CN104387324A - Method for preparing 4-bromo-3-chloromethyl-1-methyl-1H-pyrazole - Google Patents
Method for preparing 4-bromo-3-chloromethyl-1-methyl-1H-pyrazole Download PDFInfo
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a method for preparing 4-bromo-3-chloromethyl-1-methyl-1H-pyrazole. The method is characterized in that 1,3-dimethyl pyrazole serving as a raw material is subjected to oxidation, esterification, bromination, reducition and chlorination, thereby obtaining a target product. As a novel synthesis route is provided, and a synthesis method is optimized and screened, the defects in the prior art that the yield is low, the reaction is complex and the purification difficulty is high are overcome, and a product which is high in yield, simple in treatment process and high in purity is obtained.
Description
Technical field
The present invention relates to a kind of synthetic method of organic compound, particularly the preparation method of the bromo-3-chloromethyl of a kind of 4--1-methyl isophthalic acid H-pyrazoles.
Background technology
Its structure of the bromo-3-chloromethyl of 4--1-methyl isophthalic acid H-pyrazoles is simple, and active group is many, and be a kind of good intermediate, its derivative known relates to the fields such as medicine, aerospace, functional materials, refining of petroleum.
But, in synthesis technique disclosed in prior art, often there is purification difficult, side reaction be many, reaction yield is low, product purity is low, be not suitable for the problems such as large-scale industrial production.
Summary of the invention
The present invention is intended to overcome above-mentioned defect, provides a kind of new synthetic route, and is optimized screening to synthetic method, obtain a kind of productive rate high, and treatment process is simple, the product that purity is high.
The invention provides the preparation method of the bromo-3-chloromethyl of a kind of 4--1-methyl isophthalic acid H-pyrazoles, it is characterized in that: with 1,3-dimethyl pyrazole for raw material, by obtaining target product after oxidation, esterification, bromo, reduction, chlorination.
Particularly, 1,3-dimethyl pyrazole is oxidized to 1-methyl-3-carboxyl-pyrazoles by above-mentioned being oxidized to;
Above-mentioned esterification obtains 1-methyl-3-ester group-pyrazoles by first carboxylic acid halides, rear alcoholysis reaction;
Above-mentioned bromination is for being the bromo-1-methyl of 4--3-ester group-pyrazoles by 1-methyl-3-ester group-pyrazoles halogenation;
Bromo-for 4-1-methyl-3-ester group-pyrazoles is reduced to the bromo-1-methyl of 4--3-methylol pyrazoles by above-mentioned being reduced to;
Above-mentioned chlorination is for being the bromo-1-methyl of 4--3-chloromethyl pyrazoles by the halogenation of bromo-for 4-1-methyl-3-methylol pyrazoles.
Reaction equation is as follows:
The concrete technology step of above-mentioned reaction process is as follows:
Step one, oxygenant is soluble in water, be warming up to 40-60 DEG C, drip the aqueous solution of 1,3-dimethyl pyrazole;
Step 2, add oxygenant, controlling temperature of reaction is 60-65 DEG C of reaction 2-4 hour in batches;
Step 3, with methyl alcohol cancellation reaction, through aftertreatment obtain intermediate product one.
In the step of above-mentioned to three, its anti-application apparatus should possess stirring, liquid droping port, put the function such as the equipment of punching, well heater, and wherein, scour prevention can be three buffering balls.
In step one is to two, the mass ratio of above-mentioned 1,3-dimethyl pyrazole and oxygenant summation is 1:4-6;
Wherein, in above-mentioned steps one, in oxygenant and described step 2, the mass ratio of oxygenant is 1:1.5-2.
Above-mentioned oxygenant is optional from for alkyl being oxidized to arbitrary oxygenant of carboxylic acid, most preferably from potassium permanganate.
Particularly, in step one, reaction should stop heating when being warming up to 60 DEG C, along with the instillation reacting liquid temperature of substrate can rise to 70-80 degree, controls rate of addition to guarantee temperature of reaction within 80 DEG C in order to avoid punching material, preferably drips off in 3 hours.
In addition, for the solvent of dissolved oxidant and 1,3-dimethyl pyrazole optional be neat solvent or the mixed solvent of 80-120 DEG C from boiling point.Its mass concentration is 10-40%.
