Patent ID: 8420818

Claim:
A process for the preparation of pyrido[2,1-a]isoquinoline derivatives of the formula wherein R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy and lower alkenyl, wherein lower alkyl, lower alkoxy and lower alkenyl may optionally be substituted by a group selected from lower alkoxycarbonyl and aryl, and of pharmaceutically acceptable salts thereof, comprising one or more of the following steps a) ring opening of (S)-4-fluoromethyl-dihydro-furan-2-one of the formula and subsequent esterification to provide the (R)-4-bromo-3-fluoromethyl-butyric acid ester of the formula wherein R 1a is lower alkyl; b) converting the (R)-4-bromo-3-fluoromethyl-butyric acid ester of the formula (2) with an N-protected glycine alkylester into a N-protected —(S)-4-(alkoxycarbonylmethyl-amino)-3-fluoromethyl-butyric acid ester of formula wherein R 1a and R 1b are lower alkyl and Prot is an amino protecting group; c) deprotection of the N-protected —(S)-4-(alkoxycarbonylmethyl-amino)-3-fluoromethyl-butyric acid ester of formula (3) and subsequent ring closure to form the ((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-acetic acid ester of formula wherein R 1b is lower alkyl; d) converting the ((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-acetic acid ester of formula (4) into the ((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-3-oxo-butyric acid ester of formula wherein R 1c is a protecting group, or a salt thereof; e) transforming the ((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-3-oxo-butyric acid ester of formula (5a) into the ((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-3-oxo-butyric acid of formula or a salt thereof; f) coupling the ((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-3-oxo-butyric acid of formula (5b) with an isoquinoline derivative of formula wherein R 2 , R 3 and R 4 are as above, or a salt thereof to form a compound of formula wherein R 2 , R 3 and R 4 are as above or of a salt thereof, subsequently ring closing the compound of formula (7a) with formaldehyde to form the (3S,11bS)-3-((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a] isoquinolin-2-one derivative of formula wherein R 2 , R 3 and R 4 are as above, or a salt thereof; g) transforming the (3S,11bS)-3-((S)-4-fluoromethyl-2-oxo-pyrrolidin-1-yl)-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a] isoquinolin-2-one derivative of formula (7b) into the (S)-1-((2S,3S,11bS)-2-N-protected-amino-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a] isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one of formula wherein R 2 , R 3 and R 4 and Prot are as above, or a salt thereof; h) removing the protecting group Prot in the (S)-1-((2S,3S,11bS)-2-N-protected-amino-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one of formula (8).