Title of Invention

A PROCESS FOR PREPARATION OF CARBAMATE ESTERS

Abstract

A process for the preparation of carbamate esters by reacting an alcohol with an amine in an aprotic solvent selected from dimethylsulphoxide (DMSO), dimethylformamide (DMF), acetonitrile and hexamethyl phosphoramide (HMPA) with CO2, in the presence of triphenylphosphine (Ph3P) and diethylazadicarboxylate (DEAD) at temperature ranging between 80-120°C for a period of 3-5 hers., diluting the reaction mixture with distilled water, extracting with water immiscrible organic solvent selected from benzene, toluence, ethyl acetate, and removal of the solvent to get the desired product.

Full Text

The present invention provides a process for preparation of carbamate esters . It relates to a process for the preparation of organic carbamates, particularly relates to the preparation of carbamates of formula I, wherein R is an alkyl group containing 1-10 carbon atoms or an aromatic group such as phenyl, naphthyl, phenanthryl, or a heteroaromatic such as quinoline, benzopyrans, n is 1 to 10 R1 and R2 individually is a lower alkyl selected from methyl, ethyl, propyl, butyl, amyl, or a branched chain lower alkyl selected from isopropyl, isoamyl, or a cycloalkyl containing 3 to 8 carbon atoms, or an alkyl-aryl selected from benzyl, ethyl-phenyl, or an aromatic group such as phenyl, substituited phenyl, naphthyl. Organic carbamates find use as agrochemicals (pesticides, fungicides, herbicides) (Ghosh, SK, Mc. Kee, SP, Thompson, WJ, Darke, PL, Zugay, JC J. org. Chem. 1993, 56, 1025-1025), pharmaceuticals (Adams, P. Barson, FA, Chem. Rev. 1965, 65, 567), 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) Prior Art Synthesis of carbamates has been described by direct alcoholysis of phosgene and its derivatives (Satchell, S, Chem. Rev. 1975,4, 231), aminolysis of chloroformates. (Formula Removed) (Raucher, J. Synthetic Commun. 1985, J_5_, 1025) and alcoholysis of isocyanates (Entelis, N.; Russ. Chem. Rev. 1966, 35. 917-950) as shown in equations 1 and 2 respectively. In all these above processes, highly toxic and harmful reagents such as phosgene or its derivatives are used. In the recent past carbon dioxide, a cheap and harmless reagent has been used for carbamate ester synthesis (Aresta, M.; Quranta, E. Tetrahedron, 1992, 48, 1515-1530 & Inesi, A.; Muccinate, V.; Rossi, L. J. Org. Chem, 1998 63^1337-1338) utilizing alkyl halides as starting material but this method takes much more time and gives poor yield. Furthermore this method uses of cesium carbonate which is costly. Conversion of alkyl halides to carbamates has also been achieved through a more condusive method using C(V base system (Chaturvedi, D.; & Ray, S. Indian patent application no: 0457DEL2003, filing date: 25 th march 2003). In an alternative procedure alcoholic tosylates have been converted into carbamates by their treatment with CCV K2CO3 in dry DMSO in the presence of TBAI as a phase transfer catalyst (Chaturvedi, D.; Kumar, A.; Ray, S. Indian Patent application no: 0774DEL2002, filing date: 25. 7. 2002) and carbamate esters have been also prepared by using alkyl halides as a starting material in the CCV K^COs system using catalytic amount of TBAI (Chaturvedi, D.; Kumar, A.; Ray, S. Indian patent application no: 1190DEL2003). The main objective of the present invention is to provide a one pot synthesis of carbamate esters using Mitsunobu's reagent. The another objective of the present invention is to provide a convenient, economical method avoiding use of hazardous material. According to the present invention provides a process for the preparation of carbamate esters of formula I, (Formula Removed) wherein R is an alkyl group containing 1-10 carbon atoms or an aromatic group such as phenyl, naphthyl, phenanthryl, or a heteroaromatic selected from quinoline and benzopyrans; n is 1 tolO;, RI and R2 individually is a lower alkyl selected from methyl, ethyl, propyl, butyl, amyl; or a branched chain lower alkyl selected from isopropyl, isoamyl; or a cycloalkyl containing 3 to 8 carbon atoms; or an alkyl-aryl selected from benzyl, ethyl-phenyl; or an aromatic group selected from phenyl, substituted phenyl, naphthyl, which comprises reacting an appropriate alcohol of formula II, (Formula Removed) wherein R is same as defined above in formula I and n is 1-10 with an appropriate amine of formula III, (Formula Removed) wherein RI and R2 individually is same as defined above for the formula I; in an organic aprotic solvent selected from dimethylsulphoxide (DMSO), dimethylformamide(DMF), acetonitrile and hexamethyl phosphoramide (HMPA) with CO2j in the presence of triphenylphosphine (PhsP) and