Wherein, oxidizing agent solution is preferably the aqueous solution, and its mass concentration is preferably 15-20%;
1,3-dimethyl pyrazole solution is preferably the aqueous solution, and its mass concentration is preferably 15-25%.
In step 2, the process in batches adding residual oxidizing agent (as: potassium permanganate) preferably completed in 3 hours.
After terminating reaction process, with methyl alcohol (ethanol, propyl alcohol etc. also can be used cannot to dissolve the solvent of Manganse Dioxide) with the unnecessary potassium permanganate of cancellation; Wherein, the consumption of methyl alcohol is the methyl alcohol of every gram of 1,3-dimethyl pyrazole relative usage 3-4ml.
Cross the insoluble impurity such as the solid that filters reacted Manganse Dioxide, after filtrate being concentrated into the volume of 1/4-1/2, employing concentration is that pH value of solution is adjusted to 3-4 by the diluted acid of 10-40%.
Under the condition of 80-90 DEG C, solvent is boiled off acquisition solid matter.
Due to more inorganic salt can be produced after adjust ph, for the impact avoiding residual substance to react next step, with alcoholic solution equal solvent, product need be dissolved, therefore, preferably with solid: the ratio of methyl alcohol (also can use the product such as ethanol, propyl alcohol suitable solvents)=1:6-15 dissolves above-mentioned solid matter, cross and filter insolubles, obtain intermediate product one after concentrated filtrate, productive rate is 75-95%.
In addition, the filtration procedure related in above-mentioned multiple technique preferably adopts silica gel and diatomite to be layered on filter paper, thus accelerates filtration velocity.
Step 4, in the solvent solution of above-mentioned intermediate product one, drip the DMF of catalytic amount, reaction system is warming up to 75 DEG C;
After step 5, dropping thionyl chloride, within 30-60 minute, become clarification to reaction solution in 70-80 DEG C of insulation;
After step 6, dropping anhydrous methanol, back flow reaction 30-60 minute;
Step 7, through aftertreatment obtain intermediate product two;
In above-mentioned steps four to six, the mass ratio of intermediate product one, thionyl chloride and anhydrous methanol is 1:1.4-1.8:1-1.5.Reaction is preferably carried out in anhydrous conditions.
Particularly, in step 4, intermediate product one is preferred before the reaction to react after it pulverizing.
Solvent can be selected from the solvent that the boiling points such as toluene, benzene, dichlorobenzene are 60-150 DEG C.
In step 5, absorb heat due to the process system dripping sulfur oxychloride and release the process of a large amount of gas, should rate of addition be controlled in order to avoid punching material.
In step 6, due to low-temp methanol and acyl chloride reaction slower, vigorous reaction suddenly can be caused as accumulated a large amount of methyl alcohol in reaction system, thus cause the risk that punching material and a large amount of by product produce, larger impact can be produced on industrial production, therefore, under the environment of above-mentioned temperature of reaction should be kept, drip anhydrous methanol, because this process venting effect is violent, still should controls rate of addition in operation and prevent discharge.
In addition, the concrete treatment process of step 7 is: when reaction solution cools to 40 DEG C, and obtain intermediate product two by removed under reduced pressure solvent, productive rate is 89-99%.
Owing to very easily producing impurity in above process, so the carrying out reacted strictly should be controlled.
Step 8, under the environment of nitrogen protection, the solvent solution of intermediate product two is cooled to after below 10 DEG C, adds C5H6Br2N2O2 in batches;
Step 9, through aftertreatment obtain intermediate product three;
In step 8, intermediate product two is 1:1-1.5 with the mass ratio of C5H6Br2N2O2.
Particularly, in step 8, solvent can be selected from methylene dichloride, chloroform, chlorobenzene, toluene equal solvent, and the mass concentration of the solvent solution of intermediate product two is 30-50%.
Add the thermopositive reaction of C5H6Br2N2O2 process system, in the process of dropping, often present solution turned yellow, become muddy phenomenon, in addition, should be carefully slow when adding C5H6Br2N2O2, after adding, its thermopositive reaction has lag-effect, and the too fast meeting added causes temperature of reaction uncontrollable.In addition, also should control temperature of reaction well, the too high meeting of temperature makes that product becomes assorted, side reaction takes place frequently.Temperature of reaction is made not higher than 15 DEG C preferably by the speed controlling to add C5H6Br2N2O2.
