WO2007054213A1 - Process for continuously preparing difluorobenzene derivatives with long operating times - Google Patents
Process for continuously preparing difluorobenzene derivatives with long operating times Download PDFInfo
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- WO2007054213A1 WO2007054213A1 PCT/EP2006/010403 EP2006010403W WO2007054213A1 WO 2007054213 A1 WO2007054213 A1 WO 2007054213A1 EP 2006010403 W EP2006010403 W EP 2006010403W WO 2007054213 A1 WO2007054213 A1 WO 2007054213A1
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- process according
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- difluorobenzene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
Definitions
- the invention relates to a continuous process for industrially preparing difluorobenzene derivatives with a long operating time.
- Substituted difluorobenzenes for example 2,3-difluorotoluene, are valuable intermediates, for example for the pharmaceuticals, crop protection and electronics industry. It is therefore of permanent interest to these industries to find industrially utilizable and very inexpensive processes for preparing these difluorobenzene derivatives.
- EP 1010703 Bl therefore describes a continuous reaction for preparing aryl-metal compounds and their reaction with electrophiles.
- the advantage of the two- stage process described is that, owing to the typically relatively small reactor volume in conjunction with a continuous reaction, only small amounts of the intermediates which are explosive from a safety point of view are present in the reactor. In the case of explosive decomposition, the effects are therefore controllable from a safety point of view, so that even operation of the reactor or performance of the reaction above the decomposition temperature is acceptable from a safety point of view.
- page 4 line 30 is, for example, a reduction in the cooling performance required and accordingly lower production costs.
- EP 1010703 Bl therefore discloses a process with which the starting materials are reacted at temperatures of -40 0 C to + 40 0 C (Claim 10).
- a disadvantage of the process described is that, when certain reactants are used, for example 1 ,2-difluorobenzene, the claimed temperature range employed is above the decomposition temperature of -50 0 C (cf. EP 1010703 Bl, page 3, line 14) and a constant decomposition, albeit slow decomposition under the reaction conditions, is unavoidable.
- One problem is the resulting effect on the reactor operating time as a consequence of continuing blockage.
- the cause of this blockage is that the decomposition products formed include insoluble salts (for example, lithium fluoride) and high molecular weight fractions from the uncontrolled side reactions of the arynes formed. Owing to the desired long operating time in continuous plants, there is thus accumulation of these decomposition products in conjunction with a pressure rise in the reactor. As a consequence, the operation of the reactor must frequently be interrupted for cleaning.
- the reaction is carried out in two stages in a continuous manner with a lithiation of the 1 ,2-difluorobenzene derivates in the first reaction step.
- the characteristic parameters are a reactor temperature between -55 0 C and -45°C at a residence time between 1 and 60 minutes, preferably 2 to 10 minutes and more preferably 3 to 5 minutes, with a narrow residence time distribution in a suitable mixer-heat exchanger.
- Suitable mixer-heat exchangers in this context refer to modules which feature high mixing performance, high heat transfer performance and a low degree of backmixing. It has been found that, surprisingly, the temperature window of -55°C to -45°C constitutes an optimum with regard to minimal decomposition and simultaneously sufficient solubility of the lithium intermediate formed. Sufficient solubility of the lithium intermediate formed is absolutely necessary in the process according to the invention, since blockage of the reactor otherwise leads to short operating times.
- the additions of the electrophile for the second reaction stage are carried out at higher temperatures between -55°C and 0 0 C, preferably between -45°C and -15 0 C and more preferably between -40 0 C and -30 0 C using residence times in the range from 0.1 second to 60 minutes, preferably 0.5 second to 5 minutes and more preferably 1 second to 10 seconds.
- the present invention thus provides a process for continuously preparing substituted 1,2- difluorobenzenes, comprising, in a first step, the reaction of an optionally substituted 1,2- difluorobenzene as a starting material with a lithiating agent at a temperature of -55°C to -45°C and a mean residence time of 1 to 10 minutes and, in a second step, the reaction with an electrophile at a temperature of -55°C to 0 0 C and a mean residence time of 0.1 second to 10 minutes.
- Suitable starting materials for the process according to the invention are derivatives of 1 ,2-difluorobenzene which has at least one hydrogen atom in the ortho-position to a fluorine atom.
