Title of Invention

A PROCESS FOR PREPARATION OF ORGANIC CARBAMATES

Abstract

The present invention relates to a process for the preparation of organic carbamates. Organic carbamates find use as intermediates in organic synthesis as blocking groups. The process is economical and avoids use of hazardous material. The starting material is tosylate esters which is reacted with alkyl amine in aprotic solvent in presence of metal carbonate and a base at a temperature between 50 to 120 °C to obtain organic carbamates of formula I. Wherein R is an alkyl group containing 1-16 carbon atoms or an aromatic group such as phenyl, naphthyl, phenathryl, or a heteroaromatic such as quinoline, benzopyrans, n is 1 to 16, R1 is a lower alkyl such as methyl, ethyl, propyl, butyl, amyl or a branched chain lower alkyl such as isopropyl, isoamyl, or a cycloalkyi containing 3 to 8 carbon atoms, or an alkylaryl such as benzyl, ethylphenyl or an aromatic group such as phenyl, substituted phenyl, naphthyl

Full Text

The present invention relates to a process for the preparation of organic carbamates. This invention particularly relates to the preparation of carbamates of formula 1, wherein R is an alkyl group containing 1-16 carbon atoms or an aromatic group such as phenyl, naphthyl, phenathryl, or a heteroaromatic such as quinoline, benzopyrans, n is 1 to 16, R1 is a lower alkyl group such as methyl, ethyl, propyl, butyl, amyl or a branched chain lower alkyl such as isopropyl, isoamyl, or a cycloalkyl containing 3 to 8 carbon atoms, or an alkylaryl such as benzyl, ethylphenyl or an aromatic group such as phenyl, substituted phenyl, naphthyl. (Formula Removed) Organic carbamates find use as intermediates in organic synthesis as blocking groups (Greene, T.W., Wuts, PGM. Protecting Groups in Organic Synthesis, 2nd Ed. John Wiley and Sons Inc. New York 1991, p315, in combinatorial chemistry (PoZo, M., Gotor, V. Tetrahedron 1993, 49, 4321-4326). Synthesis of carbamates has been described by direct alcoholysis of phosgene and its derivatives (Satchell, S, Chem. Rev. 1975, 4, 231) anubiktsus if cgkirifimates (Rabcgerm H, Synthetic Commun. 1985, 15, 1025) and alcoholysis of isocyanates (Entelis, N, Russ. Chem. Rev. 1966, 35, 917-950) as shown in equations 1 and 2 respectively. (Formula Removed) In all these above processes, highly toxic and harmful reagents such as phosgene or its derivative are used. In the recent past carbon dioxide, a cheap and harmless reagent has been used for carbamate synthesis (Aresta, M. Quranta, E. Tetrahedron 1992, 48, 1515- 1530; Inesi, A, Muccinate, V;Rossi,LJ.Org.Chem, 1998 63, 1337-1338) utilizing alkyl halides as starting material. The main objective of the invention is to provide a process for the preparation of organic carbamtes. Another objective of the present invention is to provide a convenient, economical method avoiding use of hazardous material. Accordingly, the present invention provides a process for the preparation of carbamate of formula 1 (Formula Removed) Wherein R is an alkyl group containing 1-16 carbon atoms or an aromatic group such as phenyl, naphthyl, phenathryl, or a heteroaromatic such as quinoline, benzopyrans, n is 1 to 16, R1 is a lower alkyl such as methyl, ethyl, propyl, butyl, amyl or a branched chain lower alkyl such as isopropyl, isoamyl, or a cycloalkyl containing 3 to 8 carbon atoms, or an alkylaryl such as benzyl, ethylphenyl or an aromatic group such as phenyl, substituted phenyl, naphthyl, which comprises; reacting a tosyl ester of formula II (Formula Removed) Wherein