CN103508839A - Making method of a,a-difluoro aromatic compound - Google Patents
Making method of a,a-difluoro aromatic compound Download PDFInfo
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- CN103508839A CN103508839A CN201310251196.7A CN201310251196A CN103508839A CN 103508839 A CN103508839 A CN 103508839A CN 201310251196 A CN201310251196 A CN 201310251196A CN 103508839 A CN103508839 A CN 103508839A
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- RFGSSAFWYPVKEC-UHFFFAOYSA-N BC(CC=C1)CC=C1C(F)=O Chemical compound BC(CC=C1)CC=C1C(F)=O RFGSSAFWYPVKEC-UHFFFAOYSA-N 0.000 description 1
- OPPZXSHNADAQES-UHFFFAOYSA-N Cc(cc1)ccc1C(F)=O Chemical compound Cc(cc1)ccc1C(F)=O OPPZXSHNADAQES-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides an industrial making method of a,a-difluoro aromatic compound (direct bonding of CF2 base and aromatic nucleus) hardly expecting high yield; the method does not need catalyst with high toxicity, has simple reaction device, is simple in operation, low in cost, and excellent in yield. The method comprises the step of using aromatic series or haloid reaction solvent, replacing ethylene series with 1-chlorine-1aromatic nucleus, and the step of reacting the 1-chlorine-1aromatic nucleus with hydrogen fluoride. The 1-chlorine-1aromatic nucleus used to replace ethylene and the hydrogen fluoride can be obtained in a large amount with low cost. The employed reaction condition is relaxing, so selectivity is high and yield is excellent, and high purity product can be obtained through easy applied purification process. Furthermore, catalyst with high toxicity is not needed, reaction device is simple and operation is simple. So, the industrial making method of the a,a-difluoro aromatic compound is very useful.
Description
Technical field
The present invention relates to α, the manufacture method of α-difluoro aromatics.
Background technology
α, α-difluoro aromatics is important (for example patent documentation 1) as doctor's pesticide intermediate.As the representational manufacture method of this compound, can list the deoxidation bifluoride reaction (non-patent literature 1,2) of the aromatic carbonyl that uses DAST or Deoxo-Fluor.
On the other hand, as the technology associated with the present invention, the α that makes alpha-chloro cinnamic vinylchlorid position and hydrogen fluoride reaction (addition, replacement) is disclosed, the manufacture method of α-difluoro ethylbenzene (non-patent literature 3).
Prior art document
Patent documentation
Patent documentation 1: No. 2011/154298, International Publication
Non-patent literature
The non-patent literature 1:J.Org.Chem.(U.S.), 1975, the 40th volume, p.574
The non-patent literature 2:J.Org.Chem.(U.S.), 1999, the 64th volume, p.7048
The non-patent literature 3:J.Org.Chem.(U.S.), 1962, the 27th volume, p.4015
Summary of the invention
the problem that invention will solve
The manufacture method of recording in non-patent literature 1 and 2 is owing to having used expensive fluorizating agent to be not suitable for industry manufacture.
The liquid phase method of manufacture method and the yield of vapor phase process low (being respectively 28%, 11%) in non-patent literature 3, recorded.In addition, vapor phase process needs the red precipitate that toxicity is high to support the catalyzer in gac, and the numerous and diverse operation of reaction unit is also numerous and diverse in addition.
Known conventionally in the manufacture of humorous position difluoro compound (geminal difluoro compound), the difluoro methylene (CF in target compound
2) whether base have considerable influence with aromatic nucleus Direct Bonding to yield.For example, reported to the manufacture method of the triple bond addition 2 hydrofluoric humorous position of the molecule difluoro compounds of acetylide [the J.Org.Chem.(U.S.), 1979, the 44th volume, p.3872, non-patent literature 3], although 2,2-difluoro hexane and 3,3-difluoro hexane can obtain (being respectively 70%, 75%) by high yield, but only with low yield, obtain α, α-difluoro ethylbenzene [liquid phase method 18%.The bromo-4-(1 of comparative example 1:1-, 1-bis-fluoro ethyls) benzene is also less than 5%].In addition, reported via thering are 2 trifluoromethyl ketonic oxygen (CF
3cO
2) base acylal carbonyl compound deoxidation bifluoride reaction [J.Fluorine Chem.(Holland), 2010, the 131st volume, p.29, Japanese kokai publication hei 1-199922], although 1,1-difluoro hexanaphthene can reproduce the high yield (91%) of record, α, the yield of α-difluoro ethylbenzene can not be realized [record yield 90% completely, comparative example 2: be less than the bromo-4-(1 of 10%, 1-, 1-bis-fluoro ethyls) benzene is also 15% left and right].In addition, the inventor etc. have carried out patent application (manufacture method of the humorous position of Japanese Patent Application 2011-166797/ difluoro compound), the CF in this manufacture method in target compound to comprising the manufacture method of the humorous position difluoro compound that makes the operation that fluorine-containing sulfuric acid enol ester class reacts with fluorizating agent
2in the situation of base and aromatic nucleus Direct Bonding, yield is also non-reduces (comparative example 3 and 4 relatively) by accident.
As mentioned above, at the α that is difficult to expect high yield, α-difluoro aromatics (CF
2base and aromatic nucleus Direct Bonding) manufacture in, strong expectation do not need the simple and operation of catalyzer, reaction unit that toxicity is high also easy, can be cheaply and the method for yield industry manufacture well.
Incidentally, the inventor etc. have carried out 2 patent applications associated with the present invention (Japanese Patent Application 2012-045360, Japanese Patent Application 2012-045361), due to unexposed in the present patent application fashion so be described simply.The former patent application is to comprise the α that makes the operation that the chloro-1-aromatic nucleus of 1-substituted ethylene class reacts with the salt being formed with hydrogen fluoride by organic bases or title complex, the manufacture method of α-difluoro aromatics, the latter's patent application is to comprise the α that makes the operation that the fluoro-1-aromatic nucleus of 1-substituted ethylene class reacts with fluorizating agent, the manufacture method of α-difluoro aromatics.These patent applications are very useful as industrially preparing process, but to compare cost high with the present invention, need to use salt or title complex or the fluoro-1-aromatic nucleus of the 1-substituted ethylene class being formed by organic bases and hydrogen fluoride.
for the scheme of dealing with problems
The further investigations such as the inventor, found that the reaction of expectation can be carried out well, thereby reaches the present invention by the ether using as reaction solvent in the liquid phase method of non-patent literature 3 being replaced by the reaction solvent of fragrant family or halogen family.In addition, the also clear and definite removal method of the suitable raw material matrix in the present invention, reaction conditions (hydrofluoric addition means, hydrofluoric consumption and temperature of reaction) and by product.