- suitable starting materials are, for example, 1 ,2-difluorobenzene itself or derivatives of 1,2-difluorobenzene which have, as substituents on the aromatic, no further functional groups which influence the polarity or the reactivity with regard to the ortho-lithiation on the aromatic.
- substituents are therefore preferably considered to be optionally branched alkyl side chains, more preferably methyl groups.
- Particularly preferred starting materials are 2,3-difluorotoluene, l,2-difluoro-4,5-dimethylbenzene and 1,2-difluorobenzene.
- lithiating agents are, for example, n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, ethyllithium, n-propyllithium, i-propyllithium and particularly suitably n-hexyl lithium, since the latter forms no gaseous by-products in the presence of water traces (the hydrolysis of n-butyllithium affords, for example, butane and lithium hydroxide).
- the formation of a biphasic reaction mixture gas/liquid
- heat transfer and mixing are promoted in the case of monophasic flow.
- Suitable solvents for the alkyl-metal compounds are hydrocarbons, for example, pentane, heptane, benzene, toluene, xylene and hexane. It is particularly suitable to use commercially available 2.1 to 2.5 M solutions of hexyllithium in hexane, which are sold, for example, by Chemetall.
- a molar ratio of lithiating agent to starting material of 0.8:1 to 1.2: 1, preferably of 1:1 is used, and they are mixed together continuously in the form of one mass stream.
- Suitable solvents for the difluorobenzene derivative preferably include the ethereal solvents which are conventionally used for reactions with strong bases for example, diethyl ether, tert-butyl methyl ether, dioxane, or more preferably tetrahydrofuran. Mixtures of these solvents can be used if required, provided that this does not reduce the solubility of the lithium intermediate.
- the concentration of the starting material in the first stage is typically 0.5 M to 5 M, preferably 1 M to 1.5 M and more preferably 1.2 M to 1.4 M.
- concentrations of the reactants are desired, since the costs for the solvent removal are minimized in - A - this way.
- mixer/heat exchanger combinations are used.
- Typical features of such modules are flow channels with high surface-to-volume ratios, in which suitable structures, for example including conventional static mixers for increasing the heat transfer performance, are introduced.
- suitable structures are, for example, a faceted mixer from Ehrfeld-Mikrotechnik BTS,
- Kenics It is likewise possible to use high-efficiency plate heat exchangers or microscale heat exchangers.
- the connection of mixer and heat exchanger must be designed so as to be free of dead volume or at least low in dead volume. Ideally, efficient heat transfer is carried out actually during the mixing operation.
- the structures used have low pressure drops of below 1 bar/m at typical throughputs of 1 kg/h to 50 kg/h. Moreover, such modules feature a narrow residence time distribution with Bodenstein numbers above 100, usually in a range between 500 and 800.
- the second stage of the process according to the invention comprises the reaction of the lithium intermediate with an electrophile.
- electrophiles are, for example, alkylating agents, for example dimethyl sulphate or methyl iodide, ketones, for example cyclohexanone, silylating agents, for example trimethylsilyl chloride, trialkyl borates, for example trimethyl borate or carboxamides, for example dimethyl formamide.
- Solvents suitable for the second step are the ethereal solvents already listed above, preferably tetrahydrofuran. Preferred concentrations of the electrophile are in the range from 1 M to 5 M, preferably at about 2 M. (M corresponds to mol/1)
- a molar ratio of the lithiated aromatic to the electrophile of typically 1 :1 to 1 :2, preferably of 1 : 1.1, is used, and they are mixed together continuously in the form of one volume stream.
- the mixer/heat exchangers used for the second stage are again the modules with the properties already mentioned above.
- the process according to the invention is suitable for a reaction in which both reaction steps are carried out in a microstructured apparatus.
- the residence volume in the reactor is such that the reaction mixture, after a residence time of 10 seconds, is passed into a receiver in which it is worked up by customary processes.
- the conversion based on 1,2-difluorobenzene was 93%.
- the operating time of the process described is 8 hours.
- Example 1 concentration, streams, residence times and reactors used
- the reactor temperature in the second stage likewise remains at -30 0 C.
- the yield at 92% is only slightly lower than in Example 1.
- the operating time of the process described at approx. 3 hours is, however, significantly below the value found in Example 1.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a continuous process for industrially preparing difluorobenzene derivatives with a long operating time.