R is as defined above in formula 1 and n is 1-16 with an amine of formula III, (Formula Removed) Wherein R1 is selected from a group consisting of a lower alkyl, branched chain lower alkyl, cycloalkyl, an alkylaryl, or an aryl group as defined above for the formula 1 in an organic aprotic solvent selected from dimethylsulphoxide (DMSO), dimethylformamide (DMF) acetonitrile, hexamethylphosphoramide (HMPA) in presence of CO2/metal carbonate selected from K2CO3 Na2CO3, in presence of a base selected from tetrabutylammonium iodide (TBAI), benzyltrimethylammonium hydroxide (Triton B), at a temperature ranging between 50-120°C for a period ranging between 3-7 hrs, diluting the reaction mixture with water, extracting with water-immicible organic solvent as herein described and removing the solvent to get the desired carbamate. In an embodiment of the invention the aprotic organic solvent used may be selected from dimethylsulphoxide (DMSO), dimethylformamide (DMF) acetonitrile, hexamethylphosphoramide (HMPA). In another embodiment of the invention the aprotic solvent used may be preferably dimethylsulphoxide for alkylamines. In yet another embodiment of the invention aprotic solvent used may be preferably HMPA for aromatic amines. In still another embodiment of the invention the metal carbonate used may be selected from Na2CO3, K2CO3. In yet another embodiment of the invention a preferred base used may be TBA for alkylamines. In further embodiment of the invention a preferred base used may be Triton B for aromatic amines. In still embodiment of the embodiment of the invention the preferred temperature used may be ranging between 80 to 120°C. In another embodiment of the invention extraction of carbamtes may be carried out using organic solvent selected from benzene, toluene, ethyl acetate. The starting tosylate esters were prepared from corresponding alcohols, by reacting with p-toluene sulphonyl chloride following known routes. Organic carbamates may be prepared by reacting the tosylate ester with alkyl amine in an aprotic solvent in presence of metal carbonate and a base and CC/2 at a temperature ranging between 50 to 120°C. Schematic representation of the process of carbamates is given below R-O-(CH2)n-OTs + NHi-Rl + CO2 »• R-O-(CHi )n-OCONHR 1 II III l The following examples are given by way of illustration and should not construed the scope of the invention . Example 1: Butyl n-octvl carbamate Anhydrous potassium carbonate (5 gms), n-octylamine(0.854ml>0.005 mole) were taken in dry DMSO ( 25ml). Now purified €62 gas was rapidly bubbled into it at 90°C for 1 hr, then tetrabutylammoniumiodide (0.2gm,0.0005mole) was added in it. Reaction was further continued for 1/2 hr; butyloxytosylate (0.5gm, 0.002 mole) was added in it. Reaction was continued till the completion of the reaction (4 hrs) as checked by TLC. Reaction mixture was poured into distilled water (50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get butyl n-octylcarbamate.Oil yield 0.43 gm, 90.52%). Example 2: Isoamvl n-octvl carbamate Anhydrous pot.carbonate (5gms), n-octylamine(0.854 ml,0.005 mole)were taken in dry DMSO (25ml) .Purified CO2 gas was rapidly bubbled into it at 100°C for 1 hr. Now tetrabutylammoniumiodide (0.190 gm,0.0005 mole) was added in it. Reaction was continued for 1/2 hr. Isoamyloxytosylate (0.5gm, 0.002 mole) was added in it. Reaction was further continued till the completion of reaction (6 hrs) as checked by TLC. Reaction mixture was poured into distilled water (50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get