Particularly, by using the reaction solvent of fragrant family or halogen family to make the chloro-1-aromatic nucleus of 1-substituted ethylene class and hydrogen fluoride reaction, can manufacture well α by yield, α-difluoro aromatics.In addition, the chloro-1-aromatic nucleus of the 1-substituted ethylene class preferably aromatic nucleus position of 1 is aromatic hydrocarbyl or substituted aromatic alkyl, and 2 substituting groups of 2 are hydrogen atom, and products therefrom is as doctor's pesticide intermediate particularly important.In addition, by independent or arbitrary combination, adopt specific reaction conditions below, can obtain α with extra high selectivity, α-difluoro aromatics.As specific reaction conditions, can list, by the reaction solvent dilution 1-chloro-1-aromatic nucleus substituted ethylene class of fragrant family or halogen family and by hydrogen fluoride, with the state of gas, be blown into this solution; Hydrofluoric consumption is 2.0～10mol with respect to the chloro-1-aromatic nucleus of 1mol1-substituted ethylene class; And temperature of reaction is 0～50 ℃.
Finally, by by target compound α, the aromatic series acyl fluorides containing as by product in α-difluoro aromatics converts aromatic carboxylic acid to or aromatic amides removes, and can obtain α with extra high purity, α-difluoro aromatics.
That is, the invention provides the α that comprises [technical scheme 1] to [technical scheme 6], the manufacture method of α-difluoro aromatics.In the present invention, disclosed manufacture method there all was not report in the past, was novel.
[technical scheme 1]
A α who represents with general formula [2], the manufacture method of α-difluoro aromatics, it comprises that the reaction solvent of the fragrant family of use or halogen family makes with the chloro-1-aromatic nucleus of the 1-substituted ethylene class of general formula [1] expression and the operation of hydrogen fluoride reaction.
General formula [1]:
[in formula, Ar
1represent fragrant cyclic group or substituted aroma cyclic group, R
1and R
2represent independently respectively hydrogen atom, alkyl, substituted alkyl, fragrant cyclic group or substituted aroma cyclic group, Ar
1with R
1, Ar
1with R
2, or R
1with R
2optionally by covalent linkage, form ring type structure.]
General formula [2]:
[in formula, Ar
1, R
1and R
2identical with general formula [1].]
[technical scheme 2]
According to the method for recording in technical scheme 1, wherein, the 1-chloro-1-aromatic nucleus substituted ethylene class of the chloro-1-aromatic nucleus of the 1-substituted ethylene class that the general formula [1] of take represents as representing with general formula [3], the α representing with general formula [2], α-difluoro aromatics is the α representing with general formula [4], α-difluoro aromatics
General formula [3]:
[in formula, Ar
2represent aromatic hydrocarbyl or substituted aromatic alkyl.]
[in formula, Ar
2identical with the definition in general formula [3].]
[technical scheme 3]
Method according to recording in technical scheme 1 or technical scheme 2, is characterized in that, with the reaction solvent of fragrant family or halogen family, dilutes the chloro-1-aromatic nucleus of 1-substituted ethylene class, and hydrogen fluoride is blown into this solution with the state of gas.
[technical scheme 4]
The method of recording in any one in technical scheme 1～technical scheme 3, is characterized in that, hydrofluoric consumption is 2.0～10mol with respect to the chloro-1-aromatic nucleus of 1mol1-substituted ethylene class.
[technical scheme 5]
The method of recording in any one in technical scheme 1～technical scheme 4, is characterized in that, temperature of reaction is 0～50 ℃.
[technical scheme 6]
The method of recording in any one in technical scheme 1～technical scheme 5, it is characterized in that, it then carries out following purification process: by target compound α, the aromatic series acyl fluorides containing as by product in α-difluoro aromatics converts aromatic carboxylic acid to or aromatic amides removes.
the effect of invention
The chloro-1-aromatic nucleus of the 1-substituted ethylene class of using in the present invention and hydrogen fluoride can obtain with a large amount of scales cheaply.In addition, because the reaction conditions adopting relaxes, therefore selectivity is high, yield is also good, can obtain by the purification process of easy enforcement high purity product.In addition, do not need the catalyzer that toxicity is high, reaction unit is simple and operation is also easy.Like this, the present invention is as α, and the industrially preparing process of α-difluoro aromatics is extremely useful.
In addition, the present invention compares with non-patent literature 3, can obtain target compound with especially high yield and [with reference to the liquid phase method of non-patent literature 3, similarly manufacture the bromo-4-(1 of 1-, 1-bis-fluoro ethyls), in the situation of benzene, while using ether as reaction solvent, the growing amount of target compound is respectively chloroform, toluene with embodiments of the invention 1 with 2(reaction solvent) compare considerably less (comparative example 7)].In addition, even at the growing amount that does not use target compound under the condition of no solvent of reaction solvent (neat condition) also considerably less (comparative example 5 and 6), therefore the clear and definite necessity of using reaction solvent, and the clear and definite reaction solvent of fragrant family or halogen family rather than the importance of ether system used.
Embodiment
To α of the present invention, the manufacture method of α-difluoro aromatics is elaborated.
Scope of the present invention is not subject to these explanation limitations, except following example, can suitably change to implement in the scope of harmless main idea of the present invention.In addition, whole publications of quoting in this manual, prior art document for example, the patent documentations such as Publication, patent application, other non-patent literature and distribution books enter this specification sheets as reference group.