Description
Process for continuously preparing difluorobenzene derivatives with long operating times
The invention relates to a continuous process for industrially preparing difluorobenzene derivatives with a long operating time.
Substituted difluorobenzenes, for example 2,3-difluorotoluene, are valuable intermediates, for example for the pharmaceuticals, crop protection and electronics industry. It is therefore of permanent interest to these industries to find industrially utilizable and very inexpensive processes for preparing these difluorobenzene derivatives.
Various routes to the preparation of such compounds have been described in the literature. Laboratory methods for the preparation of 2,3-difluorophenyl components (benzaldehydes, arylcarbinols and acetophenones) by means of batch synthesis have been known since 1965 (Chemical Communications (1965), (22), 582). A disadvantage of the process described there is that, owing to the two-stage reaction, on completion of the first stage, a lithiated intermediate (2,3- difluorophenyllithium derivative) is present, which tends to strongly exothermic decomposition above a certain temperature. At this point, a considerable endangerment potential is thus accumulated in the reactor, which, for example, in the event of failure of the reactor cooling, can lead to explosive decomposition. The process is therefore unsuitable for industrial synthesis.
To avoid this endangerment, EP 1010703 Bl therefore describes a continuous reaction for preparing aryl-metal compounds and their reaction with electrophiles. The advantage of the two- stage process described is that, owing to the typically relatively small reactor volume in conjunction with a continuous reaction, only small amounts of the intermediates which are explosive from a safety point of view are present in the reactor. In the case of explosive decomposition, the effects are therefore controllable from a safety point of view, so that even operation of the reactor or performance of the reaction above the decomposition temperature is acceptable from a safety point of view. The consequence of this, as described in EP 1010703 Bl, page 4 line 30 is, for example, a reduction in the cooling performance required and accordingly lower production costs. Moreover, at higher temperatures, an increase in the reaction rate takes place, so that it is also likewise possible to react less reactive aromatics. With regard to the temperature, EP 1010703 Bl therefore discloses a process with which the starting materials are reacted at temperatures of -400C to + 400C (Claim 10).
A disadvantage of the process described is that, when certain reactants are used, for example 1 ,2-difluorobenzene, the claimed temperature range employed is above the decomposition temperature of -500C (cf. EP 1010703 Bl, page 3, line 14) and a constant decomposition, albeit slow decomposition under the reaction conditions, is unavoidable.
One problem is the resulting effect on the reactor operating time as a consequence of continuing blockage. The cause of this blockage is that the decomposition products formed include insoluble salts (for example, lithium fluoride) and high molecular weight fractions from the uncontrolled side reactions of the arynes formed. Owing to the desired long operating time in continuous plants, there is thus accumulation of these decomposition products in conjunction with a pressure rise in the reactor. As a consequence, the operation of the reactor must frequently be interrupted for cleaning.
Proceeding from the prior art, it is thus an object of the invention to solve these problems and disadvantages of the known processes by providing a novel process for preparing substituted difluorobenzene derivatives. The invention described here therefore provides a process in which long operating times can be achieved using industrially relevant concentrations and throughputs with a comparatively favourable cost structure.
It has been found that, surprisingly, selection of characteristic process parameters and suitable mixer-heat exchanger combinations allows corresponding difluorobenzene derivatives to be prepared with long operating times. In this case, the reaction is carried out in two stages in a continuous manner with a lithiation of the 1 ,2-difluorobenzene derivates in the first reaction step. For this process step, the characteristic parameters are a reactor temperature between -550C and -45°C at a residence time between 1 and 60 minutes, preferably 2 to 10 minutes and more preferably 3 to 5 minutes, with a narrow residence time distribution in a suitable mixer-heat exchanger.
Suitable mixer-heat exchangers in this context refer to modules which feature high mixing performance, high heat transfer performance and a low degree of backmixing. It has been found that, surprisingly, the temperature window of -55°C to -45°C constitutes an optimum with regard to minimal decomposition and simultaneously sufficient solubility of the lithium intermediate formed. Sufficient solubility of the lithium intermediate formed is absolutely necessary in the process according to the invention, since blockage of the reactor otherwise leads to short operating times. It has also been found that, surprisingly, the additions of the electrophile for the second reaction stage are carried out at higher temperatures between -55°C and 00C, preferably between -45°C and -150C and more preferably between -400C and -300C using residence times in the range from 0.1 second to 60 minutes, preferably 0.5 second to 5 minutes and more preferably 1 second to 10 seconds.