isoamyl n-octylcarbamate. Oil( yield 0.357 gm, 73.12%). Example 3: n-Pentvl n-butvlcarbamate Anhydrous pot. carbonate (5 gms), n-butylamine(0.510ml,0.005 mole) were taken in dry DMSO ( 25ml). Purified CO2 gas was rapidly bubbled into it at 70°Cfor 1 hr. Now tetrabutyl ammonium iodide (0.190 gm,0.0005 mole) was added in it. Reaction was further continued for 1/2 hr. n- Pentyloxytosylate (0.5 gm, 0.002 mole) was added in it. Reaction was further continued till the completion of the reaction (5 hrs) as checked by TLC. Reaction mixture was poured into distilled water, extracted with ethyl acetate thrice. The organic layer was separated and dried over anhydrous sodium sulphate and concentrated to get n-pentyl n-butylcarbamate. Oil (yield 0.289 gm, 75.12%). Example 4: n-Hexvl cvclohexvlcarbamate Anhydrous pot. carbonate (5 gms), cyclohexyl amine(0.558 ml,0.005 mole) were taken in dry DMSO (25 ml). Purified CO2 gas was rapidly bubbled into it at 80°C for 1 hr. Now tetrabutyl ammonium iodide (0.180 gm,0.0005 mole) was added in it. Reaction was continued for 1/2 hr. n-hexyloxytosylate (0.5gm, 0.002 mole) was added in it. Reaction was further continued till the completion of the reaction( 5hrs) as checked by TLC. Reaction mixture was poured into distilled water (50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-hexyl cyclohexylcarbamate m.p.l39-140°C (yield 0.382 gm, 88.25 %). Example 5: n-Hexvl propvlcarbamate Anhydrous pot. carbonate (5gms), propylamine(0.401 ml,0.005 mole) were taken in dry DMSO (25ml) .Purified CO2 gas was rapidlly bubbled into it at 110°C for 1 hr. Now tetrabutylammonium iodide (0.180 gm,0.0005 mole) was added in it. Reaction was continued for 1/2 hr. n-Hexyloxytosylate (0.5gm, 0.002 mole) was added in it. Reaction was further continued till the completion of the reaction(4 hrs) as checked by TLC. Reaction mixture was poured into distilled water(50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-hexyl propylcarhamate.Oi! (yield 0.263 gm,72.26 %). Example 6: n-Octvl 3-methoxv benzyl carbamate Anhydrous pot. carbonate (5gms), m- methoxybenzylamine (0.574 ml,0.004 mole) were taken in dry DMSO (25ml) .Purified CO2 gas was rapidly bubbled into it at 80°C for 1 hr. Now tetrabutyl ammonium iodide (0.162 gm,0.0004 mole) was added in it. Reaction was continued for 1/2 hr. n- Octyloxytosylate (0.5gm, 0.002 mole) was added in it. Reaction was further continued till the completion of the reaction (7hrs) as checked by TLC.Reaction mixture was poured into distilled water(50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-octyl 3- mehoxybenzylcarbamate (m.p.l37°C, Yield 0.45 Igm, 90.03 %). Example .7: n-Decvl n-butvl carbamate A mixture of anhydrous pot. carbonate (6gms), n-butylamine(0.476 ml,0.004 mole) was taken in dry DMSO (25ml) .Purified CO2 gas was rapidly bubbled into it at 100°C for 1 hr. Now tetrabutyl ammonium iodide (0.148 gm,0.0004 mole) was added in it. Reaction was continued for 1/2 hr. n-Octyloxy tosylate (0.5gm, 0.0016 mole) was added in it. Reaction was further continued for the completion of reaction(4 hrs) as checked by TLC. Reaction mixture was poured into distilled water (50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-decyl n-butylcarbamate Oil (yield0.383 gm, 79.29%). Example 8: 3-Phenvlpropvl n-hexvl carbamate A mixure of anhydrous pot. carbonate (5 gms), hexyl amine(0.569 ml,0.004 mole) was taken in dry DMSO (25 ml) . Purified CO2 gas was rapidly bubbled into it at 80°C for 1 hr. Now tetrabutyl ammonium iodide (0.159 gm,0.0004 mole) was added in