In step 9, the concrete steps of aftertreatment are: reaction solution is slowly joined in water (with the water of reaction product two 1-4 times of quality), stir 30-60 minute, separatory, the organic layer sodium sulfite solution (with the sodium sulfite solution of reaction product two 1-4 times of quality) of 10% concentration washs to the constant indigo plant of potassium iodide starch test paper, separatory, consider that residuals can cause the bad result of subsequent reactions, as remaining of solid insoluble and consuming excessively of red aluminium, organic layer preferably adopts saturated sodium bicarbonate solution to wash at least one times, each volume is reaction product two 1-4 weight doubly, separatory, concentration of organic layers obtains intermediate product three, productive rate is 75-90%.
Step 10, under the environment of nitrogen protection, the solvent solution of intermediate product three to be cooled to after below-10 DEG C, to drip reductive agent, reaction 30-60 minute; When after dropping reversed order, productive rate is extremely low.
Step 11, through aftertreatment obtain intermediate product four;
In step 10, described intermediate product three is 1:1.5-2 with the mol ratio of reductive agent.
Reductive agent can be sodium borohydride, boron trifluoride diethyl etherate, sodium, ethanol etc., but uses the productive rate of traditional reductive agent extremely low, most preferably is red aluminium.
Particularly, in step 10, solvent can be selected from toluene, benzene, chlorobenzene, dichlorobenzene, to toluene, dimethylbenzene etc., the mass concentration of the solvent solution of intermediate product three is 20-35%.
In the process dripping reductive agent, just start there is micro-moisture in reaction system, caused dripping the venting of red aluminium, in addition, because the too high meeting of temperature causes pyrazole ring to be reduced, therefore, the speed of dropping reductive agent should be controlled to guarantee that temperature of reaction is within 0 DEG C.
After red aluminium is added dropwise to complete, its temperature of reaction preferably controls within the scope of-10-0 DEG C.
In step 11, the concrete technology step of aftertreatment is, for dripping saturated sodium bicarbonate solution in intermediate product three twice to treble amount when hierarchy of control temperature is within 20 DEG C, stir 30-60 minute, separatory, turbid liquid layer toluene (also can be benzene, chlorobenzene, dichlorobenzene, to toluene, dimethylbenzene etc.) extraction, (each consumption is that intermediate product three twice is to treble amount), concentration of organic layers obtain intermediate product four at least one times to merge organic layer, washing.Its productive rate is 75-90%.
Step 12, the solvent solution of intermediate product four is warming up to 70 after, drip thionyl chloride, reaction 30-60 minute;
Step 13, obtain 4-bromo-3-chloromethyl-1-methyl isophthalic acid H-pyrazoles through aftertreatment.
In step 12, described intermediate product four is 1:2-2.5 with the mol ratio of thionyl chloride.
Particularly, in step 12, solvent can be selected from toluene, benzene, chlorobenzene, dichlorobenzene, to toluene, dimethylbenzene etc., the mass concentration of the solvent solution of intermediate product four is 30-50%.
Due to the process system heat absorption deflation course of dropping thionyl chloride, just start there is micro-moisture in reaction system, caused dripping thionyl chloride venting violent, the speed of dropping thionyl chloride should have been controlled to guarantee that reaction is carried out under the environment of not rushing material.
In step 13, after the reaction solution be cooled within 40 DEG C is deviate from solvent, obtain the thick product that purity is 79-85%, productive rate is 90-99%.
By the concrete technology step of bromo-for above-mentioned 4-3-chloromethyl-1-methyl isophthalic acid H-pyrazoles purifying be: cross post decolouring and recrystallization at least one times; Wherein, the above-mentioned elutriant crossing post employing is selected from the mixture of one or more in ethyl acetate, methyl acetate, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, acetone, ether, Skellysolve A, normal hexane, hexanaphthene; Reagent for above-mentioned recrystallization is selected from the mixture of one or more in ethyl acetate, methyl acetate, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, acetone, ether, Skellysolve A, normal hexane, hexanaphthene.
Its purity of product after purifying reaches 97.3-99.5%, productive rate in this step reaches 80-90%, and the yield in total synthetic route reaches 50-65%.
effect of the present invention
The present invention devises a kind of new synthetic route for the synthesis of the bromo-3-chloromethyl of 4--1-methyl isophthalic acid H-pyrazoles.
