BACKGROUND OF THE INVENTION Protection of compounds containing an active hydrogen like, amine, phenols and thiols forms an integral part of synthesis.

Conventional protecting groups are t-BOC (di-tert-butyl dicarbonate) which reacts with amines to form a carbamate. Introduction of this BOC protection group is normally carried out by reacting the amine with BOC anhydride in the presence of a base. The other protecting groups normally used are FMOC-Chloride for introducing the flurQr'omenthyl group, Alloc-Chloride for introducing the allyl carbamate group and CBZ-chloride for introducing the benzyloxy carbamate group in the case of amines.

Traditionally different reaction conditions are employed to introduce specific protective groups, namely a basic reaction medium for introducing the BOC and Alloe groups and an acidic medium for introducing the FMOC groups.

The present invention describes a simple and efficient method for introducing different protecting groups essentially by a single

reaction condition, namely, alumina impregnated with a basic hydroxide under mild conditions.

Aromatic nucleophilic substitution is carried out by the displacement of a halo group using strong nucleophilies. The reaction conditions are harsh and the yields are often very poor. Improved methods were developed for the displacement using a metal based catalyst like copper and a strong base like potassium tert-butoxide.

The reaction is specific and the yields are poor. Mixture of palladium based reagents like, palladium acetate, palladium hydroxide or palladium dibenzylidiene acetone complex and a phosphine ligand in the presence of base like sodium tert-butoxide offers a versatile procedure for the nucelophilic displacement of the aromatic halo group. The reaction utilizes phosphines, which are not readily available and palladium reagents which are expensive and possess disposal problems and thus not suitable for industrial scale operations.

The process for this invention could be used for the nucleophilic substitution of aromatic halides containing electron withdrawing groups to give substituted aromatic, which finds extensive use in the preparation of fine chemicals, which are starting materials for active pharmaceutical intermediates.

A variety of methods are available in the literature for the nucleophilic substitution of aromatic halides which are herein incorporated as reference. Palladium is the chosen metal of choice for effecting the coupling of aromatic halides with a variety of nucleophiles. Often the reaction conditions involves the use of trialkyl or triaryl phosphine and a palladium catalyst. Stephen Buchwald et. al., (J. Org. Chem., 2000, 65, 1158-1174 and references cited

therein) describes an efficient method for the amination of aryl chlorides, bromides and triflates using aryl phosphines, palladium complex and a base.

Scott Sawyer et. al., (J. Org Chem, 1998, 63,6338-6343) have demonstrated the synthesis of diaryl ethers, diaryl thioethers and diaryl amines by nucleophilic substitution of the aryl halides using KF- alumina, 18-crown-6 conditions. The disadvantage of this method is the usage of 18-crown-6 as a complexing agent for the reaction. The reaction also requires a more tedious work up by partitioning the reaction mixture with an organic solvent and aqueous media.

Conventional methods employ the nucleophilic conditions using K2C03-DMF conditions which employs high reaction temperatures which may be not readily employed in industrial scale operations.

OBJECTIVES OF THE INVENTION Accordingly, the main objective of this invention is to provide a solid catalyst, which can easily be removed from the reaction mixture and thus facilitates easy work-up procedures for the incorporation of protecting groups for amines, alcohols and thiols and for the nucleophilic substitution.

Another important feature is the easy handling and disposal procedure of the spent catalyst.

The reaction avoids the use of toxic and expensive solvents and thus is environmentally friendly The reaction conditions are simple and hence can be easily employed for industrial scale preparations.

SUMMARY OF THE INVENTION The main finding of this invention is that, the said catalyst shows remarkable activity in the reactions for introducing protecting groups for amines, alcohols, phenols and thiols. A wide variety of protecting groups can be introduced in a mild and efficient manner at ambient temperatures.

Other important finding of this invention is that the reaction conditions are so mild and simple that it can be easily scaled up for industrial scale preparations.

The main advantages of the process of this invention over the prior art processes for such reactions are as follows : 1. The active catalyst can be very easily prepared in large quanities and can be stored without any appreciable loss of activity.

2. The catalyst can be used for introducing protective groups of a wide range as indicated on practically any amines, alcohols, phenols or thiols.

3. The catalyst used being heterogenous can be separated from the reaction products by simple filtration.

4. The reaction can be carried out in any solvent, polar or non-polar as demonstrated using dioxan, dicholoromethane etc.