diethylazadicarboxylate (DEAD) i.e.Mitsunobu's reagent, at an elevated temperature ranging between 80-120°C for a period of 3-5 hrs; diluting the reaction mixture with distilled water, extraction with water immiscible organic solvent such as benzene, toluene, ethyl acetate, and removal of the solvent to get the desired product. In an embodiment of the present inventionthe aprotic solvent used is preferably DMSO. The following examples are given by way of illustration and should not construed to limit the scope of the reaction Example 1: 2-Phenylethyl n-butyl carbamate. n-Butyl amine (0.828 ml, 0.009 mole) was taken in dry DMSO (60 ml) and dried CO2 gas was rapidly bubbled into it at 90°C for 1/2 hr. To the reaction mixture triphenyl phosphine (2.2 gm, 0.009 mole) was added and then diethylazadicarboxylate (1.33 ml, 0.009 mole) was slowly added in two or three small portions. Now 2-phenylethyl alcohol (1 ml, 0.009 mole) was added in it. Reaction was continued till the completion of the reaction (3.5 hrs) as checked by TLC. Reaction mixture was poured into distilled water (80ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get 2-phenylethyl n-butylcarbamate, oil (Yield 1.68 gm, 90.5%). Example 2:3-Phenylpropyl n-hexyl carbamate. n-Hexyl amine (0.98 ml, 0.007 mole) was taken in dry DMSO (60 ml) and dried CO2 gas was rapidly bubbled into it at 90°C for 1/2 hr. To the reaction mixture triphenyl phosphine (1.92 gm, 0.007 mole) was added and then diethylazadicarboxylate (1.27 ml, 0.007 mole) was slowly added in two or three small portions. Now 3-phenylpropyl alcohol (1 ml, 0.007 mole) was added in it. Reaction was continued till the completion of the reaction (3 hrs) as checked by TLC. Reaction mixture was poured into distilled water (80ml) 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 1.83 gm, 95%). Example 3:2-PhenyIethyI di-isopropyl carbamate. Diisopropyl anrine (1.17ml, 0.009 mole) was taken in dry DMSO (60 ml) and dried CO2 gas was rapidly bubbled into it at 95 °C for 1/2 hr. To the reaction mixture triphenyl phosphine (2.2 gm, 0.009 mole) was added and then diethylazadicarboxylate (1.33 ml, 0.009 mole) was slowly added in two or three small portions. Now 2-phenylethyl alcohol (1 ml, 0.009 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 (80ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get 2-phenylethyl di-isoproylcarbamate, oil (Yield 1.68 gm, 81 %). Example 4: 2-Phenylpropyl diisopropyl carbamate. Diisopropyl amine (0.98 ml, 0.007 mole) was taken in dry DMSO (60 ml) and dried CO2 gas was rapidly bubbled into it at 100°C for 1/2 hr. To the reaction mixture triphenyl phosphine (1.92 gm, 0.007 mole) was added and then diethylazadicarboxylate (1.27 ml, 0.007 mole) was slowly added in two or three small portions. Now 3-phenyl propyl alcohol (1 ml, 0.007 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 (80ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get 3-phenylpropyI di-isopropyl carbamate, oil (Yield 1.65 gm, 85.6 %). Example 5: n-Dodecyl n-hexylcarbamate. n-Hexyl amine (0.63 ml, 0.005 mole) was taken in dry DMSO (60 ml) and dried CO2 gas was rapidly bubbled into'it at 95°C for 1/2 hr. To the reaction mixture triphenyl phosphine (1.25 gm, 0.005 mole) was added and then diethylazadicarboxylate (0.83 ml, 0.005 mole) was slowly added in two or three small portions. Now n-dodecyl alcohol (1 ml, 0.005 mole) was added in it. Reaction was continued till the completion of the reaction (3.5 hrs) as checked by TLC. Reaction mixture was poured into distilled water (80ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-dodecyl n-hexyl carbamate, oil (Yield 1.47 gm, 96.5 %). Example 6: n-Octyl 3-methoxybenzyl carbamate. m-Methoxy benzyl amine (0.82 ml, 0.006 mole) was taken in dry DMSO (60 ml) and dried COa gas was rapidly bubbled into it at 90°C for 1/2 hr. To the reaction mixture triphenyl phosphine (1.7 gm, 0.006 mole) was added and then diethylazadicarboxylate (1.2 ml, 0.006 mole) was slowly added in two or three small portions. Now n-dodecyl alcohol (1 ml, 0.006 mole) was added in it. Reaction was continued till the completion of the reaction (3.5 hrs) as checked by TLC. Reaction mixture was poured into distilled water (80ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-octyl 3-methoxybenzyl carbamate, m.p.l37°C (Yield 1.72 gm, 92.4%). Example-7: n-Hexyl n-butyl carbamate. n-Butyl amine (0.8 ml, 0.008 mole) was taken in dry DMSO (60 ml) and dried CO2 gas was rapidly bubbled into it at 100°C for 1/2 hr. To the reaction mixture triphenyl phosphine (2 gm, 0.008 mole) was added and then diethylazadicarboxylate (1.4 ml, 0.008 mole) was slowly added in two or three small portions. Now n-hexyl alcohol (1 ml, 0.008 mole) was added in it. Reaction was continued till the completion of the reaction (4hrs) as checked by TLC. Reaction mixture was poured into distilled water (80ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-dodecyl n-hexyl carbamate, oil (Yield 1.43 gm, 89.2 %). Example 8: n-Hexyl cyclohexylcarbamate. n-Cyclohexyl amine (0.92 ml, 0.008 mole) was taken in dry DMSO (60 ml) and dried CO2 gas was rapidly bubbled into it at 95°C for 1/2 hr. To the reaction mixture triphenyl phosphine (2 gm, 0.008 mole) was added and then diethylazadicarboxylate (1.4 ml, 0.008 mole) was slowly added in two or three small portions. Now n-dodecyl alcohol (1 ml, 0.008 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 ( 80ml) and extrated with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-hexyl cyclohexyl carbamate, oil ( Yield 1.63 gm, 90.4 % ). Example 9: Isoamyl n-hexyl carbamate n-Hexyl amine (1.21 ml, 0.009 mole ) was taken in dry DMSO ( 60 ml) and dried CO2 gas (2.4 gm, 0.009 mole) was added and then diethylazadicarboxylate (1.6 ml, 0.009 mole) was slowly added in two or three small portions. Now isoamyl alcohol (1 ml, 0.009 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 (80ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get isoamyl n-hexyl carbamate, oil (Yield 1.82 gm, 92.4 %). Example 10: n-Pentyl isoamyl carbamate. n-Isoamyl amine (1 ml, 0.009 mole) was taken in dry DMSO (60 ml) and dried CCh gas was rapidly bubbled into it at 100°C for 1/2 hr. To the reaction mixture triphenyl phosphine (2.4 gm, 0.009 mole) was added and then diethylazadicarboxylate (1.6 ml, 0.009 mole) was slowly added in two or three small portions. Now n-penryl alcohol (1 ml, 0.009 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 (80ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-Pentylisoamylcarbamate, oil (Yield 1.66 gm, 89.8 %). Example 11: n-Buryl n-hexylcarbamate. n-Hexyl amine (1.45 ml, 0.01 mole) was taken in dry DMSO (60 ml) and dried CO2 gas was rapidly bubbled into it at 100°C for 1/2 hr. To the reaction mixture triphenyl phosphine (2.87 gm, 0.01 mole) was added and then diethylazadicarboxylate (1.9 ml, 0.01 mole) was slowly added in two or three small portions. Now n-butyl alcohol (1 ml, 0.01 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 (80ml) and extracted with ethyl acetate thrice. Organic layer was separated and dried over anhydrous sodium sulphate, and then concentrated to get n-dodecyl n-hexyl carbamate, oil (Yield 1.9 gm, 86.5 %). Example 12: 2-Naphthyloxyethyl cyclohexyl carbamate. n-Butyl amine (0.53 ml, 0.005 mole) was taken in dry DMSO (60 ml) and dried CC>2 gas was rapidly bubbled into it at 95°C for 1/2 hr. To the reaction mixture triphenyl phosphine (1.4 gm, 0.005 mole) was added and then diethylazadicarboxylate (0.926 ml, 0.005 mole) was slowly added in two or three small portions. Now 2-naphthyloxy ethyl alcohol (1 ml, 0.005 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 (80ml) 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 1.47 gm, 96.5 %). We claim: 1. A process for the preparation of carbamate esters of formula 1, (Formula Removed) wherein R is an alkyl group containing 1-10 carbon atoms or an aromatic group such as phenyl, naphthyl, or a heteroaromatic selected from quinoline and benzopyrans, n is 1 to 10, R1 and R2 individually is a lower alkyl selected from methyl, ethyl, propyl, butyl, amyl, or a branched chain lower alkyl selected from isopropyl, isoamyl, or a cycloalkyl containing 3 to 8 carbon atoms, or an alkyl-aryl selected from benzyl, ethyl-phenyl, or an aromatic group selected from phenyl, substituted phenyl, naphthyl, which comprises reacting an alcohol of formula II, (Formula Removed) wherein R is same as defined above in formula I and n is 1-10 with an amine of formula III (Formula Removed) wherein R1 and R2 individually is same as defined above for the formula I, in an organic aprotic solvent selected from dimethylsulphoxide (DMSO), dimethylformamide (DMF), acetonitrile and hexamethyl phosphoramide (HMPA) with CO2, in the presence of triphenylphosphine (Ph3P) and diethylazadicarboxylate (DEAD) at temperature ranging between 80-120°C for a period of 3-5 hers., diluting the reaction mixture with distilled water, extracting with water immiscrible organic solvent selected from benzene, toluence, ethyl acetate, and removal of the solvent to get the desired product. 2. A process as claimed in claim 1, wherein the aprotic solvent used is preferably dimethyl sulphoxide . 3. A process for preparation of carbamate esters as herein described with reference to examples accompanying the specification.

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