Have employed oxidation, esterification, bromo, reduction, chlorination five step synthesis method in the present invention, obtain single step productive rate and reach more than 80%, whole productive rate reaches the result of more than 50%.In the process of reaction, produce multiple intermediate product, but fresh few generation can produce dysgenic by product or other impurity to subsequent reactions, after each step completes, the basic reaction that can participate in next step without the need to purifying, substantially can realize the needs of suitability for industrialized production, its operating process is simple.
In addition, go back the precaution of each step of reaction of strict regulation in the present invention, as in step one, the speed of dropping 1,3-dimethyl pyrazole should be controlled to guarantee that temperature of reaction is within 80 DEG C; In step 5, the speed that should control to drip thionyl chloride is carried out under the environment of not rushing material to guarantee to react; In step 8, should control to add the speed of C5H6Br2N2O2 to guarantee that temperature of reaction is within 15 DEG C in batches; In step 10, the speed of dropping reductive agent should be controlled to guarantee that temperature of reaction is within 0 DEG C; In step 12, the speed that should control to drip thionyl chloride carries out requirement such as grade to guarantee to react under the environment of not rushing material.Considered critical to obtain the approach of optimum yields.
In addition, also explicitly pointed out optimum response ratio and optimum response reagent in the present invention, and found, as adopt other go back original reagent carry out the step of reducing time, can produce the impurity affecting productive rate and subsequent reactions in a large number, and productive rate is extremely low, seriously limits industrial needs.
Therefore, the present invention by providing a kind of new synthetic route, and is optimized screening to synthetic method, overcomes that productive rate in prior art is low, reaction is complicated, purifying difficulty defect, and obtain a kind of productive rate high, treatment process is simple, the product that purity is high.
Embodiment
Embodiment one, 1,3-dimethyl pyrazole is oxidized to 1-methyl-3-carboxyl-pyrazoles
(1), reaction equation is as follows:
(2), concrete technology step:
160g potassium permanganate is dissolved in 1L water and is placed in 5L four-hole boiling flask, connect mechanical stirring flatly, connect dropping funnel flatly, on another muzzle, continuous print three buffering balls are with erosion control material, be warming up to 40,1 of slow instillation 100g, 3-dimethyl pyrazole (being dissolved in 500mL water), heating jacket power supply is pulled out when reacting liquid temperature rises to 60 degree, along with the instillation reacting liquid temperature of substrate can rise to 70-80 degree, control rate of addition to guarantee temperature of reaction within 80 degree in order to avoid punching material (rise to 80 degree time stopping tear drop), within 3 hours, drip off (middle control 1).Drip to finish and add remaining 240g potassium permanganate in batches, within 3 hours, add.Reinforced Bi Fanying is at 65 degree (when temperature of reaction is 60 degree, difference is little) reaction 2h, and some TLC board raw material has reacted complete (middle control 2) substantially.
In said process, the add-on ratio of twice potassium permanganate can be adjusted to the different ratioss such as 1:1.5 or 2 or 2.5.
React the complete 300mL that adds in reaction flask and (also can adopt 350mL, 400mL, 450mL, 500mL) methyl alcohol is with the unnecessary potassium permanganate of cancellation, Manganse Dioxide in reaction flask is filtered out, filtrate is revolved and steams to 800mL (or 1/2 of cumulative volume, 1/3, 1/4) pH3-4 is adjusted with dilute hydrochloric acid during left and right, again water is revolved and evaporate (80-90 degree), add methyl alcohol 800mL in the solid obtained and (also can adopt 850mL, 900mL, 950mL, 1000mL), pull an oar half an hour, elimination is insoluble to the white solid (this solid is inorganic salt) of methyl alcohol, collect filtrate, be spin-dried for, obtain 85.2g faint yellow solid, HPLC purity 89.8% (middle control 3).
