JP2001278833A - Method of preparing 4'-isobutyl acetophenone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of producing 4'-isobutyl-acetophenone from isobutylbenezene. SOLUTION: In the presence of a zeolite-β catalyst, isobutyl-benzene is allowed to react with acetic anhydride as an acylating agent at 60-165 deg.C for 2-12 hours, then the catalyst is separated from the reaction mixture by filtration and the objective product, 4'-isobutyl acetophenone, is collected through the conventional process.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 4'-isobutylacetophenone (4-IBAP) by Friedel-Crafts acylation of isobutylbenzene. More specifically, the invention uses acetic anhydride as an acylating agent in the presence of nanocrystalline, microcrystalline and
-Isobutylacetophenone (4-IBAP).

[0002]

2. Description of the Related Art 4'-isobutylacetophenone (4-IBAP)
Is 2- (4-isobutylphenyl) propionic acid (trade name:
Ibuprofen), a well-known non-steroidal anti-inflammatory drug, antipyretic, analgesic and an important intermediate for other pharmaceutical uses.

The present invention specifically eliminates the use of stoichiometric amounts of corrosive toxic aluminum chloride and hydrogen fluoride as Friedel-Crafts reactants, uses acetic anhydride as the acylating agent, and uses zeolite β as the catalyst. Use isobutylbenzene to convert 4'-isobutylacetophenone (4-IBA
It relates to an environmentally convenient method for preparing P).

A publication by Baddley et al., Journal of Che
Referring to Mical Society, 1956, 4943, 4'-isobutylacetophenone is prepared by Friedel-Crafts acetylation of isobutylbenzene and acetyl chloride using aluminum chloride as a catalyst.
Referring to U.S. Pat.No. 3,385,886, the first step in the process, ibuprofen, is produced by Friedel-Crafts acetylation of isobutylbenzene and acetyl chloride in the presence of aluminum chloride.
Preparation of 4'-isobutylacetophenone.
The disadvantages of all of the above methods are the use of stoichiometric amounts of anhydrous aluminum chloride, a harmful material that leaves a large amount of solid waste after the reaction, and a lengthy separation step from the alumina gel to obtain the product. is there.

[0005] With reference to Japanese Patent Publication No. 60 (1985) -188,343 (prior disclosure), 4'-isobutylacetophenone was prepared by reacting acetic anhydride with hydrogen fluoride as a catalyst. It is prepared by acetylating isobutylbenzene using a combination of hydrogen and boron trifluoride, using acetyl fluoride as an acetylating agent. Reference is made to U.S. Pat. You. 4'-isobutylacetophenone is an intermediate in the process for producing ibuprofen. Disadvantages of the above process are that hydrogen fluoride is extremely toxic and corrosive, generates a large amount of solid waste after the reaction, and requires industrially expensive equipment to work with hydrofluoric acid. And

There are inherent deficiencies when using conventional Lewis acid metal chlorides for Friedel-Crafts acylation, because they are non-renewable and complex with the carbonyl product formed. It requires more than stoichiometric amounts. The work of hydrolyzing the resulting intermediate complex results in the formation of large amounts of waste products, which are time-consuming and expensive to separate.

It is clear that various methods have been used for the preparation of 4'-isobutylacetophenone. Therefore, there is a need for a method of preparing 4'-isobutylacetophenone that is simple to operate and can be performed in non-toxic and non-corrosive media. Furthermore, the catalyst should be easy to separate and reusable.

[0008]

SUMMARY OF THE INVENTION The main object of the present invention is to:
A method for preparing 4′-isobutylacetophenone from isobutylbenzene, which is carried out in the presence of nanocrystalline, microcrystalline and metal-exchanged zeolite β catalyst at a temperature range of 60-165 ° C. for 2-12 hours Reacting isobutylbenzene with acetic anhydride as an acylating agent, separating the catalyst from the reaction mixture by filtration, recovering the product by conventional methods, and obviating the disadvantages detailed above. Become.

