CN85101737A - Preparation 2,4,5-trihalogenated benzene and 2,3,4, the derivative method of 5-tetrahalogeno-benzene - Google Patents

Preparation 2,4,5-trihalogenated benzene and 2,3,4, the derivative method of 5-tetrahalogeno-benzene Download PDF

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CN85101737A
CN85101737A CN85101737.1A CN85101737A CN85101737A CN 85101737 A CN85101737 A CN 85101737A CN 85101737 A CN85101737 A CN 85101737A CN 85101737 A CN85101737 A CN 85101737A
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benzene
chloro
trifluoro
formyl
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CN1013370B (en
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埃里奇·克劳肯
彼得森
克劳斯·格罗哈
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Bayer AG
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Abstract

The invention relates to 2,4,5-trihalogenated benzene and 2,3,4, derivative of 5-tetrahalogeno-benzene and preparation method thereof.This compound is the synthetic important intermediate of high reactivity antimicrobial agent.

Description

Preparation 2,4,5-trihalogenated benzene and 2,3,4, the derivative method of 5-tetrahalogeno-benzene
The invention relates to 2,4,5-trihalogenated benzene and 2,3,4, derivative of 5-tetrahalogeno-benzene and preparation method thereof.Compound of the present invention is the important intermediate of synthetic high reactivity antimicrobial agent.
Found the structure formula I
Figure 85101737_IMG4
2,4,5-trihalogenated benzene and 2,3,4, the derivative of 5-tetrahalogeno-benzene.
In the formula, R representative-COOH ,-COCl ,-COF ,-CN ,-CONH 2,-CH 2OH ,-CH 2Cl ,-CHCl 2,-CCl 3Or-CHO,
R 1Represent H, Cl or F and
R 2Represent Cl or F,
Can only R 1Or R 2Be fluorine.
May mention following compounds especially:
2,4,5-trifluoro-benzene formyl fluoride;
2,3,4-three fluoro-5-chlorinated benzene formyl fluorides;
2,4,5-three fluoro-3-chlorinated benzene formyl chlorides;
2,4-two fluoro-3,5-dichlorobenzene formyl fluoride.
Also find 2,4 of structure formula I, 5-trihalogenated benzene and 2,3,4, the preparation method of the derivative of 5-tetrahalogeno-benzene.
Figure 85101737_IMG5
In the formula, R ' representative-COOH ,-COCl ,-COF ,-CN ,-CONH 2,-CH 2OH ,-CH 2Cl ,-CHCl 2,-CCl 3Or-CHO,
R 1Represent H, Cl or F and
R 2Represent Cl or F,
Can only R 1Or R 2It is fluorine.
At high temperature, make 2,3,4,5-tetrachlorobenzene base nitrile and Potassium monofluoride react in solvent, and use known method, and the nitrile compounds that produces is changed into the structure formula I and makes said derivative.
People also find, 2,3,4 of structure formula II, the preparation method of the derivative of 5-tetrahalogeno-benzene.
In the formula, R ' representative-COCl ,-COF and
R represents Cl or F.
With 2,3,4,5-tetrachlorobenzene formyl chloride or 2,3,4,5-tetrachlorobenzene formyl fluoride (seeing European patent NO.-57,844) after fluoridizing in position with hydrogen fluoride, at high temperature, reacts in solvent with Potassium monofluoride and to make said derivative.
The consumption of Potassium monofluoride depends on substituted amount of chlorine atom order, replaces a chlorine atom and uses 1 mole of Potassium monofluoride at least, but be generally 1.1～1.5 moles, replaces a chlorine atom at most with 2 moles of Potassium monofluorides; In addition, the amount of Potassium monofluoride does not have actual influence to degree of fluorination, makes this method become uneconomical on the contrary.Yet, if use hydrogen fluoride earlier 2,3,4,5-tetrachlorobenzene formyl chloride is fluoridized, then, will be from this reaction the actual output that obtains 2,3,4,5-chlorinated benzene formyl fluoride and Potassium monofluoride carry out the Cl/F substitution reaction, and so, we just can save the Potassium monofluoride of part costliness.Because the activity of the bigger acyl fluorides group of electronegativity is bigger, the minimizing of Repone K amount in the higher and reactant of thermostability, secondary is fluoridized comprehensive nuclear fluorizated balance of having improved.
