Title of Invention | "AN IMPROVED PROCESS FOR PREPARATION OF PENTA SUBSTITUTED PYRIDINES" |
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Abstract | An imroved process for the preparation of pentasubstituted pyridines: An improved process for the preparation of pentasubstituted ipyridines by aromatizing dihydropyridine and reacting with oxidizing agent selected from iodine/inorganic base or peroxide optionally in presence of a metal catalyst in an organic solvent at a temperature ranging between -5 to 100°C for a period ranging between 30 minutes to 28 hours, recovering and separating pentasubstituted pyridines by conventional methods. |
Full Text | The present invention relates to an improved process for the preparation of pentasubstituted pyridines. Pentasubstituted pyridines 1 shown in the drawing accompanying this specification are synthetic intermediate required in production of drugs such as cerivastatin, a drug used in the administration of atheroscerolosis and drugs used for other metabolic disorder. The pentasubstituted pyridines 1 are produced from corresponding 1,4-dihydropyridines 2 which in turn are obtained by 3 component Hanztsch synthesis from an aldehyde, a ß-keto ester or a nitrile and ammonia. (Chem. Review 1996, 96, 339). The oxidative aromatisation of 1,4-dihydropyridines produces pyridine. The prior art of conversion of pentasubstituted 1,4-dihydropyridine to pentasubstituted pyridine is documented in several reviews. [J. Kuthen; Industrial Engineering Chemistry, Product. Research and Development, 1982, 21, 191; A. Saurius, G. Dubus; Heterocycles, 1988, 27, 221; A,. I. Meyer ea al Chemical Reviews, 1982, 82, 223. and references cited in a recent paper by R.S. Verma etal, Tetrahedron Letters, 1999, 40, 21]. The oxidizing agents which can effect oxidative aromatisation of 1,4-dihydropyridines 2 to pyridines 1 include 2,3-dichloro-5, 6-dicyanobenzoquinone (DDQ), salts and derivatives of toxic transitional metal elements such as Cr, Mn, Bi, Ce etc and nitric acid, bromine etc. The high cost and toxic nature of DDQ makes it prohibitive to use in large scale production of pentasubstituted pyridines 1. The use of transitional metal salts pose environmental problems and requires tedious effluent treatment. The other oxidizing agents such as bromine, nitric acid. Invariably produces undesired side products e.g. bromopyridines or nitro pyridines. The conversion efficiency of oxidation by aerial oxygen in presence of noble metal catalysts is low. The main object of the present invention is to provide an improved process of preparation of penta substituted pyridines 1 in high yield from pent substituted 1,4-dihydropyridines 2 by employing a environmentally benign, convenient, safe regent which obviates the drawbacks as detailed above. Accordingly, the present invention relates to an improved process for the preparation of pentasubstituted pyridines of formula 1 shown in the drawing accompanying this specification wherein R1= R5 = methyl, ethyl, isopropyl, cyclopropyl, pentyl, phenyl, benzyl, 2-phenylethyl and R2=R4 nitrile, phenyl, carbmethoxy, carboethoxy, R3=alkyl, isobutyl, aryl aryalkyl, substituted aryl which comprises aromatizing dihydropyridine of formula 2 wherein R1, R2, R3, R4, R5 are same as given for formula 1 by reacting with oxidizing agent selected from iodine/inorganic base or peroxide such as herein described optionally in presence of a metal catalyst in an organic solvent at a temperature ranging between -5 to 100°C for a period ranging between 30 minutes to 28 hours, recovering and separating pentasubstituted pyridines by conventional methods. In an embodiment of the invention the solvent used for aromatization by iodine/inorganic base may be selected from chlorinated hydrocarbon such as dichloromethane, chloroform, dichloroethane, ethers such as diethyl ether, dioxane, THF, ester such as ethyl acetate, isopropyl acetate, preferably dichloromethane. In another embodiment of the invention the amount of iodine employing to oxidize compound of formula 2 to penta substituted pyridine 1of formula, is 1 to 4 molar proportion preferably 2 molar proportion with respect to dihydropyridine. In yet another embodiment of the invention the oxidative aromatization of 2 to 1 may be carried between 0 to 70 ° c preferably at 35° to 55 °c. In still another embodiment of the invention iodine may be removed by treatment of sodium thiosulphate and products may be isolated conveniently by recrystallization or distillation. In still another embodiment of the invention the aromatisation of 2 to 1. may be carried out in presence of a metal catalyst selected from Ni, W, Mo V, Co, Rh, Ru Pd, Pt preferably Pd. In yet another embodiment of the invention the metal catalyst may be supported on an inert medium such as silica gel, alumina, zeolite, char- coal preferably char -coal. In still another embodiment of the invention the oxidizing agent used in (X)nversion of 2 to 1 may be selected from hydrogen peroxide, cumene hydro peroxide, tert-butyl hydro peroxide preferably tert-butyl hydroperoxide. In another embodiment of the invention the solvent used during oxidation with peroxide may be selected from benzene, toluene, dichloromethane, , acetic acid propionic acid preferably a mixture of toluene and acetic acid. In the drawing accompanying this specification figure 1 represents penta-substituted pyridines, and fig figure 2 represents penta-substituted pyridines 1,4-dihydro pyridin. 