The R of the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1]<sup TranNum="143">1</sup>and R<sup TranNum="144">2</sup>represent independently respectively hydrogen atom, alkyl, substituted alkyl, fragrant cyclic group or substituted aroma cyclic group.R wherein<sup TranNum="145">1</sup>and R<sup TranNum="146">2</sup>all be preferably hydrogen atom.This alkyl be carbon number 1～18, straight chain shape or branched chain type or the alkyl of ring type (in more than 3 situation of carbon number).This fragrance cyclic group be carbon number 1～18, the aromatic hydrocarbyl such as phenyl, naphthyl and anthryl; Or pyrryl (also comprising nitrogen protective), pyridyl, furyl, thienyl, indyl (also comprising nitrogen protective), quinolyl, benzofuryl and benzothienyl etc. contain the heteroatomic aromatic heterocycles such as nitrogen-atoms, Sauerstoffatom or sulphur atom.This substituted alkyl and substituted aroma cyclic group have substituting group with quantity and combination arbitrarily arbitrarily respectively on the carbon atom arbitrarily of aforesaid alkyl and fragrant cyclic group or nitrogen-atoms.Described substituting group is the halogen atom of fluorine, chlorine, bromine and iodine; The low alkyl groups such as nitro, methyl, ethyl and propyl group; The rudimentary alkylhalide groups such as methyl fluoride, chloromethyl and brooethyl; The lower alkoxies such as methoxyl group, oxyethyl group and propoxy-; The rudimentary halogen alkoxyl groups such as fluorine methoxyl group, chlorine methoxyl group and bromine methoxyl group; The low-grade acyloxies such as methanoyl, acetoxyl group, propionyloxy and butyryl acyloxy; The elementary alkoxy carbonyls such as cyano group, methoxycarbonyl, ethoxy carbonyl and propoxycarbonyl; The fragrant cyclic groups such as phenyl, naphthyl, anthryl, pyrryl (also comprising nitrogen protective), pyridyl, furyl, thienyl, indyl (also comprising nitrogen protective), quinolyl, benzofuryl and benzothienyl; The protective of protective, hydroxyl and the hydroxyl of the protective of carboxyl, carboxyl, amino, amino etc.In addition, about this substituted alkyl, the singly-bound of carbon-to-carbon arbitrarily of aforesaid alkyl can be changed to carbon-to-carbon double bond or carbon-to-carbon triple bond with quantity arbitrarily and combination arbitrarily, and (certainly, the alkyl that these parts are changed to unsaturated link(age) can have aforesaid substituting group similarly.In addition, although also have to the hydrofluoric possibility of these unsaturated link(age) additions, by the reaction that adopts suitable reaction conditions of the present invention optionally only to expect).In addition, in this manual, " rudimentary " refers to the meaning of material carbon number 1～6, straight chain shape or branched chain type or ring type (in more than 3 situation of carbon number).In addition; in " the fragrant cyclic group " of aforesaid " described substituting group ", can replace have halogen atom, the protective of the protective of nitro, low alkyl group, rudimentary alkylhalide group, lower alkoxy, rudimentary halogen alkoxyl group, methanoyl, low-grade acyloxy, cyano group, elementary alkoxy carbonyl, carboxyl, carboxyl, amino, amino protective, hydroxyl and hydroxyl etc.In addition; the protecting group of pyrryl, indyl, carboxyl, amino and hydroxyl is the blocking group in organic synthesis; the 3rd edition; 1999, john wiley & sons, Inc.(Protective Groups in Organic Synthesis; Third Edition; 1999, john wiley & sons, the protecting group of recording in Inc.) etc.
The Ar of the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1]
1represent fragrant cyclic group or substituted aroma cyclic group.The R of this fragrance cyclic group and substituted aroma cyclic group and the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1]
1and R
2fragrant cyclic group and the substituted aroma cyclic group of middle record are identical.Wherein optimization aromatic alkyl or substituted aromatic alkyl.
The Ar of the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1]
1with R
1, Ar
1with R
2, or R
1with R
2optionally by covalent linkage, form ring type structure.Particularly, at Ar
1with R
1, Ar
1with R
2, or R
1with R
2between can (also can be situated between by heteroatomss such as nitrogen-atoms, Sauerstoffatom or sulphur atoms) to each other and with quantity arbitrarily and combine arbitrarily by covalent linkage and form ring type structure (such as monocyclic, condensation polycyclic formula, crosslinked, volution, the ring set etc.) substituting group (hydrogen atom) of covalent linkage [wherein, can not participate in except] at carbon atom arbitrarily.
As the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1], preferred Ar
1for aromatic hydrocarbyl or substituted aromatic alkyl and R
1and R
2be hydrogen atom (corresponding with the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [3]).
The chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1] can be compiled the 4th edition experimental chemistry lecture 19 organic synthesis I hydrocarbon halogen compound Wan Shan Co., Ltd. p.416～460 with reference to Japanization association; Synthetic I hydrocarbon halide Wan Shan Co., Ltd. p.374～443 of the 5th edition experimental chemistry lecture 13 organic compound is compiled by Japanization association, and (the 4th edition experimentization of the Knitting of Japanization association learned Talk seat 19 organic synthesis I hydrocarbon halogen compound Wan Shan Co., Ltd. p.416～460; The 5th edition experimentization of the Knitting of Japanization association learned synthetic I hydrocarbon halide Wan Shan Co., Ltd. p.374～443 of Talk seat 13 organic compound) etc. similarly manufacture (reference example 1,2).According to the preparation method of raw material matrix, have as by product and contain the α representing with general formula [5], the situation of α-dichloro aromatics.
General formula [5]
[in formula, Ar
1represent fragrant cyclic group or substituted aroma cyclic group, R
1and R
2represent independently respectively hydrogen atom, alkyl, substituted alkyl, fragrant cyclic group or substituted aroma cyclic group, Ar
1with R
1, Ar
1with R
2, or R
1with R
2optionally by covalent linkage, form ring type structure.This alkyl, substituted alkyl, fragrant cyclic group and substituted aroma cyclic group are identical with the group of recording in the chloro-1-aromatic nucleus of 1-substituted ethylene class representing with general formula [1]].Existence also can be usingd comparatively good yield from this by product and be obtained the α as target compound of the present invention, the situation of α-difluoro aromatics.Therefore, even if contain the α representing with general formula [5] in the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1], α-dichloro aromatics is as submember (the chloro-1-aromatic nucleus of 1-substituted ethylene class > α, the relation of α-dichloro aromatics), in situation, also as the raw material matrix of recording in claim of the present invention, treat.
The reaction solvent of fragrance family is the aromatic hydrocarbons of the carbon numbers 6～12 such as benzene, toluene, ethylbenzene, dimethylbenzene and mesitylene.This aromatic hydrocarbons can have the substituting groups such as elementary alkoxy carbonyl such as halogen atom, nitro, cyano group, methoxycarbonyl, ethoxy carbonyl and propoxycarbonyl of fluorine, chlorine, bromine and iodine on carbon atom arbitrarily with quantity and combination arbitrarily arbitrarily, particularly, can list chlorobenzene, dichlorobenzene, α, α, α-phenylfluoroform, oil of mirbane, benzonitrile and ethyl benzoate etc.
The reaction solvent of halogen family is methylene dichloride, chloroform, tetracol phenixin, 1, halogenation paraffinic hydrocarbons or the halogenated olefine of the carbon numbers 1～8 such as 2-ethylene dichloride, trieline and zellon.Halogen atom, except chlorine, can also adopt fluorine, bromine and iodine, can on carbon atom, with quantity and combination arbitrarily arbitrarily, have halogen atom arbitrarily.
About reaction solvent, wherein preferably toluene, chlorobenzene, α, α, α-phenylfluoroform, methylene dichloride, chloroform and 1,2-ethylene dichloride, α particularly preferably, α, α-phenylfluoroform, methylene dichloride, chloroform and 1,2-ethylene dichloride.The reaction solvent of fragrance family and halogen family can be used alone or in combination.In addition, can be by ester system, N such as ether system, vinyl acetic monomer and the n-butyl acetates such as aliphatics hydrocarbon system, Anaesthetie Ether and the tetrahydrofuran (THF)s such as normal hexane and normal heptane, the reaction solvents such as the nitrile systems such as the acid amides such as dinethylformamide and DMI system, acetonitrile and propionitrile and methyl-sulphoxide; With fragrant family or (and) reaction solvent of halogen family is used in combination.