(3), the treatment process of control in reaction:
(4), the screening of reaction conditions:
Embodiment two, be 1-methyl-3-ester group-pyrazoles by 1-methyl-3-carboxyl-pyrazoles esterification
(1), reaction equation is as follows:
(2), concrete technology step:
1-methylpyrazole-3-formic acid the 180g of pulverizing is placed in the four-hole boiling flask of a 500mL, add toluene 360g, instill 5 N, N '-dimethyl methane amide (DMF), stir, reaction is white casse liquid, when being warmed up to 75 DEG C, start to drip sulfur oxychloride, dropping process is absorbed heat, but venting is violent, control rate of addition in order to avoid punching material, at 75 DEG C of insulated and stirred 30min after sulfur oxychloride is added dropwise to complete, reaction solution becomes clarification, then anhydrous methanol is dripped in this temperature, venting is violent, control rate of addition, methyl alcohol is added dropwise to complete rear backflow 30min, sampling detection (middle control 1) then reaction solution cools to 40 DEG C, reaction solution removed under reduced pressure solvent (60-70 degree), obtain 1-methylpyrazole-3-methyl-formiate 172.4g, without purifying, be directly used in next step reaction.
(3), the treatment process of control in reaction:
(4), the screening of reaction conditions:
Embodiment three, be the bromo-1-methyl of 4--3-ester group-pyrazoles by 1-methyl-3-ester group-pyrazoles halogenation
(1), reaction equation is as follows:
(2), concrete technology step:
1-methylpyrazole-3-methyl-formiate 140g and methylene dichloride 320ml is added in reaction flask; nitrogen protection, stirs clarification, the outer ice bath cooling of reaction flask; when interior temperature 10 DEG C; add C5H6Br2N2O2 157.3g, adition process heat release, solution turned yellow in batches; become muddy; control the speed adding C5H6Br2N2O2, make temperature of reaction not higher than 15 DEG C, add rear some plate TLC (middle control 1).Without raw material, aftertreatment, reaction solution is slowly joined 300g and (also can adopt 350mL, 400mL, 450mL, 500mL) in water, stir 30min, layering, the organic layer sodium sulfite solution 200g of 10% concentration (also can adopt 150g, 250g, 300g) wash once, the constant indigo plant of potassium iodide starch test paper, layering, then organic layer saturated sodium bicarbonate solution washes three times, each 200g (also can adopt 150g, 250g, 300g), organic layer removed under reduced pressure solvent (30-40 degree), obtain 4-bromo-1-methyl-3-pyrazoles carboxylic ester methyl ester 214.1g (middle control 2).Product can be directly used in next step reaction without purifying.
(3), the treatment process of control in reaction:
(4), the screening of reaction conditions:
Embodiment four, bromo-for 4-1-methyl-3-ester group-pyrazoles is reduced to the bromo-1-methyl of 4--3-methylol pyrazoles
(1), reaction equation is as follows:
(2), concrete technology step:
Reaction system nitrogen protection, puts into flask by bromo-for 4-1-methyl-3-pyrazoles carboxylic ester methyl ester 171g, adds toluene (also can adopt chlorobenzene, benzene, to toluene etc.) 600g, stirs clarification, flask ethanol-the dry ice bath cooling.As Nei Wen-10 DEG C, start to drip the red aluminium of 455g (toluene solution of 70%), dripped process heat release, and just started there is micro-moisture in reaction system, cause dripping the venting of red aluminium, control the speed dripping red aluminium, make temperature be no more than 0 DEG C.30min is stirred-10-0 DEG C of temperature after red aluminium is added dropwise to complete, sampling detection does not have raw material (middle control 1), start to drip the saturated sodium carbonate solution of 350g, just start to drip heat release venting violent, control rate of addition, reacting liquid temperature is made to be no more than 20 DEG C, saturated sodium bicarbonate solution is added dropwise to complete rear stirring 30min, then stratification, separate organic layer, another layer of dirty solution 100g toluene (also can adopt 150g, 250g, the chlorobenzene of 300g, benzene, to toluene etc.) extraction, use 100g (also can adopt 150g after layering again, 250g, the chlorobenzene of 300g, benzene, to toluene etc.) toluene extraction is once, merge organic layer, (also 150g can be adopted with 200g, 250g, 300g) washing once, then organic layer removed under reduced pressure solvent (60-70 degree), obtain the bromo-1-methyl of 4--3-methylol pyrazoles 141.3g, solidified on standing (middle control 2).Not purified, be directly used in next step reaction.
