CN104744305A - Synthesis method of 2,4-dichloro-3-cyan-5-fluorobenzoic acid - Google Patents
Synthesis method of 2,4-dichloro-3-cyan-5-fluorobenzoic acid Download PDFInfo
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Abstract
The invention discloses a synthesis method for 2,4-dichloro-3-cyan-5-fluorobenzoic acid, and belongs to the technical field of chemical synthesis. The synthesis method is characterized by comprising the following steps: (1) reacting 2,6-dichloro-3-fluorobenzamide with a bromination reagent to obtain 2,6-dichloro-3-fluo-5-brombenzamide; (2) performing dehydration reaction on 2,6-dichloro-3-fluo-5-brombenzamide under the action of a dehydrating agent to obtain 2,6-dichloro-3-fluo-5-bromobenzylcyanide; (3) under the action of an alkyl magnesium halide reagent, so as to obtain an aryl magnesium halide intermediate from 2,6-dichloro-3- fluo-5-bromobenzylcyanide, reacting the aryl magnesium halide intermediate with carbon dioxide to obtain 2,4-dichloro-3-cyan-5-fluorobenzoic acid. The synthesis route has the advantages that the raw materials are cheap and easily available, the reaction yield is high, the synthesis conditions are mild, the process safety is good, the pollution is less, and the like. The synthesis method is suitable for industrial production.
Description
Technical field:
The invention belongs to chemosynthesis technical field, specifically, relate to the synthetic method of the chloro-3-cyano group of a kind of 2,4-bis--5-fluorobenzoic acid.
Background technology:
The chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid is the key intermediate preparing novel fluorine quinolones finafloxacin.On December 17th, 2014, through U.S. food Drug Administration (FDA) approval, finafloxacin official listing, trade(brand)name Xtoro, is used for the treatment of acute otitis externa.
At present, the synthetic method of published 2,4-bis-chloro-3-cyano group-5-fluorobenzoic acids mainly contains following three kinds:
(1) patent US6229040 discloses with 5-fluoro-1; 3-dimethylbenzene is raw material, under Louis acid catalysis, obtain the chloro-5-of 2,4-bis-fluoro-1 with chlorine reaction; 3-dimethylbenzene; be obtained by reacting the fluoro-3-dichloromethyl of the chloro-5-of 2,4-bis--1-benzenyl trichloride further with chlorine, then through be hydrolyzed 2; the fluoro-3-formylbenzoate of the chloro-5-of 4-bis-; last and azanol reaction, then obtain the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid through dehydration.The method synthesis step is long, overall yield of reaction low (less than 30%), and operating procedure is complicated, and therefore practicality is not strong.
(2) patent US4908366 discloses with 2, the chloro-5-fluorobenzoic acid of 4-bis-is raw material, first 2 are obtained through nitrated, 4-dichloro-3-nitro-5-fluorobenzoic acid, subsequently by nitroreduction, obtain the chloro-3-amino-5-fluorobenzoic acid of 2,4-bis-, the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid is obtained again through diazotization/sandmeyer reaction.The method produces a large amount of acid waste water in nitration reaction one step, and sandmeyer reaction yield not high and need use severe toxicity cuprous cyanide and sodium cyanide, in suitability for industrialized production, there is serious potential safety hazard.
(3) patent CN102603571 discloses with the chloro-3-fluorobenzonitrile of 2,6-bis-for raw material, first through bromo-reaction, obtains the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-, then obtains the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid through grignard exchange/carboxylation reaction.Although the method synthesis step is shorter, the chloro-3-fluorobenzonitrile of raw material 2,6-bis-is expensive to be not easy to obtain, thus limits the widespread use of the method.
Disclosed in patent CN102531961 the chloro-3-fluorobenzonitrile of a kind of 2,6-bis-preparation method in, propose with the chloro-3-fluoro acetophenone of 2,6-bis-for raw material, through chloro, ammonia solution, the obtained chloro-3-fluorobenzonitrile of 2,6-bis-of dehydration three-step reaction.
Although CN102531961 solves 2, the preparation problem of the chloro-3-fluorobenzonitrile of 6-bis-, seem to make the technical scheme of CN102603571 realize becoming possibility at heavy industrialization, but after applicant implements according to such scheme, find the effect not obtaining anticipation, analyze its reason to find: 2, the chloro-3-fluorobenzonitrile of 6-bis-is carrying out in bromo-reaction process, very easily there is hydrolytic side reactions in the cyano group in molecule, make in bromination product containing more hydrolysising by-product 2, the fluoro-5-brombenzamide of the chloro-3-of 6-bis-, if not purifying in addition, very adverse influence is caused by follow-up grignard exchange/carboxylation reaction, if give purifying, then operation sequence can be increased, reduce reaction yield.
