Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSITUTED 4-METHYL-COUMARIN

Abstract

The present invention involves a reaction that was carried out by heating ethylactoacetate and substituted phenol in the presence of 10-mo1% of iodine at 80oC. After completion, the reaction mixture was poured into ice-cold water, containing sodium thiosulphate and the products were separated by filtration. The crude product was purified by re-crystallization from hot ethanol to afford pure coumarin derivative of formula 3 (Schemie-3).

Full Text

This invention relates to an improved process for the preparation of substituted 4-methyi coumarin of general formula (I), wherein R is Me and R1 is selected from the group consisting of OH, COCH3, NH2 and CH3. More particularly, the present invention relates to an improved process for the preparation of 7-hydroxy-4-methyl coumarin (Coumarin 47 or Coumarin 460) and 7-amino-4-methyl coumarin (Umbelliferon-47). (Formula Removed) Of the large number of naturally occurring flavour compounds coumarin is one of the most widely distributed in the Plant kingdom. The coumarin and its derivatives are interesting from the point of view of their chemical constitution, a group of lactones derived from o-hydroxy cinnamic acid. In the class of coumarins, 4-methyl coumarins have enjoyed a special status as they form the care of industrially important coumarins like coumarin 47 or coumarin 460 on umbelliferon-47. The synthesis of coumarins and their derivatives has attended considerable attention from organic and medicinal chemists for many years as a large number of natural products contain this heterocyclic nucleus. They are widely used as additives in food, perfumes, cosmetics, pharmaceuticals and in the preparation of insecticides, optical bright-energy and dispersed fluorescent and laser dyes. The synthesis of 4-methyl coumarin derivatives have been mainly reported via the Pachmans condensation using various catalysts. Reference may be made to A. Russell. J. R. Frve. Org. Synth.. 1941. 21, 22, wherein von Pechmann reaction leads to various substituted coumarin derivatives. Classically, the process consists of the condensation of phenols with ß-keto esters in the presence of a variety of reagents and gives good yields of 4-substituted coumarins. Several acid catalysts have been used in the von Pechmann reaction including sulfuric acid, aluminium chloride, phosphorus pentoxide and trifluoroacetic acid. However, these catalysts have to be used in excess; for example, sulphuric acid in ten to twelve equivalent (H. von Pechmann. C. Duisberq. Chem. Ber. 1884. 17. 929). in fluoroacetic acid in three to four equivalents. (L. L. Woodes: J. Sapp. J. Org. Chem.. 1962. 27. 3703) and phosphorous pentoxide is required in a five fold excess (A. Robertson, W. F. Sandrock; C. B. Henry. J. Chem. Soc. 1931. 2426). Moreover, in some cases, mixtures of substituted phenols, j3-keto esters and the acidic catalyst were allowed to stand overnight or for a number of days or were heated above 150°C and undesired side products such as chromones in addition to coumarins were obtained. As a result, the disposal of excess acid waste leads to environmental pollution. Another reference may be made to B. M. Trost. F. D. Toste. J. Am. Chem. Soc, 1996. 118. 6305. wherein Trost and Toste reported a expensive Pd(0)-catalysed addition of phenols to alkynates in formic acid giving coumarins. In their reaction however, a Pd(0) species acts as the actual catalyst. The formic acid plays the important role in the catalytic cycle. Still another reference may be made to S. Hesse and G. Kirsch. Tetrahedron Lett.. 2002. 43.1213. wherein a rapid access to coumarin derivatives using Vilsmeier-Haack and Suzuki Cross-coupling reactions is described. Another reference may be made to I. Yavari. R. Hekmat-Shoar and A. Zonouzi. Tetrahedron Lett.. 1998. 39. 