The consumption of reaction solvent is not particularly limited, as long as the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1] with respect to 1mol is used 0.05L(liter) above, be preferably 0.1～10L, be particularly preferably 0.2～5L.
Hydrofluoric consumption is not particularly limited, as long as the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1] with respect to 1mol is used 1.6mol above, is preferably 1.8～15mol, is particularly preferably 2.0～10mol.Even although larger excessive use does not have special problem (embodiment 2) yet, in the situation that being envisioned for industrially preparing process from not preferred economically.In addition, according to hydrofluoric addition means (embodiment 7 with embodiment 8 relatively), if excessive use has the situation (certainly, if adopt suitable addition means, even if excessive use selectivity also reduces hardly) of the elective reduction of target compound.In addition,, if use required in theory minimum (2 equivalent), can access sufficient turnover ratio (embodiment 3,7).According to these understanding, judge that it is 2.0～10mol(table 1 that hydrofluoric suitable consumption take with respect to 1mol the chloro-1-aromatic nucleus of the 1-substituted ethylene class that general formula [1] represents).
Hydrofluoric addition means is not particularly limited, the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1] by the reaction solvent dilution with fragrant family or halogen family, and hydrogen fluoride is blown into this solution with the state of gas, generally speaking can obtain good result (embodiment 1～3,10).Make embodiment that raw material matrix, reaction solvent, hydrofluoric consumption and temperature of reaction are consistent relatively in (embodiment 10 with embodiment 6,7 relatively), also can confirm the availability (table 1) of this addition means.
Temperature of reaction is not particularly limited, as long as under the scope of-50～+ 100 ℃, is preferably-25～+ 75 ℃, is particularly preferably 0～+ 50 ℃.If temperature of reaction is high, with the contacting and cannot carry out smoothly, the situation (embodiment 4) that has turnover ratio to reduce on the contrary of hydrogen fluoride (20 ℃ of boiling points).On the other hand, even also can obtain sufficient turnover ratio (embodiment 5,9) at 0 ℃.In the situation that being envisioned for industrially preparing process, not preferred economically for the burden of the equipment that carries out under further low temperature (being less than 0 ℃).Therefore, judge that suitable temperature of reaction is 0～+ 50 ℃ (table 1).
Reaction times is not particularly limited, need only at 48 hours with interior scope, due to according to raw material matrix, reaction solvent and reaction conditions and difference, therefore preferably by analysis means such as gas-chromatography, liquid chromatography, nucleus magnetic resonance, the situation of being undertaken of reaction is followed the trail of, will almost confirm that moment less than the minimizing of raw material matrix is as terminal.
The present invention, by make its reaction under the existence of acid catalyst, has and can obtain with especially good yield the situation of target compound.But, by adopting suitable reaction conditions of the present invention, even the reaction that also can successfully expect in the situation that not there is not acid catalyst (acid catalyst is not necessarily in the present invention).As described acid catalyst, can list hydrogenchloride, hydrogen bromide, sulfuric acid, nitric acid, perchloric acid, fluorosulfuric acid, Tetrafluoroboric acid, phosphofluoric acid, hexafluoro-antimonic acid, boron trifluoride, antimony trifluoride, antimony pentafluoride, butter of antimony, antimony pentachloride, three and fluoridize the mineral acids such as antimony butter, iodine pentafluoride and iodine heptafluoride; And the organic acid such as 2,2,2 tfifluoroethyl alcohol, HFIP, formic acid, acetic acid, trifluoracetic acid, Tricholroacetic Acid, propionic acid, oxalic acid, methanesulfonic, tosic acid and trifluoromethayl sulfonic acid.These acid catalysts can be used alone or in combination.
Aftertreatment, by adopting common operation in organic synthesis, can access the α representing with general formula [2], α-difluoro aromatics.Crude product can be purified to high purity by activated carbon treatment, fractionation, recrystallization, column chromatography etc. as required.
In the present invention, according to the raw material matrix adopting, reaction solvent and reaction conditions, have the secondary situation that generates the aromatic series acyl fluorides representing with general formula [6].
General formula [6]:
[in formula, Ar
3represent fragrant cyclic group or substituted aroma cyclic group.This fragrance cyclic group and substituted aroma cyclic group are identical with the group of recording in the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing with general formula [1].]
This aromatic series acyl fluorides and target compound α, the boiling point of α-difluoro aromatics very approaches that { difference of the hold-time in the gas chromatographic analysis of embodiment 1 is 0.1 minute [bromo-4-(1 of target compound 1-, 1-bis-fluoro ethyls) benzene and by product 4-bromobenzene formyl fluoride is poor], the difference of hold-time in the gas chromatographic analysis of embodiment 3 is 0.2 minute (target compound 1, 1-difluoro ethylbenzene vs. by product benzoyl fluoride) }, using fractionation, also cannot be effectively separated [target compound can not say the compound that thermostability is high (non-patent literature 3), the fractionation that at high temperature cost is carried out is for a long time not just suitable method of purification originally].
Therefore, find using the aromatic series acyl fluorides containing as by product optionally convert the different aromatic carboxylic acid of physical property (solvability, boiling point etc.) to, the method for purification that aromatic amides removes is very effective on the high purity product that obtains target compound.Particularly, the target compound that contains by product (reaction end of a period liquid, recovery organic layer, runic, distillation product etc.) is applied to hydrolysis or amidation (ammonia solution), under the unreacted state of target compound, only by product is optionally changed, can easily be obtained high purity product by easy separatory operation, the simple distillation that thermal load is few etc.Hydrolysis and amidated switch condition can be with reference to similarly adopting at the conventional switch condition to aliphatics or aromatic series acyl chlorides of organic synthesis.For example, can compile the synthetic of new experimental chemistry lecture 14 organic compound and react ［ II］Wan Shan Co., Ltd. p.921～1000 and 1134～1189 with reference to Japanization association, the 4th edition experimental chemistry lecture 22 organic synthesis VI acid amino acid peptide Wan Shan Co., Ltd. p.1～43 and 137～173 are compiled by Japanization association, the amino Tai Wanshan of synthetic IV carboxylic acid Co., Ltd. p.1～34 and 118～154 of the 5th edition experimental chemistry lecture 16 organic compound is compiled by Japanization association, or the blocking group in organic synthesis, the third edition, 1999, John Wiley&Sons, new experimentization Talk seat 14 is compiled by Inc.(Japanization association the anti-Applied［ II］Wan Shan of Machine compou nd synthesis と Co., Ltd. p.921～1000 and 1134～1189, the 4th edition experimentization Talk seat 22 compiled by Japanization association the synthetic VI acid of Machine ア ミ ノ acid ペプ チドWan Shan Co., Ltd. p.1～43 and 137～173, the 5th edition experimentization Talk seat 16 compiled by Japanization association Machine compou nd synthesis IV カ Le ボ Application acid ア ミ ノ acid ペプ チドWan Shan Co., Ltd. p.1～34 and 118～154, or Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley&Sons, Inc.) etc. similarly adopt.