Summary of the invention:
In order to overcome the deficiency of the existing synthetic technology of 2,4-bis-chloro-3-cyano group-5-fluorobenzoic acid, the object of the present invention is to provide a kind of raw material cheap and easy to get, side reaction is few, the synthetic method of 2, the 4-bis-chloro-3-cyano group-5-fluorobenzoic acids that reaction yield is high.
The technical solution used in the present invention is as follows:
The synthetic method of the chloro-3-cyano group of a kind of 2,4-bis--5-fluorobenzoic acid, is characterized in that, comprise the following steps:
(1), 2,6-bis-chloro-3-fluorobenzamides (I) and brominated reagent react, and obtains the fluoro-5-brombenzamide (II) of the chloro-3-of 2,6-bis-;
(2), there is dehydration reaction in the fluoro-5-brombenzamide (II) of 2,6-bis-chloro-3-of step (1) gained under dewatering agent effect, obtains the fluoro-5-bromobenzylcyanide (III) of the chloro-3-of 2,6-bis-;
(3), the fluoro-5-bromobenzylcyanide (III) of 2,6-bis-chloro-3-of step (2) gained under the effect of alkyl halide azoviolet, obtain aryl magnesium halide intermediate, then with carbon dioxide reaction, obtain the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid (IV).
The synthetic route that the present invention adopts can represent with following reaction formula:
Reaction designing principle of the present invention is as follows:
The present invention is with 2, the chloro-3-fluorobenzamide of 6-bis-is raw material, first carry out bromo-reaction, carry out dehydration reaction again, the key intermediate 2 obtained, the chloro-3-of 6-bis-fluoro-5-bromobenzylcyanide through grignard exchange/carboxylated, obtain the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid, in bromo-reaction and dehydration reaction, side reaction and by product are all less, and raw material is cheap and easy to get, reaction yield is high, has fundamentally got rid of the deficiency existed in existing synthesis technique, be conducive to the suitability for industrialized production of the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid.
The further setting of the present invention is as follows:
In step (1):
Described brominated reagent be selected from following one or more: N-bromo acetamide, N-bromo-succinimide, C5H6Br2N2O2.Because the molecular structure of different brominated reagent is different, cause different brominated reagents when reacting with compound (I), amount of substance required is in theory also different, as N-bromo acetamide, N-bromo-succinimide, an active bromine is only had in molecular structure, the theoretical amount that itself and compound (I) react is 1.0 equivalents of the amount of substance of compound (I), and has two active bromines in C5H6Br2N2O2, and the theoretical amount that therefore itself and compound (I) react only needs 0.5 equivalent.The increase of brominated reagent consumption, although bromo-reaction speed can be accelerated, Reaction time shorten, but the probability that two bromo side reactions occur also can increase thereupon, in many-sided factors such as comprehensive cost, efficiency, yield and product purity, the ratio of the amount of substance of preferred brominated reagent and compound (I) is: 0.5:1 ~ 2.0:1.
Can reaction solvent have vital impact smoothly on bromo-reaction.Suitable reaction solvent can improve the selectivity of bromo-reaction, suppresses the generation of two bromo side reactions, reduces the consumption of brominated reagent, improves product purity.Conventional bromo-reaction solvent has the chlorinated hydrocarbon solvent such as methylene dichloride, trichloromethane, tetracol phenixin, the ether solvent such as ether, tetrahydrofuran (THF), DMF, sulfuric acid etc.The present invention is preferably the sulfuric acid of mass concentration 90 ~ 98%, and solvent load is 1 ~ 10 times of compound (I) quality.
Temperature of reaction also has significant impact to bromo-reaction, too low temperature of reaction, although two bromo side reactions can be suppressed, but speed of response is slower, reaction times is long, be unfavorable for enhancing productivity, too high temperature of reaction, although can Reaction time shorten, but be unfavorable for the side reaction of suppression two bromo, cause the decline of product purity, in addition, too high temperature of reaction also can cause having more free bromine to generate in reaction process, not only increase the consumption of brominated reagent, and all can cause disadvantageous effect to production environment maintenance and environment protection etc., confirm through experiment, preferred temperature of reaction is 0 ~ 50
oc.
In order to reduce the ratio of two bromo by products, improve reaction yield and product purity, need to carry out positive monitoring to reaction process in reaction process, after compound (I) disappears substantially, in time cancellation process is carried out to reaction system, more highly purified compound (II) can be obtained, if to disappear follow-up reneing the long reaction times at compound (I), the quick increase of two bromo by products will be caused.