2, 3, diisopropyl-3, 5-dicarboethoxy-4-(4-fluorophenyl) pyhdilne is represented by Fig3 figure 4 represents 2, 3, diisopropyi-3, 5-dicarboethoxy-4-{4-fluorophenyl)-1:, 4 dihydro pyridilne 4, (R=F) Figure 5 represents 2, 6 dimethyl-3, 5-dicarbomethoxyi4r( 4-chlorophenyl) pvridine(R=Cl. 2, 6 dimethyl-3, 5-dicarbomethoxy-4-( 4 -chlorophenyl) 1 , 4-dihydroyridine is represented by 6 ( R= CI). the present invention provides an improved process for the preparation penta-substituted pyndines which comprises of reacting penta-substituted dihydropyhdines 2 (where R1= alkyl, aryl, aryl alkyl R2= nitrile, carboxyalkyl; R3 aryl alkyl, R 4= alkyl, aryl, R 5 = alkyl aryl, arylalky! in an aprotic solvent such as toluene, acetonitrile, dichloromethane, chloroform, 1, 4-dioxane, diethyl ether, dichloromethane preferably dichloromethane with iodine in presence of inorganic base such as potassium carbonate , sodium bicarbonate , lithium carbonate , sodium carbonate preferably potassium carbonate at temp. between-5° c to 100° C preferably at 35 ° c. to afford penta-substituted pyridine (1) in 80 - 92 % yield , alternatively reaction of pent substituted dihydropyridine 2_in acetic acid with an oxidizing agent such as per acetic acid , hydrogen peroxide, cumene hydro peroxide, tert - butyl hydroperoxide preferably tert-butyl hydro peroxide in presence of a catalyst such as palladium black ,5 % pd on alumina, platinum oxide, Pt / C preferably 5% palladium on charcoal in ratio of 0.1-10 %_mole percentage preferably 2 mole % at 0 - 60 ° C preferably at 40 °C to afford pent substituted pyridines of formula 1 in 85 % yield . In an embodiment of the present invention 1,4-dihydropyridines are oxidized to pyridines I by the mediation of iodine in presence of an inorganic base in excellent yield. In another embodiment of the present invention penta-substituted 1,4-pyridines are treated with hydroperoxides in presence of noble metal catalysts to furnish corresponding pyridines in high yield. The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention. Example 1 To a stirred slurry of 2, 6 di-isopropyl-3, 5-dicarboethoxy-4-(4-fluorophenyl) -1, 4 dihydro pyridilne 4, (R=F) (40 .4 g, 0.1 mol) in dichloroethane (200 ml), iodine (14 g ), anhydrous potassium carbonate (12 g ) were added and slurry is stirred for 28 hrs at ambient temperature. The slurry was washed with (300 ml) of water, sodium thiosulphate solution and finally dried over anhydrous sodium sulphate, filtrated and evaporated. This crude product after crystallization from hexane gave 34 g of the product 3 (R = F ). M . P. 78-80. N M R: CDCI3 0.95 (d, 12 H), 1.2 (t, 6 H), 3.8 ( m,2 H), 4,2 ( m,4 H), 7.4 (m, 4 H) Example 2 : To a stirred slurry of 2, 6, diisopropyl -3,5- dicarboethoxy-4- (4 -chlorophenyl ) -1, 4 dihydro pyridilne 4 , ( R=CI) (80.8 g , 0.2M ) in DCE , iodine (50 g ), anhydrous potassium carbonate (40 g ) were added and slurry was stirred for 12 hrs at 50 °. C. The mixture is cooled and diluted with ether. The organic layer was separated and washed with sodium thiosulphate 5%, 2 x 100 ml, saturated with brine (1x100 ml ) , and dried anhydrous sodium sulphate, filtered, and evaporation of solution offered 78.8 g crude which is recrystillazation from Hexane to obtain 73 .0 g of crystalline product 3 (R= CI) (90 %), m.p. : 82-84 ° c N M R: CDCI3 1.0 5 (d,12 H),1.24 (t, 6 H)„ 3.8 5( m,2 H) , 4,23 ( m,4 H), 7.4 8(m,4 H) Example 3 : To stirred solution of 2, 6-diethyl-3, 5- dicarbomethoxy, 4-(4-chlorohenyl)-1, 4- dihydropyridine 6 (3.6g) in toluene 30 ml), palladium charcoal (10 %, 0 . 