A straightforward and efficient synthesis of praziquantel enantiomers and their 4′-hydroxy derivatives

A new method for the synthesis of praziquantel enantiomers via resolution of praziquanamine with (S)-(+)-naproxen was developed. The four 4′-hydroxy derivatives were obtained through each single praziquanamine enantiomer, coupling with cis- and trans-4-(benzyloxy)cyclohexanecarboxylic acids and subsequent hydrogenolysis for the deprotection of the 4′-OH cyclohexane residue. Additionally, the in vitro cysticidal activity of the compounds was tested, finding that (R)-(−)-praziquantel is the eutomer.

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(R)-(−)-2-((S)-2-(6-Methoxynaphthalen-2-yl)propanoyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-oneC26H26N2O3de >99%[α]D20=-23.2 (c 1, CHCl3)Source of chirality: (S)-(+)-naproxenAbsolute configuration: (11bR,2′S)

(S)-(+)-2-((S)-2-(6-Methoxynaphthalen-2-yl)propanoyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-oneC26H26N2O3de >99%[α]D20=+128.4 (c 0.5, CHCl3)Source of chirality: (S)-(+)-naproxenAbsolute configuration: (11bS,2′S)

(R)-(−)-1,2,3,6,7,11b-Hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one, ((R)-(−)-praziquanamine)C12H14N2Oee >99%[α]D20=-306.1 (c 1, CHCl3)Source of chirality: (S)-(+)-naproxenAbsolute configuration: (R)

(R)-(−)-2-(Cyclohexanecarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-oneC19H24N2O2ee >99%[α]D20=-147.5 (c 1, CHCl3)Source of chirality: (R)-(−)-praziquanamineAbsolute configuration: (R)

(R)-(−)-2-(cis-4-(Benzyloxy)cyclohexanecarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-oneC26H30N2O3ee >99%[α]D20=-99.2 (c 1, CHCl3)Source of chirality: (R)-(−)-praziquanamineAbsolute configuration: (R)

(R)-(−)-2-(trans-4-(Benzyloxy)cyclohexanecarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-oneC26H30N2O3ee >99%[α]D20=-97.0 (c 1, CHCl3)Source of chirality: (R)-(−)-praziquanamineAbsolute configuration: (R)

(R)-(−)-2-(cis-4-Hydroxycyclohexanecarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one((R)-(−)-cis-4′-hydroxypraziquantel)C19H24N2O3ee >99%[α]D20=-148.0 (c 1, CHCl3)Source of chirality: (R)-(−)-praziquanamineAbsolute configuration: (R)

(R)-(−)-2-(trans-4′-Hydroxycyclohexanecarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one monohydrate, ((R)-(−)-trans-4′-hydroxypraziquantel monohydrate)C19H24N2O3·H2Oee >99%[α]D20=-135.4 (c 1, CHCl3)Source of chirality: (R)-(−)-praziquanamineAbsolute configuration: (R)