KR840002824A - Method for producing N-oxide compound - Google Patents

Abstract

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Description

Method for producing N-oxide compound

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Claims (12)

a) terminating the compound of formula (II) or a tautomer or corresponding tautomer mixture thereof, or b) a compound of formula P _y -CHO (III) or a reactive and functional derivative thereof Reacting with a compound of (IV) or with a tautomer or corresponding tautomer mixture thereof, or c) in the compound of formula (V), converts Ac ₁ ° and / or Ac ₂ ° groups to Ac ₁ and / or Ac ₂ groups, or d) For compounds of formula (VI), the Py ₀ group is oxidized to form the corresponding N-oxidopyridol group: When R ₂ or R ₃ is hydroxy-lower alkyl, it forms a 2-oxy-1-oxo-lower alkylene group together with the adjacent acyl group Ac ₁ or Ac _2, and the carbonyl group is a 1,4-dihydropyridine ring. Compounds of formula (I) bonded to 3- or 5-membered carbon atoms include those of formulas (II), (IV), (V), wherein R ₂ or R ₃ represents a free or esterified hydroxy containing lower alkyl; The starting material of (VI) and Ac ₁ or Ac ₂ or Ac ₁ ° or Ac ₂ ° of the general formula (V) are starting materials representing esterified carboxyl groups and are formed directly under the reaction conditions of one of the processes of a) to b). In the starting materials of the general formulas (II) to (VI), as long as these materials have salt-forming groups, they may be used in the form of their salts (here, P _y , P ₁ , R ₂ , R _3, are as defined in to the Ac ₁ and Ac _2), a compound represented by the general formula (ⅰ) with, if necessary, create the by the general formula (ⅰ) The free compound of formula (I), which is converted into a compound and / or if necessary, converts the resulting salt into a free compound or another salt, and / or, if necessary, has a salt-forming group, Salts of compounds of formula (I) having N-oxide compounds of formula (I) and salt-forming groups, characterized in that they are converted and / or if necessary, a mixture of the resulting isomers is separated into individual isomers. How to manufacture. In the above formula, P _y represents an unsubstituted or substituted N-oxidopyridyl group, R ₁ represents hydrogen or unsubstituted or substituted lower alkyl, One of R ₂ and R ₃ represents lower alkyl and the other is hydrogen; Lower alkyl; lower alkyl containing free, etherified or esterified carboxy, oxo, functionally modified carboxy or free or substituted amino or imino; Functionally diseased carboxy; Or free or substituted amino, wherein amino group R ₂ or R ₃ is bonded to lower alkyl group R ₁ , or when R ₂ or R ₃ represents hydroxy-lower alkyl, this hydroxy-lower alkyl is an adjacent acyl group Together with Ac ₁ or Ac ₂ form a 2-oxy-1-oxo-lower alkylene group, the carbonyl group being bonded to the 3- or 5-membered carbon atom of the 1,4-dihydropyridine ring.), Ac ₁ and Ac ₂ each represent an acyl group of an acid, One of the X and Y groups represents a group of the general formula —NH—R ₁ , the other represents a hydroxy or a group of the general formula NH—R ₁ , One of the Ac ₁ ° and Ac ₂ ° groups represents a group that can be converted to an Ac ₁ or Ac ₂ group, the other represents a group that can be converted to Ac ₁ or Ac ₂ or Ac ₁ or Ac ₂ , P _y0 represents an unsubstituted or substituted pyridyl group. The method of claim 1, wherein pyridine-3-carboxaldehyde-1-oxide is reacted with acetoacetic acid ethyl ester and ammonia to give 2,6-dimethyl-4- (1-oxido-3-pyridyl) -1,4 -Dihydropyridine-3,5-dicarboxylic acid diethyl ester. The method of claim 1, wherein 2-methylpyridine-3-carboxaldehyde-1-oxide is reacted with acetoacetic acid ethyl ester and ammonia to give 2,6-dimethyl-4- (2-methyl-1-oxido-3- Pyridyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester. The method of claim 1, wherein 2-chloropyridine-3-carboxaldehyde-1-oxide is reacted with acetoacetic acid and ammonia to give 2,6-dimethyl-4- (2-chloro-1-oxido-3-pyridyl ) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester. The method of claim 1, wherein 2-methylthiopyridine-3-carboxaldehyde-1-oxide is reacted with acetoacetic acid ethyl ester and ammonia to give 2,6-dimethyl-4- (2-methylthio-1-oxydo- 3-pyridyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester. The method of claim 1, wherein 2-methoxypyridine-3-carboxaldehyde-1-oxide is reacted with acetoacetic acid ethyl ester and ammonia to give 2,6-dimethyl-4- (1-oxido-2-methoxy- 3-pyridyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester. The method of claim 1, wherein 2-methylsulfinyl-3-carboxaldehyde-1-oxide is reacted with acetoacetic acid and ammonia to give 2,6-dimethyl-4- (2-methylsulfinyl-1-oxydo-3 Pyridyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester. The reaction mixture of claim 1, wherein the pyridine-3-carboxaldehyde-1-oxide is reacted with 3-aminocrotonic acid ethyl ester and 4-chloroacetoacetic acid ethyl ester. Pyridyl) -5-oxo-1,4,5,7-tetrahydrofuro [3,4-b] pyridine-3-carboxylic acid ethyl ester. The method of claim 1, wherein 2-chloropyridine-3-carboxaldehyde-1-oxide is reacted with 3-aminocrotonic acid ethyl ester and 4-chloro-acetoacetic acid ethyl ester to react with 2-methyl-4- (1-oxy Fig. 2-Chloro-3-pyridyl) -5-oxo-1,4,5,7-tetrahydrofuro [3,4-b] pyridine-3-carboxylic acid ethyl ester. The method of claim 1, wherein 2-methylpyridine-3-carboxaldehyde-1-oxide is reacted with 3-aminocrotonic acid ethyl ester and 4-chloroacetoacetic acid ethyl ester to obtain 4- (1-oxido-2-methyl 3-pyridyl) -5-oxo-1,4,5,7-tetrahydrofuro [3,4-b] pyridine-3-carboxylic acid ethyl ester. 2-methylthiopyridine-3-carboxaldehyde-1-oxide, 3-aminocrotonic acid ethyl ester and 4-chloro-acetoacetic acid ethyl ester to react with 2-methyl-4- (1-oxido-2-methyl Thio-3-pyridyl) -5-oxo-1,4,5,7-tetrahydrofuro [3,4-b] pyridine-3-carboxylic acid ethyl ester. The process according to any one of claims 1 to 5, characterized in that the resulting compound of formula (I) having a salt-forming group is converted into a pharmaceutically acceptable acid addition salt. ※ Note: This is to be disclosed based on the first application.