In step (2):
Described dewatering agent be selected from following one or more: sulfur oxychloride, phosphorus oxychloride, oxalyl chloride, two (trichloromethyl) carbonic ether.In view of the molecular structure of different dewatering agent is different, and the difference in dehydration mechanism, in theory, when with sulfur oxychloride, oxalyl chloride for dewatering agent time, the ratio of the amount of substance of dewatering agent and compound (II) is 1:1, when being dewatering agent with phosphorus oxychloride, two (trichloromethyl) carbonic ether, the ratio of the amount of substance of dewatering agent and compound (II) is 1:3.Certainly, when reality uses, more thoroughly can react in order to ensure raw material, and obtain the speed of response expected, dewatering agent actual amount is often greater than theoretical amount.In the present invention, preferred dewatering agent and compound (II) amount of substance ratio be: 1.0:3 ~ 3.0:1.
Dehydration reaction should be carried out in suitable solvent, solvent be selected from following one or more: methylene dichloride, trichloromethane, tetracol phenixin, 1, the chlorinated hydrocarbon solvent such as 2-ethylene dichloride, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, the esters solvent such as n-butyl acetate, tert.-butyl acetate, the aromatic hydrocarbon solvent such as toluene, chlorobenzene.When using the dewatering agent be in a liquid state under normal temperature, as sulfur oxychloride, phosphorus oxychloride, oxalyl chloride, also excessive dewatering agent can be adopted to use as solvent, by distillation, dewatering agent is reclaimed after the completion of reaction, this mode can avoid the use of organic solvent, is conducive to the recycling of excessive dehydration agent.Solvent load determines primarily of the solvability of solvent and the stirring condition of system; solvent load is very few; be unfavorable for dissolving and the dispersion of raw material; solvent load is too much; then can increase production cost, reduce production efficiency, also have disadvantageous effect to environment protection; therefore, preferred solvent load is 0.5 ~ 10 times of the quality of compound (II).
The selection of temperature of reaction is relevant to solvent for use.In order to fast reaction speed, suitably can improve temperature of reaction, until reach the boiling point of solvent for use, namely system is reacted at reflux.The raising of temperature of reaction, although can fast reaction speed, too high temperature of reaction also can increase side reaction, be unfavorable for the raising of product purity, too low temperature of reaction, then speed of response can be caused excessively slow, reduce production efficiency, therefore, preferred temperature of reaction is: 20 ~ 150
oc.
In step (3):
Described alkyl halide azoviolet, is also called alkyl Grignard reagent, refers to the solution be made up of the alkyl halide magnesium of activity and the ether solvent of inertia.For alkyl halide magnesium, its moieties is the alkane of C1 ~ C4, and halogen can be chlorine or bromine.Alkyl halide magnesium be selected from following one or more: methylmagnesium-chloride, methyl-magnesium-bromide, ethylmagnesium chloride, ethylmagnesium bromide, n-propyl magnesium chloride, n-propyl magnesium bromide, isopropylmagnesium chloride, isopropyl magnesium bromide, n-butylmagnesium chloride magnesium, normal-butyl magnesium bromide, isobutyl-magnesium chloride, selenium alkynide, sec-butyl magnesium chloride, sec-butyl magnesium bromide, tertiary butyl magnesium chloride, tertiary butyl magnesium bromide.Ether solvent used, be selected from following one or more: ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran.Alkyl halide azoviolet can be made by oneself, also can use the finished product of commercially available standard specifications, and Homemade method can consult relevant open source literature.For self-control alkyl halide azoviolet, use can being needed according to actual, make the solution meeting concentration requirement, for the finished product of commercially available standard specifications, then by adopting the mode of dilution, required concentration can be made into.The alkyl halide azoviolet of different concns specification, reaction is had a certain impact, be mainly manifested in: the alkyl halide azoviolet crossing lower concentration, reaction density can be made on the low side, production efficiency is caused to decline, production cost rises, the alkyl halide azoviolet of excessive concentrations, then may there is the phenomenon of alkyl halide magnesium crystallization, thus affect the stirring condition of system or the smoothness that feeds intake of alkyl halide azoviolet, therefore, the concentration of the active al magnesium halide contained in preferred alkyl halide azoviolet is: 0.5 ~ 3.0 mole often liter.Alkyl halide magnesium and compound (III) carry out grignard permutoid reaction, its theoretical amount is 1.0 equivalents of the amount of substance of compound (III), but consider the impurity of a small amount of moisture and other consumption alkyl halide magnesium that may contain in raw material, the actual amount of alkyl halide azoviolet should suitably increase, but too much alkyl halide azoviolet only can increase production cost, reaction can not be made to carry out advantageously, therefore, when reality uses, the material of active al alkyl halide contained in alkyl halide azoviolet and compound (III) ratio preferably: 1.0:1 ~ 2.0:1.
Reaction need be carried out in a suitable solvent, to reduce the generation of side reaction.Described solvent, be selected from following one or more: the ether solvents such as ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, the aromatic hydrocarbon solvent such as toluene, ethylbenzene.The selection of solvent, ether solvent that can be used with alkyl halide azoviolet is identical, also can be different, but selects identical solvent, is conducive to the recycling of solvent, in industrial production advantageously.Adding of solvent, main purpose is dissolved and decentralized compound (III), makes material be in one preferably dispersion state, be beneficial to the carrying out reacted, very few or too much solvent load, all can cause disadvantageous effect to reaction, and preferred solvent load is 1 ~ 15 times of compound (III) quality.
