in step b, improve the receipts of S1
Rate and purity；The organic solvent (acetonitrile) and the volume mass ratio of compound M1 are 5~15mL：1g.
To ensure that raw material M1 can fully react in step a, the time of the reaction is 2~8h；Also can use TLC,
The methods of HPLC, detects the response situation of raw material M1, to determine the reaction end of step a.
Wherein, in Rynaxypyr impurity preparation process described above, wherein, Rynaxypyr described above
In impurity preparation process, in step b, the step for adding acid is further included；The acid is the concentrated sulfuric acid；The dosage and step of the concentrated sulfuric acid
The molar ratio of compound M1 is 0.1~5 in rapid a：1；Preferably, the dosage of the concentrated sulfuric acid is rubbed with compound M1 in step a
You are than being 1~5：1.
Since the present invention is using two-step reaction one kettle way preparation S1, the operation that isolates and purifies of intermediate, and step b are eliminated
It is middle need add more amount the concentrated sulfuric acid when, heat release is larger, should suitably cool down；In step a, after completion of the reaction, work as system temperature
When being down to 0~50 DEG C, blackish green liquid is obtained, it contains cotton-shaped accessory substance, for the ease of filtering, can add filter aid, therefore,
The operation of the filtering is：Diatomite is added into system after completion of the reaction, stirs 5~20min, filtering, filter cake is with right amount
The organic solvent washing identical with step a 2~4 times.
In the method for the present invention step b, the oxidant is potassium peroxydisulfate, persulfuric acid acid sodium or ammonium persulfate；In order to improve
The yield and purity of S1, the dosage of the oxidant are 1~2 with the molar ratio of M1 in step a.The concentrated sulfuric acid plays catalytic action, is
Conversion is complete, and in step b, the dosage of the concentrated sulfuric acid is 0.1~5 with the molar ratio of M1 in step a；Preferably, it is described dense
The dosage of sulfuric acid and the molar ratio of M1 in step a are 1~5.
In step b, (3-6h need to be generally reacted) after completion of the reaction, golden yellow thick substances are generated, using column chromatography for separation
Purifying, the operation of the column chromatography for separation are：System after completion of the reaction is filtered, takes filtrate, filter cake is with identical with step a
Organic solvent washing, merges organic phase, be concentrated under reduced pressure organic phase, with ethyl acetate：N-hexane=1：10~20 solvent into
Row column chromatography for separation.
Optimization, a kind of Rynaxypyr impurity preparation process (being used to prepare Rynaxypyr impurity S1), the work
Skill comprises the following steps：
Step a, the mixture of compound M1, bromating agent and acetonitrile is reacted under 20 DEG C to solvent boiling point, reaction 2
After~8,0~50 DEG C is cooled to, diatomite is added into system after completion of the reaction, stirs 5~20min, filtering, filter cake is used suitable
Measure acetonitrile to wash 2~4 times, obtain reaction solution A；The bromating agent is tribromo oxygen phosphorus or phosphorus pentabromide；The acetonitrile and compound M1
Volume mass ratio be 5~15mL：1g；
Step b, the mixture of reaction solution A, oxidant and the concentrated sulfuric acid is heated to being reacted under 0 DEG C~solvent boiling point,
After completion of the reaction, system after completion of the reaction is filtered, takes filtrate, the filter cake organic solvent washing identical with step a, merges
Organic phase, be concentrated under reduced pressure organic phase, with ethyl acetate：N-hexane=1：10~20 solvent carries out column chromatography for separation, obtains chlorine
Worm benzamide impurity S1；The oxidant is at least one of potassium peroxydisulfate, persulfuric acid acid sodium or ammonium persulfate；The oxygen
The dosage of agent and the molar ratio of M1 in step a are 1~2：1；The dosage of the concentrated sulfuric acid and the molar ratio of M1 in step a are 1
~5：1.
