WO2007044270A1 - Process for producing high purity ketones by friedel-crafts acylation at low temperature - Google Patents

Process for producing high purity ketones by friedel-crafts acylation at low temperature Download PDF

Info

Publication number
WO2007044270A1
WO2007044270A1 PCT/US2006/038286 US2006038286W WO2007044270A1 WO 2007044270 A1 WO2007044270 A1 WO 2007044270A1 US 2006038286 W US2006038286 W US 2006038286W WO 2007044270 A1 WO2007044270 A1 WO 2007044270A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
process
alkylbenzene
acylated
para
meta
Prior art date
Application number
PCT/US2006/038286
Other languages
French (fr)
Inventor
Thanikavelu Manimaran
Alvin E. Harkins
Original Assignee
Albemarle Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46Friedel-Crafts reactions

Abstract

The present invention relates to improved conditions for the Friedel-Crafts acylation of alkylbenzenes and to application of these improved conditions to the synthesis of para-isobutyl acetophenone and ibuprofen. The reaction conditions include operating the reaction at a temperature below 0°C and typically below -10° C.

Description

PROCESS FOR PRODUCING HIGH PURITY KETONES BY FRIEDEL-CRAFTS ACYLATION AT LOW TEMPERATURE

FIELD OF THE INVENTION

[0001] The present invention relates to improved conditions for the Friedel-Crafts acylation of alkylbenzenes and to application of these improved conditions to the synthesis of para-isobutyl acetophenone.

BACKGROUND

[0002] Friedel-Crafts acylation is one of the most important methods for manufacturing acylated benzene derivatives. The reaction typically utilizes an acylating agent such as an acyl chloride, acyl fluoride, or acyl anhydride and an electrophilic catalyst such as aluminum chloride, boron trifluoride, or hydrogen fluoride. Acylations under these conditions typically stop after one equivalent of the acyl group is added to the alkylbenzene starting material, because the acylated product is much less reactive toward the electrophilic acylating agent than the starting material.

[0003] However, where the starting material is a substituted benzene derivative like a mono-substituted alkylbenzene, for example, the acylation can occur at different positions on the benzene ring relative to the alkyl group, so the reaction often produces a mixture of isomeric mono-acyl products. The predominant regioisomer produced depends heavily on the nature of the starting material, acylating agent, and catalyst. The ratio of major to minor products (regioisomers) often depends on other factors as well, such as the concentration, solvent, and temperature. Furthermore, the acylated product may participate in other reactions such as, for example, Aldol condensation reactions. These other reactions are problematic because they reduce the yield of the desired product and often form by-products that substantially increase the difficulty of isolating the desired product in high purity. [0004] One of the most important Friedel-Crafts acylations in pharmaceutical manufacturing.is the acetylation of isobutylbenzene (IBB) to produce para-isobutyl acetophenone (p-IBAP), which is a key intermediate in one process for the manufacture of ibuprofen, see Scheme 1.

SCHEME-I

Acetylation

Figure imgf000003_0002
Figure imgf000003_0001

IBB IBAP

Reduction

Figure imgf000003_0003

Ibuprofen [0005] Ibuprofen is the active ingredient in Motrin® and Nuprin® and is probably the most widely used non-steroidal anti-inflarnmatory drug other than aspirin. Methods for acetylating IBB in high yield while minimizing by-product formation are therefore needed. The present invention provides such methods and the methods can be applied to other

alkylbenzenes with similar results.

[0006] Several methods for producing p-IBAP and converting it into ibuprofen have been described. For example, U.S. Patent No. 4,981,995 describes the acetylation of EBB with excess acetic anhydride using anhydrous HF as the catalyst at a temperature of 800C. After work-up, GC analysis showed 85% conversion of p-IBB and only 81% selectivity for the desired p-IBAP isomer. IBAP was then isolated and converted to ibuprofen by reduction of the carbonyl of p-IBAP to an alcohol followed by carbonylation with a palladium catalyst and carbon monoxide under a variety of conditions.

[0007] Commonly, Friedel-Crafts acylation reactions are run at or above room temperature. However, there are examples wherein the reaction proceeds at lower temperatures. For example, according to U.S. Patent No. 4,981,995, the reaction is typically run at 0°C to 120°C for 0.5 to 5 hours. Further, Baddely, et al., J. Chem. Soc. 1956, 4943-45, reports preparation of p-IBAP via Friedel-Crafts acylation of IBB with acetyl chloride using aluminum chloride, and Japanese Patent Publication No. 60 188,643 (1985) discloses the same transformation with acetyl fluoride and HF or HF-BF3 as the catalyst.