(3), the treatment process of control in reaction:
(4), the screening of reaction conditions:
Embodiment five, be the bromo-1-methyl of 4--3-chloromethyl pyrazoles by the halogenation of bromo-for 4-1-methyl-3-methylol pyrazoles
(1), reaction equation is as follows:
(2), concrete technology step:
Bromo-for 4-1-methyl-3-methylol pyrazoles 121g is put into flask, add toluene 340g, stir and heat up, when interior temperature 70 DEG C, start to drip thionyl chloride 213g, dripped process heat absorption venting, just start there is micro-moisture in reaction system, cause dripping thionyl chloride venting violent, control the speed dripping thionyl chloride, make reaction solution not rush material.Stir 30min (middle control 1) at about 70 DEG C after thionyl chloride is added dropwise to complete, raw material disappears, and then cools to 40 degree, reaction solution removed under reduced pressure solvent (60-70 degree), obtains the thick product 145g of 4-bromo-1-methyl-3-chloromethyl pyrazoles.
Purifying:
Product 500g silica gel is thick crosses post, removing color, eluent ethylacetate: normal hexane=1:4.The white solid of 112 grams is obtained after precipitation.Then add the crystallization of 170g normal hexane, after heating for dissolving, normal temperature leaves standstill crystallization and obtains product 67g.With obtained 57 grams of products in the past and mixed, leave standstill crystallization with normal temperature after the heat of solution of 160g Virahol and obtain product 90g, content 97.3% (middle control 2).
(3), the treatment process of control in reaction:
(4), the screening of reaction conditions:
Claims (10)
1. a preparation method for the bromo-3-chloromethyl of 4--1-methyl isophthalic acid H-pyrazoles, is characterized in that: with 1,3-dimethyl pyrazole for raw material, by obtaining target product after oxidation, esterification, bromo, reduction, chlorination.
2. the preparation method of the bromo-3-chloromethyl of a kind of 4-as claimed in claim 1-1-methyl isophthalic acid H-pyrazoles, is characterized in that:
1,3-dimethyl pyrazole is oxidized to 1-methyl-3-carboxyl-pyrazoles by described being oxidized to;
Described esterification obtains 1-methyl-3-ester group-pyrazoles by first carboxylic acid halides, rear alcoholysis reaction;
Described bromination is for being the bromo-1-methyl of 4--3-ester group-pyrazoles by 1-methyl-3-ester group-pyrazoles halogenation;
Bromo-for 4-1-methyl-3-ester group-pyrazoles is reduced to the bromo-1-methyl of 4--3-methylol pyrazoles by described being reduced to;
Described chlorination is for being the bromo-1-methyl of 4--3-chloromethyl pyrazoles by the halogenation of bromo-for 4-1-methyl-3-methylol pyrazoles.
3. the preparation method of the bromo-3-chloromethyl of a kind of 4-as claimed in claim 2-1-methyl isophthalic acid H-pyrazoles, it is characterized in that, concrete technology step is as follows:
Step one, oxygenant is soluble in water, be warming up to 40-60 DEG C, drip the aqueous solution of 1,3-dimethyl pyrazole;
Step 2, add oxygenant, controlling temperature of reaction is 60-65 DEG C of reaction 2-4 hour in batches;
Step 3, with methyl alcohol cancellation reaction, through aftertreatment obtain intermediate product one;
Step 4, in the solvent solution of intermediate product one, drip the DMF of catalytic amount, reaction system is warming up to 75 DEG C;
After step 5, dropping thionyl chloride, within 30-60 minute, become clarification to reaction solution in 70-80 DEG C of insulation;
After step 6, dropping anhydrous methanol, back flow reaction 30-60 minute;
Step 7, through aftertreatment obtain intermediate product two;
Step 8, under the environment of nitrogen protection, the solvent solution of intermediate product two is cooled to after below 10 DEG C, adds C5H6Br2N2O2 in batches;
Step 9, through aftertreatment obtain intermediate product three;
Step 10, under the environment of nitrogen protection, the solvent solution of intermediate product three to be cooled to after below-10 DEG C, to drip reductive agent, reaction 30-60 minute;
Step 11, through aftertreatment obtain intermediate product four;
Step 12, the solvent solution of intermediate product four is warming up to 70 DEG C after, drip thionyl chloride, reaction 30-60 minute;
Step 13, obtain 4-bromo-3-chloromethyl-1-methyl isophthalic acid H-pyrazoles through aftertreatment.