it. Reaction was continued for 1/2 hr.3- Phenylpropyloxy tosylate (0.5gm, 0.0017 mole) was added in it. Reaction was further continued till the completion of the reaction( 4 hrs) as checked by TLC. Reaction mixture was poured into distilled water (50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get 3- phenylpropyl n- hexylcarbamate Oil (yield 0.384gm, 80.06 %). Example 9: 2-Naphthvloxvethvl cvclohexvl carbamate A mixture of anhydrous pot.carbonate(5gms) ,cyclohexylamine (0.391ml,0.003 mole) was taken in dry DMSO (25 ml). Purified CO2 gas was rapidly bubbled into it at 85°C for 1 hr. Now tetrabutyl ammonium iodide (0.134 gm,0.0004 mole) was added in it. Reaction was continued for 1/2 hr.2-napthloxyethyloxytosylate (0.5gm, 0.0015 mole) was added in it. Reaction was further continued the completion of the reaction(4 hrs) as checked by TLC. Reaction mixture was poured into distilled water (50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get 2- naphthyloxy ethyl cyclohexylcarbamate (m.p.99°C , yield 0.33gm, 70.0 %). Example 10: 2-Phenvlethvl isopropvl carbamate A mixture of anhydrous pot.carbonate (5 gms), di-isopropylamine (0.634 ml, 0.0045 mole) was taken in dry DMSO (25 ml). Purified CO2 gas was rapidly bubbled into it at 90°C for 1 hr. Now tetrabutyl ammonium iodide (0.167 gm, 0.0004 mole) was added in it. Reaction was continued for 1/2 hr. 2-Phenylethyloxytosylate (0.5gm, 0.0018 mole) was added in it. Reaction was further continued till the completion of the reaction(4 hrs) as checked by TLC. Reaction mixture was poured into distilled water (50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get 2-phenylethyl isopropylcarbamate. Oil (yield 0.382 gm, 71.13 %). Example 11 :n-Octvl 3-methoxv benzyl carbamate Anhydrous pot. carbonate (5gms), m- methoxybenzylamine (0.574 ml,0.004 mole) were taken in dry DMF (30 ml) .Purified CO2 gas was rapidly bubbled into it at 90°C for 1 hr. Now tetrabutyl ammonium iodide (0.162 gm,0.0004 mole) was added in it. Reaction was continued for 1/2 hr. n-Octyloxytosylate (0.5gm, 0.0018 mole) was added in it. Reaction was further continued till the completion of the reaction(4 hrs) as checked by TLC. Reaction mixture was poured into distilled water(50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-octyl 3- methoxybenzylcarbamate (m.p.!37°C, Yield 0.405gm, 78.64 %). Example 12: Butyl n-octvl carbamate Anhydrous potassium carbonate (5 gms), n-octylamine(0.826ml,0.005 mole) were taken in dry DMF (30ml). Now purified CO2 gas was bubbled into it at 110°C for 1 hr then tetrabutyl ammonium iodide (0.2gm,0.0005mole) was added in it. Reaction was further continued for 1/2 hr; butyloxytosylate (O.Sgm, 0.002 mole) was added in it. Reaction was continued till the the completion of the reaction (4 hrs) as checked by TLC. Reaction mixture was poured into distilled water (50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get butyl n-octylcarbamate.Oil yield 0.398 gm, 83.78%). Example 13: Isoamvl n-octvl carbamate Anhydrous pot.carbonate (5gms), n-octylamine(0.854ml,0.005 mole)were taken in dry acetonitrile (25ml) .Purified CC>2 gas was rapidly bubbled into it at 80°C for 1 hr. Now tetrabutyl ammonium iodide (0.190 gm,0.0005 mole) was added in it. Reaction was continued for 1/2 hr. Isoamyloxytosylate (O.Sgm, 0.002 mole) was added in it. Reaction was further continued for till the completion of reaction (6 hrs) as checked by TLC. Reaction mixture was poured into distilled water (50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get isoamyl noctylcarbamate. Oil( yield 