BRIEF SUMMARY OF THE INVENTION

[0008] The present invention provides novel methods for the Friedel-Crafts acylation of alkylbenzenes to yield para-acylated mono-alkylbenzenes as well as other acylated alkylbenzenes. The novel reaction conditions disclosed herein include operating the reaction at a temperature below 00C and typically below -1O0C. Additionally, the alkylbenzene may be used in slight excess relative to the acylating agent and Friedel-Crafts catalyst, and the reaction can be run with excess alkylbenzene acting as the reaction solvent or as a part of the reaction solvent system. The methods of the invention are especially useful for the preparation of an intermediate used for making ibuprofen.

[0009] Thus in one aspect, the invention provides a method for making acylated alkylbenzene compounds by acylation of an allcylbenzene, where the acylation reaction is conducted at a temperature below 0°C. The reaction temperature may be even lower, say such as below -100C or below -15°C. The reaction can also be conducted at lower temperatures still, say such as below -200C, below -300C, or below -400C and at temperatures as low as about -75°C.

[0010] The reaction conditions lead to preparation of the para isomer in high selectivity relative to other isomers. In some embodiments, where the alkylbenzene is a mono-substituted benzene such as toluene or isobutylbenene, the ratio of para isomer to the total of ortho and meta isomers combined is at least about 50:1. Ih other embodiments, the ratio is at least about 80: 1 or higher, for example at -75°C, the ratio is about 350:1.

[0011] The acylating agent maybe an acyl chloride, acyl fluoride, acyl bromide, or acyl anhydride, e.g., acetyl chloride, acetyl fluoride, acetyl bromide, or acetic anhydride. In one embodiment, the alkylbenzene is isobutyl benzene (IBB) and the acylating agent is acetyl chloride.

[0012] The acylation catalyst may be a metal salt, preferably AlCl3, FeCl3, or AlBr3, but it may be selected from the group consisting of A1C13, BF3, HF, FeCl3, GaCl3, SbCl5, ZnCl2, ZnBr2, SnCl4, AlBr3, FeBr3, and GaBr3. In one embodiment, the acylating agent is acetylchlori.de and the acylation catalyst is aluminum trichloride.

[0013] A non-alkylbenzene solvent or excess alkylbenzene may be employed as the reaction solvent. Suitable non-alkylbenzene solvents include polyhalogenated alkanes such as dichloromethane, dichloroethane or chloroform, or a relatively electron-deficient aromatic solvent such as chlorobenzene or nitrobenzene. When excess alkylbenzene is being used as the solvent and the alkylbenzene is isobutylbenzene, the acylation may be conducted with a 10-20% molar excess of the alkylbenzene as the reaction solvent, or with a 10-60% molar excess of the alkylbenzene as the reaction solvent, or with 1-2 molar equivalents of the alkylbenzene as the reaction solvent relative to the acylating agent used. Both non- alkylbenzene solvents and excess alkylbenzene can be used in combination. No matter the solvent system selected, the solvent system obtains a liquid reaction mass and essentially inert in the reaction mass.

[0014] As mentioned above, the invention provides a particularly useful method to produce para-isobutyl acetophenone (p-EBAP) from isobutyl benzene. In a preferred embodiment, isobutylbenzene is acylated with acetyl chloride in the presence of an aluminum chloride catalyst. The reaction may be conducted at a temperature of — 10°C or below, say at -15°C, -200C, or -300C or lower. These conditions provide good para-isomer selectivity, say at least about 50:1 relative to the total amount of ortho and meta acylated products and preferably at least about .80:1.

[0015] Another aspect of the invention provides an improved process for the synthesis of ibuprofen that includes an acylation according to the methods described above. In this instance, the product of the foregoing acylation is a ketone, which is subsequently reduced. More specifically, the acylation produces p-IBAP, which is subsequently partially reduced to provide an alcohol or fully reduced to a methylene. Ih the production of ibuprofen, the reduction produces an aryl alcohol, and the aryl alcohol is carbonylated to the final product (ibuprofen). The carbonylation may be performed by methods such as those using carbon monoxide and palladium catalysts as described in U.S. Patent No. 4,981,995, the disclosure of which is incorporated herein by reference. Alternatively, the aryl alcohol may be dehydrated to an olefin, which is similarly carbonylated with carbon monoxide and a

palladium catalyst to produce ibuprofen.