The present invention thus provides a process for continuously preparing substituted 1,2- difluorobenzenes, comprising, in a first step, the reaction of an optionally substituted 1,2- difluorobenzene as a starting material with a lithiating agent at a temperature of -55°C to -45°C
and a mean residence time of 1 to 10 minutes and, in a second step, the reaction with an electrophile at a temperature of -55°C to 00C and a mean residence time of 0.1 second to 10 minutes.
Suitable starting materials for the process according to the invention are derivatives of 1 ,2-difluorobenzene which has at least one hydrogen atom in the ortho-position to a fluorine atom.
Examples of suitable starting materials are, for example, 1 ,2-difluorobenzene itself or derivatives of 1,2-difluorobenzene which have, as substituents on the aromatic, no further functional groups which influence the polarity or the reactivity with regard to the ortho-lithiation on the aromatic.
Such substituents are therefore preferably considered to be optionally branched alkyl side chains, more preferably methyl groups. Particularly preferred starting materials are 2,3-difluorotoluene, l,2-difluoro-4,5-dimethylbenzene and 1,2-difluorobenzene.
For the lithiation of the starting material, the lithium compounds common in organic chemistry are used. Suitable lithiating agents are, for example, n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, ethyllithium, n-propyllithium, i-propyllithium and particularly suitably n-hexyl lithium, since the latter forms no gaseous by-products in the presence of water traces (the hydrolysis of n-butyllithium affords, for example, butane and lithium hydroxide). In this way, the formation of a biphasic reaction mixture (gas/liquid) is avoided, which offers process technology advantages in the case of conduct in reaction channels. For example, heat transfer and mixing are promoted in the case of monophasic flow.
Suitable solvents for the alkyl-metal compounds are hydrocarbons, for example, pentane, heptane, benzene, toluene, xylene and hexane. It is particularly suitable to use commercially available 2.1 to 2.5 M solutions of hexyllithium in hexane, which are sold, for example, by Chemetall.
With regard to the stoichiometry of the first stage, a molar ratio of lithiating agent to starting material of 0.8:1 to 1.2: 1, preferably of 1:1 is used, and they are mixed together continuously in the form of one mass stream.
Suitable solvents for the difluorobenzene derivative preferably include the ethereal solvents which are conventionally used for reactions with strong bases for example, diethyl ether, tert-butyl methyl ether, dioxane, or more preferably tetrahydrofuran. Mixtures of these solvents can be used if required, provided that this does not reduce the solubility of the lithium intermediate.
The concentration of the starting material in the first stage is typically 0.5 M to 5 M, preferably 1 M to 1.5 M and more preferably 1.2 M to 1.4 M. In principle, for the process described, high concentrations of the reactants are desired, since the costs for the solvent removal are minimized in
- A - this way. In the process according to the invention, it has, however, been found that long reactor operating times have been found by complying with the concentrations specified and correspondingly avoiding the precipitation of the intermediates.
For efficient heat removal, mixer/heat exchanger combinations are used. Typical features of such modules are flow channels with high surface-to-volume ratios, in which suitable structures, for example including conventional static mixers for increasing the heat transfer performance, are introduced. Suitable structures are, for example, a faceted mixer from Ehrfeld-Mikrotechnik BTS,
Germany, and also classical static mixing systems which are sold by Sulzer, Germany or by
Kenics. It is likewise possible to use high-efficiency plate heat exchangers or microscale heat exchangers. In this case, the connection of mixer and heat exchanger must be designed so as to be free of dead volume or at least low in dead volume. Ideally, efficient heat transfer is carried out actually during the mixing operation.
The structures used have low pressure drops of below 1 bar/m at typical throughputs of 1 kg/h to 50 kg/h. Moreover, such modules feature a narrow residence time distribution with Bodenstein numbers above 100, usually in a range between 500 and 800.
Particular features of such combinations are surface-to-volume ratios above 1000 nrVm3, ideally these ratios are above 4000 m2/m3. The achievable cooling performances are in the range from 10 to 500 kW/m2. In the course of or directly after the mixing of the reactants, modules with cooling performances above 100 kW/m2 are ideally used.