Below describe hydrolysis and amidated concrete conversion example, but be not defined in these.
About hydrolysis, by the operation of the alkaline aqueous solution washings such as lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide of the use 0.1～50% such as reaction end of a period liquid or recovery organic layer, be easy and effective.The consumption of these alkaline aqueous solutions is not particularly limited, as long as the pH of the water layer after washing is more than 9.
If adopt such switch condition, the aromatic carboxylic acid of hydrolysis adopts the form of corresponding an alkali metal salt, and such state is also treated as " converting aromatic carboxylic acid to " included situation of recording in claim.
Amidation is carried out with the aliphatics of the carbon numbers 1～18 such as ammonia or methylamine, dimethylamine, ethylamine, diethylamine, n-propyl amine, di-n-propyl amine, isopropylamine, diisopropylamine, n-butylamine, di-n-butyl amine, aniline, Ortho Toluidine, meta-aminotoluene and para-totuidine or aromatic amine etc.The consumption of these ammonia or this aliphatics or aromatic amine etc. is not particularly limited, also can the ammonia of residual ionization or the amount of this aliphatics or aromatic amine etc. after the conversion of by product as long as use.
Hydrolysis or amidated temperature of reaction are not particularly limited, and need only the scope at-30～+ 100 ℃, are preferably-20～+ 75 ℃, are particularly preferably-10～+ 50 ℃.
Hydrolysis or amidated reaction times are not particularly limited, need only at 24 hours with interior scope, due to according to the content of by product and switch condition and difference, therefore preferably by analysis means such as gas-chromatography, liquid chromatography, nucleus magnetic resonance, the situation of being undertaken of conversion is followed the trail of, will almost confirm that moment less than the minimizing of by product is as terminal.
The aromatic carboxylic acid (also comprising corresponding an alkali metal salt) of having changed by hydrolysis moves to the layer of alkaline aqueous solution, can remove by easy separatory operation.In addition, the aromatic amides of having changed by amidation, because boiling point becomes especially high, therefore can remove as still defective material by the few simple distillation of thermal load (also comprising flash distillation).
[embodiment]
Below, by embodiment, embodiments of the present invention are specifically described, but the present invention is not limited to these embodiment.
Embodiment 1
In the reaction vessel of fluoro-resin lining, add 77.4g(gas chromatographic purity 74.6%, α, α-dichloro aromatics 21.2%, amounts to 330mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class and the 294mL(0.891L/mol that represent) chloroform, in this solution at 20 ℃ on one side companion's nitrogen on one side with the state of gas with within 4 hours 20 minutes, being blown into 52.3g(2.61mol, 7.91eq) (scavenging line is set makes it can not form pressurized state to hydrogen fluoride, further scavenging line is cooled to 0 ℃ and prevents dispersing of chloroform), at this temperature, stir 1 hour 30 minutes.In reaction end of a period liquid, be blown into 1 hour nitrogen (driving remaining hydrogenchloride and hydrogen fluoride out of), with 300mL5% sodium bicarbonate aqueous solution washing (water layer pH8), use anhydrous magnesium sulfate drying.By reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, the purity of α-difluoro aromatics is respectively 100%, 89.3%(4-bromoacetophenone is 4.7%).By recovery organic layer is carried out to concentrating under reduced pressure, obtain α, the runic 94.0g of α-difluoro aromatics.By by the fractionation of runic total amount (64～71 ℃ of boiling points, degree of decompression 0.6～0.5kPa), obtain 55.4g purification product.The gas chromatographic purity of purification product is that 98.6%(4-bromoacetophenone is 0.3%).The yield that purity converted is 75%.In purification product, contain with following formula:
The aromatic series acyl fluorides 0.9% representing.α in gas chromatographic analysis, the difference of the hold-time of α-difluoro aromatics and aromatic series acyl fluorides is 0.1 minute.Purification product are shown below
1h and
19f-NMR.
1h-NMR(reference material: Me
4si, deuterated solvent: CDCl
3), δ ppm:1.89(t, 3H), 7.46(Ar-H, 4H).
19f-NMR(reference material: C
6f
6, deuterated solvent: CDCl
3), δ ppm:73.93(q, 2F).
Embodiment 2
In the reaction vessel of fluoro-resin lining, add 3.00g(gas chromatographic purity 86.4%, α, α-dichloro aromatics 10.8%, amounts to 13.2mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class and the 31.2mL(2.36L/mol that represent) toluene, in this solution at 20 ℃ on one side companion's nitrogen on one side with the state of gas with within 1 hour 10 minutes, being blown into 18.9g(945mmol, 71.6eq) (scavenging line is set makes it can not form pressurized state to hydrogen fluoride, further scavenging line is cooled to 0 ℃ and prevents dispersing of toluene), at this temperature, stir 2 hours 25 minutes.Carry out post-processing operation similarly to Example 1, by reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, the purity of α-difluoro aromatics is respectively 100%, 81.8%(4-bromoacetophenone is 3.5%).In reclaiming organic layer, contain with following formula:
The aromatic series acyl fluorides 1.6% representing.Reclaim the contained α of organic layer, α-difluoro aromatics
1h and
19f-NMR is identical with embodiment 1.
Embodiment 3
In the reaction vessel of fluoro-resin lining, add 100g(gas chromatographic purity 99.3%, α, α-dichloro aromatics 0.3%, amounts to 718mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class and the 380mL(0.529L/mol that represent) chloroform, in this solution at 20 ℃ on one side companion's nitrogen on one side with the state of gas with within 4 hours, being blown into 51.9g(2.59mol, 3.61eq) (scavenging line is set makes it can not form pressurized state to hydrogen fluoride, further scavenging line is cooled to 0 ℃ and prevents dispersing of chloroform), at this temperature, stir 1 hour 5 minutes.To reaction end of a period liquid, be blown into 1 hour 5 minutes nitrogen (driving remaining hydrogenchloride and hydrogen fluoride out of), with 300mL5% sodium bicarbonate aqueous solution washing (water layer pH8).By reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, the purity of α-difluoro aromatics is respectively 100%, 92.6%(methyl phenyl ketone is 1.0%).By recovery organic layer is carried out to concentrating under reduced pressure, obtain α, the runic 230g of α-difluoro aromatics.By by the fractionation of runic total amount (40～61 ℃ of boiling points, degree of decompression 5.2～1.8kPa), obtain 77.5g purification product.The gas chromatographic purity of purification product is that 99.5%(methyl phenyl ketone is for being less than 0.1%).The yield that purity converted is 76%.In purification product, contain with following formula:
The aromatic series acyl fluorides 0.2% representing.α in gas chromatographic analysis, the difference of the hold-time of α-difluoro aromatics and aromatic series acyl fluorides is 0.2 minute.Purification product are shown below
1h and
19f-NMR.
