Process for the preparation of acyl heteroaromatic compounds from heteroaromatic compounds by metal ion exchanged clays

The present invention relates to a process for the preparation of the acyl heteroaromatic compounds useful as important intermediates for drugs, pharmaceuticals and flavouring agents, said process comprising reacting an heteroaromatic compound selected from furan, thiophene and pyrrole with a C2-C5 acid anhydride as an acylating agent employing metal ion exchanged clays as catalysts at temperatures in the range of 0-130.degree. C. for a period of 1-24 h, and separating the acyl heteroaromatic compound by a conventional method to obtain a product of high purity.

FIELD OF THE INVENTION
 The present invention relates to an improved process for the preparation of
 acyl heteroaromatic compounds from heteroaromatic compounds, important
 intermediates for drugs, pharmaceuticals and flavoring agents for
 foodstuffs. More particularly, this invention relates a process for the
 preparation of acyl heteroaromatic compounds of high purity from
 heteroaromatic compounds using C2-C5 acid anhydrides as acylating agents
 in the presence of metal exchanged clays.
 BACKGROUND OF THE INVENTION
 This invention particularly relates to an ecofriendly process for the
 preparation of acyl heteroaromatic compounds from heteroaromatic compounds
 using acid anhydrides as acylating agents and metal exchanged clays as
 catalysts dispensing the use of stoichiometric amounts of corrosive, toxic
 aluminium chloride and other Lewis and protic acids as Friedel-Crafts
 reagents. The acylated products are valuable intermediates for drugs,
 pharmaceuticals, flavours and fragrances.
 2-acetylthiophene is normally prepared by Friedel-Crafts acetylation of
 thiophene with acetic acid, acetyl chloride or acetic anhydride in the
 presence of a Lewis acid or a proton acid. The product is purified by
 distillation and it regularly contains from 1-2% of 3-acetyl thiophene as
 an impurity. For most purposes 2 -acetylthiophene of 98-99% is adequate.
 PRIOR ART REFERENCES
 Reference may be made to publication by Finan et al, Journal Chemical
 Society, 2728, 1963 Wherein 2-acylfuran derivatives are prepared from
 furans using BF.sub.3.Et.sub.2 O. The Drawbacks are BF.sub.3.Et.sub.2 O is
 expensive and difficult to handle.
 Reference may be made to a U.S. Pat. No. 4,266,066 wherein acylated
 compounds are prepared by reacting carboxylic acid halides, in particular
 carboxylic acid chlorides, with aluminium-alkyl compounds at a temperature
 between 20-100.degree. C. The reaction mixture is worked up in usual
 manner, suitably by decomposition with water followed by distillation. The
 draw-backs in the above processes are the use of stoichiometric amounts of
 aluminium compounds, an hazardous material that leaves large amount of
 solid wastes after the reaction and tedious separation process from the
 alumina get to obtain the product.
 Reference may be made to a German patent, Ger. Offen. DE3,618,964 and to a
 publication by Hoelderich et al., Studies in Surface Science and
 Catalysts, 49A,69, 1989, wherein a procedure for vapour phase acylation of
 heteroaromatics with acylating agents in the presence of zeolite catalysts
 is describes. The main drawbacks are the yields of the acyl
 heteroaromatics are poor, 23-41% and the vapor phase reaction requires
 more energies.
 Reference may be made to Kirk-Othmer, Encyclopedia of Chemical Technology,
 Vol 24, IVth edition, p38,1997, wherein acylation of thiophene is carried
 out with acid anhydrides in presence of phosphoric acid or other catalysts
 like AlCl.sub.2, SnCl.sub.4 ZnCl.sub.2 with acid chlorides. The draw back
 is all the reactions give between 0.5% and 2.0% of 3-isomer. There has
 been much striving to find catalyst systems that minimize the 3-isomer
 content attempting to meet the customers specification.
 Reference may be made to a U.S. Pat. No. 5,371,240 wherein
 3-acetylthiophene contaminating 2-acetylthiophene, is removed by a
 selective electrophilic substitution process, bromination, followed by
 fractional distillation. The drawback is an additional step, bromination
 is required to get the pure product.
 Reference may be made to a publication by Fripiat et al., Journal
 Catalysis, 182, 257, 1999 wherein the acylation of thiophene with butyryl
 chloride is been carried out in the presence of zeolites in quantitative
 yields in liquid phase. The draw back is synthetic zeolites are expensive.
 The inherent disadvantages in the use of conventional Lewis acid metal
 chlorides for Friedel-Crafts acylation are that they are non-regenerable
 and require more than stoichiometric amounts because of complexation with
 the carbonyl product formed. Work-up to decompose the resultant
 intermediate complex by hydrolysis forms a large amount of waste product
 and separation is lengthy and expensive.