Described carbonic acid gas can be gasiform carbonic acid gas, also can be the dry ice of solid state.For atmospheric carbon dioxide, gas at normal temperature can be adopted directly to pass into the mode of system, can also adopt by interchanger to carbon dioxide carry out pre-cooled after, then pass into the mode of system.Solid dry ice can adopt disposable or add the mode of system in batches, can also adopt the mode obtained system containing aryl magnesium halide intermediate joined in Solid dry ice.The consumption of carbonic acid gas is as the criterion to guarantee that the middle physical efficiency of aryl magnesium halide is fully reacted, and all uses excessive carbonic acid gas when general.
Can temperature of reaction have important impact smoothly on reaction.According to the difference of step of reaction, temperature of reaction is also different.Carry out at compound (III) and alkyl halide magnesium the stage that grignard permutoid reaction prepares aryl magnesium halide intermediate, reaction system should keep relatively low temperature, and to reduce the generation of side reaction, in this stage, preferred temperature of reaction is-80 ~-30
oc.Prepare the stage of compound (IV) at aryl magnesium halide intermediate and carbon dioxide reaction, temperature of reaction comparatively can suitably improve previous stage, in this stage, and preferred temperature of reaction degree-80 ~ 40
oc.In same step of reaction, also as required, necessary change can be carried out in corresponding temperature range, to suppress the generation of side reaction, reduce raw material and remain, improve reaction yield and product purity.
Compared with prior art, its useful effect is embodied in the present invention:
(1) selection of raw material: with 2, the chloro-3-fluorobenzamide of 6-bis-is raw material, through bromo, dehydration, grignard exchange/carboxylated three-step reaction, the chloro-3-cyano group of preparation 2,4-bis--5-fluorobenzoic acid, with existing with 2, the chloro-3-fluorobenzonitrile of 6-bis-is that the synthetic route of raw material is compared, raw material is more cheap and easy to get, and avoids the use of the prussiate of severe toxicity, and process safety is high, production environment is healthy.
(2) selection of operational path: operational path takes bromo---dehydration---grignard exchange/carboxylated three-step reaction, fundamentally get rid of the reaction of the high risks such as the chlorination used in existing synthesis technique, nitrated, diazotization/sandmeyer reaction, high pollution, there is the advantages such as reactions steps is short, reaction conditions is gentle, process safety is high, environmentally friendly, meet the development trend that current global chemical chemical enterprise is constantly paid attention to EHS;
On the other hand, in bromo-reaction and dehydration reaction, side reaction is few, the content of the fluoro-5-brombenzamide of 2,6-bis-chloro-3-in the chloro-3-of effective reduction key intermediate 2,6-bis-fluoro-5-bromobenzylcyanide, the key intermediate 2 of synthesis, the chloro-3-of 6-bis-fluoro-5-bromobenzylcyanide carrying out before grignard exchange/carboxylation reaction prepares the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid, without the need to unnecessary purification process operation;
(3) improvement of processing parameter: by selecting and the optimization of other reaction parameter the proportioning raw materials in reaction, solvent, inhibit the generation of side reaction on the one hand, effectively raise the yield of reaction on the other hand, the total recovery more than 85% of three-step reaction, higher than the total recovery of current published synthetic route, and greatly reducing due to side reaction, product purity can reach more than 99%, meets the specification of quality as bulk drug intermediate.
Below in conjunction with embodiment, the invention will be further described.
Embodiment:
Embodiment one:
Add the chloro-3-fluorobenzamide of 2,6-bis-31.2 grams in 100 milliliters of reaction flasks, C5H6Br2N2O2 23.6 grams, 50 grams, the sulfuric acid of mass concentration 98%, in 0 ~ 5
oCstirring reaction 40 hours.Reaction system be quenched in 150 grams of frozen water, filter, filter cake, through washing, drying, obtains the fluoro-5-brombenzamide of the chloro-3-of 2,6-bis-42.2 grams, yield 98%.
Embodiment two:
Add the chloro-3-fluorobenzamide of 2,6-bis-35 grams in 500 milliliters of reaction flasks, N-bromo acetamide 46.3 grams, 200 grams, the sulfuric acid of mass concentration 95%, in 30 ~ 35
oCstirring reaction 25 hours.Reaction system be quenched in 300 grams of frozen water, filter, filter cake, through washing, drying, obtains the fluoro-5-brombenzamide of the chloro-3-of 2,6-bis-47.7 grams, yield 99%.