1h-NMR(reference material: Me
4si, deuterated solvent: CDCl
3), δ ppm:1.92(t, 3H), 7.47(Ar-H, 5H).
19f-NMR(reference material: C
6f
6, deuterated solvent: CDCl
3), δ ppm:74.02(q, 2F).
Embodiment 4
In the reaction vessel of fluoro-resin lining, add 10.0g(gas chromatographic purity 100%, 46.0mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class and the 38.0mL(0.826L/mol that represent) chloroform, in this solution at 50 ℃ on one side companion's nitrogen on one side with the state of gas with within 5 hours, being blown into 12.2g(610mmol, 13.3eq) (scavenging line is set makes it can not form pressurized state to hydrogen fluoride, further scavenging line is cooled to 0 ℃ and prevents dispersing of chloroform), at this temperature, stir 2 hours 55 minutes.Carry out post-processing operation similarly to Example 1, by reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, the purity of α-difluoro aromatics is respectively 41%, 24.8%(4-bromoacetophenone is 0.9%).In reclaiming organic layer, contain with following formula:
The aromatic series acyl fluorides 0.9% representing.Reclaim the contained α of organic layer, α-difluoro aromatics
1h and
19f-NMR is identical with embodiment 1.
Embodiment 5
In the reaction vessel of fluoro-resin lining, add 10.0g(gas chromatographic purity 100%, 46.0mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class and the 38.0mL(0.826L/mol that represent) chloroform, in this solution, at 0 ℃, with liquid state gradation, add 4.00g(200mmol, 4.35eq) hydrogen fluoride, at this temperature, stir 6 hours 20 minutes.Carry out post-processing operation similarly to Example 1, by reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, the purity of α-difluoro aromatics is respectively 100%, 50.2%(4-bromoacetophenone is 18.6%).In reclaiming organic layer, contain with following formula:
The aromatic series acyl fluorides 1.6% representing.Reclaim the contained α of organic layer, α-difluoro aromatics
1h and
19f-NMR is identical with embodiment 1.
Embodiment 6
In the pressure-resistant reaction vessel of fluoro-resin lining, add 10.0g(gas chromatographic purity 100%, 46.0mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class and the 38.0mL(0.826L/mol that represent) chloroform, in this solution, at 0 ℃, with liquid state gradation, add 3.65g(182mmol, 3.96eq) hydrogen fluoride, at 20 ℃, stir 3 hours 25 minutes.Carry out post-processing operation similarly to Example 1, by reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, the purity of α-difluoro aromatics is respectively 100%, 65.9%(4-bromoacetophenone is 14.0%).In reclaiming organic layer, contain with following formula:
The aromatic series acyl fluorides 1.1% representing.Reclaim organic layer based on marker method (
19f-NMR, reference material: yield phenyl-hexafluoride) is 54%.Reclaim the contained α of organic layer, α-difluoro aromatics
1h and
19f-NMR is identical with embodiment 1.
Embodiment 7
Pressure-resistant reaction vessel with the cooling fluoro-resin lining of ice bath, adds 2.92g(146mmol, 3.17eq with liquid state) hydrogen fluoride, in hydrogen fluoride, add with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class 10.0g(gas chromatographic purity 100% representing, 46.0mmol, 1.00eq) chloroformic solution [solvent load 38.0mL(0.826L/mol)], at 20 ℃, stir 3 hours.Carry out post-processing operation similarly to Example 1, by reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, it is 19.4% that the purity of α-difluoro aromatics is respectively 99%, 60.8%(4-bromoacetophenone).In reclaiming organic layer, contain with following formula:
The aromatic series acyl fluorides 1.1% representing.Reclaim organic layer based on marker method (
19f-NMR, reference material: yield phenyl-hexafluoride) is 44%.Reclaim the contained α of organic layer, α-difluoro aromatics
1h and
19f-NMR is identical with embodiment 1.
Embodiment 8
Pressure-resistant reaction vessel with the cooling fluoro-resin lining of ice bath, adds 9.20g(460mmol, 10.0eq with liquid state) hydrogen fluoride, in hydrogen fluoride, add with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class 10.0g(gas chromatographic purity 100% representing, 46.0mmol, 1.00eq) chloroformic solution [solvent load 38.0mL(0.826L/mol)], at 20 ℃, stir 3 hours.Carry out post-processing operation similarly to Example 1, by reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, the purity of α-difluoro aromatics is respectively 100%, 41.0%(4-bromoacetophenone is 44.4%).In reclaiming organic layer, contain with following formula:
The aromatic series acyl fluorides 2.4% representing.Reclaim the contained α of organic layer, α-difluoro aromatics
1h and
19f-NMR is identical with embodiment 1.
Embodiment 9
Reaction vessel with the cooling fluoro-resin lining of ice bath, add hydrogen fluoride 3.60g(180mmol, chloroformic solution 4.01eq) [solvent load 38.0mL(0.846L/mol)], in this solution at 0～3 ℃, with within 36 minutes, adding 9.77g(gas chromatographic purity 100%, 44.9mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class representing stirs 5 minutes at this temperature.Carry out post-processing operation similarly to Example 1, by reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, it is 18.1% that the purity of α-difluoro aromatics is respectively 91%, 58.8%(4-bromoacetophenone).In reclaiming organic layer, contain with following formula:
The aromatic series acyl fluorides 1.9% representing.Reclaim organic layer based on marker method (
19f-NMR, reference material: yield phenyl-hexafluoride) is 46%.Reclaim the contained α of organic layer, α-difluoro aromatics
1h and
19f-NMR is identical with embodiment 1.
Embodiment 10
In the reaction vessel of fluoro-resin lining, add 50.0g(gas chromatographic purity 100%, 230mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class and the 190mL(0.826L/mol that represent) chloroform, in this solution at 20 ℃ on one side companion's nitrogen on one side with the state of gas with within 2 hours, being blown into 17.6g(880mmol, 3.83eq) (scavenging line is set makes it can not form pressurized state to hydrogen fluoride, further scavenging line is cooled to 0 ℃ and prevents dispersing of chloroform), at this temperature, stir 1 hour 20 minutes.In reaction end of a period liquid, be blown into nitrogen (driving remaining hydrogenchloride and hydrogen fluoride out of), add 300mL5% aqueous sodium hydroxide solution, at 20 ℃, stir 1 hour washing (water layer pH11, corresponding with the hydrolysis of aromatic series acyl fluorides based on 2 phase systems), with anhydrous magnesium sulfate drying, carry out concentrating under reduced pressure, obtain thus with following formula:
The α representing, the runic 111g of α-difluoro aromatics.By runic total amount being carried out to simple distillation (52～53 ℃ of boiling points, degree of decompression 0.4kPa), obtain 26.2g purification product.The gas chromatographic purity of purification product is that 99.7%(4-bromoacetophenone is 0.1%).The yield that purity converted is 51%.In purification product, do not contain with following formula completely:
The aromatic series acyl fluorides (not detecting) representing.
