Method for the separation of intermediates which may be used for the preparation of escitalopram

A method for the isolation and purification of a compound having the formula

• wherein R is cyano, halogen, CF3—(CF2)n—SO2—O—, —CHO, —CH2NO2, —CH2Cl, —CH2Br, —CH3, —COOR6, —CONR6R7, or a group of formula
• wherein
• n is 0-8,
• R6 and R7 are independently selected from optionally substituted C1-6-alkyl, optionally substituted aryl-C1-6-alkyl, and optionally substituted aryl,
• Z′ in formula (VII) is O or S,
• R8 and R9 are independently hydrogen or C1-6-alkyl or R8 and R9 together form a C2-5-alkylene chain thereby forming a spiro ring,
• R10 is hydrogen or C1-6-alkyl, and
• R11 is hydrogen, C1-6-alkyl, a carboxy group, or a precursor group thereto, or R10 and R11 together form a C2-5-alkylene chain thereby forming a spiro ring,
• the dotted line represents a double or single bond,
• Hal is halogen,
• Z is a dimethylaminomethyl group, —CH2-L, —CH2—NO2, cyano, aldehyde, —CH2—O-Pg, —CH2—NPg1Pg2, —CH2—NMePg1, —CO—N(CH3)2, —CH(A1R12)(A1R13), -(A1R14)(A2R15)(A3R16), —COOR17, or —CH═CH—R18, wherein
• Pg is a protection group for an alcohol group,
• Pg1 and Pg2 are each independently a protection group for an amino group,
• R12 and R13 are independently C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, or an optionally alkyl-substituted aryl or aralkyl group, or R12 and R13 together form a chain of 2 to 4 carbon atoms,
• each of R14-R18 are independently C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, or optionally C1-6-alkyl-substituted aryl or aryl-C1-6-alkyl,
• A1, A2 and A3 are independently O or S, and
• L is a leaving group,
• W is O or S,
• Y is a bond, O, S or NH,
• and R1 is C1-10-alkyl, C2-10-alkenyl or C2-10-alkynyl all of which may optionally be substituted with one or more substituents selected from C1-10-alkoxy, C1-10-alkylthio, halogen, nitro, cyano, di-(C1-10-alkyl)amino, aryl, aryloxy, arylthio and heteroaryl, or R1 is aryl, wherein any of the aryl and heteroaryl groups may optionally be substituted one or more times with substituents selected from C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C1-10-alkoxy, C1-10-alkylthio, halogen, nitro, cyano, and di-(C1-10-alkyl)amino, or a salt thereof,
• and/or a diol of formula
• wherein R, Z, Hal and the dotted line are as defined above, or a salt thereof, from a mixture containing the compound of formula (IV) and the diol of formula (II), comprising:
• a) reacting said mixture containing the compound of formula (IV) and the diol of formula (II) with a cyclic anhydride or imide of formula
• wherein X is —(CHR′″)n—, wherein n is 0-2;
• and R′, R″, and R′″ are independently selected from hydrogen, C1-6-alkyl, C1-6-alkoxy, aryloxy, C1-6-acyloxy, and aryl-CO—O, wherein each aryl may be substituted with C1-6-alkyl, or R′ and R″ in an anhydride of formula (Ia) together are —O—CR4R5—O—, wherein R4 and R5 are independently hydrogen or C1-6-alkyl, or R′ and R″ in an anhydride of formula (Ib) are adjacent and together with the two carbon atoms to which they are attached form a benzene ring;
• one of Q1 and Q2 is nitrogen and the other is carbon, or both are carbon;
• A is C1-6-alkylene, phenylene, or naphthylene wherein the C1-6-alkylene, phenylene, or naphthylene groups may optionally be substituted one or more times with C1-6-alkyl;
• to form a mixture of the compound of formula (IV) and an ester having the formula
• wherein R, Z and Hal are as defined above and V is —CHR′—X—CR″—COOH, —X—CHR″—CO—NH-A-COOH, —CHR″—X—CO—NH-A-COOH,
• wherein R′, R″, X, and A are as defined above;
• b) separating the compound of formula (IV) from the ester of formula (V) by a method selected from the group consisting of:
• i) allowing the acid of formula (V) or a salt thereof to precipitate from the reaction mixture, and separating the precipitate of the compound of formula (V) or a salt thereof from the reaction mixture, optionally followed by isolation of the compound of formula (IV) or a salt thereof from the reaction mixture;
• ii) partitioning between an organic solvent and an aqueous solvent whereby the compound of formula (IV) will be dissolved in the organic phase whereas the compound of formula (V) will be dissolved in the aqueous phase, separating the phases, and optionally isolating the compound of formula (IV) or a salt thereof and/or isolating the compound of formula (V) or a salt thereof;
• and
• iii) adsorbing the compound of formula (V) on a basic resin, separating the solvent containing the compound of formula (IV) from the resin, desorbing the compound of formula (V) from the basic resin, and optionally isolating the compound of formula (IV) or a salt thereof and/or isolating the compound of formula (V) or a salt thereof.