On the above-mentioned Process ba- sis for preparing S1, invention still further provides second of Rynaxypyr impurity S2
Preparation process, it comprises the following steps：
Step c, the Rynaxypyr impurity S1 that step b is obtained is converted to obtain Rynaxypyr impurity S2：
In the preparation process of Rynaxypyr impurity S2, acid catalysis or alkali catalyzed hydrolysis can be used.It is preferred that base catalysis,
Available alkali includes the hydroxide of alkali metal, such as NaOH, KOH.Reaction can carry out in the mixed system of water and alcohol.
More specifically embodiment is：
Step c, Jiang Shui, methanol and sodium hydroxide are uniformly mixed, and are cooled to 15~25 DEG C, add step b institutes thereto
Rynaxypyr impurity S1, remove methanol after completion of the reaction, add water, water is mutually extracted with ethyl acetate, then by water phase pH
2~3 are adjusted to, is stirred, is filtered, drying, obtains Rynaxypyr impurity S2.
Wherein, in Rynaxypyr impurity preparation process described above, in step c, the dosage of the sodium hydroxide
Molar ratio with the addition of Rynaxypyr impurity S1 is 1~3：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step c, methanol and Rynaxypyr
The mass ratio of the addition of impurity S1 is 1~4：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step c, Rynaxypyr is being added
Before impurity S1, the mass ratio of water and the addition of Rynaxypyr impurity S1 is 1~4：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step c, time of the reaction for 2~
10h。
In the method for the present invention step c, when after completion of the reaction, main component is the sodium salt of S2 in system, can use subtract at this time
Most of methanol in the mode removal systems such as pressure, avoids influencing follow-up effect of extracting, then adds 0.5-2 times and measures water (relatively
In the quality of Rynaxypyr impurity S1), water is mutually extracted 2~4 times with appropriate ethyl acetate, and removal is gone organic miscellaneous in water phase
Matter, then water phase pH is adjusted to 2~3 using 10~38% hydrochloric acid, and stir, target product is precipitated out as far as possible, filter, dry
It is dry, up to Rynaxypyr impurity S2；The temperature of the drying is 50~60 DEG C, and the time is 2~6h.
On the above-mentioned Process ba- sis for preparing S2, invention still further provides the third Rynaxypyr impurity S3
Preparation process, it comprises the following steps：
Step d, in the presence of sulfonic acid chloride class compound, by the obtained Rynaxypyr impurity S2 of step c and chemical combination
Thing M3 reacts, and reaction finishes, and obtains Rynaxypyr impurity S3：
Wherein, in Rynaxypyr impurity preparation process described above, in step d, sulfonic acid chloride class compound is first
Sulfonic acid chloride or paratoluensulfonyl chloride.
Wherein, in Rynaxypyr impurity preparation process described above, in step d, the use of sulfonic acid chloride class compound
The molar ratio of amount and the addition of Rynaxypyr impurity S2 is 1~1.5：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step d, dosage and the chlorine worm of the M3
The molar ratio of the addition of benzamide impurity S2 is 1~1.5：1.
More specifically embodiment is：
Step d, Rynaxypyr impurity S2 obtained by step c is uniformly mixed with M3, acetonitrile, pyridine, -5 DEG C~0 DEG C,
The mixture of acetonitrile and mesyl chloride is added dropwise, drop finishes, and after 2~4h of insulation reaction, warms naturally to 15~25 DEG C, adds water, after
After 1~2h of continuous stirring, filtered, washing, drying, obtain Rynaxypyr impurity S3.
Wherein, in Rynaxypyr impurity preparation process described above, in step d, the acetonitrile and chlorine worm benzene first
The volume mass ratio of amide impurities S2 is 5~15mL：1g.
Wherein, in Rynaxypyr impurity preparation process described above, in step d, the dosage chlorine worm of the pyridine
The molar ratio of the addition of benzamide impurity S2 is 1~5：1.
Wherein, in Rynaxypyr impurity preparation process described above, in step d, the dosage and acetonitrile of the water
Mass ratio be 0.25~0.5:1.
To avoid the loss of S3, while impurity is removed as far as possible, using 30~50% acetonitrile solutions washing filter cake twice, so
Afterwards 2~6h is dried at 50~60 DEG C.
The present invention is described in further detail below by test example and embodiment, but is not therefore protected the present invention
Scope is limited among the embodiment described scope.