DETAILED DESCRIPTION OF THE INVENTION

[0016] As stated above, Friedel-Crafts acylation of alkylbenzene compounds can be accomplished at temperatures below room temperature, such as below 00C, below -10°C, below — 15°C, and even at lower teiiipoiatuics such as —30°C iu about — 75°C. By appropriate selection of the acylating agent and the electrophilic catalyst used, as well as the solvent and concentration, such acylation reactions have been shown to give high yields and especially good selectivity for para-acylated products without forming significant quantities of other isomers. Such conditions also reduce the occurrence of undesired side reactions, such as the Aldol reactions mentioned above.

[0017] The surprising discoveries of the present method are the higher yield and significant improvement in purity of the downstream products made from the acylated alkylbenzenes produced by the low temperature acylation process. For example, when this process is used to make p-IBAP, the yield of p-IBAP is about 10 percent higher than that obtained by the process of incorporated U.S. Patent No. 4,981,995 and about 5 percent higher than that obtained by a process runs at 5°C - 100C. More importantly, the product obtained by the low temperature acylation process of this invention is highly pure. It is well-known in the art that when p-IBAP of high purity (>98%) is used to make ibuprofen, the isolation and purification of the final product are greatly simplified. In general, when the acylation reaction or conditions described herein are used to make an intermediate, the improved acylation conditions provide an unexpected simplification of the overall process, because the acylation conditions of this invention substantially reduce the formation, of certain side products, such as, isomeric acylated alkylbenzenes, which are difficult to remove. Because of the improved process of this invention, the final product is produced with fewer purification steps, likely reducing the cost of manufacturing the final product as well as the volume and disposal costs of associated waste streams.

[0018] Generally, the alkylbenzenes suitable for the process of the invention are Ci _ C4 linear or branch allcyl or alkoxy mono-substituted benzene such as toluene, isobutylbenzene, n-butyl benzene, and anisole.

[0019] The acylating agent suitable of the process of the invention is typically an acyl halide or an acyl anhydride, e.g., acetyl fluoride, acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, benzoyl chloride, benzoyl bromide, acetic anhydride, propionic anhydride and benzoic anhydride.

[0020] The catalyst used with the invention generally is electrophilic, and commonly is a metal salt. Exemplary metal salts include, but are not limited to, AlCl3, FeCl3, GaCl3, SbCIs, ZnCl2, ZnBr2, SnCl4, AlBr3, FeBr3, and GaBr3. Other electrophilic compounds, such as HF or BF3 may also be used. In one embodiment of the present invention, the catalyst is aluminum chloride or ferric chloride. In another embodiment, the catalyst is aluminum tribromide. Typically, when the acylating agent is acetyl chloride, aluminum chloride is used as the catalyst. When the catalyst is a metal salt, the amount of catalyst used is equal to the amount of acylating agent used, though a molar excess of 10% to 20% of either the acylating agent or catalyst relative to the other can be used without significantly affecting the outcome of the reaction. When other catalysts such as HF or BF3 are used, the catalyst may be in excess relative to the acylating agent and the molar quantity of the catalyst optionally exceed the molar quantity of the alkylbenzene.

[0021] Unlike most known methods for making acylated alkylbenzenes, the present conditions do not use an excess of the acylating agent relative to the amount of alkylbenzene. Instead, at least one equivalent of alkylbenzene per equivalent of acylating agent is used and typically at least a 10% molar excess of alkylbenzene is used in the methods of the present invention. Excess amounts of alkylbenzene up to about 80% molar excess are suitable.

[0022] The excess alkylbenzene can serve as the solvent for the reaction, or the reaction may be run with only one molar equivalent or a small excess of alkylbenzene plus another non-alkylbenzene solvent. Typically, the reaction is run without non-alkylbenzene solvent. The reaction is run at -10 to -300C and it is often run with 1.1 - 1.6 or 1.1 - 2.0 moles of alkylbenzene per mole of acylating agent. For the acylation of IBB to make p- IBAP, for example, the reaction is commonly run with a 10% to 60% molar excess of IBB relative to the acylating agent. When the reaction temperature is below about -300C, the non-alkylbenzene solvent may facilitate mixing and maintaining the desired temperature throughout the reaction mass, which is usually a suspension. Other solvents, which may be used as the non-alkylbenzene solvent, include chloroform, dichloroethane, chlorobenzene, nitrobenzene, and the like. Mixtures of these solvents may also be employed.

