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Preparation of 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-α]-pyrimidin-4-one Disclosure Number: IPCOM000242154D
Publication Date: 2015-Jun-20
Document File: 1 page(s) / 29K

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Preparation of 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-α]-pyrimidin-4-one with minimization of deschloro impurity, 3-(2-ethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-α]-pyrimidin-4-one (compound-3)

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Preparation of 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-α]-pyrimidin-4-one


3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-α]-pyrimidin-4-one (Compound-2) is an important intermediate in the synthesis of paliperidone.

Compound-2 is conventionally synthesized by hydrogenation of the corresponding precursor, viz. 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-α]-pyrimidin-4-one (Compound-1). During the hydrogenation reaction, it is observed that the dechlorinated compound, 3-(2-ethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-α]-pyrimidin-4-one (compound-3) is formed as a major impurity to an extent of 39% with the desired compound-2 formed to the extent of 37% (Scheme-1).

However, when a halogenated solvent is employed as solvent, the impurity formation is reduced to 8.8% while the desired compound (2) is formed to the extent of 80%. The halogenated solvents include aliphatic, aromatic and alicyclic halogenated solvents but are not limited to this class. The halogenated solvents are selected from the group comprising of chloroform, dichloromethane, ethylene dichloride etc.

Scheme-1: Preparation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-α]-pyrimidin-4-one (Compound-2)

Example 1

3-(2-Chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-α]-pyrimidin-4-one (Compound-1) was dissolved in dichloromethane and...