Test example 1
In order to make using M1 as raw material, two-step reaction one kettle way prepares Rynaxypyr impurity S1 and is smoothed out, this hair
It is bright that the bromination for preparing S1 for raw material, has been investigated with the bromo- 1- of 3- (3- chloropyridine -2- bases) -1H- pyrazole-5-ethyl formates (i.e. M2)
System, its reaction equation are as follows：
M21.0g (0.003mol), 10.0g acetonitriles, tribromo oxygen phosphorus 0.95g are added in 50mL there-necked flasks
(0.0033mol), is warming up to reflux (T=82 DEG C), insulation reflux 2h, TLC monitoring, generates without target product S1.
As a result prove：Bromination as raw material, is only added using the bromo- 1- of 3- (3- chloropyridine -2- bases) -1H- pyrazole-5-ethyl formates
When agent is without adding oxidant, which cannot occur；The step bromination reaction needs to be oxidized agent and is cooperateed with bromating agent, from
And be conducive to bromination reaction.
Embodiment 1：The preparation of Rynaxypyr impurity S1
(1) prepared by the method for fractional steps
A, 10.0g M1 (0.037mol), 60.0g acetonitriles and 5.3g tribromo oxygen phosphorus are added in 100mL there-necked flasks
(0.018mol), is heated to 82 DEG C, there is obvious reflux, and insulated and stirred 2h, is naturally cooling to less than 50 DEG C, obtains blackish green
Liquid, contains floccule；2.0g diatomite is added, stirs 10min, filtering, filter cake is washed 2 times with 2.0g acetonitriles, is merged organic
Phase, obtains reaction solution A；Reaction solution A is added in saturated sodium bicarbonate aqueous solution, is extracted with dichloromethane, organic phase decompression is dense
Contracting, obtains 10.3g M2, yield 97.3%, and HPLC purity is more than 99%.
B, take M210.3g (0.036mol), 60.0g acetonitriles, 5.3g tribromo oxygen phosphorus (0.018mol) that step a obtains,
15.0g potassium peroxydisulfates (0.056mol) are added in 100mL there-necked flasks, and stirring, is added dropwise the 7.3g concentrated sulfuric acids (0.074mol), are had obvious
Heat release, is heated to reflux (82 DEG C), insulation reflux 3h, has golden yellow thick substances to generate, Temperature fall, mistake after being added dropwise to complete
Filter, takes filtrate, and filter cake is washed (2.0g × 2) with acetonitrile, merges organic phase；Be concentrated under reduced pressure organic phase, column chromatography for separation, expansion
Agent：Ethyl acetate：N-hexane=1：15, obtain 11.4g buff white solid Rynaxypyr impurity S1, yield：77.4%,
HPLC：97.8%.
(2) prepared by one kettle way
A, 10.0g M1 (0.037mol), 60.0g acetonitriles and 10.6g tribromo oxygen phosphorus are added in 100mL there-necked flasks
(0.037mol), is heated to 82 DEG C, there is obvious reflux, and insulated and stirred 2h, is naturally cooling to less than 50 DEG C, obtains blackish green
Liquid, contains floccule；2.0g diatomite is added, stirs 10min, filtering, filter cake is washed 2 times with 2.0g acetonitriles, is merged organic
Phase, obtains reaction solution A, and, to be blackish green, the HPLC purity of HPLC detections reaction solution A, wherein M2 are 98%, are preserved stand-by for it；
B, reaction solution A, 15.0g potassium peroxydisulfate (0.056mol) obtained by step a are added in 100mL there-necked flasks, stirred, drop
Add the 7.3g concentrated sulfuric acids (0.074mol), there is obvious heat release, reflux (82 DEG C) is heated to after being added dropwise to complete, insulation reflux 3h, there is gold
Clear yellow viscous material generates, Temperature fall, and filtering, takes filtrate, and filter cake is washed (2.0g × 2) with acetonitrile, merges organic phase；Decompression
Concentrate organic phase, column chromatography for separation, solvent：Ethyl acetate：N-hexane=1：15, obtain 10.9g buff white solid chlorine worm benzene first
Amide impurities S1, yield：71.8%, HPLC：97.3%.