The second stage of the process according to the invention comprises the reaction of the lithium intermediate with an electrophile. Suitable electrophiles are, for example, alkylating agents, for example dimethyl sulphate or methyl iodide, ketones, for example cyclohexanone, silylating agents, for example trimethylsilyl chloride, trialkyl borates, for example trimethyl borate or carboxamides, for example dimethyl formamide.
Solvents suitable for the second step are the ethereal solvents already listed above, preferably tetrahydrofuran. Preferred concentrations of the electrophile are in the range from 1 M to 5 M, preferably at about 2 M. (M corresponds to mol/1)
In the second reaction stage, a molar ratio of the lithiated aromatic to the electrophile of typically 1 :1 to 1 :2, preferably of 1 : 1.1, is used, and they are mixed together continuously in the form of one volume stream.
The mixer/heat exchangers used for the second stage are again the modules with the properties already mentioned above.
The process according to the invention is suitable for a reaction in which both reaction steps are carried out in a microstructured apparatus.
The examples which follow are intended to illustrate the process according to the invention but without restricting it.
Example 1
5.9 kg/h of a 1.3 M solution of 1 ,2-difluorobenzene in tetrahydrofuran were reacted in a mixer/heat exchanger combination with a mass stream of 2.4 kg/h consisting of a 2.5 M solution of hexyllithium in hexane at -45°C. After a residence time of 4 minutes, the reaction mixture leaves the reactor with a temperature of -45°C and is .mixed in a further mixer/heat exchanger combination with a stream of 2.95 kg/h of a 3.1 M solution of dimethylformamide in tetrahydrofuran which is precooled to a temperature of -300C. The residence volume in the reactor is such that the reaction mixture, after a residence time of 10 seconds, is passed into a receiver in which it is worked up by customary processes. The conversion based on 1,2-difluorobenzene was 93%. The operating time of the process described is 8 hours.
Example 2
The experiment is carried out analogously to Example 1 (concentrations, streams, residence times and reactors used), except that a higher temperature in the first reaction stage at -300C is used. The reactor temperature in the second stage likewise remains at -300C. The yield at 92% is only slightly lower than in Example 1. The operating time of the process described at approx. 3 hours is, however, significantly below the value found in Example 1.
Example 3
At a temperature of -450C, 6.6 kg/h of a 1.2 M solution of 2,3-difluorotoluene in tetrahydrofuran are combined in a mixer/heat exchanger combination with a mass stream of 2.7 kg/h consisting of a 2.5 M solution of hexyllithium in hexane. After a residence time of 5 minutes, a stream of 3.6 kg/h of a 2.4 M solution of dimethyl sulphate in tetrahydrofuran, which is precooled to a temperature of -300C, is mixed in in a further mixer/heat exchanger combination. After a residence time of 10 seconds, the reaction mixture is passed into a receiver and worked up by customary processes. The conversion based on 2,3-difluorotoluene was 94%. The operating time of the process described is 8 hours.
Claims
1. Process for continuously preparing substituted 1 ,2-difluorobenzenes, comprising, in a first step, the reaction of an optionally substituted 1 ,2-difluorobenzene as a starting material with a lithiating agent at a temperature of -45°C to -55°C and a mean residence time of 1 to 60 minutes and, in a second step, the reaction with an electrophile at a temperature of 00C to -55°C and a mean residence time of 0.1 second to 10 minutes.
2. Process according to Claim 1, characterized in that the starting material is selected from the group consisting of 2,3-difluorotoluene, l,2-difluoro-4,5-dimethylbenzene and 1 ,2-difluorobenzene.
3. Process according to Claim 1 or 2 characterized in that the lithiating agent used is an alkyllithium reagent, e.g. n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, ethyllithium, n-propyllithium, i-propyllithium and n-hexyllithium.
4. Process according to one of the preceding claims, characterized in that the lithiating agent is n-hexyllithium.
5. Process according to one of the preceding claims, characterized in that the first step is carried out in an ethereal solvent.
6. Process according to one of the preceding claims, characterized in that the electrophile is selected from the group consisting of alkylating agents, ketones, silylating agents, trialkyl borates, and carboxylic acid derivatives, e.g. carboxamides or carboxylic esters.