Embodiment three:
Add the chloro-3-fluorobenzamide of 2,6-bis-21 grams in 500 milliliters of reaction flasks, N-bromo-succinimide 26.7 grams, 210 grams, the sulfuric acid of mass concentration 90%, in 45 ~ 50
oCstirring reaction 30 hours.Reaction system be quenched in 500 grams of frozen water, filter, filter cake, through washing, drying, obtains the fluoro-5-brombenzamide of the chloro-3-of 2,6-bis-28.4 grams, yield 98%.
Embodiment four:
Add the fluoro-5-brombenzamide of the chloro-3-of 2,6-bis-28.7 grams in 500 milliliters of reaction flasks, chlorobenzene 287, stirring at room temperature, slowly drip phosphorus oxychloride 15.3 grams, after dropwising, system is warming up to backflow, reacts 10 hours.System underpressure distillation recovery chlorobenzene, residue adds 100 grams, water, stirs, and after system dispersion, filters, and filter cake, through washing, drying, obtains the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-26.6 grams, yield 99%.
Embodiment five:
2 are added in 250 milliliters of reaction flasks, the fluoro-5-brombenzamide of the chloro-3-of 6-bis-30 grams, ethyl acetate 120 grams, system is warming up to backflow, slowly drip the mixing solutions of 60 grams of ethyl acetate of 11.5 grams of two (trichloromethyl) carbonic ethers, after dropwising, system continues reaction 12 hours under reflux state.System Distillation recovery ethyl acetate, residue adds 100 grams, water, stirs, and after system dispersion, filters, and filter cake, through washing, drying, obtains the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-27.6 grams, yield 98%.
Embodiment six:
Add the fluoro-5-brombenzamide of the chloro-3-of 2,6-bis-43 grams in 500 milliliters of reaction flasks, sulfur oxychloride 215 grams, system is warming up to backflow, reacts 15 hours.System Distillation recovery sulfur oxychloride, residue adds 200 grams, water, stirs, and after system dispersion, filter, filter cake, through washing and drying, obtains the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-39.1 grams, yield 97%.
Embodiment seven:
Add the fluoro-5-brombenzamide of the chloro-3-of 2,6-bis-57.4 grams in 250 milliliters of reaction flasks, 1,2-ethylene dichloride 30 grams, sulfur oxychloride 71.4 grams, system is warming up to backflow, reacts 20 hours.System distillating recovering solvent, residue adds 200 grams, water, stirs, and after system dispersion, filters, and filter cake, through washing, drying, obtains the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-52.2 grams, yield 97%.
Embodiment eight:
Add the fluoro-5-brombenzamide of the chloro-3-of 2,6-bis-40 grams in 250 milliliters of reaction flasks, methylene dichloride 80 grams, stirring at room temperature, drip oxalyl chloride 35.4 grams, after dropwising, system is warming up to backflow, reacts 20 hours.System Distillation recovery methylene dichloride, residue adds 150 grams, water, stirs, and after system dispersion, filters, and filter cake, through washing, drying, obtains the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-36.7 grams, yield 98%.
Embodiment nine:
Add the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-25 grams, tetrahydrofuran (THF) 150 grams in 500 milliliters of dry reaction flasks, stir and be cooled to-70 ~-80
oc, slowly drips the tetrahydrofuran solution 51 milliliters of the isopropylmagnesium chloride of 2 moles often liter, after dropwising, in-70 ~-80
oc continues reaction 1 hour.In system, slowly pass into carbon dioxide, and naturally rise again to room temperature, stop logical carbonic acid gas, add 150 grams, water, stir a moment, leave standstill, divide except organic phase, aqueous phase hydrochloric acid adjusts pH to 1, is extracted with ethyl acetate three times, combined ethyl acetate layer, drying, concentrated, obtain the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid 20.2 grams, yield 93%, purity 99.4%.
Embodiment ten:
Add the tetrahydrofuran solution 223 milliliters of the tertiary butyl magnesium chloride of 1 mole often liter in 500 milliliters of dry reaction flasks, stir and be cooled to-50 ~-60
oc, slowly drips the mixing solutions of 30 gram of 2,6-fluoro-5-bromobenzylcyanide of bis-chloro-3-and 120 grams of ether, after dropwising, in-50 ~-60
oc continues reaction 1 hour.In system, slowly pass into carbon dioxide, and naturally rise again to room temperature, stop logical carbonic acid gas, add 200 grams, water, stir a moment, leave standstill, divide except organic phase, aqueous phase hydrochloric acid adjusts pH to 1, is extracted with ethyl acetate three times, combined ethyl acetate layer, drying, concentrated, obtain the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid 23.7 grams, yield 91%, purity 99.2%.