Can be the inert solvent that becomes known for fluoridation as nuclear fluorizated solvent, as, dimethylformamide, dimethyl sulfoxide (DMSO), Jr-methyl-2-pyrrolidone, diethyl sulfone, or the like, the tetramethylene sulfone preferably used.
Temperature of reaction is according to required degree of fluorination, between 160～260 ℃.Under lower temperature, still find to have not fluorizated product of nucleus, and under higher temperature, it is known 2,3,4 to have generated the overwhelming majority, and the 5-tetrafluoro (is seen the open P3318145 of German Patent, 1983.5.18) for benzoyl fluoride.
Because tetrahalogeno-benzene formyl halogenide-at first generate eight halogenated diphenyl ketone in reaction mixture-show thermolability, therefore, during fluoridation, constantly remove required reaction product with the distillatory method in the reaction compartment and be proved to be useful.Because regulate the dividing potential drop of distillation pressure to the fluoridation mixture continuously, said process has been realized in a separation column easily.
Find that also with 2,4,5-trifluoro-benzene formyl chloride reacts, and obtains 2,4,5-three fluoro-3-chlorinated benzene formic acid make the reaction of this acid and thionyl chloride obtain 2,4,5-three fluoro-3-chlorinated benzene formyl chlorides again.2,4,5-trifluoro-benzene formic acid is as the raw material of this process open (W.A.Skinnev, J.Chem.Eng.Data 13,587(1968) for J.I.de Graw, M.Cory).According to literature cite, from 2-amino-4,5-phenyl-difluoride manthanoate thanks to the method for graceful reaction with crust Hereby, through NH 2/ F replacement makes 2,4,5-three fluoro-3-chlorinated benzene formic acid, and productive rate is very low.Yet 2,4-two chloro-5-fluorobenzene formyl chlorides are at DE-OS(Germany prospectus) 3,142,856 be US Patent specification 4,439, open in 620.People find also that now in a solvent, preferably the tetramethylene sulfone under 180～230 ℃ of temperature, is fluoridized with Potassium monofluoride, obtain with direct method new 2,4,5-trifluoro-benzene formyl fluoride, productive rate is very high.2,4,5-trifluoro-benzene formyl fluoride, the method with alkaline hydrolysis in fact is converted into 2,4,5-trifluoro-benzene formic acid quantitatively.
2,4, the chlorination of 5-trifluoro-benzoic acid is under molten state, depresses and/or in solvent, as chlorsulfonic acid or oleum, at the halogen agent delivery, as what carry out under the existence of iodine adding.In this reaction, obtain 2,4,5-three fluoro-3-chlorinated benzene formic acid.Yet, because still contain unchanged raw material and some 2,4 in the reaction mixture, 5-three fluoro-3,6-dichlorobenzene formic acid, crude mixture without intermediate section from, handle with thionyl chloride, promptly obtain through rectifying required 2,4,5-three fluoro-3-chlorinated benzene formyl chlorides.Yet, separate more favourable through the acid fluoride distillation.