5. The catalyst in non-corrosive and hence can be easily handled in very large volumes.

6. The catalyst in non-toxic and hence offers very easy disposal methods and also affords environmental friendly reaction conditions.

DETAILED DESCRIPTION OF THE INVENTION This invention particularly relates to the preparation of alumina impregnated with lithium hydroxide and the solid thus obtained is then used for incorporating a wide variety of protecting groups on amines, alcohols, phenols and thiol.

The process for this invention could be used for the protection of amines, alcohols, phenols, thiols, which finds extensive use in the preparation of fine chemicals, which are starting materials for active pharmaceutical intermediates.

N-protected amino acids and other amines, ethers and thioethers are used as intermediates in a number of organic synthesis.

Both the homogeneous and heterogeneous catalyzed processes for the protection of the said compounds are known in the prior art.

A catalyst comprising of alumina impregnated with a base chosen from alkali or alkaline earth hydroxides.

The catalyst where the base is lithium hydroxide.

The catalyst where the lithium hydroxide content in alumina varies from 0.3 to 3% by weight.

The process for the preparation of the catalyst comprising of: a) treating an aqueous solution of the metal hydroxide with alumina in an organic solvent, b) drying the resulting catalyst mixture.

The process for the preparation of the catalyst where the organic solvent is selected from dichloromethane, dioxan, toluene, acetonitrile or dimethyl formamide (DMF).

The process for the preparation of the where drying is carried out in vacuum.

The use of the catalyst for treating amines, both primary and secondary and chosen from aromatic, aliphatic, heterocyclic, cyclic with the protecting groups chosen from di-tert-butyl dicarbonate (Boc anhydride), 9-Fluorenylmethoxycarbonyl chloride (Fmoc-CI), 9- Fluorenylmethoxy carbonyl N-hydroxy succinimide (Fmoc-OSu), Allyoxycarbonyl (Alloc), benzyl chloroformate (CBZ-CI), acetic anhydride, trifluoroacetic anhydride, acid chloride, sulfonyl chlorides to give the corresponding N-protected compounds.

The use of the catalyst for treating alcohols, primary, secondary or tertiary and chosen from aromatic, aliphatic, heterocyclic, cyclic with the protecting groups chosen from di-tert-butyl dicarbonate (Boc anhydride), 9-Fluorenylmethoxycarbonyl chloride (Fmoc-CI), 9- Fluorenylmethoxy carbonyl N-hydroxy succinimide (Fmoc-OSu), Allyoxycarbonyl (Alloc), benzyl chloroformate (CBZ-CI), acetic anhydride, trifluoroacetic anhydride, acid chloride, sulfonyl to give the corresponding 0-protected ethers.

The use of the catalyst for treating thiols, primary, secondary or tertiary and chosen from aromatic, aliphatic, heterocyclic, cyclic with the protecting groups chosen di-tert-butyl dicarbonate (Boc anhydride), 9-Fluorenylmethoxycarbonyl chloride (Fmoc-Cl) r 9- Fluorenylmethoxy carbonyl N-hydroxy succinimide (Fmoc-OSu), Allyoxycarbonyl (Alloc), benzyl chloroformate (CBZ-CI), acetic anhydride, trifluoroacetic anhydride, acid chloride, sulfonyl chlorides to give the corresponding S-protected compounds.

The use of the catalyst for treating amines, alcohols and thiols for nucleophilic substitutions.

The process of treating amines where the amine is selected from primary, secondary, aromatic, aliphatic, heterocyclic or cyclic with an aromatic halide containing an electron withdrawing group chosen from nitro, aldehyde, acid, ester, amide or nitrile to give the corresponding substituted aniline derivatives.

The process of treating alcohol where the alcohol is selected from primary, secondary or tertiary and chosen from aromatic, aliphatic, heterocyclic, cyclic with an aromatic halide containing an electron withdrawing group chosen from nitro, aldehyde, acid, ester, amide or nitrile to give the corresponding substituted ether derivatives.

The process of treating thiols where the thiol is selected from primary, secondary or tertiary and chosen from aromatic, aliphatic, heterocyclic, cyclic with an aromatic halide containing an electron withdrawing group chosen from nitro, aldehyde, acid, ester, amide or nitrile to give the corresponding substituted thioether derivatives.