Another object of the present invention is to use as catalysts nanocrystalline zeolite beta and microcrystalline zeolite beta and metal-exchanged nanocrystalline zeolite beta and microcrystalline zeolite beta.

It is a further object of the present invention that the metal ions selected for the exchange of nanocrystalline and microcrystalline zeolite β are Fe ³⁺ , Zn ²⁺ , Ce ³⁺ and La ²⁺ That is.

Yet another object of the present invention is to use acetic anhydride as the acylating agent.

Still another object of the present invention is to use isobutylbenzene as a reaction solvent.

Yet another object of the present invention is that the ratio of isobutylbenzene to the acylating agent is from 5: 1 to 1: 5.

It is a further object of the present invention that the amount of catalyst is from 10 to 50% by weight, based on the acylating agent, acetic anhydride.

It is a further object of the present invention that the reaction
At a temperature in the range of 2 ° C for 2-24 hours.

[0016]

SUMMARY OF THE INVENTION The novelty of the present invention is the first use of nanocrystalline and microcrystalline and metal-exchanged nanocrystalline and microcrystalline zeolite beta for the acylation of isobutylbenzene. It is in. Reducing the particle size of zeolite β increases the density of acidic sites and the surface area of zeolite, which are essential factors for enhancing the activity of the acylation reaction.
In fact, the activity of these nanocrystalline and microcrystalline forms increases several times over conventional zeolites. As a result of this, the acylation of isobutylbenzene is successfully performed for the first time in considerable yield. 4'-isobutylacetophenone is obtained in a simple manner, including filtering the catalyst from the reaction mixture and recovering the product in a conventional manner.

[0017]

Accordingly, the present invention provides a process for preparing 4'-isobutylacetophenone, an important intermediate of the widely used non-steroidal anti-inflammatory drug ibuprofen, wherein said process comprises Reaction of isobutylbenzene with acetic anhydride as an acylating agent in the presence of crystalline, microcrystalline and transmetalated zeolite β catalyst in the temperature range of 60-165 ° C for 2-12 hours, Separating the catalyst from the mixture by filtration and recovering the product by conventional methods.

In an embodiment of the invention, metal-exchanged nanocrystalline and microcrystalline zeolite β are used as catalyst.

In an embodiment of the present invention, the nanocrystalline and microcrystalline zeolite β has a particle size of 10 nm to 100 nm.
And from 1 μm to 50 μm.

In another embodiment of the invention, the metal ions selected for the exchange of nanocrystalline and microcrystalline zeolite β are Fe ³⁺ , Zn ²⁺ , Ce ³⁺ and La ²⁺ .

In yet another embodiment of the present invention, acetic anhydride is used as the acylating agent. In yet another embodiment of the present invention, the reaction is carried out in a temperature range of 60-165 ° C for 2-24 hours.

In yet another embodiment of the present invention, the catalyst is separated from the reaction mixture by filtration.

Scientific Explanation: In nanocrystalline and microcrystalline zeolite β, the density of acidic sites is increased by breaking the aluminum silicate rings and increasing the number of broken ends. The surface area of these particles also increases with decreasing zeolite particle size. Increasing the density of acidic sites results in an increase in the number of acyl cations generated in the Friedel-Crafts acylation electrophilic substitution reaction, thus enhancing the activity of the reaction. Thus, nanocrystalline, microcrystalline, metal-exchanged zeolite β
For the first time, the increase in the density of acidic sites present in Friedel-Crafts acylation of isobutylbenzene will occur.

The nanocrystalline, microcrystalline, and transmetallic zeolite β was prepared as described in Example 1 and the isobutylbenzene was acylated using acetic anhydride as the acylating agent as described in the example. Used when

The following examples are intended to illustrate the invention, but not to limit the scope of the invention.