7. Process according to one of the preceding claims, characterized in that the molar ratio of lithiating agent to starting material in the first stage is 0.8: 1 to 1.2: 1.
8. Process according to one of the preceding claims characterized in that the concentration of the starting material in the first stage is between 0.5 M and 2.5 M.
9. Process according to one of the preceding claims, characterized in that at least one of the reaction steps is carried out in a microstructured apparatus.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE200510054090 DE102005054090A1 (en) | 2005-11-12 | 2005-11-12 | Process for the continuous production of difluorobenzene derivatives with a long service life |
| DE102005054090.2 | 2005-11-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007054213A1 true WO2007054213A1 (en) | 2007-05-18 |
Family
ID=37734931
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2006/010403 WO2007054213A1 (en) | 2005-11-12 | 2006-10-30 | Process for continuously preparing difluorobenzene derivatives with long operating times |
Country Status (3)
| Country | Link |
|---|---|
| DE (1) | DE102005054090A1 (en) |
| TW (1) | TW200730472A (en) |
| WO (1) | WO2007054213A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102019008481A1 (en) | 2018-12-21 | 2020-06-25 | Merck Patent Gmbh | Continuous process for the functionalization of fluorinated benzene compounds in the flow tube |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5279764A (en) * | 1988-03-10 | 1994-01-18 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Dihalogenobenzene derivatives |
| EP1010703A2 (en) * | 1998-12-19 | 2000-06-21 | MERCK PATENT GmbH | Process for preparing aryl metal compounds and their conversion with electrophiles |
| WO2003033505A1 (en) * | 2001-10-12 | 2003-04-24 | Clariant Gmbh | Method for organometallic production of organic intermediate products via lithium amide bases |
| WO2003033503A2 (en) * | 2001-10-12 | 2003-04-24 | Clariant Gmbh | Method for producing, via organometallic compounds, organic intermediate products |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5162577A (en) * | 1990-02-13 | 1992-11-10 | Hoffmann-La Roche Inc. | Process for lithiation of 1,3-bis(trifluoromethyl)benzene |
| DE19858855A1 (en) * | 1998-12-19 | 2000-06-21 | Merck Patent Gmbh | Process for the preparation of ortho-substituted aryl metal compounds and their reaction with electrophiles |
-
2005
- 2005-11-12 DE DE200510054090 patent/DE102005054090A1/en not_active Withdrawn
-
2006
- 2006-10-30 WO PCT/EP2006/010403 patent/WO2007054213A1/en active Application Filing
- 2006-11-10 TW TW095141591A patent/TW200730472A/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5279764A (en) * | 1988-03-10 | 1994-01-18 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Dihalogenobenzene derivatives |
| EP1010703A2 (en) * | 1998-12-19 | 2000-06-21 | MERCK PATENT GmbH | Process for preparing aryl metal compounds and their conversion with electrophiles |
| WO2003033505A1 (en) * | 2001-10-12 | 2003-04-24 | Clariant Gmbh | Method for organometallic production of organic intermediate products via lithium amide bases |
| WO2003033503A2 (en) * | 2001-10-12 | 2003-04-24 | Clariant Gmbh | Method for producing, via organometallic compounds, organic intermediate products |
Non-Patent Citations (2)
| Title |
|---|
| HARPER ET AL: "Reactions of organomettalics with fluoroaromatic compounds.", J. ORG. CHEM., vol. 29, 1964, pages 2385, XP002421538 * |
| ROE ET AL: "The preparation of 1,2,3-trifluorobenzene and of 2,3- and 2,6-difluorophenyl compounds.", CHEMICAL COMMUNICATIONS, vol. 22, 1965, pages 692, XP009079499 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102019008481A1 (en) | 2018-12-21 | 2020-06-25 | Merck Patent Gmbh | Continuous process for the functionalization of fluorinated benzene compounds in the flow tube |
| CN111349110A (en) * | 2018-12-21 | 2020-06-30 | 默克专利股份有限公司 | Continuous process for the functionalization of fluorinated benzene compounds in flow tubes |
Also Published As
| Publication number | Publication date |
|---|---|
| DE102005054090A1 (en) | 2007-05-16 |
| TW200730472A (en) | 2007-08-16 |
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