 Obviously, different approaches have been employed for the preparation of
 acyl heteroaromatic compounds. There was therefore a need for a process
 for the preparation of acyl heteroaromatic compounds which is simple to
 operate and can be carried out in a media which are not toxic and/or
 corrosive. Moreover the catalyst should be simple to separate and
 reusable.
 OBJECTS OF THE INVENTION
 The main object of the present invention is to provide an improved process
 for the preparation of acylheteroaromatic compounds from heteroaromatic
 compounds selected from thiophene, furan and pyrrole using C2-C5 acid
 anhydrides as acylating agents in the presence of metal ion exchanged
 clays at a temperature in the range of 0 to 130.degree. C. for 1-24 h and
 separating the acyl heteroaromatic compound by a conventional method to
 obtain a product of high purity, which obviates the drawbacks as detailed
 above.
 Another object of the present invention is the use of the metal ion
 exchanged clays as catalysts, sourced from cheaper and natural clays.
 Another object of the present invention is metal ions selected for exchange
 are Fe.sup.3+,Zn.sup.2+,Cu.sup.2+,Al,.sup.3+ La.sup.3+
 Another object of the present invention is heteroaromtic compounds selected
 are thiophene, furan and pyrrole.
 Still another object of the present invention is quantity of catalyst used
 is 1 to 30% by weight with respect to the acylating agent.
 Still another object of the present invention is the use of C2-C5 acid
 anhydrides as acylating agents.
 Still another object of the present invention is the ratio of
 heteroaromatic compound and acylating agent is 5:1 to 1:5.
 Yet another object of the present invention is the reaction is effected at
 a temperature in the range of 0 to 130.degree. C. for 1-24 h.
 SUMMARY OF THE INVENTION
 The novelty of the present invention lies in the use of metal ion exchanged
 clays obtained easily by ion exchange process from naturally available
 montmorillonite and acid treated montmorillonite for the acylation of
 heteroaromatic compounds such as furan, thiophene, and pyrrole to afford
 2-acyl heteroaromatic compounds selectively &gt;99% in excellent yields for
 the first time. The 2-acyl heteroaromatic compounds thus obtained are
 devoid of the regioisomer, 3-acyl heteroaromatic compound usual
 contaminant in the acylation process employing soluble Lewis acids. Thus
 this invention offers highly pure and desired isomer to be used as an
 intermediate for specialised drugs and pharmaceuticals. Unlike soluble
 Lewis acids, the solid catalysts employed here does not produce any
 effluents. Since the catalyst is cheap and reusable for several times
 under mild reaction conditions, the process invented here is not only
 ecofriendly but also economically viable.

DETAILED DESCRIPTION OF THE INVENTION
 Accordingly, the present invention provides an improved process for the
 preparation of acyl heteroaromatic compounds, important intermediates for
 drugs, pharmaceuticals and flavouring agents wherein the said process
 comprises reacting an heteroaromatic compound selected from furan,
 thiophene and pyrrole with a C2-C5 acid anhydride as an acylating agent
 employing metal ion exchanged clays as catalysts at temperatures in the
 range of 0-130.degree. C. for a period of 1-24 h, and separating the acyl
 heteroaromatic compound by a conventional method to obtain a product of
 high purity.
 In an embodiment of the invention, the catalysts used are metal ion
 exchanged clays.
 In an embodiment of the invention, the catalysts used are the metal ion
 exchanged clays which are obtained easily from natural montmorillonites or
 acid treated montmorillonites.
 In an embodiment of the invention metal exchanged clays used are Fe.sup.3+,
 Zn.sup.2+, Cu.sup.2+, Al.sup.3+ La.sup.3+ exchanged clays.
 In an embodiment of the invention the metal ion exchanged clays are
 prepared from cheaper and naturally available clays.
 In an embodiment of the invention metal ions used for exchange are
 Fe.sup.3+, Zn.sup.2+, Cu.sup.2+, Al.sup.3+ La.sup.3+.
 In an embodiment of the invention, acylating agents used are selected from
 C2-C5 acid anhydrides, acetic anhydride to valeric anhydride.
 In another embodiment of the present invention, the reaction is,
 preferably, effected at a temperature in the range of 20 to 80.degree. C.
 for 2-12 hrs.
 In yet another embodiment of the present invention, the affords 2-acyl
 heteroaromatic compound selectively &gt;99% in excellent yield.
 In still another embodiment of the present invention, the 2-acyl
 heteraromatic compound obtained can be directly used without further
 purification to obtain specialised drugs and pharmaceuticals.