The nitrile compounds process, as be hydrolyzed into carboxylic acid, change the process of chloride of acid again into thionyl chloride, manage and can use, obtain corresponding acyl halide.By chloride of acid and fluorizating agent,, obtain acid fluoride as anhydrous hydrofluoric acid or alkaline metal fluoride cpd reaction.On the contrary, prepare chloride of acid from acid fluoride if desired, then use the method for an exquisiteness, promptly with the silicon tetrachloride reaction, having in the presence of a large amount of aluminum chloride of katalysis, making is suitable in this way.Halogeno-benzene methyl alcohol can be by acyl halide, and acid fluoride preferably is with NaBH 4Make through a reaction stably.
By halogeno-benzene methyl alcohol and thionyl chloride reaction, press actual yield, obtain corresponding benzyl chloride, the latter then obtains corresponding xylylene dichlorides and benzenyl trichloride with the further chlorination of chlorine.
Halogeno-benzene formaldehyde, preferably acid can be obtained by the hydrolysis of halo xylylene dichlorides, and corresponding halo benzenyl trichloride hydrolysis then obtains corresponding chloride of acid and acid.
Compound of the present invention is as the raw material of synthetic medicament.
Compound of the present invention can be converted into highly active antibiont 1-cyclopropyl-6,8-dihalo-1,4-dihydro-4-oxo-7-(1-piperazinyl)-the 3-quinoline carboxylic acid.Should carry out by synthetic route in the following example, with 2,3,4-three fluoro-5-chloro benzyl fluorides are as raw material.
Figure 85101737_IMG7
Example 1
2,4,5-trifluoro-benzene formyl fluoride.
2,4-two chloro-5-fluorobenzene formyl fluoride (98 ℃/15 millibars of boiling points, n 20 D: 1.5355), by 2,4,5-trifluoro-benzene formyl chloride (113 ℃/14 millibars of boiling points, n 20 D: 1.5722) and anhydrous hydrofluoric acid make.
878g2,4-two chloro-5-fluorobenzene formyl fluorides and 2350 milliliters of tetramethylene sulfones reacted 3.5 hours at 200 ℃ with the 1142g anhydrous hydrogen fluoride in the three-necked flask that has agitator, thermometer and rectifying column.Therebetween, overhead product constantly obtains through rectifying column, and original pressure is 750 millibars, last stage reaction pressure is 80 millibars, and rough overhead product is through secondary rectifying, obtain the 486g(theoretical yield 65.5%) 2,4, and 5-trifluoro-benzene formyl fluoride (boiling point: 52-53 ℃/20 millibars, n 20 D: 1.4530).
Subsequently, through using the aqueous sodium hydroxide solution hydrolysis, acidifying, filtration, drying obtain 2,4 by actual yield, 5-trifluoro-benzene formic acid (fusing point: 95 ℃).
Example 2
2,3,4,5-tetrachlorobenzene formyl chloride
2994g 2,3,4,5-tetrachlorobenzene formyl chloride (boiling point: 118 ℃/0.5 millibar, fusing point: 38 ℃) in methylene dichloride, fluoridize with anhydrous hydrofluoric acid at 60 ℃, distill out hydrogen fluoride and solvent, obtain 2749g 2,3,4,5-tetrachlorobenzene formyl fluoride (fusing point: 52～53 ℃).
The material of this tittle and 2914g anhydrous hydrogen fluoride and 7250 milliliters of tetramethylene sulfones heat in three-necked flask, distill out about 500 ml solns at first, to remove some residual water again, reaction mixture is heated to 240 ℃ then, violent stirring is 4.5 hours simultaneously.Therebetween, reaction pressure constantly drops to 500 millibars from initial 800 millibars.At this moment, the fluorinated product mixture obtains through rectifying column as overhead product, and it obtains 1840g, obtains following product through secondary rectifying:
206g 2,3,4, and the 5-tetrafluoro is for benzoyl fluoride, boiling point: 45～47 ℃/20 millibars, and n 20 D: 1.4372;
954g 5-chloro-2,3,4-trifluoro-benzene formyl fluoride, boiling point: 68～70 ℃/20 millibars, n 20 D: 1.4764;