[0023] Because an excess of the acylating agent is not used, the reaction typically leaves at least some unreacted alkylbenzene, which is conveniently separated from the product by distillation, or it may be carried forward through at least one additional step in the process without interfering significantly with subsequent reactions. Typically, the alkylbenzene is a liquid that will not participate in subsequent reactions, and, for example, it can conveniently be removed when a solid intermediate or final product is prepared.

[0024] The order of mixing of the reactants for the acylation reaction is not important, as long as the reaction temperature is appropriately maintained. Thus the acylating agent and catalyst can be premixed and added to me alkylbenzene; or the alkylbenzene and the acylating reagent can be mixed, and the catalyst added slowly; or the alkylbenzene and catalyst can be mixed and the acylating agent added last. When the acylating agent and catalyst are pre-mixed, it is sometimes preferable to add a solvent to them and to mix them at a temperature of about 00C or lower. Appropriate solvents for this purpose include those specified as optional solvents for the acylation reaction itself.

[0025] The invention provides an improved process for the synthesis of ibuprofen that includes an acylation according to the methods described above. For example, when the acylation produces p-IBAP, the p-IBAP may be partially reduced to provide an alcohol, and then the alcohol can be carbonylated to produce ibuprofen. Ih one such example, the p-IBAP is reduced to an aryl alcohol, and the aryl alcohol is carbonylated to produce ibuprofen. The carbonylation may be achieved by methods such as those using CO and palladium catalysts as described in incorporated U.S. Patent No. 4,981,995. Alternatively, the aryl alcohol is dehydrated to an olefin, which is similarly carbonylated with CO and a palladium catalyst to produce ibuprofen.

[0026] The terms "optional" and "optionally" denote that the step or component following the term may, but need not be, a part of the process.

[0027] The following examples illustrate selected embodiments of the invention and are intended in no way as limitations upon its scope.

EXAMPLES

[0028] Comparative Example 1 illustrates the acylation reaction run at a temperature within the range disclosed in U.S. Patent No. 4,981,995 for comparison. The remaining examples illustrate the improvements provided by certain aspects and embodiments of the present invention.

Example 1 (Comparative)

[0029] A 3-necked flask was charged with 40.8 g (0.3 mol) of isobutyl benzene (IBB) and stirred at 5°C. Acetyl chloride (16.1 g, 0.21 mol) and anhydrous aluminum chloride (26.5 g, 0.20 mol) were combined in an addition funnel and slowly added to the IBB; the temperature of the reaction was maintained between 5 and 10°C throughout the addition, which took about 1.5 hr. The mixture was stirred at 50C for one hour, and was then poured onto crushed ice with vigorous stirring. GC analysis of the organic phase, excluding the unreacted IBB, showed 90.0% p-EBAP and 2.1% m-IBAP and several higher boiling impurities (about 7%). The ratio of p-IBAP to m-IBAP is about 43:1.

Example 2

[0030] The reaction described in Example 1 was repeated, except the reaction temperature was maintained at -100C throughout the addition of the acetyl chloride- alumrnum trichloride mixture. GC analysis of the organic phase, excluding the unreacted IBB, showed 97.7% p-IBAP and 1.5% m-IBAP and substantially less of the high-boiling impurities (about 1%). The ratio of p-IBAP to m-IBAP is about 65:1.

Example 3

[0031] The reaction described in Example 1 was repeated, except the reaction temperature was maintained at -150C throughout the addition of the acetyl chloride- aluminum trichloride mixture. GC analysis of the organic phase, excluding the unreacted IBB, showed 98.5% p-IBAP and 1.2% m-IBAP and substantially less of the high-boiling impurities (about 0.3%). The ratio of p-IBAP to m-IBAP is about 82:1.