[0026]

EXAMPLES Example 1 Preparation of the Catalyst a) The appropriate molar ratios of tetraethyl orthosilicate and aluminum nitrate were used to achieve the desired zeolite β Si / Al ratio in the range of 5 to 100. . Water is added to tetraethyl orthosilicate and stirred. To this solution, a tetraethylammonium hydroxide solution of aluminum nitrate and nonahydrate is added dropwise with a pressure control funnel while stirring. After addition, the solution is brought to 50 ° C
And then keep at 135 ° C. for 1 week in an autoclave for crystallization. The solid was then filtered and air dried. The obtained solid was calcined at 500 ° C. b) Microcrystalline zeolite β-I Microcrystalline zeolite β-I was obtained by mechanical decomposition of the obtained zeolite β as described above (1 μm-10 μm, 95%). c) Microcrystalline zeolite β-II Microcrystalline zeolite β has various particle sizes (5 μm to 50 μm) by reducing the aging time during the synthesis of zeolite β by the above method to 48 hours instead of one week.
m, 85%). d) Nanocrystalline zeolite β Nanocrystalline zeolite β can be obtained from the homogenized solution prepared in the first step of zeolite β in various particle sizes (from 10 nm to 10 nm).
0 nm), but zeolite β continues to crystallize at various times by reducing the aging time to control the nucleation and growth of the zeolite during synthesis. Next, the solid was separated by centrifugation, and the obtained solid was washed with distilled water and dried at 100 ° C. e) Metal-exchanged zeolite β Synthesized 10 g of zeolite β or microcrystalline zeolite β of Si / Al = 15 has a metal chloride content of 1 wt% to 10 wt% (Ce ³⁺ , Fe ³⁺ , Zn ²⁺ and La ²⁺ ) solution was subjected to an ion exchange step by stirring at 80 ° C. for 6 hours. The resulting zeolite is washed with deionized water and 12
Dried at 0 ° C. Thereafter, the metal-exchanged zeolite was calcined at 500 ° C. for 6 hours. f) H ⁺ exchanged zeolite β Zeolite β is a 1 molar NH ₄ Cl solution (10 ml / g zeolite)
And stirred at 60 ° C. for 6 hours, the resulting solid was washed with deionized water and dried at 120 ° C. Thereafter, the ammonium-exchanged zeolite is calcined at 500 ° C.
^{+ An} exchanged zeolite β was obtained.

Example 2 Isobutylbenzene (40 mmo)
l), acetic anhydride (10 mmol) and zeolite β catalyst (0.5 g)
Was placed in a round bottom flask (50 ml) and stirred at a temperature of 130 ° C. under a nitrogen atmosphere. After completion of the reaction (after gas chromatography), the reaction mixture was filtered and the reaction mixture was distilled to obtain crude product. Yield: 0.11 g.

Example 3 Isobutylbenzene (1.5 mol
l), a mixture of acetic anhydride (0.375 mol) and microcrystalline zeolite β-I catalyst (20 g) were stirred at 130 ° C. under a nitrogen atmosphere in a round bottom flask (1 liter). After completion of the reaction (after gas chromatography), the reaction mixture was filtered and the reaction mixture was distilled to obtain crude product. Yield: 13.4
g.

Example 4 Isobutylbenzene (40 mmo)
l), a mixture of acetic anhydride (10 mmol) and microcrystalline zeolite β-II catalyst (0.5 g) were placed in a round bottom flask (50 ml) and stirred at 130 ° C. under a nitrogen atmosphere. After the reaction is completed (after gas chromatography), the reaction mixture is filtered and the reaction mixture is distilled to obtain a crude product. Yield: 0.42
g.

Example 5 Isobutylbenzene (40 mmo)
l), acetic anhydride (10 mmol) and H ⁺ -exchanged microcrystalline zeolite β-I catalyst (0.5 g) were placed in a round bottom flask (50 ml) and stirred at 130 ° C. under a nitrogen atmosphere.
After the reaction is completed (after gas chromatography), the reaction mixture is filtered and the reaction mixture is distilled to obtain a crude product. Yield: 0.36g.

