Patent EA-002243-B1 (EA)
Title: Method of synthesis of pyrrole amides
Inventor: RAGAN JOHN ANTHONY
IPC: C07D209/52
Filed: 1998-10-21
Abstract: 1. A method for preparing a compound of the formula   wherein R<1> and R<2> are independently selected from hydrogen and C1-C6 alkyl; and Ar is phenyl or heterocycle; or phenyl or heterocycle substituted with up to three substituents selected from C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 perflouroalkyl, C1-C6 alkoxy, C1-C6 perfluoroalkoxy, F, Cl, Br, -O-(CH2)k-O-, or (CH2)mNR<1>R<2>; or Ar is 4-(N-methyl-N-tert-butylcarboxyaminomethyl)phenyl, wherein n is an integer selected from 0 to 2; m is an integer selected from 0 to 6; and k is an integer selected from 1 or 2; which comprises: 1) Reacting a compound of the formula   with an excess of an acid chloroanhydride or acid anhydride in a reaction inert solvent containing an excess of an acid acceptor until reaction is completed; 2) Adding an equivalent amount of NH2-Ar to the solution of step 1 and holding until reaction is completed. 2. A method for preparing a compound of the formula   which comprises: reacting a compound of formula I prepared by the method of Claim 1 with an excess of ammonium source in a reaction inert solvent at an elevated temperature until reaction is completed. 3. The method of Claim 2 wherein Ar is selected from the group consisting of 2-fluoro-4-methoxyphenyl, 4-(N-methyl-N-tert-butylcarboxyaminomethyl)phenyl, 4-ethoxyphenyl or 4-methoxyphenyl, 4-fluorophenyl, 4-pyridyl or 3-pyridyl, 6-(2-hydroxyethoxy)-3-pyridyl, and benzo[1,3]dioxol-5-yl. 4. The method of Claim 1 wherein n is 2 and R<1> and R<2> are hydrogen. 5. The method of Claim 1 wherein n is 1 and R<1> and R<2> are methyl. 6. The method of Claim 1 wherein n is one and R<1> and R<2> are hydrogen. 7. The method of Claim 1 wherein n is zero and R<1> and R<2> are hydrogen. 8. The method of Claim 1 wherein n is 1, R<1> is methyl and R<2> is hydrogen. 9. A compound which is selected from the group consisting of 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylic acid, 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylic acid (2-fluoro-4-methoxyphenyl)amide, 6,6-dimethyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (2-fluoro-4-methoxyphenyl)amide, 4-[(4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carbonyl)amino]benzyl-methylcarbamic acid tert-butyl ester, 4-Oxo-5,6-dihydro-4H-cyclopenta[b]furan-3-carboxylic acid (4-ethoxyphenyl)amide, 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylic acid benzo[1,3]dioxol-5ylamide, 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylic acid-(4-methoxyphenyl)amide, 6-Methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (4-fluorophenyl)amide, 6-Methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid pyridin-4-ylamide 6-Methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid pyridin-3-ylamide, and 6-Methyl-4-oxo4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid [6-(2-hydroxyethoxy)pyridin-3-yl]-amide. 10. A compound which is 4-[(4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)amino]benzylmethylcarbamic acid tert-butyl ester. 11. A method of Claim 2, wherein Ar is 4-(N-methyl-N-tert-butylcarboxyaminomethyl)phenyl, wherein the product of method of Claim 2 is additionally put into reaction with water at acid presence. 12. A method of Claim 1 wherein said acid chloroanhydride is ethylchloroformate.