Incidentally, by the gas chromatographic analysis of reaction end of a period liquid, turnover ratio and α, the purity of α-difluoro aromatics and aromatic series acyl fluorides is respectively 99%, 74.4%(4-bromoacetophenone is 16.5%), 0.7%.
[reference example 1]
At 289mL(0.576L/mol) in toluene, add 131g(629mmol, 1.25eq) phosphorus pentachloride and 100g(502mmol, 1.00eq) with following formula:
The 4-bromoacetophenone representing, is set in 73 ℃ by oil bath temperature, stirs 3 hours (generation hydrogenchloride).In reaction end of a period liquid, add 116mL toluene, be injected in 300mL frozen water, with 200mL water washing, reclaim organic layer, with the washing of 200mL10% salt solution, carry out concentrating under reduced pressure, obtain thus with following formula:
The runic 154g of the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing.
By by carrying out fractionation (92～104 ℃ of boiling points, degree of decompression 0.3kPa) by the runic total amount of the chloro-1-aromatic nucleus of 1-obtained above substituted ethylene class, obtain thus 77.4g purification product.The gas chromatographic purity of purification product is 74.6%, contains respectively with following formula:
The α representing, α-dichloro aromatics 21.2% and 4-bromoacetophenone 1.7%.The yield that purity converted (also comprising α, α-dichloro aromatics) is 66%.Purification product are shown below
1h-NMR.
1h-NMR(reference material: Me
4si, deuterated solvent: CDCl
3), δ ppm:5.54(d,
1h), 5.77(d,
1h), 7.52(Ar-H, 2H), 7.62(Ar-H, 2H).
[reference example 2]
At 212g(2.00mol, 1.00eq) with following formula:
In the ethylbenzene representing, add 1.84g(11.2mmol, 0.00560eq) 2, the two isopropyl cyanides of 2 '-azepine, while stir within 1.00mol/ hour, to be blown into 4 hours 30 minutes chlorine (Cl at 20～50 ℃ of interior temperature
2) (be total to 4.50mol, 2.25eq; α, α-dichloride), at 113～134 ℃ of interior temperature, stir 2 hours 30 minutes (dechlorination hydrogenation).Repeatedly carry out same reaction, merge reaction end of a period liquid fractionation (86 ℃ of boiling points, degree of decompression 3.5kPa), obtain thus 288g with following formula:
The purification product of the chloro-1-aromatic nucleus of the 1-substituted ethylene class representing.The gas chromatographic purity of purification product is that 99.5%(does not contain α, α-dichloro aromatics).The yield that purity converted is 52%.Purification product are shown below
1h-NMR
1h-NMR(reference material: Me
4si, deuterated solvent: CDCl
3), δ ppm:5.52(m,
1h), 5.76(m,
1h), 7.36(Ar-H, 3H), 7.63(Ar-H, 2H).
[comparative example 1]
In the reaction vessel of fluoro-resin lining, add 220mg(11.0mmol, 19.9eq) hydrogen fluoride and 0.300mL(0.543L/mol) methylene dichloride, be cooled to 5 ℃, add 100mg(0.552mmol, 1.00eq) with following formula:
The bromo-4-acetylenylbenzene of 1-(2 phase system) representing, at this temperature, vigorous stirring is 2 hours.With 5mL chloroform diluting reaction end of a period liquid, use 5mL water washing, with the washing of 5mL5% wet chemical, will reclaim organic layer use based on
19the marker method of F-NMR (internal standard material: α, α, α-phenylfluoroform) is carried out quantitatively, result only containing be less than 27.6 μ mol with following formula:
The bromo-4-(1 of 1-representing, 1-bis-fluoro ethyls) benzene.Yield based on marker method is less than 5%.By reclaiming the gas chromatographic analysis of organic layer, turnover ratio and purity are respectively 100%, 0.6%(4-bromoacetophenone is 87.5%).
[comparative example 2]
At 1.00g(8.32mmol, 1.00eq) with following formula:
In the methyl phenyl ketone representing, add 4.37g(20.8mmol, 2.50eq) trifluoro-acetic anhydride stirs 4 days at 35 ℃.By the gas chromatographic analysis of reaction end of a period liquid, turnover ratio and with following formula:
What represent has 2 CF
3cO
2the acylal of base and with following formula:
The purity of the trifluoracetic acid enol ester representing is respectively 52%, 15.2%, 16.4%.Reaction end of a period liquid is carried out to the post-processing operation same with the embodiment 1 of Japanese kokai publication hei 1-199922, further carries out the same operation of fluoridizing, only containing be less than 0.832mmol with following formula:
The α representing, α-difluoro ethylbenzene.Yield based on marker method is less than 10%.
As raw material matrix, use 4-bromoacetophenone in addition and carried out same acylal chemical industry order and fluoridized operation, the corresponding bromo-4-(1 of 1-, 1-bis-fluoro ethyls) yield of benzene is 15% left and right.
On the other hand, use cyclohexanone obtain yield be 87% 1,1-difluoro hexanaphthene.
[comparative example 3]
The reaction vessel of fluoro-resin lining is immersed in during the refrigeration agent of-5 ℃ bathes, adds 3.45g(172mmol, 20.0eq) hydrogen fluoride, 2.00g(8.61mmol, 1.00eq) with following formula:
The fluorine-containing sulfuric acid enol ester class, the 0.200mL(0.0232L/mol that represent) chloroform and 196mg(1.72mmol, 0.200eq) trifluoracetic acid stirs 3 hours 15 minutes at-5 ℃.With 10mL chloroform diluting reaction end of a period liquid, with 10mL and 5mL water washing 2 times, with the washing of 10mL10% wet chemical, with the washing of 5mL10% salt solution, to reclaim organic layer use based on
19the marker method of F-NMR (internal standard material: phenyl-hexafluoride) quantitative, result contains with following formula:
The humorous position difluoro compound 6.59mmol representing.Yield based on marker method is 77%.Illustrate below
19f-NMR.
19f-NMR(reference material: C
6f
6, deuterated solvent: CDCl
3), δ ppm:71.45(m, 2F).