This invention provides a process for the preparation of the active alumina catalyst impregnated with the metal hydroxide chosen from alkali or alkaline metals of general formula Formula 1 {M(OH)n} where n = 1 or 2 and M = Li or Mg or Ca or Na Reacting the solid alumina-metal hydroxide catalyst with an amine of formula II with a protecting group chosen from di-tert-butyl dicarbonate (referred to Boc anhydride), 9-Fluorenylmethoxycarbonyl chloride (Fmoc-Cl), 9-Fluorenylmethoxy carbonyl N-hydroxy succinimide (Fmoc-OSu), Allyoxycarbonyl (Alloc), benzyl chloroformate

(CBZ-Cl3, acetic anhydride, trifluoroacetic anhydride, acid chloride, sulfonyl chlorides to give the corresponding N-protected compounds. formula II (R1R2NH) where R1 = H, alkyl, aryl, aralkyl, hetero, heteroalkyl, cyclic and R2=H, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, hetero, heteroalkyl, cyclic with a condition that R1 and R2 are may equal to H, Reacting the solid alumina-metal hydroxide catalyst with an alcohol of formula III with a protecting group chosen from di-tert-butyl dicarbonate (referred to Boc anhydride), 9-Fluorenylmethoxycarbonyl chloride (Fmoc-Cl), 9-Fluorenylmethoxy carbonyl N-hydroxy succinimide (Fmoc-OSu), Allyoxycarbonyl (Alloc), benzyl chloroformate (CBZ-CI), acetic anhydride, trifluoroacetic anhydride, acid chloride, sulfonyl chlorides to give the corresponding ethers formula III (R3OH) where R3 = alkyl, cycloalkyl, aryl, aralkyl, heterocrclíc, heteroalkyl, substituted aryl Reacting the solid alumina-metal hydroxide catalyst with an thiol of formula IV with a protecting group chosen from di-tert-butyl dicarbonate (referred to Boc anhydride), 9-Fluorenylmethoxycarbonyl chloride (Fmoc-CI), 9-Fluorenylmethoxy carbonyl N-hydroxy succinimide (Fmoc-OSu), Allyoxycarbonyl (Alloc), benzyl chloroformate (CBZ-CI), acetic anhydride, trifluoroacetic anhydride, acid chloride, sulfonyl chlorides to give the corresponding thioethers

Formula IV (R4SH) where R4 = alkyl, cycloalkyl, aryl, aralkyl, heterocyclic, heteroalkyl, substituted aryl The process involves reacting the substrate namely, amines, alcohols or thiols mentioned above with active alumina catalyst containing the metal hydroxide in a solvent chosen from dichloromethane, dioxan, toluene, acetonitriler dimethyl formamide, dimethyl sulfoxide, diisopropyl ether, methyl tert-butyl ether, cyclohexane at ambient temperatures and removal of the active metal catalyst by simple filtration followed by removal of solvent gives the desired protected compounds.

Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula V with a variety of amines of formula II chosen from both primary and secondary and are optionally chosen from alkyl, aryl, aralkyl, cycloalkyl, heterocyclic and heteroalkyl amines to give the substituted anilines.

Formula V whereXmaybe fluoro, chloro, bromo and optionally substituted at ortho, meta or para position to the nitro groUp Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula V with a variety of alcohols of formula III chosen from primary, secondary and tertiary and are optionally chosen from alkyl, cycloalkyl, heterocyclic, phenol and substituted phenol to give the substituted ethers.

Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula V with a variety of thiols of formula IV chosen from alkyl, aryl, aralkyl, heterocyclic, cyclic to give the substituted thioether.

Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula VI with a variety of amines of formula II both primary and secondary and are optionally chosen from alkyl, aryl, aralkyl, cycloalkyl, heterocyclic, heteroalkyl amines to give the substituted anilines.

Formula VI where X=fluoro, chloro, bromo and optionally substituted at olthol meta or para posltlon to the aldehyde group Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula VI with a variety of alcohols of formula III primary, secondary and tertiary and are optionally chosen from alkyl, cycloalkyl, heterocyclic, phenol and substituted phenol to give the substituted ethers.

Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula VI with a variety of thiols of formula IV chosen from allcyl, aryl, aralkyl, heterocyclic, cyclic to give the substituted thioether.

Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula VII with a variety of amines of formula II chosen from both primary and secondary and are optionally chosen

from alkyl, aryl, aralkyl, cycloalkyl, heterocyclic, heteroalkyl amines to give the substituted anilines. <BR> <BR> <P>Formula VII where X=flecoro, chloro, bromo and optionally substituted at ortho, meta or para position to the cyano group Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula VII with a variety of alcohols of formula III chosen from primary, secondary and tertiary and are optionally chosen from alkyl, cycloalkyl, heterocyclic, phenol and substituted phenol to give the substituted ethers.

Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula VII with a variety of thiols of formula IV chosen from alkyl, aryl, aralkyl, heterocyclic, cyclic to give the substituted thioether.

This methodology was successfully used in the synthesis of 2- piperidinobenzonitrile (example-11) which is an important intermediate in the synthesis of subsituted phenyl acetamide, repaglinide which is used in the lowering of blood-sugar levels.

Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula VIII with a variety of amines of formula II chosen both primary and secondary and are optionally chosen from alkyl, aryl, aralkyl, cycloalkyl, heterocyclic, heteroalkyl amines to give the substituted anilines.

Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula VIII with a variety of alcohols of formula III chosen primary, secondary and tertiary and are optionally chosen from alkyl, cycloalkyl, heterocyclic, phenol and substituted phenol to give the substituted ethers.

Reacting the solid alumina-metal hydroxide catalyst with an aromatic halide of formula VIII with a variety of thiols of formula IV chosen from alkyl, aryl, aralkyl, heterocyclic, cyclic to give the substituted thioether.

Formula VIII (where X = F, Cl or Br and G = OH, OR1, NR2R3) where 1, R2 3 cycloalkyl aryl,, aralkyl<BR> substituted aiyg and optionally substituted at ortho, meta or para positions The process involves reacting the substrate namely, amines, alcohols or thiols with the aromatic halide mentioned above with active alumina catalyst containing the metal hydroxide in a solvent chosen from dichloromethane, dioxan, toluene, acetonitrile, dimethyl formamide, dimethyl sulfoxide, diisopropyl ether, methyl ter-butyl ether, cyclohexane at ambient temperatures and removal of the active metal catalyst by simple filtration followed by removal of solvent gives the desired protected compounds.

Reaction of the amines, namely aniline with aryl halides like 2- chloronitrobenzene in dioxane afforded the nitro anilines. The reaction

appears to be quite general as different amines chosen from both primary and secondary and also optionally being aromatic, aliphatic, cycloalkyl etc., were attempted and the substutition proceeded fairly smoothly to give the substituted nitro anilines.

The invention is further illustrated with examples below, which are not intended to be limiting.

Example-1 To 5g of aniline in 50m ! of dichloromethane, 3N solution of lithium hydroxide absorbed in basic alumina (1. 3g of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 5min and benzyl chloroformate was added slowly over a period of 10min at room temperature. After 3h, the catalyst was filtered off and the solid bed was washed throughly with dichloromethane. Removal of solvent and crystallization by addition of petroleum ether affords the product in 95% yield.

Example-2 To 5g of aniline in 50moi of dichloromethanet 3N solution of lithium hydroxide absorbed in basic alumina (1. 3g of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 5min and allyl chloroformate was added slowly over a period of 10min at room temperature. After 3h, the catalyst was filtered off and the solid bed was washed thoroughly with dichloromethane. Removal of solvent and crystallization by addition of petroleum ether affords the product in 75% yield.

Example-3 To 5g of aniline in 50moi of dichloromethane, 3N solution of lithium hydroxide absorbed in basic alumina (1. 3g of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 5min and boc anhydride was added slowly over a period of 10min at room temperature. After 12h, the catalyst was filtered off and the solid bed was washed thoroughly with dichloromethane. Removal of solvent and crystallization by addition of petroleum ether affords the product in 80% yield.

Example-4 To 5g of aniline in 50ml of dichloromethane, 3N solution of lithium hydroxide absorbed in basic alumina (1.3g of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 5min and Fmoc-OSU was added slowly over a period of 10min at room temperature. After 12h, the catalyst was filtered off and the solid bed was washed thoroughly with dichloromethane. Removal of solvent and crystallization by addition of petroleum ether affords the product in 95% yield.

Example-5 To 5g of 4-piperidone in 50moi of dichloromethane, 3N solution of lithium hydroxide absorbed in basic alumina (1. 3g of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 5min and boc anhydride was added slowly over a period of 10min at room temperature. After 12h, the catalyst was filtered off and the solid bed was washed thoroughly with dichloromethane. Removal of solvent

and crystallization by addition of petroleum ether affords the product in 80% yield.

Example-6 To 5g of 4-piperidone in 50ml of dichloromethane, 3N solution of lithium hydroxide absorbed in basic alumina (1. 3g of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 5min and allyl chloroformate was added slowly over a period of 10min at room temperature. After 12h, the catalyst was filtered off and the solid bed was washed thoroughly with dichloromethane. Removal of solvent and crystallization by addition of petroleum ether affords the product in 95% yield.