 One more embodiment of the present invention, the ratio of the
 heteroaromatic compound and acylating agent is 5:1 and the solvents
 selected for reaction are heteroaromatics and self solvents.
 SCIENTIFIC EXPLANATION
 The use of metal ion exchanged clays obtained easily by cation exchanged
 process from naturally available montmorillonite and acid treated
 montmorillonite for the acylation of heteroaromatic compounds such as
 furan, thiophene, and pyrrole afforded 2-acyl heteroaromatics selectively
 &gt;99% in excellent yields. Lewis acidity predominantly present in clays
 generates acyl cation electrophile effectively from acid anhydride, a
 prerequisite for Friedel-Crafts electrophilic substitution. The formation
 of 2-acyl heteroaromatic compound selectively is due to electronic effects
 favoured by strong Lewis acidity of the clay catalysts used here that
 generates facile electrophile. Unlike soluble Lewis acids, the solid
 catalysts employed here does not produce any effluents. Since the catalyst
 is cheap, reusable for several times under mild reaction conditions, the
 process invented here is not only ecofriendly but also economically
 viable.
 Metal ion exchanged clays are prepared as in example 1 and employed them in
 the acylation of heteroaromatic compounds with acid anhydrides as
 described in the examples.
 The following examples are given by way of illustration of the present
 invention and therefore should not be construed to limit the scope of the
 invention.
 EXAMPLE 1
 Catalyst Preparation
 a) K10 montmorillonite--Montmorillonite employed in the synthesis was
 obtained from (Fluka Grade K10) with exchange capacity of 8.0 equiv.
 b) Fe.sup.3+ -exchanged montmorillonite catalyst: To a 1 lt. stirred
 aqueous solution of FeCl.sub.3 (1.0M), 80 g of K10-montmorillonite was
 added. Stirring maintained for 16-30 hrs in order to saturate the exchange
 capacity of montmorillonite K10 . The clay suspension was centrifuged and
 the supernatant solution was discharged. The clay catalyst was filtered,
 and washed with distilled water and the washing cycles were repeated until
 disappearance of Cl.sup.- ions from the discarded water. The clay was
 dried overnight in an oven at 120.degree. C. and finely ground in a
 mortar.
 c) Zn.sup.2+ -exchanged catalyst: It was prepared in the same manner as in
 example b, stirring 1M solution of ZnCl.sub.2 and 80 g of K10
 montmorillonite.
 EXAMPLE 2
 A mixture of pyrrole (40 mmoles) acetic anhydride (10 mmoles) and Fe.sup.3+
 -exchanged clay catalyst (0.5 g) were stirred in a round bottomed flask
 (50 ml) under nitrogen atmosphere at room temperature. After completion of
 the reaction (followed by G.C. ), the mixture was filtered and distilled
 the reaction mixture to obtain the crude product. Yield: 0.9 g
 EXAMPLE 3
 A mixture of pyrrole (40 mmoles) acetic anhydride (10 mmole) and Fe.sup.3+
 -exchanged clay catalyst (0.5 g) were stirred in a round bottomed flask
 (50 ml) under nitrogen atmosphere at 80.degree. C. temperature. After
 completion of the reaction (followed by G.C.), the reaction mixture was
 filtered and distilled the reaction mixture to obtain the crude product.
 Yield: 1.0 g
 EXAMPLE 4
 A mixture of pyrrole (40 mmoles) acetic anhydride (10 mmoles) and K10
 montmorillonite catalyst (0.5 g) were stirred in a round bottomed flask
 (50 ml) under nitrogen atmosphere at 80.degree. C. temperature. After
 completion of the reaction (followed by G.C.), the reaction mixture was
 filtered and distilled the reaction mixture to obtain the crude product.
 Yield: 0.6 g
 EXAMPLE 5
 A mixture of pyrrole (40 mmoles) acetic anhydride (10 mmoles) and Zn.sup.2+
 -exchanged clay catalyst (0.5 g) were stirred in a round bottomed flask
 (50 ml) under nitrogen atmosphere at 80.degree. C. temperature. After
 completion of the reaction (followed by G.C.), the reaction mixture was
 filtered and distilled the reaction mixture to obtain the crude product.