The hydrogen of the present embodiment one kettle way preparation gained Rynaxypyr impurity S1, which is composed, is：1H NMR(400MHz,DMSO-
d6)：δ 8.77 (d, J=2.1Hz, 1H), 8.74 (d, J=2.1Hz, 1H), 7.38 (s, 1H), 4.19 (q, J=7.1Hz, 2H),
1.12 (t, J=7.1Hz, 3H).
Embodiment 2：The preparation of Rynaxypyr impurity S2
10.0g water, 15.0g methanol and 0.6g sodium hydroxides (0.015mol) are added in 100mL single port bottles, is stirred, when
When temperature is reduced to room temperature, 5.0g Rynaxypyr impurity S1 (0.012mol) are added, 3h is reacted, most of first is removed under reduced pressure
Alcohol, add 5.0g water, be extracted twice with 5g ethyl acetate, 30% hydrochloric acid solutions of 2.7g are mutually slowly added dropwise in water, be adjusted to pH=2~
3,1h, filtering are stirred, 55 DEG C of vacuum drying ovens dry 2h, obtain 4.2g white solid Rynaxypyr impurity S3, yield 90.2%,
HPLC：96.5%.
The hydrogen of Rynaxypyr impurity S2 obtained by the present embodiment, which is composed, is：1H NMR(400MHz,DMSO-d6)：δ8.60(d,
J=2.1Hz, 1H), 8.48 (d, J=2.1Hz, 1H), 6.51 (s, 1H), 13.95 (br, 1H).
Embodiment 3：The preparation of Rynaxypyr impurity S3
2.0g Rynaxypyr impurity S2 (0.0052mol), 1.09g M3 are added in 100mL there-necked flasks
(0.0055mol), 15g acetonitriles and 1.24g pyridines (0.016mol), are stirred, cooling, -5 DEG C of whens start to be added dropwise 5g acetonitriles and
The mixture of 0.72g mesyl chlorides (0.0063mol), is added dropwise to complete within 10min, insulated and stirred 2h, has a large amount of solids to separate out,
Naturally heat up, 7g water is added during room temperature, continue to stir 1h, filtering, filter cake is washed twice with 30% acetonitrile solution 2g, and 55 DEG C very
Empty oven for drying 4h, obtains 2.8g white solid Rynaxypyr impurity S3, yield 95.6%, HPLC：98.4%.
The hydrogen of Rynaxypyr impurity S3 obtained by the present embodiment, which is composed, is：1H NMR(400MHz,DMSO-d6)：δ10.31
(s, 1H), 8.68 (d, J=2.1Hz, 1H), 8.62 (d, J=2.1Hz, 1H), 8.26 (d, J=5.1Hz, 1H), 7.48 (d, J=
2.5Hz, 1H), 7.41 (s, 1H), 7.34 (d, J=2.5Hz, 1H), 2.65 (d, J=4.6Hz, 3H), 2.15 (s, 3H).
Claims (15)
1. Rynaxypyr impurity preparation process, it is characterised in that：Comprise the following steps：
Step a, compound M2 is prepared；
Step b, in the case of oxidant and bromating agent are simultaneous, chlorine worm benzoyl is prepared by raw material of compound M2
Amine impurity S1；
The compound M2 is：
The Rynaxypyr impurity S1 is：
2. Rynaxypyr impurity preparation process according to claim 1, it is characterised in that：In step a, the preparation
The operation of compound M2 is：Compound M1 and bromating agent are reacted to obtain compound M2；
The compound M1 is：
3. Rynaxypyr impurity preparation process according to claim 1 or 2, it is characterised in that：The bromating agent is
At least one of tribromo oxygen phosphorus, phosphorus pentabromide, phosphorus tribromide, two bromo trialkyl phosphines, two bromodiphenyl-phosphines；It is preferred that tribromo
Oxygen phosphorus or phosphorus pentabromide.
4. the Rynaxypyr impurity preparation process according to Claims 2 or 3, it is characterised in that：The step a and step
Rapid b is carried out using one kettle way.