4. the preparation method of the bromo-3-chloromethyl of a kind of 4-as claimed in claim 3-1-methyl isophthalic acid H-pyrazoles, is characterized in that:
In step one is to two, the mass ratio of described 1,3-dimethyl pyrazole and oxygenant summation is 1:4-6;
In step 4 to six, the mass ratio of described intermediate product one, thionyl chloride and anhydrous methanol is 1:1.4-1.8:1-1.5;
In step 8, described intermediate product two is 1:1-1.5 with the mass ratio of C5H6Br2N2O2;
In step 10, described intermediate product three is 1:1.5-2 with the mol ratio of reductive agent;
In step 12, described intermediate product four is 1:2-2.5 with the mol ratio of thionyl chloride.
5. the preparation method of the bromo-3-chloromethyl of a kind of 4-as claimed in claim 3-1-methyl isophthalic acid H-pyrazoles, is characterized in that:
In described step one, in oxygenant and described step 2, the mass ratio of oxygenant is 1:1.5-2.
6. the preparation method of the bromo-3-chloromethyl of a kind of 4-as claimed in claim 3-1-methyl isophthalic acid H-pyrazoles, is characterized in that:
Described reductive agent is red aluminium.
7. the preparation method of the bromo-3-chloromethyl of a kind of 4-as claimed in claim 3-1-methyl isophthalic acid H-pyrazoles, is characterized in that:
Described oxygenant is potassium permanganate.
8. the preparation method of the bromo-3-chloromethyl of a kind of 4-as claimed in claim 3-1-methyl isophthalic acid H-pyrazoles, is characterized in that:
In step one, control the speed of dropping 1,3-dimethyl pyrazole to guarantee that temperature of reaction is within 80 DEG C;
In step 5, the speed controlling to drip thionyl chloride is carried out under the environment of not rushing material to guarantee to react;
In step 8, control adds the speed of C5H6Br2N2O2 to guarantee that temperature of reaction is within 15 DEG C in batches;
In step 10, control the speed of dropping reductive agent to guarantee that temperature of reaction is within 0 DEG C;
In step 12, the speed controlling to drip thionyl chloride is carried out under the environment of not rushing material to guarantee to react.
9. the preparation method of the bromo-3-chloromethyl of a kind of 4-as claimed in claim 3-1-methyl isophthalic acid H-pyrazoles, is characterized in that:
The concrete steps of step 3 are with after methyl alcohol cancellation reaction, after filtration, concentrated, regulation system pH to 3-4, control temperature be concentrated within 90 DEG C solid-state, with dissolve with methanol, filtration, concentrated after obtain intermediate product one;
The concrete steps of step 9 be reaction solution is slowly added to the water, stir 30-60 minute, separatory, the sodium sulfite solution washing of organic layer 10% concentration, separatory, the washing of organic layer saturated sodium bicarbonate solution, separatory, concentration of organic layers obtain intermediate product three;
The concrete steps of step 11 are hierarchy of control temperature drips saturated sodium bicarbonate solution when being within 20 DEG C, stir 30-60 minute, separatory, the extraction of turbid liquid layer toluene, merge organic layer, washing, concentration of organic layers obtain intermediate product four.
10. the preparation method of the bromo-3-chloromethyl of a kind of 4--1-methyl isophthalic acid H-pyrazoles as described in as arbitrary in claim 3-9, it is characterized in that, by the concrete technology step of bromo-for described 4-3-chloromethyl-1-methyl isophthalic acid H-pyrazoles purifying be: cross post decolouring and recrystallization at least one times;
Wherein, the described elutriant crossing post employing is selected from the mixture of one or more in ethyl acetate, methyl acetate, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, acetone, ether, Skellysolve A, normal hexane, hexanaphthene;
Reagent for described recrystallization is selected from the mixture of one or more in ethyl acetate, methyl acetate, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, acetone, ether, Skellysolve A, normal hexane, hexanaphthene.
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| US20120165331A1 (en) * | 2010-12-22 | 2012-06-28 | Sangamesh Badiger | Di/tri-aza-spiro-C9-C11alkanes |
| WO2014114186A1 (en) * | 2013-01-24 | 2014-07-31 | 山东亨利医药科技有限责任公司 | Jnk inhibitors |
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| US20120165331A1 (en) * | 2010-12-22 | 2012-06-28 | Sangamesh Badiger | Di/tri-aza-spiro-C9-C11alkanes |
| WO2014114186A1 (en) * | 2013-01-24 | 2014-07-31 | 山东亨利医药科技有限责任公司 | Jnk inhibitors |
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