330g 3,5-two chloro-2, and 4-phenyl-difluoride formyl fluoride, boiling point: 97 ℃/20 millibars, n 20 D: 1.5148.
64g 5-chloro-2,3,4-trifluoro-benzene formyl fluoride and 13g silicon tetrachloride heat in the presence of the 0.1g aluminum trifluoride, and reaction finishes when reaching about 100 ℃ since 35 ℃.Resistates obtains following product through distillation:
62g 5-chloro-2,3, the 4-trifluorobenzoyl chloride, boiling point: 88 ℃/14 millibars, n 20 D: 1.5146.
Also correspondingly obtain 3,5-two chloro-2-4-phenyl-difluoride formyl chlorides, as boiling point of liquid: 113～114 ℃/15 millibars, n 20 D: 1.5512.
If with 5-chloro-2,3,4-trifluoro-benzene formyl fluoride is handled with sodium hydroxide solution simply.Through acidifying, drying, obtain 5-chloro-2,3, the crystallization of 4-trifluoro-benzene formic acid, fusing point: 123～124 ℃.
Correspondingly obtain 3,5-two chloro-2,4-phenyl-difluoride formic acid, fusing point: 179 ℃.
Example 3
5-chloro-2,3,4 trifluoro-benzene methyl alcohol.
At first with 62g NaBH 4Add in 320 milliliters of dioxanes, under reflux temperature, in more than 6 hours, adding is dissolved in 640 milliliters of 319g 5-chloro-2,3 in the dioxane, 4-trifluoro-benzene formyl fluoride then.Under refluxad, seethed with excitement one hour again, mixture is poured on ice, regulating pH value with the salt solution dilution is 1, uses the dichloromethane extraction organic phase, through distillation, obtains 261g 2,3,4-three fluoro-5-chlorinated benzene methyl alcohol, boiling point: 109 ℃/12 millibars.
Equally, from 3,5-two chloro-2,4-phenyl-difluoride formyl fluoride obtains 3,5-two chloro-2,4-phenyl-difluoride methyl alcohol, the xln boiling point: 134 ℃/13 millibars, fusing point: 55 ℃.
Example 4
3-chloro-2,4,5-trifluoro-benzene formyl fluoride.
150g 2,4,5-trifluoro-benzene formic acid is dissolved in 150 milliliters of chlorsulfonic acids, behind the adding 3g iodine, carries out chlorination with chlorine at 50～60 ℃, and the raw material 35～50% is stopped chlorination reaction by after lightization, and mixture is decomposed carefully on ice.
Obtain examining mixture and dry (, the making sample purification obtain 3-chloro-2,4,5-trifluoro-benzene formic acid (114～115 ℃ of fusing points)) of halogenated acid through repeating crystallization with vacuum filtration.
With excessive thionyl chloride and add several dimethylformamides, rough mixture is converted into the mixture of chloride of acid.Sample obtains 3-chloro-2,4 through rectifying, 5-trifluoro-benzene formyl chloride, and boiling point: 94 ℃/18 millibars, n 20 D: 1.5164.
At-5 ℃, the resistates in stainless steel autoclave adds 100 milliliters of anhydrous hydrogen fluorides.After the volatile hydrogen chloride amount reduces, mixture is heated to 60 ℃ rapidly, make to react completely, handle through distillation, isolate 38g 3-chloro-2,4,5-trifluoro-benzene formyl fluoride, boiling point: 65 ℃/18 millibars, n 20 D: 1.4760.
Use NaBH 4The reduction acid fluoride obtains 3-chloro-2,4,5-trifluoro-benzene methyl alcohol, and boiling point: 109 ℃/10 millibars, fusing point: 32 ℃.
This alcohol in sulfolysis matter, is used the sodium dichromate 99 oxidation at 20～25 ℃, obtains 2,4,5-three fluoro-3-chlorinated benzene formaldehyde, and boiling point: 72 ℃/12 millibars, n 20 D: 1.5055, slow crystalline melt point: 31～32 ℃.
Example 5
2,3,4, the fluoridizing of 5-tetrachlorobenzene nitrile
2,3,4,5-tetrachlorobenzene nitrile, fusing point: 123～125 ℃ (by 2,3,4,5-tetrachlorobenzene formyl chloride (fusing point: 30 ℃) is through 2,3, and 4,5-tetrachlorobenzene methane amide (fusing point: 206 ℃) makes), in the tetramethylene sulfone, fluoridize with hydrogen fluoride, obtain following product through the rectifying fluorizating mixture:
2,3,4,5-four fluoro benzonitriles, boiling point: 59 ℃/15 millibars, n 20 D: 1.4562;
5-chloro-2,3,4-trifluoro-benzene nitrile, boiling point: 78 ℃/14 millibars, n 20 D: 1.4960; With
3,5-two chloro-2,4-phenyl-difluoride nitrile, boiling point: 113 ℃/19 millibars, fusing point: 39～40 ℃.
Example 6
3,5-two chloro-2,4-phenyl-difluoride methane amide
At first, add 620 milliliters of strong aquas and 600 ml waters, drop by drop add the 458g(2 mole at 40～50 ℃) 3,5-two chloro-2,4-phenyl-difluoride formyl fluoride, then, mixture was stirred 30 minutes at 50 ℃, obtain throw out with suction filtration, throw out washes with water and is dry, obtain the 408g(theoretical yield 90%) 3,5-two chloro-2,4-phenyl-difluoride methane amide (163～164 ℃ of fusing points).
Equally also obtain following product:
5-chloro-2,3,4-trifluoro-benzene methane amide, fusing point: 135～137 ℃;
3-chloro-2,4,5-trifluoro-benzene methane amide, fusing point: 125 ℃;
2,4,5-trifluoro-benzene methane amide, fusing point: 145～147 ℃;
2,3,4,5-trichloro-benzene methane amide, fusing point: 206 ℃.
Example 7
3,5-two chloro-2,4-difluoro benzyl chlorine
At room temperature, at first add 350 milliliters of thionyl chloride and a dimethyl formamide, dropwise add the 375g(1.76 mole again) 3,5-two chloro-2,4-phenyl-difluoride methyl alcohol, heated mixt under refluxad is not till having gaseous volatilization, distill out excessive thionyl chloride, residuum through vacuum filtration obtain the 386g(theoretical yield 95%) 3,5-two chloro-2,4-difluoro benzyl fluorine, boiling point: 107 ℃/12 millibars, n 20 D: 1.5368.
Obtain following product similarly:
5-chloro-2,3,4-three fluoro benzyl chlorides, boiling point: 78 ℃/13 milli tails, n 20 D: 1.4972 and
3-chloro-2,4,5-three fluoro benzyl chlorides, boiling point: 80 ℃/16 millibars, n 20 D: 1.4966.
Example 8
5-chloro-2,3, the chloro of 4-three fluoro benzyl chlorides
At first, add the 187g(0.87 mole) 5-chloro-2,3,4-three fluoro benzyl chlorides under 100～105 ℃ and UV-irradiation, carry out chlorination with the chlorine that is less than stoichiometric quantity then.According to gas chromatographic analysis, rough mixture contains 66%5-chloro-2,3,4-three chloro toluene dichloride and 32%5-chloro-2,3,4-three fluoro trichlorotoluene zotrichlorides.Obtain following product through distillation:
The 94g(theoretical yield 43%) 5-chloro-2,3,4-three fluoro toluene dichloride, boiling point: 88 ℃/12 millibars, n 20 D: 1.5082;
The 33g(theoretical yield 13%) 5-chloro-2,3,4-three fluoro trichlorotoluene zotrichlorides, boiling point: 104 ℃/12 millibars, n 20 D: 1.5235.
Can obtain following product similarly:
3,5-two chloro-2,4-two fluoro toluene dichloride, boiling point: 114 ℃/14 millibars, n 20 D: 1.5443;
3,5-two chloro-2,4-two fluoro trichlorotoluene zotrichlorides, boiling point: 128 ℃/14 millibars, fusing point: 43 ℃.
Example 9
5-chloro-2,3,4-trifluoro-benzene formaldehyde
At 40 ℃, the 72g(0.29 mole) 5-chloro-2,3,4-three fluoro toluene dichloride add in 220g 95% vitriol oil, and 40 ℃ of stirrings of Heng temperature are till no gaseous volatilization.
Resistates is poured on ice, uses dichloromethane extraction, the organic phase drying over sodium sulfate, through concentrating and distillation, obtain the 18g(theoretical yield 32%) 5-chloro-2,3,4-trifluoro-benzene formaldehyde, boiling point: 75 ℃/15 millibars, n 20 D: 1.5020.
Obtain similarly, 3,5-two chloro-2,4-phenyl-difluoride formaldehyde, boiling point: 98 ℃/14 millibars, fusing point: 32 ℃.
Errata
Figure 85101737_IMG8