Embodiment 11:
Add 2.3 grams, fresh magnesium powder, methyl tertiary butyl ether 140 grams in 500 milliliters of dry reaction flasks, iodine one granule, system is warming up to 40 ~ 50
oC, slowly pass into methyl chloride gas, disappear to magnesium powder.System is cooled to-30 ~-40
oc, slowly drips the mixing solutions of 15 gram of 2,6-fluoro-5-bromobenzylcyanide of bis-chloro-3-and 45 grams of methyl tertiary butyl ethers, after dropwising, in-30 ~-40
oc continues reaction 1 hour.System temperature control-30 ~-40
oc, passes into through-20
oCrefrigerant precooling carbon dioxide but, every 1 hour sampling analysis, disappears to intermediate, stop logical carbonic acid gas, system is risen again to room temperature, adds 100 grams, water, stir a moment, leave standstill, divide except organic phase, aqueous phase hydrochloric acid adjusts pH to 1, is extracted with ethyl acetate three times, combined ethyl acetate layer, drying, concentrated, obtain the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid 12.0 grams, yield 92%, purity 99.1%.
Embodiment 12:
Add fresh magnesium chips 4.8 grams, 2-methyltetrahydrofuran 120 grams in 500 milliliters of dry reaction flasks, iodine one granule, system is warming up to 40 ~ 50
oC, slowly drip chloroisopropane 15.7 grams, after dropwising, in 40 ~ 50
oc continues reaction 5 hours.System is cooled to-60 ~-70
oC, slowly drip the mixing solutions of 35.8 gram of 2,6-fluoro-5-bromobenzylcyanide of bis-chloro-3-and 35.8 grams of 2-methyltetrahydrofurans, after dropwising, in-60 ~-70
oc continues reaction 1 hour.In system, add 50 grams, dry ice, after finishing, system is risen again naturally to room temperature in batches, adds 200 grams, water, adjust pH to 1 with hydrochloric acid, stir a moment, separate organic phase, aqueous phase 2-methyltetrahydrofuran extracting twice, merges organic phase, with the sodium hydroxide solution reextraction secondary of 10%, merge gained aqueous phase, adjust pH to 1 with concentrated hydrochloric acid, be extracted with ethyl acetate three times, combined ethyl acetate layer, drying, concentrated, obtain 2, the chloro-3-cyano group of 4-bis--5-fluorobenzoic acid 28.1 grams, yield 90%, purity 99.4%.
Embodiment 13:
Add the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-26.9 grams, ether 215 grams in 500 milliliters of dry reaction flasks, stir and be cooled to-40 ~-50
oc, slowly drips the tetrahydrofuran solution 40 milliliters of the ethylmagnesium bromide of 3.0 moles often liter, after dropwising, in-40 ~-50
oc continues reaction 1 hour.In system, slowly pass into carbon dioxide, and naturally rise again to room temperature, stop logical carbonic acid gas, in system, add 200 grams, water, stir a moment, leave standstill, divide except organic phase, aqueous phase hydrochloric acid adjusts pH to 1, is extracted with ethyl acetate three times, combined ethyl acetate layer, drying, concentrated, obtain the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid 21.5 grams, yield 92%, purity 99.3%.
Comparative example:
(1), dehydration, bromo, grignard exchange/carboxylated synthetic route is adopted:
2 are added in 500 milliliters of reaction flasks, the chloro-3-fluorobenzamide of 6-bis-41.6 grams (0.2 mol), n-butyl acetate 200 grams, system is warming up to backflow, slowly drip the mixing solutions of 100 grams of n-butyl acetates of 35.6 grams of two (trichloromethyl) carbonic ethers (0.12 mol), after dropwising, under reflux state, continue reaction 15 hours.System Distillation recovery butylacetate, residue adds 200 grams, water, stirs, and after system dispersion, filters, and filter cake, through washing, drying, obtains the chloro-3-fluorobenzonitrile of 2,6-bis-36.5 grams, yield 96.1%, purity 97.6%.
Add above-mentioned 2,6-bis-chloro-3-fluorobenzonitrile 28.5 grams (0.15 mol) in 500 milliliters of reaction flasks, N-bromo-succinimide 40.1 grams (0.225 mol), 250 grams, the sulfuric acid of mass concentration 98%, in 25 ~ 30
oCstirring reaction 30 hours.Reaction system be quenched in 400 grams of frozen water, filter, filter cake, through washing, drying, obtains the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-39.4 grams, yield 97.7%, the chloro-3-of purity 91.0%, 2,6-bis-fluoro-5-Bromophenacyl amine content 7.8%.
Add the tetrahydrofuran solution 120 milliliters of the isopropylmagnesium chloride of 1 mole often liter in 500 milliliters of dry reaction flasks, stir and be cooled to-60 ~-70
oc, slowly drips the mixing solutions of above-mentioned 2,6-bis-chloro-3-fluoro-5-bromobenzylcyanide 26.9 grams (0.1 mol) and 100 grams of tetrahydrofuran (THF)s, after dropwising, in-60 ~-70
oc continues reaction 1 hour.In system, slowly pass into carbon dioxide, and naturally rise again to room temperature, stop logical carbonic acid gas, add 300 grams, water, stir a moment, leave standstill, divide except organic phase, aqueous phase hydrochloric acid adjusts pH to 1, is extracted with ethyl acetate three times, combined ethyl acetate layer, drying, concentrated, obtain the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid 18.5 grams, yield 79.1%, purity 98.6%.