 Yield: 0.9 g
 EXAMPLE 6
 A mixture of thiophene (50 mmol), acetic anhydride (10 mmol) and Fe.sup.3+
 -exchanged clay catalyst (0.5 g) were stirred in a round bottomed flask
 (50 ml) under nitrogen atmosphere at room temperature. After completion of
 the reaction (followed by G.C.), the reaction mixture was filtered and
 distilled the reaction mixture to obtain the crude product. Yield: 0.7 g
 EXAMPLE 7
 A mixture of thiophene (50 mmol), acetic anhydride (10 mmol) and Fe.sup.3+
 -exchanged clay catalyst (0.5 g) were stirred in a round bottomed flask
 (50 ml) under nitrogen atmosphere at 80.degree. C. temperature. After
 completion of the reaction (followed by G.C.), the reaction mixture was
 filtered and distilled the reaction mixture to obtain the crude product.
 Yield: 1.2 g
 EXAMPLE 8
 A mixture of thiophene (50 mmol), acetic anhydride (10 mmol) and Zn.sup.2+
 -exchanged clay catalyst (0.5 g) were stirred in a round bottomed flask
 (50 ml) under nitrogen atmosphere at 80.degree. C. temperature. After
 completion of the reaction (followed by G.C.), the reaction mixture was
 filtered and distilled the reaction mixture to obtain the crude product.
 Yield: 1.1 g
 EXAMPLE 9
 A mixture of furan (50 mmol), acetic anhydride (10 mmol) and Fe.sup.3+
 -exchanged clay catalyst (0.5 g) were stirred in a round bottomed flask
 (50 ml) under nitrogen atmosphere at room temperature. After completion of
 the reaction (followed by G.C.), the reaction mixture was filtered and
 distilled the reaction mixture to obtain the crude product. Yield: 1.0 g
 EXAMPLE 10
 A mixture of furan (50 mmol), acetic anhydride (10 mmol) and Fe.sup.3+
 -exchanged clay catalyst (0.5 g) were stirred in a round bottomed flask
 (50 ml) under nitrogen atmosphere at room temperature. After completion of
 the reaction (followed by G.C.), the reaction mixture was filtered and
 distilled the reaction mixture to obtain the crude product. Yield: 0.9 g
 EXAMPLE 11
 A mixture of furan (50 mmol), acetic anhydride (10 mmol) and Zn.sup.2+
 -exchanged clay catalyst (0.5 g) were stirred in a round bottomed flask
 (50 ml) under nitrogen atmosphere at room temperature. After completion of
 the reaction (followed by G.C.), the reaction mixture was filtered and
 distilled the reaction mixture to obtain the crude product. Yield: 0.8 g
 TABLE 1
 Acetylation of heteroaromatic compounds with acetic anhydride in the
 presence of metal
 ion exchanged clays
 Product
 distribution
 Example Heteroaromatic Temp Time Isolated 2-Acetyl
 No. compound Catalyst (.degree. C.) (h) Yields(%).sup.a
 heteroatom others
 2 Pyrrole Fe.sup.3+ -mont. RT 12 86 &gt;99%
 --
 3 Pyrrole Fe.sup.3+ -mont. 80 6 98 95
 5
 4 Pyrrole K10-mont. 80 8 60 96
 4
 5 pyrrole Zn.sup.2+ -mont. 80 6 87 95
 5
 6 Thiophene Fe.sup.3+ -mont RT 8 56 &gt;99%
 --
 7 Thiophene Fe.sup.3+ -mont. 80 5 97 &gt;99%
 --
 8 Thiophene Zn.sup.2+ -mont. 80 5 92 &gt;99%
 --
 9 Furan Fe.sup.3+ -mont. 40 8 98 92
 8
 10 Furan Fe.sup.3+ -mont. RT 12 82 &gt;99%
 --
 11 Furan Zn.sup.2+ -mont. RT 12 77 &gt;99%
 --
 .sup.a based on acetic anhydride
 The present process has several advantages as described below:
 1. A novel and ecofriendly process for the manufacture of acyl
 heteroaromatic compounds.
 2. The present process eliminates the use of corrosive and stoichiometric
 quantities aluminium chloride and other Lewis and protic acid catalysts.
 3. Metal ion exchanged have been used as catalysts for the acylation of
 heteroaromatic compounds in excellent yields for the first time.
 4. The selectively towards 2-acyl heteroaromatic compounds is greater than
 99% in the presence of clays as catalysts.
 5. The product is devoid of 3-acyl heteroaromatic compound, usually formed
 in the acylation process using soluble Lewis acids.
 6. The 2-acyl heteroaromatic compounds thus obtained can be directly used
 for the preparation of specialised drugs and pharmaceuticals.
 7. Work-up procedure is simple.
 8. The present process envisages no disposal problem as the catalyst can be
 used for several cycles. The catalyst was subjected to several recycles
 which displayed consistent activity.
 9. The present process is environmentally safe since there is no disposal
 problem.
 10. The process is economical.