1 g ) was added . To the resulting slurry, a solution of tert-butylhydroperoxide (70 %, 5 ml) in acetic acid (15ml) is added and stirred of 40 minutes. The catalyst is filtered and filtrate with 15 % sodium bicarbonate solution, organic layer separated followed by washing it with brine, drying and filtration afforded the crude product which is recrystallized from hexanes yield 2.9 (74 %). m.p: 55-57 °c N M R: CDCI3 1.7 5 (s, 6 H),3.8 5( m,2 H), 3,9 3 ( s,6 H), 7.4 8(m,4 ). Advantages: The following are the advantage achieved in the present invention. The oxidizing agents hitherto known to convert penta-substituted dihydropyridine are compound of Manganese, Chromium, Bismuth and dichlorodicyanoquinone. (DDQ) The employment of these reagents require disposal of solid waste. The other known reagent used are nitric acid, bromine etc. which gives undesired side products. DDQ is highly toxic and costly reagent. Use of iodine or peroxides described in the present invention eliminate above problem and affords high yield of pure product i.e. pentasubstituted pyridines 1 Iodine is a cheap and non hazardous agent. No effluent treatment or solid disposal is required during the work up of the product. The other reagent i.e. tert-butylhydroperoxide employed in the conversion of dihydropyridine 2 to pyridine 1 is also safe and requires no waste product disposal. As the iodine and peroxides are cheap, safe and convenient reagents, production of pentasubstituted pyridines employing these reagents have advantages over Mn, Cr or DDQ. We claim ; 1. An improved process for the preparation of pentasubstituted pyridines of formula 1 shown in the drawing accompanying this specification wherein R1 = R5 = methyl, ethyl, isopropyl, cyclopropyl, pentyl, phenyl, benzyl, 2-phenylethyl and R2=R4 nitrite, phenyl, carbmethoxy, carboethoxy, R3=alkyl, isobutyl, aryl aryalkyi, substituted aryl which comprises aromatizing dihydropyridine of formula 2 wherein R1, R2, R3, R4, R5 are same as given for formula 1 by reacting with oxidizing agent selected from iodine/inorganic base or peroxide such as herein described optionally in presence of a metal catalyst in an organic solvent at a temperature ranging between -5 to 100°C for a period ranging between 30 minutes to 28 hours, recovering and separating pentasubstituted pyridines by conventional methods. 2. An improved process as claimed in claim 1 wherein the solvent used for aromatization by iodine/inorganic base is selected from chlorinated hydrocarbon such dichloromethane, chloroform, dichioroethane, ethers such as diethyl ether, dioxane, THF, ester such as ethyl acetate, isopropyl acetate, preferably dichloromethane. 3. An improved process as claimed in claims 1-2 wherein the inorganic base used is selected from sodium bi-carbonate, potassium bi-carbonate, sodium acetate, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate preferably potassium carbonate. 4. An improved process as claimed in claims 1-3 wherein the amount of iodine employing to oxidize compound of formula 2 to penta substituted pyridine of formula 1 is 1 to 4 molar proportion preferably 2 molar proportion with respect to dihydropyridine. 5. An improved process as claimed in claims 1-4 wherein the oxidative aromatization of formula 2 to 1 is carried between 0 to 70°C preferably at 35° to 55°C. 6. An improved process as claimed in claims 1-5 wherein excess of iodine is removed by treatment of sodium thiosulphate and product is isolated conveniently by recrystallization or distillation. 7. An improved process as claimed in claims 1-6 wherein aromatisation of formula 2 to 1 is carried out in presence of a metal catalyst selected from Ni, W, Mo V, Co, Rh, Ru, Pd, Pt preferably Pd. 8. An improved process as claimed in claims 1-7 wherein metal catalyst is supported on an inert medium selected from silica gel, alumina, zeolite, charcoal preferably char-coal. 9. An improved process as claimed in claims 1-8 wherein oxidizing agent used in conversion of formula 2 to 1 is selected from hydrogen peroxide, cumene hydro peroxide, tert-butyl hydro peroxide preferably tert-butyl hydroperoxide. 10. An improved process as claimed in claims 1-9 wherein solvent used during oxidation with peroxide is selected from benzene, toluene, dichloromethane, acetic acid propionic acid preferably a mixture of toluene and acetic acid. 11. An improved process for preparation of penta-substituted pyridines substantially as herein described with reference to the examples and drawing accompanying this specification. |
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162-del-2002-claims(cancelled).pdf
162-del-2002-complete specification(granted).pdf
162-del-2002-correspondence-others.pdf
162-del-2002-correspondence-po.pdf
162-del-2002-description (complete).pdf
Patent Number | 195684 | ||||||||||||
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Indian Patent Application Number | 162/DEL/2002 | ||||||||||||
PG Journal Number | 31/2009 | ||||||||||||
Publication Date | 31-Jul-2009 | ||||||||||||
Grant Date | 21-Apr-2006 | ||||||||||||
Date of Filing | 28-Feb-2002 | ||||||||||||
Name of Patentee | COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH | ||||||||||||
Applicant Address | RAFI MARG NEW DELHI 110001 INDIA. | ||||||||||||
Inventors:
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PCT International Classification Number | C07D 211/00 | ||||||||||||
PCT International Application Number | N/A | ||||||||||||
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