Example 4

[0032] The reaction described in Example 1 was repeated, except the reaction temperature was maintained at -45°C throughout the addition of the acetyl chloride- aluminum trichloride mixture. GC analysis of the organic phase, excluding the unreacted IBB, showed 99.1% p-IBAP and 0.6% m-IBAP and substantially less of the high-boiling impurities (about 0.3%). The ratio of p-IBAP to m-IBAP is about 165:1.

Example 5

[0033] A 3-necked flask was cooled at -35°C under an inert atmosphere. Acetyl chloride (16.1 g, 0.21 mol) and isobutyl benzene (IBB, 40.8 g, 0.3 mol) were added, and the mixture was mechanically stirred. Anhydrous aluminum chloride (26.5 g, 0.20 mol) was then

slowly fed in from an addition funnel over about 2 hours, while the reaction temperature was kept below -30°C. The mixture was stirred at -300C for another hour, and was then poured onto crushed ice with vigorous stirring. GC analysis of the organic phase from the reaction mixture, excluding the unreacted IBB, showed 98.8% p-IBAP and 0.8% m-IBAP and small amounts of the high-boiling impurities (about 0.4%). The ratio of p-IBAP to m-IBAP is about 124:1.

Example 6

[0034] A solution of equiniolar amounts of aluminum trichloride and acetyl chloride in dichloroniethane was prepared by combining the two reagents in dichloromethane and filtering to remove insoluble materials. An aliquot containing 50 mmol of each reagent in about 50 g of dichloromethane was then added dropwise to a solution of IBB (7.5 g, 56 mmol) in 20 g dichloromethane which had been cooled to -750C. The reaction mixture was kept between -70 and -75°C throughout the addition, and was then stirred at this temperature for an additional 2.5 hours. It was then poured over ice with vigorous stirring. GC analysis of the organic phase from the reaction mixture, excluding the unreacted IBB, showed 99.6% p-IBAP and 0.3% m-IBAP and trace amount of the high-boiling impurities (about 0.1%). The ratio of p-IBAP to m-EBAP is >300:l.

[0035] This invention is susceptible to considerable variation in its practice. Therefore the foregoing description is not intended to limit, and should not be construed as limiting, the invention to the particular examples presented hereinabove. Rather, what is intended to be covered is as set forth in the ensuring claims and the equivalents thereof permitted as a matter of law.