(2), bromo, dehydration, grignard exchange/carboxylated synthetic route is adopted:
Add the chloro-3-fluorobenzamide of 2,6-bis-41.6 grams (0.2 mol) in 500 milliliters of reaction flasks, N-bromo-succinimide 53.4 grams (0.3 mol), 250 grams, the sulfuric acid of mass concentration 98%, in 25 ~ 30
oCstirring reaction 30 hours.Reaction system be quenched in 400 grams of frozen water, filter, filter cake, through washing, drying, obtains the fluoro-5-brombenzamide of the chloro-3-of 2,6-bis-56.3 grams, yield 98.1%, purity 98.8%.
Above-mentioned 2 are added in 500 milliliters of reaction flasks, the fluoro-5-brombenzamide of the chloro-3-of 6-bis-43.0 grams (0.15 mol), n-butyl acetate 200 grams, system is warming up to backflow, slowly drip the mixing solutions of 100 grams of n-butyl acetates of 26.7 grams of two (trichloromethyl) carbonic ethers (0.09 mol), after dropwising, under reflux state, continue reaction 15 hours.System Distillation recovery butylacetate, residue adds 200 grams, water, stirs, after system dispersion, filter, filter cake, through washing, drying, obtains the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-39.7 grams, yield 98.4%, the chloro-3-of purity 98.9%, 2,6-bis-fluoro-5-Bromophenacyl amine content 0.1%.
Add the tetrahydrofuran solution 120 milliliters of the isopropylmagnesium chloride of 1 mole often liter in 500 milliliters of dry reaction flasks, stir and be cooled to-60 ~-70
oc, slowly drips the mixing solutions of above-mentioned 2,6-bis-chloro-3-fluoro-5-bromobenzylcyanide 26.9 grams (0.1 mol) and 100 grams of tetrahydrofuran (THF)s, after dropwising, in-60 ~-70
oc continues reaction 1 hour.In system, slowly pass into carbon dioxide, and naturally rise again to room temperature, stop logical carbonic acid gas, add 300 grams, water, stir a moment, leave standstill, divide except organic phase, aqueous phase hydrochloric acid adjusts pH to 1, is extracted with ethyl acetate three times, combined ethyl acetate layer, drying, concentrated, obtain the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid 21.5 grams, yield 92.3%, purity 99.3%.
Claims (10)
1. the synthetic method of bis-chloro-3-cyano group-5-fluorobenzoic acids, is characterized in that, comprise the following steps:
(1), 2,6-bis-chloro-3-fluorobenzamides and brominated reagent react, and obtains the fluoro-5-brombenzamide of the chloro-3-of 2,6-bis-;
(2), there is dehydration reaction in the fluoro-5-brombenzamide of 2,6-bis-chloro-3-of step (1) gained under dewatering agent effect, obtains the fluoro-5-bromobenzylcyanide of the chloro-3-of 2,6-bis-;
(3), the fluoro-5-bromobenzylcyanide of 2,6-bis-chloro-3-of step (2) gained under the effect of alkyl halide azoviolet, obtain aryl magnesium halide intermediate, then with carbon dioxide reaction, obtain the chloro-3-cyano group of 2,4-bis--5-fluorobenzoic acid.
2. according to claim 1 a kind of 2, the synthetic method of the chloro-3-cyano group of 4-bis--5-fluorobenzoic acid, it is characterized in that: in step (1), described brominated reagent be selected from following one or more: N-bromo acetamide, N-bromo-succinimide, C5H6Br2N2O2, the ratio of the amount of substance of brominated reagent and the chloro-3-fluorobenzamide of 2,6-bis-is: 0.5:1 ~ 2.0:1.
3. the synthetic method of a kind of 2,4-bis-chloro-3-cyano group-5-fluorobenzoic acids according to claim 1, is characterized in that: in step (1), reaction is carried out in a solvent, solvent is the sulfuric acid of mass concentration 90 ~ 98%, and consumption is 1 ~ 10 times of 2,6-bis-chloro-3-fluorobenzamide quality.
4. the synthetic method of a kind of 2,4-bis-chloro-3-cyano group-5-fluorobenzoic acids according to claim 1, it is characterized in that: in step (1), temperature of reaction is 0 ~ 50
oc.