0.315 gm, 62.74 %). Example 14: 3- Phenylpropyl n-hexvl carbamate A mixure of anhydrous pot. carbonate (5 gms), hexyl amine(0.569 ml,0.004 mole) was taken in dry HMPA (35 ml) . Purified CO2 gas was rapidly bubbled into it at 80°C for 1 hr. Now tetrabutyl ammonium iodide (0.159 gm,0.0004mole) was added in it. Reaction was continued for 1/2 hr.3- Phenylpropyloxy tosylate (0.5gm, 0.0017 mole) was added in it. Reaction was further continued till the completion of the reaction(6 hrs) as checked by TLC. Reaction mixture was poured into distilled water (50ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get 3- phenylpropyl n-hexylcarbamate Oil (yield 0.347gm, 72.14 %). We claim: 1. A process for the preparation of carbamate of formula 1 (Formula Removed) Wherein R is an alkyl group containing 1-16 carbon atoms or an aromatic group such as phenyl, naphthyl, phenathryl, or a heteroaromatic such as quinoline, benzopyrans, n is 1 to 16, R1 is a lower alkyl such as methyl, ethyl, propyl, butyl, amyl or a branched chain lower alkyl such as isopropyl, isoamyl, or a cycloalkyi containing 3 to 8 carbon atoms, or an alkylaryl such as benzyl, ethylphenyl or an aromatic group such as phenyl, substituted phenyl, naphthyl, which comprises; reacting a tosyl ester of formula II (Formula Removed) Wherein R is as defined above in formula 1 and n is 1-16 with an amine of formula III, (Formula Removed) Wherein R1 is selected from a group consisting of a lower alkyl, branched chain lower alkyl, cycloalkyi, an alkylaryl, or an aryl group as defined above for the formula 1 in an organic aprotic solvent selected from dimethylsulphoxide (DMSO), dimethylformamide (DMF) acetonitrile, hexamethylphosphoramide (HMPA) in presence of CO2/metal carbonate selected from K2C03 Na2CO3, in presence of a base selected from tetrabutylammonium iodide (TBAI), benzyltrimethylammonium hydroxide (Triton B), at a temperature ranging between 50-120°C for a period ranging between 3-7 hrs, diluting the reaction mixture with water, extracting with water-immicible organic solvent as herein described and removing the solvent to get the desired carbamate. 2. A process as claimed in claim 1, wherein the aprotic solvent used is preferably dimethylsulphoxide for alkylamines. 3. A process as claimed in claims 1-2, wherein a preferred base used is TBAI for alkylaimes. 4. A process as claimed in claims 1-3, wherein the preferred temperature is ranging between 80 to 120°C. 5. A process as claimed in claims 1-6, wherein the water immicible solvent used is selected from benzene, toluene, ethylacetate. 6. A process for preparation of organic carbamtes substantially as described with reference to the examples.

Documents:

774-DEL-2002-Abstract-(13-02-2009).pdf

774-del-2002-abstract.pdf

774-DEL-2002-Claims-(05-03-2009).pdf

774-DEL-2002-Claims-(13-02-2009).pdf

774-del-2002-claims.pdf

774-del-2002-complete specification (granted).pdf

774-DEL-2002-Correspondence-Others-(05-03-2009).pdf

774-DEL-2002-Correspondence-Others-(13-02-2009).pdf

774-DEL-2002-Correspondence-Others-(16-03-2009).pdf

774-del-2002-correspondence-others.pdf

774-del-2002-correspondence-po.pdf

774-del-2002-description (complete)-(05-03-2009).pdf

774-DEL-2002-Description (Complete)-(13-02-2009).pdf

774-del-2002-description (complete).pdf

774-DEL-2002-Form-1-(05-03-2009).pdf

774-DEL-2002-Form-1-(16-03-2009).pdf

774-del-2002-form-1.pdf

774-del-2002-form-18.pdf

774-DEL-2002-Form-2-(13-02-2009).pdf

774-del-2002-form-2.pdf

774-DEL-2002-Form-3-(13-02-2009).pdf

774-del-2002-form-3.pdf