Claims

CLAIMS:
1. A process to prepare acylated alkylbenzene compounds and derivatives thereof comprising acylating an alkylbenzene with an acylating agent at a temperature below about 00C.
2. The process of claim 1, wherein said acylation occurs at a temperature below about -10°C.
3. The process of claim 1, wherein said acylation occurs at a temperature below about -15°C.
4. The process of claim 1, wherein said acylation occurs at a temperature in the range of from about -2O0C to about -75°C.
5. The process of claim 1, wherein molar ratio of said alkylbenzene to said acylating agent is between about 1.0 and about 2.0.
6. The process of claim 1, wherein said acylation produces para-, meta-, and optionally ortho- isomers of said acylated alkylbenzene, and wherein the molar ratio of said para-isomer to said meta- and ortho- isomers combined is at least about 50:1.
7. The process of claim 6, wherein said ratio of said para-isomer to said meta- and ortho- isomers combined is at least about 80:1.
8. The process of claim 1, wherein said acylating agent is selected from the group consisting of acetyl fluoride, acetyl chloride, acetyl bromide, and acetic anhydride.
9. The process of claim 1, wherein said alkylbenzene compound is isobutylbenzene.
10. The process of claim 1, wherein said acetylation occurs in the presence of an
electrophilic catalyst.
11. The process of claim 10, wherein said electrophilic catalyst is selected from the
group consisting OfAlCl3, BF3, HF5 FeCl3, GaCl3, SbCl5, ZnCl2, ZnBr2, SnCl4, AlBr3, FeBr3, and GaBr3.
12. The process of claim 11, wherein said acetylation occurs at a temperature below about -150C.
13. The process of claim 10, wherein said electrophilic catalyst is AlCl3 or FeCl3.
14. A process for the preparation of para-acylated alkybenzene and derivatives thereof comprising acylating an alkylbenzene with an acylating agent in the presence of an electrophilic catalyst at a temperature below about — 10°C.
15. The process of claim 14, wherein said acylating reagent is acetyl chloride.
16. The process of claim 15, wherein said alkylbenzene compound is isobutyl benzene and said acylated alkylbenzene is para-isobutyl acetophenone.
17. The process of claim 16, wherein said electrophilic catalyst is aluminum chloride.
18. The process of claim 16, wherein said acylation occurs at a temperature below about -15°C.
19. The process of claim 14, wherein said acylation is conducted in dichloromethane.
20. The process of claim 18, wherein molar ratio of said isobutylbenzene to said acetyl chloride is between about 1:1 and about 2:1.
21. The process of claim 18, wherein said acylation produces meta-acylated alkylbenzene and optionally ortho-acylated alkylbenzene, wherein the molar ratio of said para-acylated alkylbenzene to said meta-acylated alkylbenzene and ortho-acylated alkylbenzene combined is at least about 50:1.
22. The process of claim 21 , wherein said ratio of said para-acylated alkylbenzene to said meta-acylated alkylbenzene and said ortho-acylated alkylbenzene combined is at least about 80:1.
23. A process for the preparation of para-isobutylacetophenone and derivatives thereof comprising acylating isobutylbenzene with an acylating agent in the presence of an electrophilic catalyst at a temperature below about -15°C.
24. The process of claim 23, wherein molar ratio of said isobutylbenzene to said acylating agent is between about 1:1 to about 2:1.
25. The process of claim 24, wherein said acylating agent is acetyl chloride.
26. The process of claim 25, wherein said electrophilic catalyst is aluminum chloride.
27. The process of claim 26, wherein said acylation produces meta-acylated alkylbenzene and optionally ortho-acylated alkylbenzene, wherein the molar ratio of said para-acylated alkylbenzene to said meta-acylated alkylbenzene and ortho-acylated alkylbenzene combined is at least about 80:1.
28. A reaction product comprising para-, meta-, and optionally ortho- isomers of acylated alkylbenzene wherein the molar ratio of said para- isomer to said meta- and ortho- isomers combined is at least about 50:1.
29. The reaction product of claim 28 wherein the molar ratio of said para- isomer to said meta- and ortho- isomers combined is at least about 80:1
30. The reaction product of claim 28 wherein the para-, meta- and optionally ortho- isomers are isomers of isobutyl acetophenone.
PCT/US2006/038286 2005-10-06 2006-10-02 Process for producing high purity ketones by friedel-crafts acylation at low temperature WO2007044270A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US72459105 true 2005-10-06 2005-10-06
US60/724,591 2005-10-06

Publications (1)

Publication Number Publication Date
WO2007044270A1 true true WO2007044270A1 (en) 2007-04-19

Family

ID=35999452

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/038286 WO2007044270A1 (en) 2005-10-06 2006-10-02 Process for producing high purity ketones by friedel-crafts acylation at low temperature

Country Status (1)

Country Link
WO (1) WO2007044270A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102531869A (en) * 2011-11-25 2012-07-04 常州大学 Preparation process of p-alkylacetophenone
CN106674021A (en) * 2015-11-05 2017-05-17 联化科技(盐城)有限公司 Method for preparing substituted aniline

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4981995A (en) * 1987-03-20 1991-01-01 Varadaraj Elango Method for producing ibuprofen
EP0488638A1 (en) * 1990-11-27 1992-06-03 Hoechst Celanese Corporation BF3 catalyzed acetylation of butylbenzene
WO2005037758A1 (en) * 2003-10-13 2005-04-28 Applied Research Systems Ars Holding N.V. Method for preparing para-phenyl alkynyl benzaldehydes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4981995A (en) * 1987-03-20 1991-01-01 Varadaraj Elango Method for producing ibuprofen
EP0488638A1 (en) * 1990-11-27 1992-06-03 Hoechst Celanese Corporation BF3 catalyzed acetylation of butylbenzene
WO2005037758A1 (en) * 2003-10-13 2005-04-28 Applied Research Systems Ars Holding N.V. Method for preparing para-phenyl alkynyl benzaldehydes