5. according to claim 1 a kind of 2, the synthetic method of the chloro-3-cyano group of 4-bis--5-fluorobenzoic acid, it is characterized in that: in step (2), described dewatering agent be selected from following one or more: sulfur oxychloride, phosphorus oxychloride, oxalyl chloride, two (trichloromethyl) carbonic ether, the amount of substance of dewatering agent and the fluoro-5-brombenzamide of the chloro-3-of 2,6-bis-ratio be: 1.0:3 ~ 3.0:1.
6. according to claim 1 a kind of 2, the synthetic method of the chloro-3-cyano group of 4-bis--5-fluorobenzoic acid, it is characterized in that: in step (2), reaction is carried out in a solvent, solvent be selected from following one or more: methylene dichloride, trichloromethane, tetracol phenixin, 1,2-ethylene dichloride, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, tert.-butyl acetate, toluene, chlorobenzene, sulfur oxychloride, phosphorus oxychloride, oxalyl chloride, solvent load is 0.5 ~ 10 times of the chloro-3-of 2,6-bis-fluoro-5-brombenzamide quality.
7. the synthetic method of a kind of 2,4-bis-chloro-3-cyano group-5-fluorobenzoic acids according to claim 1, is characterized in that: in step (2), temperature of reaction is: 20 ~ 150
oc.
8. according to claim 1 a kind of 2, the synthetic method of the chloro-3-cyano group of 4-bis--5-fluorobenzoic acid, it is characterized in that: in step (3), described alkyl halide magnane be selected from following one or more: methylmagnesium-chloride, methyl-magnesium-bromide, ethylmagnesium chloride, ethylmagnesium bromide, n-propyl magnesium chloride, n-propyl magnesium bromide, isopropylmagnesium chloride, isopropyl magnesium bromide, n-butylmagnesium chloride magnesium, normal-butyl magnesium bromide, isobutyl-magnesium chloride, selenium alkynide, sec-butyl magnesium chloride, sec-butyl magnesium bromide, tertiary butyl magnesium chloride, tertiary butyl magnesium bromide, alkyl halide alkane and 2, the material of the fluoro-5-bromobenzylcyanide of the chloro-3-of 6-bis-ratio be: 1.0:1 ~ 2.0:1.
9. according to claim 1 a kind of 2, the synthetic method of the chloro-3-cyano group of 4-bis--5-fluorobenzoic acid, it is characterized in that: in step (3), reaction is carried out in a solvent, solvent be selected from following one or more: ether, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, ethylbenzene, solvent load is 1 ~ 15 times of the chloro-3-of 2,6-bis-fluoro-5-bromobenzylcyanide quality.
10. according to claim 1 a kind of 2, the synthetic method of the chloro-3-cyano group of 4-bis--5-fluorobenzoic acid, is characterized in that: in step (3), 2, the fluoro-5-bromobenzylcyanide of the chloro-3-of 6-bis-and alkyl halide reactive magnesium prepare the stage of aryl magnesium halide intermediate, and temperature of reaction is :-80 ~-30
oc, prepare the chloro-3-cyano group of 2, the 4-bis--5-fluorobenzoic acid stage at aryl magnesium halide intermediate and carbon dioxide reaction, temperature of reaction is :-80 ~ 40
oc.
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| CN111072517A (en) * | 2019-12-31 | 2020-04-28 | 常州沃腾化工科技有限公司 | Preparation method of 4-amino-2-trifluoromethyl benzonitrile |
| CN114773316A (en) * | 2022-06-17 | 2022-07-22 | 上海睿跃生物科技有限公司 | Process for the preparation of 2- (2, 6-dioxo-piperidin-3-yl) -5-fluoro-isoindole-1, 3-dione |
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| CN106986883A (en) * | 2017-04-01 | 2017-07-28 | 沧州那瑞化学科技有限公司 | A kind of preparation method of thiazole |
| CN110156637A (en) * | 2019-06-18 | 2019-08-23 | 宁波美诺华药业股份有限公司 | A kind of preparation method of the chloro- 3- cyano -5- fluobenzoic acid of 2,4- bis- |
| CN111072517A (en) * | 2019-12-31 | 2020-04-28 | 常州沃腾化工科技有限公司 | Preparation method of 4-amino-2-trifluoromethyl benzonitrile |
| CN111072517B (en) * | 2019-12-31 | 2022-08-30 | 常州沃腾化工科技有限公司 | Preparation method of 4-amino-2-trifluoromethyl benzonitrile |
| CN114773316A (en) * | 2022-06-17 | 2022-07-22 | 上海睿跃生物科技有限公司 | Process for the preparation of 2- (2, 6-dioxo-piperidin-3-yl) -5-fluoro-isoindole-1, 3-dione |
| CN114773316B (en) * | 2022-06-17 | 2022-10-25 | 上海睿跃生物科技有限公司 | Preparation method of 2- (2,6-dioxo-piperidine-3-yl) -5-fluoro-isoindole-1,3-diketone |
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