Example-7 To 5g of 4-piperidone in 50mut of dichloromethane, 3N solution of lithium hydroxide absorbed in basic alumina (1.3g of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 5min and benzyl chloroformate was added slowly over a period of 10min at room temperature. After 3h, the catalyst was filtered off and the solid bed was washed thoroughly with dichloromethane. Removal of solvent and crystallization by addition of petroleum ether affords the product in 95% yield.

Example-8 To 5g of 4-piperidone in 50ml of dichloromethane, 3N solution of lithium hydroxide absorbed in basic alumina (1. 3g of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 5min and

Fmoc-OSU was added slowly over a period of 10min at room temperature. After 12h, the catalyst was filtered off and the solid bed was washed thoroughly with dichloromethane. Removal of solvent and crystallization by addition of petroleum ether affords the product in 75% yield.

Example-9 To 5g of phenol in 50moi of dichloromethane, 3N solution of lithium hydroxide absorbed in basic alumina (1. 3g of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 5min and Alloc-Cl was added slowly over a period of 10min at room temperature. After 12h, the catalyst was filtered off and the solid bed was washed thoroughly with dichloromethane. Removal of solvent and crystallization by addition of petroleum ether affords the product in 85% yield.

Example-10 To 5g of thiophenol in 50moi of dichloromethane, 3N solution of lithium hydroxide absorbed in basic alumina (1. 3g of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 5min and Alloc-Cl was added slowly over a period of 10min at room temperature. After 12h, the catalyst was filtered off and the solid bed was washed thoroughly with dichloromethane. Removal of solvent and crystallization by addition of petroleum ether affords the product in 70% yield.

Example-11 To 5g of 2-chlorobenzonitrile, 50ml of DMF was charged followed by 3N solution of lithium hydroxide adsorbed in basic alumina (2. 7g, 0. 108M solution of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 10min. Piperidine was added slowly over a period of 10min and refluxed at 120°C. Upon completion, the reagent was filtered and DMF was removed under reduced pressure.

The residue was washed with water, extracted using ethyl acetate.

Removal of ethyl acetate afforded the 2-piperidinyl) benzonitrile in 50% yield.

Example-12 To 5g of 2-fluorobenzaldehyde, 50mi of DMF was charged followed by 3N solution of lithium hydroxide adsorbed in basic alumina (2. 7g, 0. 108M solution of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 10min. Piperidine was added slowly over a period of 10min and refluxed at 120°C. Upon completion, the reagent was filtered and DMF was removed under reduced pressure.

The residue was washed with water, extracted using ethyl acetate.

Removal of ethyl acetate afforded the 2-(1-piperidinyl) benzaldehyde in 80% yield.

Example-13 To 5g of 2-fluorobenzaldehyde, 50moi of DMF was charged followed by 3N solution of lithium hydroxide adsorbed in basic alumina (2. 7g, 0.108M solution of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 10min. Cyclohexanethiol was added

slowly over a period of 10min and refluxed at 120°C. Upon completion, the reagent was filtered and DMF was removed under reduced pressure. The residue was washed with water, extracted using ethyl acetate. Removal of ethyl acetate afforded the 2- (l-cyclohexylthio) benzaldehyde in 85% yield.

Example-14 To 5g of 2-fluoronitrobenzene, 50ml of DMF was charged followed by 3N solution of lithium hydroxide adsorbed in basic alumina (2. 7g, 0.108M solution of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 10min. Aniline was added slowly over a period of 10min and refluxed at 120°C. Upon completion, the reagent was filtered and DMF was removed under reduced pressure.

The residue was washed with water, extracted using ethyl acetate.

Removal of ethyl acetate afforded the 2- (N-phenylamino) nitrobenzene in 90% yield.

Example-15 To 5g of 2-fluoronitrobenzene, 50moi of DMF was charged followed by 3N solution of lithium hydroxide adsorbed in basic alumina (2. 7g, 0.108M solution of lithium hydroxide in 7. 5g of basic alumina) and the contents were stirred for 10min. Cyclohexanethiol was added slowly over a period of 10min and refluxed at 120°C. Upon completion, the reagent was filtered and DMF was removed under reduced pressure. The residue was washed with water, extracted using ethyl acetate. Removal of ethyl acetate afforded the 2- (cyclohexylthio) nitrobenzene in 90% yield.