2391. a direct and operationally convenient approach to the synthesis of 4-carboxymethyl coumarins based on aromatic electrophilic substitution reaction between the conjugate base of substituted phenols and a vinyltriphenyl phosphonium salt was presented. Thus, reaction of phenols with dimethylacetylene dicarboxylate (DMAD) in presence of triphenylphosphine leads to the corresponding 4-carboxymethyl coumarins. (Formula Removed) Still another reference may be made to US Patent 1.920.494 (August 1. 1933). wherein Raschig found that, chloro compounds of o-cresol, when reacted with anhydrous sodium acetate gives coumarin. Processes based on chlorinated o-cresol esters have been used to a considerable extent in the commercial production of coumarin because of inexpensive starting materials such as the phosphate and carbamate. Fusion of 11dichioro-o-cresyl carbonate with potassium acetate at 150-200 °C yielded 71% of coumarin. In another reference U S Patent. 2.062.364 (December 1. 1936). G Kretchmer and C Collaud. C. A. 31 : p 711a. it was disclosed that alkali acetate in the fusion reaction could be replaced by acetic anhydride in the presence of metal catalysts, preferably 1% cobalt oxide, in which case acetyl chloride is formed and is recovered, yield of coumarin, 45%. Still another reference may be made to U S Patent. 3.859.311 (January. 1975) and 3.936.473 (February 3. 1976) that disclosed a method for producing coumarinis vinylation of phenol with methyl acrylate in acedic medium and in the presence of air. After 6 hrs, 51% coumarin and methyl-o-coumarate were produced in a condensation favouring ortho over para condensation in a ratio of 2,4:1.0. The p-coumarate, also formed, does not yield coumarin but the methyl-o-coumarate is converted into coumarin by continulusly passing it through a reaction zone at 200-350 °C. (Scheme-1). (Formula Removed) still another reference may be, made to A. J. Hoefnaqel. E. A. Gunneweqh. R. S. Downing and H. van Bekkum. J. Chem. Soc. Chem. Commun.. 1995. 225. wherein for 7-hydroxy-4-methyl coumarium which is useful as a starting material for the preparation of an insecticide (Hymeeromone) is obtained in good yields by applying zeolite H beta of Amberlyst-15. Another reference may be, made to Y. V. Subba Rao. S. J. Kerlkarni. M. Subrahmanvam and A. V. Rana Res. J. Chem. Soc. Chem. Commun.. 1993. 1456. wherein the formation of 4-methyl coumarin by cycloaddition of phenol with acetic anhydride over CeNaY zeolite has been described. Yet another reference may be made to S. Frere. V. thierv and T. Berson. Tetrahedron Lett.. 2001. 42. 2791. a synthesis of 7-amino coumarins was performed via the Peckmann reaction by microwave irradiation of the reactions on solid support (graphite/montmorillonite K10). In this convenient methodology the strong thermal effect due to graphite/microwave irradiation is associated with the acetic catalyst role of this clay. (Scheme-2). (Formula Removed) The present invention involves a reaction that was carried out by heating ethylacetoacetate and substituted phenol in the presence of 10-mol% of iodine at 80°C. After completion, the reaction mixture was poured into ice-cold water, containing sodium thiosulphate and the products were separated by filtration. The crude product was purified by re-crystallization from hot ethanol to afford pure coumarin derivative of formula 3 (Scheme-3). (Formula Removed) The novelty of the present invention lies in the use of effective molecular iodine as a catalyst in a catalytical process for the preparation of high yield of substituted 4-methyl coumarin. Accordingly the present invention provides an improved process for the preparation of substituted 4-methyl coumarin of the general formula (I), wherein R is Me and R1 is selected from the group consisting of OH, OCH3, NH2, COCH3 and CH3, which comprises (Formula Removed) reacting p-keto ester and substituted phenol in the presence of about 10mol% molecular iodine, at a temperature in the range of 60-90°C, for a period of 1-1.5 hr, pouring the above said reaction mixture into ice-cold water containing sodium thiosulphate and separating the compound by filtration followed by re-crystallization from hot alcoholic solvent to obtained the desired pure compound. In an embodiment of the present invention, the p-keto ester used is