Example 6 Isobutylbenzene (40 mmo)
l), a mixture of acetic anhydride (10 mmol) and Fe ^{3+ -exchanged} zeolite β catalyst (0.5 g) were placed in a round bottom flask (50 ml) and stirred at 130 ° C. under a nitrogen atmosphere. After the reaction is completed (after gas chromatography), the reaction mixture is filtered and the reaction mixture is distilled to obtain a crude product. Yield: 0.21
g.

Example 7 Isobutylbenzene (40 mmo)
l), a mixture of acetic anhydride (10 mmol) and La ^{3+ -exchanged} zeolite β catalyst (0.5 g) were placed in a round bottom flask (50 ml) and stirred at 130 ° C. under a nitrogen atmosphere. After the reaction is completed (after gas chromatography), the reaction mixture is filtered and the reaction mixture is distilled to obtain a crude product. Yield: 0.26
g.

Example 8 Isobutylbenzene (40 mmol),
A mixture of acetic anhydride (10 mmol) and Ce ^{3+ -exchanged} microcrystalline zeolite β-II catalyst (0.5 g) was placed in a round bottom flask (50 ml) and stirred at 130 ° C. under a nitrogen atmosphere.
After the reaction is completed (after gas chromatography), the reaction mixture is filtered and the reaction mixture is distilled to obtain a crude product. Yield: 0.52 g.

[0034]

[Table 1]

The main advantages of the present invention are: 1. A new and environmentally friendly method for preparing 4'-isobutylacetophenone. 2. The method of the present invention eliminates the use of corrosive and stoichiometric amounts of aluminum chloride. 3. Nanocrystalline, microcrystalline and metal-exchanged zeolite β were used for the first time as catalysts for the acylation of isobutylbenzene. 4. The work process is simple. 5. The method of the present invention has no disposal problems because the catalyst can be used in multiple cycles. The catalyst showed consistent activity for up to 4 degrees of recycling. 6. The method of the present invention is environmentally safe because there are no disposal problems. 7. This method is economical.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Mutiyara Satish India, A. P. , Hyderabad 500 007, Indian Institute of Chemical Technology (72) Inventor Manepari Laximi Quantum India, A. P. , Hyderabad 500007, Indian Institute of Chemical Technology (72) Inventor Kururi Venkata Sri Langanas India, A. P. , Hyderabad 500 007, Indian Institute of Chemical Technology (72) Inventor Kondaplum Vijaya Raghabang India, A. P. , Hyderabad 500 007, Indian Institute of Chemical Technology F-term (reference) 4H006 AA02 AC44 BA07 BA08 BA19 BA71 BA85 BB61 BC10 BC19 DA15 DA30 DA35 4H039 CA62 CD10 CG90

Claims (6)

[Claims] 1. The reaction of isobutylbenzene with acetic anhydride as an acylating agent in the presence of zeolite β catalyst at a temperature range of 60-165 ° C. for 2-12 hours, and separation of the catalyst from the reaction mixture by filtration. And isolating the product from isobutylbenzene by recovering the product by a conventional method.
A method for preparing isobutyl acetophenone. 2. The method according to claim 1, wherein the zeolite β catalyst is selected from nanocrystalline, microcrystalline and metal-exchanged zeolite β. 3. The nanocrystalline and microcrystalline zeolite β has a particle size from 10 nm to 100 nm and from 1 μm to 5 nm.
The method according to claim 1, wherein the thickness is up to 0 μm. 4. The metal ion selected for exchange is C
2. The method according to claim 1, wherein e ³⁺ , Zn ²⁺ , Fe ³⁺ and La ²⁺ . 5. The method according to claim 1, wherein acetic anhydride is used as the acylating agent. 6. The method according to claim 1, wherein the reaction is carried out at a temperature in the range of 60-165 ° C. for 2-24 hours.