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
G. F. HENNION ET AL.: "Friedel-Crafts Acylations of Some Sterically Hindered Alkylbenzenes" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 64, 1942, pages 2421-2422, XP002373070 AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC., US *
JAE-CHUL JUNG ET AL.: "Synthesis and antitumor activity of 4-hydroxycoumarin derivatives" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, 2004, pages 5527-5531, XP002421077 GBOXFORD *
KAZUCHIKA OHTA ET AL.: "Multiple Melting Behaviour in Square-planar trans-Bis-(1-p-n-alkylphenylbutane-1,3-dio nato)-copper(II) - The Effect of the Chain Length" MOLECULAR CRYSTALS AND LIQUID CRYSTALS., vol. 66, 1981, pages 283-294, XP008061819 GBGORDON AND BREACH, LONDON. *
KAZUCHIKA OHTA ET AL.: "Square-planar trans-Bis-(1-p-n-octylphenylbutane-1,3-dio nato)-copper(II)" MOLECULAR CRYSTALS AND LIQUID CRYSTALS., vol. 69, 1981, pages 131-142, XP008061854 GBGORDON AND BREACH, LONDON. *
KOZO SAWADA ET AL.: "4-(Benzoylindolizinyl)butyric Acids; Novel Nonsteroidal Inhibitors of Steroid 5.alpha.-Reductase. III." CHEMICAL AND PHARMACEUTICAL BULLETIN., vol. 49, no. 7, 2001, pages 799-813, XP002373068 PHARMACEUTICAL SOCIETY OF JAPAN. TOKYO., JP *
S. M. S. CHAUHAN ET AL.: "Biomimetic Oxidation of Ibuprofen with Hydrogen Peroxide" BIOORGANIC & MEDICINAL CHEMISTRY., vol. 7, 1999, pages 2629-2634, XP002373067 GBELSEVIER SCIENCE LTD. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102531869A (en) * 2011-11-25 2012-07-04 常州大学 Preparation process of p-alkylacetophenone
CN106674021A (en) * 2015-11-05 2017-05-17 联化科技(盐城)有限公司 Method for preparing substituted aniline

Similar Documents

Publication Publication Date Title
Heck Acylation, methylation, and carboxyalkylation of olefins by Group VIII metal derivatives
Gaspard‐Iloughmane et al. Bismuth (III) triflate in organic synthesis
Berk et al. General approach to highly functionalized benzylic organometallics of zinc and copper
Raston et al. Chemoselective, solvent-free aldol condensation reaction
Birch et al. The preparation of the C10 monocyclic aromatic hydrocarbons
Olah et al. Friedel—Crafts Isomerization. X. 1a Aluminum Chloride Catalyzed Isomerization of the Di-t-butylbenzenes
US4960943A (en) Process for the preparation of phenylketones etherified in the 4-position
EP0178184A1 (en) Preparation of aromatic carbonyl compounds
US2851501A (en) Production of poly alkyl indanes from styrene compounds
US5254776A (en) Synthesis of bromobiphenyls
Lotspeich Reaction of potassium cyanide with p-phenylsulfonylbenzyl bromide
EP0084742A1 (en) Process for the acylation of halogen or trihalogen methyl benzenes
US5360936A (en) Process for the preparation of substituted indanones
US4622429A (en) Process for the preparation of substituted benzaldehydes
US3994968A (en) 2-(5'-Halo-6'-methoxynaphth-2'-yl)-acrylic acid
Bonnet-Delpon et al. . alpha.-Trifluoromethyl-destabilized cations. A route to 1-(trifluoromethyl) tetralins by trifluoroacetolysis of 5-aryl-1, 1, 1-trifluoropentan-2-ols and derivatives
WO1997000850A1 (en) Process for producing 2-(halomethyl)phenylacetic acid esters
US4877915A (en) Process for preparing polyalkyl tetrahydronaphthalenes
US5243088A (en) 1-monodebromination of dibromonaphthalene compounds
JP2003119175A (en) Tert-amyloxyhalogenobenzene compound, method for producing the same, tert-amyloxycyanobiphenyl compound, method for producing the same and method for producing cyanohydroxybiphenyl compound
EP0126569A1 (en) Bromination process for preparing decabromodiphenyl ether from diphenyl ether
US4877916A (en) Process for preparing polyalkyl tetrahydronaphthalenes
Choi et al. Thermodynamically-and kinetically-controlled Friedel–Crafts alkenylation of arenes with alkynes using an acidic fluoroantimonate (V) ionic liquid as catalyst
WO1996032373A1 (en) METHOD OF PREPARING ESSENTIALLY PURE ISOMERS OF α-BIS-OXIMES
US4453012A (en) Process for the preparation of phenyl ketones

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct app. not ent. europ. phase

Ref document number: 06825297

Country of ref document: EP

Kind code of ref document: A1