ethyl acetoacetate. In yet another embodiment, the substituted phenol used is selected from the group consisting of resorcinol, 3 methyl phenol, orcinol, napthol, pholoroglucinol, m-amino phenol and acetophenone. In yet another embodiment, the temperature used is in the range of 70-80 °C. In yet another embodiment, the substituted 4 methyl coumarin obtained is selected from the group consisting of 7-hydroxy-4-methyl coumarin, 7-methoxy-4-methyl coumarin, 5-hydroxy-4,7-dimethyl coumarin, ,7-dihydroxy-4-methyl coumarin, 4-methyl-p-nathopyrone, 7-amino-4-methylcoumarin and 7-amino-4-methylcoumarin and 7-hydroxy-6-acyl. In still another embodiment, the yield of substituted 4 methyl coumarin obtained is in the range of 80-96%. The details of the method disclosed in this invention have been described in the following specific examples, which are provided to illustrate the invention only, and these should not be construed to limit the scope of the present investigation. EXAMPLE 1 a) Synthesis of 7-hydroxy-4-methyl coumarin, 3a, (R=Me, R1=OH) A mixture of resorcinol (1.10 g, 10 mmol) and ethylacetoacetate (1.30 g, 10 mmol) was heated at 80 oC in the presence of molecular iodine (0.1 g). After completion (60 min, monitored by TLC), the reacation mixture was cooled to room temperature and was poured into ice-cold water (30 ml) containing 2 g of sodium thiosulphate and stirred for 5 to 10 min. The crude product was collected by filtration under suction (water aspirator) and washed with cold water (30ml) and then recrystallised from hot ethanol to afford 7-hydroxy-4-methyl coumarin in 96% yield, mp 183-184 °C. EXAMPLE 2 b) Synthesis of 7-methoxy-4-nnethyl coumarin., 3b, (R = Me, R1 = OMe) A mixture of 3-methoxy phenol (1.29 g, 10 mmol) and ethylacetoacetate (1.30 g, 10 mmol) was heated at 80 oC in the presence of molecular iodine (0.1 g). After completion (70 min, monitored by TLC), the reacation mixture was cooled to room temperature and was poured into ice-cold water (30 ml) containing 2 g of sodium thiosulphate and stirred for 5 to 10 min. The crude product was collected by filtration under suction (water aspirator) and washed with cold water (30ml) and then recrystallised from hot ethanol to afford 7-methoxy-4-methyl coumarin in 94% yield, mp 161-162 °C. EXAMPLE 3 c) Synthesis of 5-hydroxy-4,7-dimethyl coumarin, 3c, (R = Me, R1 = OH) A mixture of orcinol (1.24 g, 10 mmol) and ethylacetoacetate (1.30 g, 10 mmol) was heated at 80 °C in the presence of molecular iodine (0.1 g). After completion (75 min, monitored by TLC), the reaction mixture was cooled to room temperature and was poured into ice-cold water (30 ml) containing 2 g of sodium thiosulphate and stirred for 5 to 10 min. The crude product was collected by filtration under suction (water aspirator) and washed with cold water (30ml) and then recrystallised from hot ethanol to afford 7-hydroxy-4-methyl coumarin in 93% yield. It forms colourless needles, mp 243-45 °C. EXAMPLE 4 d) Synthesis of 5,7-dihydroxy-4-methyl coumarin, 3d, (R = Me, R1 = OH) A mixture of pholoroglucinol (1.26 g, 10 mmol) and ethylacetoacetate (1.30 g, 10 mmol) was heated at 80 °C in the presence of molecular iodine (0.1 g). After completion (80 min, monitored by TLC), the reacation mixture was cooled to room temperature and was poured into ice-cold water (30 ml) containing 2 g of sodium thiosulphate and stirred for 5 to 10 min. The crude product was collected by filtration under suction (water aspirator) and washed with cold water (30ml) and then recrystallised from hot ethanol to afford 5,7-dihydroxy-4-methyl coumarin in 98% yield, mp 284,5-285 °C. EXAIVIPLE 5 e) Synthesis of 4-methyl-(3-nathopyrone, 3e, (R = Me) A mixture of D-napthol (1.44 g, 10 mmol) and ethylacetoacetate (1.30 g, 10 mmol) was heated at 80 °C in the presence of molecular iodine (0.1 g). After completion (130 min, monitored by TLC), the reacation mixture was cooled to room temperature and was poured into ice-cold water (30 ml) containing 2 g of sodium thiosulphate and stirred for 5 to 10 min. The crude product was collected by filtration under suction (water aspirator) and washed with cold water (30 ml) and then recrystallised from hot ethanol to afford 4-methyl-n-nathopyrone in 92% yield, mp 183-184 °C. EXAMPLE 6 f) Preparation of 7-amino-4-methylcoumarin, 3f, (R = Me, R1 = NH2). A mixture of m-aminophenol (1.09 g, 10 mmol) and ethylacetoacetate (1.30 g, 10 mmol) was heated at 80 °C in the presence of molecular iodine (0.1 g). After completion (120 min, monitored by TLC), the reacation mixture was cooled to room temperature and was poured into ice-cold water (30 ml) containing 2 g of sodium thiosulphate and stirred for 5 to 10 min. The crude product was collected by filtration under suction (water aspirator) and washed with cold water (30 ml) and allowed to dry and finally purified by column chromatography using petroleum ether-ethylacetate (3:1) as the eluent Yield 85%, mp 220-224 °C EXAMPLE 7 g) Synthesis of 7-hydroxy-6-acyl coumarin, 3g, (R =OH, R1=COMe) A mixture of acetophenone (1.50 g, 10 mmol) and ethylacetoacetate (1.30 g, 10 mmol) was heated at 80 °C in the presence of molecular iodine (0.1 g). After completion (110 min, monitored by TLC), the reacation mixture was cooled to room temperature and was poured into ice-cold water (30 ml) containing 2 g of sodium thiosulphate and stirred for 5 to 10 min. The crude product was collected by filtration under suction (water aspirator) and washed with cold water (30 ml) and allowed to dry and then recrystallised from hot ethanol to afford 7-hydroxy-6-acyl coumarin,in 80% yield, mp 163-165 °C. The main advantages of the present invention are: 1. The method is very simple and is carried out at one-pot at a temperature range of 70-80 °C. 2. The work-up procedure is very simple. 3. The product obtained from the reaction mixture is pure and the yield is 90-96%. 4. The process avoids the need for isolation of any intermediates, thereby avoiding any losses during such isolation 5. The process eliminates the use of expensive palladium and the catalyst used in very cheap 6. The process avoids the use of any organic solvents. WE Claim 1. An improved process for the preparation of substituted 4-methyl coumarin of the general formula (I), wherein R is Me and R1 is selected from the group consisting of OH, OCH3, NH2, COCH3 and CH3, which comprises Formula Removed reacting p-keto ester and substituted phenol in the presence of about 10mol% molecular iodine, at a temperature in the range of 60-90°C, for a period of 1-1.5 hr, pouring the above said reaction mixture into ice-cold water containing sodium thiosulphate and separating the compound by filtration followed by re-crystallization from hot alcoholic solvent to obtained the desired pure compound. 2. An improved process as claimed in claim 1, wherein the p-keto ester used is ethylacetoacetate. 3. An improved process as claimed in claim 1&2, wherein the substituted phenol used is selected from the group consisting of resorcinol, 3 methyl phenol, orcinol, napthol, pholoroglucinol, m-amino phenol and acetophenone. 4. An improved process as claimed in claims 1-3, wherein the temperature used is in the range of 70-80 °C. 5. An improved process as claimed in claims 1-4, wherein the substituted 4 methyl coumarin obtained is selected from the group consisting of 7-hydroxy-4-methyl coumarin, 7-methoxy-4-methyl coumarin, 5-hydroxy-4,7-dimethyl coumarin, ,7-dihydroxy-4-methyl coumarin, 4-methyl-B-nathopyrone, 7-amino-4-methylcoumarin and 7-hydroxy-6-acyl coumarin. 6. An improved process as claimed in claims 1-5, wherein the yield of substituted 4 methyl coumarin obtained is in the range of 80-96%. 7. An improved process as claimed in claims 1-6, wherein the alcoholic solvent used, for re-crystallization of the compound is selected from methanol and ethanol.

Documents:

536-del-2005-Abstract.pdf

536-del-2005-Claims.pdf

536-del-2005-Correspondence (Others).pdf

536-DEL-2005-Correspondence Others-(19-09-2011).pdf

536-del-2005-Correspondence-po.pdf

536-del-2005-Description (Complete).pdf

536-del-2005-Form-1.pdf

536-del-2005-Form-18.pdf

536-del-2005-Form-2.pdf

536-del-2005-Form-3.pdf

536-del-2005-Form-5.pdf