5. Rynaxypyr impurity preparation process according to claim 4, it is characterised in that：In step a and step b,
The bromating agent is identical bromating agent, and the bromating agent needed for step a and step b reactions once feeds intake in step a.
6. Rynaxypyr impurity preparation process according to claim 5, it is characterised in that：
Step a is：By the mixture of compound M1, bromating agent and organic solvent at a temperature of 20 DEG C to organic solvent boiling point into
Row reaction, reaction finish, and obtain reaction solution A；
Step b is：Reaction solution A obtained by step a and oxidant reaction, reaction are finished, obtain Rynaxypyr impurity S1.
7. according to claim 4-6 any one of them Rynaxypyr impurity preparation processes, it is characterised in that：Work as bromating agent
For tribromo oxygen phosphorus when, the addition of tribromo oxygen phosphorus and the molar ratio of compound M1 are 0.67~2.5 in step a：1；Work as bromating agent
For phosphorus pentabromide when, the addition of phosphorus pentabromide and the molar ratio of compound M1 are 0.4~2 in step a：1.
8. according to claim 1-7 any one of them Rynaxypyr impurity preparation processes, it is characterised in that：In step b,
Further include the step for adding acid.
9. Rynaxypyr impurity preparation process according to claim 8, it is characterised in that：The acid is the concentrated sulfuric acid.
10. Rynaxypyr impurity preparation process according to claim 9, it is characterised in that：It is described dense in step b
The dosage of sulfuric acid and the molar ratio of compound M1 in step a are 0.1~5：1；Preferably, the dosage of the concentrated sulfuric acid and step a
The molar ratio of middle compound M1 is 1~5：1.
11. according to claim 1-10 any one of them Rynaxypyr impurity preparation processes, it is characterised in that：Step b
In, the oxidant is at least one of potassium peroxydisulfate, persulfuric acid acid sodium, ammonium persulfate.
12. Rynaxypyr impurity preparation process according to claim 11, it is characterised in that：The use of the oxidant
Amount and the molar ratio of M1 in step a are 1~2：1.
13. according to claim 1-12 any one of them Rynaxypyr impurity preparation processes, it is characterised in that：Step a
Reaction with step b is carried out by solvent of acetonitrile.
14. according to claim 1-13 any one of them Rynaxypyr impurity preparation processes, it is characterised in that：Further include
Following steps：
Step c, the Rynaxypyr impurity S1 that step b is obtained further is converted, obtains Rynaxypyr impurity S2；
The Rynaxypyr impurity S2 is：
15. Rynaxypyr impurity preparation process according to claim 14, it is characterised in that：Further include following step
Suddenly：
Step d, in the presence of sulfonic acid chloride class compound, Rynaxypyr impurity S2 and compound M3 that step c is obtained
Reaction, obtains Rynaxypyr impurity S3；
The compound M3 is：
The Rynaxypyr impurity S3 is：
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| WO2003024222A1 (en) * | 2001-09-21 | 2003-03-27 | E. I. Du Pont De Nemours And Company | Anthranilamide arthropodicide treatment |
| CN1671703A (en) * | 2002-07-31 | 2005-09-21 | 纳幕尔杜邦公司 | Method for preparing fused oxazinones from ortho-amino aromatic carboxylic acid and a carboxylic acid in the presence of a sulfonyl chloride and pyridine |
| CN105085477A (en) * | 2015-09-10 | 2015-11-25 | 南京广方生物科技有限公司 | Dihalopyridylpyrazolyl amide compounds and application thereof |
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| WO2003024222A1 (en) * | 2001-09-21 | 2003-03-27 | E. I. Du Pont De Nemours And Company | Anthranilamide arthropodicide treatment |
| CN1671703A (en) * | 2002-07-31 | 2005-09-21 | 纳幕尔杜邦公司 | Method for preparing fused oxazinones from ortho-amino aromatic carboxylic acid and a carboxylic acid in the presence of a sulfonyl chloride and pyridine |
| CN105085477A (en) * | 2015-09-10 | 2015-11-25 | 南京广方生物科技有限公司 | Dihalopyridylpyrazolyl amide compounds and application thereof |
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