Claims (9)

1, structure formula I
Figure 85101737_IMG1
2,4,5-trihalogenated benzene and 2,3,4, the preparation method of the derivative of 5-tetrahalogeno-benzene, wherein: R representative-COOH ,-COCl ,-COF ,-CN ,-CONH 2,
-CH 2OH ,-CH 2Cl ,-CHCl 2,-CCl 3Or-CHO,
R 1Represent H, Cl or F and
R 2Represent Cl or F,
Only may R 1Or R 2Be fluorine,
It is characterized in that, at high temperature, 2,3,4,5-tetrachlorobenzene base nitrile reacts with Potassium monofluoride in solution, and the nitrile compounds of generation changes the compound of structure formula I in position by known method.
2, preparation method according to claim 1 is characterized in that making 2,4,5-trifluoro-benzene formyl fluoride.
3, preparation method according to claim 1 is characterized in that making 5-chloro-2,3,4-trifluoro-benzene formyl fluoride.
4, preparation method according to claim 1 is characterized in that making 3-chloro-2,3,4-trifluoro-benzene formyl chloride.
5, preparation method according to claim 1 is characterized in that making 3,5-two chloro-2,4-two these formyl fluorides of fluoro.
6, the 3-chloro-2,4, and the preparation method of 5-trifluoro-benzene formyl chloride is characterized in that, 2,4, the chlorination of 5-trifluoro-benzene formic acid obtains 3-chloro-2,4,5-trifluoro-benzene formic acid, the latter and thionyl chloride reaction.
7,2,4, the preparation method of 5-trifluoro-benzene formyl fluoride is characterized in that, at high temperature, makes 2, reacts in the solvent of 4-two chloro-5-fluorobenzene formyl chlorides and Potassium monofluoride.
8,2,3,4 of the structure formula II, the preparation method of 5-tetrahalogeno-benzene derivative,
Figure 85101737_IMG2
In the formula: R ' representative-COCl, or-COF and
R 1Represent Cl or F,
It is characterized in that, 2,3,4,5-tetrachlorobenzene formyl chloride or 2,3,4,5-tetrachlorobenzene formyl fluoride after fluoridize the suitable position of hydrofluoric acidization, at high temperature, reacts in solvent with Potassium monofluoride.
9,2,4 of the structure formula I, 5-trihalogenated benzene and 2,3,4, the derivative of 5-tetrahalogeno-benzene is used as the raw material or the intermediate of synthetic medicament,
Figure 85101737_IMG3
In the formula: R representative-COOH ,-COCl ,-COF ,-CN ,-CONH 2,-CH 2OH ,-CH 2Cl ,-CHCl 2,-CCl 3Or-CHO,
R 1Represent H, Cl or F and
R 2Represent Cl or F,
R 1And R 2Can not be fluorine simultaneously.
CN 85101737 1984-06-04 1985-04-01 Process for preparing 2,4,5-trihalogeno-and 2,3,4,5-tertrahalogeno-benzene derviatives Expired CN1013370B (en)

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CN 85101737 CN1013370B (en) 1984-06-04 1985-04-01 Process for preparing 2,4,5-trihalogeno-and 2,3,4,5-tertrahalogeno-benzene derviatives

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Cited By (2)

* Cited by examiner, † Cited by third party
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CN114835589A (en) * 2022-05-30 2022-08-02 河南金鹏化工有限公司 Preparation method of 2,4-difluoro-3,5-dichloroaniline
CN115611717A (en) * 2022-11-01 2023-01-17 上海万溯药业有限公司 Preparation method of polyfluorobenzaldehyde

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114835589A (en) * 2022-05-30 2022-08-02 河南金鹏化工有限公司 Preparation method of 2,4-difluoro-3,5-dichloroaniline
CN114835589B (en) * 2022-05-30 2024-03-15 河南金鹏化工有限公司 Preparation method of 2,4-difluoro-3,5-dichloroaniline
CN115611717A (en) * 2022-11-01 2023-01-17 上海万溯药业有限公司 Preparation method of polyfluorobenzaldehyde

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