[comparative example 4]
The reaction vessel of fluoro-resin lining is immersed in during the refrigeration agent of-5 ℃ bathes, adds 1.56g(78.0mmol, 19.7eq) hydrogen fluoride, 1.00g(3.96mmol, 1.00eq) with following formula:
The fluorine-containing sulfuric acid enol ester class, the 0.100mL(0.0253L/mol that represent) chloroform and 90.3mg(0.792mmol, 0.200eq) trifluoracetic acid stirs 3 hours at-5 ℃.With 5mL chloroform diluting reaction end of a period liquid, with 5mL and 2.5mL water washing 2 times, with the washing of 5mL10% wet chemical, with the washing of 2.5mL10% salt solution, to reclaim organic layer use based on
19the marker method of F-NMR (internal standard material: phenyl-hexafluoride) quantitative, result is only containing being less than 0.396mmol with following formula:
The humorous position difluoro compound representing.Yield based on marker method is less than 10%.
[comparative example 5]
In the reaction vessel of fluoro-resin lining, add 1.84g(92.0mmol, 20.4eq) hydrogen fluoride, be cooled to-5 ℃, add 1.06g(gas chromatographic purity 74.6%, α, α-dichloro aromatics 21.2%, altogether 4.52mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class (2 phase system) representing stirs 30 minutes at this temperature, stirs 1 hour at 5 ℃.With chloroform diluting reaction end of a period liquid, carry out post-processing operation similarly to Example 1, by reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, the purity of α-difluoro aromatics is respectively 100%, is less than 10.0%(4-bromoacetophenone is 63.5%).
[comparative example 6]
In the pressure-resistant reaction vessel of fluoro-resin lining, add 10.0g(gas chromatographic purity 100%, 46.0mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class representing adds 2.92g(146mmol, 3.17eq with liquid state gradation in raw material matrix at 0 ℃) hydrogen fluoride stirs 3 hours at 20 ℃.With chloroform diluting reaction end of a period liquid, carry out post-processing operation similarly to Example 1, by reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, the purity of α-difluoro aromatics is respectively 100%, 5.1%(4-bromoacetophenone is 24.5%).In reclaiming organic layer, contain with following formula:
The aromatic series acyl fluorides 14.4% representing.Reclaim organic layer based on marker method (
19f-NMR, reference material: yield phenyl-hexafluoride) is less than 5%.
[comparative example 7]
Pressure-resistant reaction vessel with the cooling fluoro-resin lining of ice bath, add hydrogen fluoride 9.14g(457mmol, ethereal solution 11.0eq) [solvent load 23.5mL(0.568L/mol)], in this solution at 0 ℃, with within 30 minutes, adding 9.00g(gas chromatographic purity 100%, 41.4mmol, 1.00eq) with following formula:
The chloro-1-aromatic nucleus of the 1-substituted ethylene class representing stirs 5 hours 30 minutes at this temperature, at 20 ℃, stirs whole night.Carry out post-processing operation similarly to Example 1, by reclaiming the gas chromatographic analysis of organic layer, turnover ratio and with following formula:
The α representing, it is 29.1% that the purity of α-difluoro aromatics is respectively 48%, 7.7%(4-bromoacetophenone).In reclaiming organic layer, contain with following formula:
The aromatic series acyl fluorides 1.9% representing.
Embodiment 1～10 and comparative example 5～7 the results are summarized in table 1.
Table 1
utilizability in industry
Object α of the present invention, α-difluoro aromatics can be as the utilization of doctor's pesticide intermediate.
Claims (6)
1. a α who represents with general formula [2], the manufacture method of α-difluoro aromatics, it comprises that the reaction solvent of the fragrant family of use or halogen family makes with the chloro-1-aromatic nucleus of the 1-substituted ethylene class of general formula [1] expression and the operation of hydrogen fluoride reaction,
General formula [1]:
In formula [1], Ar
1represent fragrant cyclic group or substituted aroma cyclic group, R
1and R
2represent independently respectively hydrogen atom, alkyl, substituted alkyl, fragrant cyclic group or substituted aroma cyclic group, Ar
1with R
1, Ar
1with R
2, or R
1with R
2optionally by covalent linkage, form ring type structure,
General formula [2]:
In formula [2], Ar
1, R
1and R
2identical with the definition in general formula [1].
2. method according to claim 1, wherein, the 1-chloro-1-aromatic nucleus substituted ethylene class of the chloro-1-aromatic nucleus of the 1-substituted ethylene class that the general formula [1] of take represents as representing with general formula [3], the α representing with general formula [2], α-difluoro aromatics is the α representing with general formula [4], α-difluoro aromatics
General formula [3]:
In formula [3], Ar
2represent aromatic hydrocarbyl or substituted aromatic alkyl,
General formula [4]:
In formula [4], Ar
2identical with the definition in general formula [3].
3. according to claim 1 or method claimed in claim 2, it is characterized in that, by the chloro-1-aromatic nucleus of the reaction solvent dilution 1-substituted ethylene class of fragrant family or halogen family, and hydrogen fluoride is blown into this solution with the state of gas.
4. according to the method described in any one in claim 1～claim 3, it is characterized in that, hydrofluoric consumption is 2.0～10mol with respect to the chloro-1-aromatic nucleus of 1mol1-substituted ethylene class.
5. according to the method described in any one in claim 1～claim 4, it is characterized in that, temperature of reaction is 0～50 ℃.
6. according to the method described in any one in claim 1～claim 5, it is characterized in that, it then carries out following purification process: by target compound α, the aromatic series acyl fluorides containing as by product in α-difluoro aromatics converts aromatic carboxylic acid or aromatic amides to and removes.
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| US3200159A (en) * | 1963-01-25 | 1965-08-10 | American Cyanamid Co | Vapor phase hydrofluorination of alpha-chlorostyrene |
| JPS5823849B2 (en) * | 1980-10-21 | 1983-05-18 | エヌオーケー株式会社 | Treatment method for perfluoro compound acid fluoride |
| GB9711588D0 (en) * | 1997-06-05 | 1997-07-30 | F2 Chemicals Limited | Solvent replacement |
| US6150499A (en) * | 1998-01-06 | 2000-11-21 | Specialty Coating Systems, Inc. | Process for preparation of TFPX-dichloride |
| DE102009022894A1 (en) * | 2009-05-27 | 2010-12-02 | Bayer Schering Pharma Aktiengesellschaft | Substituted piperidines |
| JP5853772B2 (en) * | 2012-03-01 | 2016-02-09 | セントラル硝子株式会社 | Method for producing α, α-difluoroaromatic compound |
| JP5853771B2 (en) * | 2012-03-01 | 2016-02-09 | セントラル硝子株式会社 | Method for producing α, α-difluoroaromatic compound |
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| CN111587235B (en) * | 2017-10-17 | 2023-04-14 | 卡利亚里大学 | Process for the alpha-H halogenation of various substituted alkylaromatic hydrocarbons on an aromatic ring |
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