Enantioseparation mandelic acid

Figure 13.18 Immobilization chemistry and its impact on enantioseparation selectivity of DNB-Leu, mandelic acid, and dichloroprop on cinchona 9-O-carbamate-based CSPs. Chromatographic conditions mobile phase MeOH 0.1 M NH4OAc AcOH 98 2 0.5 v/v/v, 1 ml/min, I = 10cm for Cll linkers [102], MeOH 0.1 M NH4OAc 80 20 v/v pHa 6, 1 ml/min, I = 15 cm for C9 linker [103],...

Table 5.3 Enantioseparation of 1-phenylethylamine derivatives with mandelic acid.

Duloxetine (LY-248686), (S)-(-i-)-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propyl-amine, is expected to be not only a new potent antidepressant but also a NE (norepinephrine) reuptake inhibitor, a 5-HT (serotonin) reuptake inhibitor, and a new treatment drug for stress urinary incontinence [18]. In order to produce an enantiopure key intermediate for the synthesis of the (S)-amine, the Eli Lilly group proposed various strategies [19]. As a result, they selected the enantioseparation of racemic 3-(dimethylamino)-l-(2-thienyl)propan-l-ol with (S)-mandelic acid by diastereomeric salt formation as the most economic and suitable process for industrial-scale production with efficient supporting techniques such as the racemization of the antipode and recycling the recovered materials [20]. However, in the process of demethylation for the preparation of (S)-Duloxetine from (S)-3-(di-methylamino)-l-(2-fhienyl)propan-l-ol, there are some critical problems, such as low yield and considerable decomposition to give impurities. Thus, a direct synthesis of (S)-Duloxetine starting from (S)-3-(methylamino)-l-(2-thienyl)propan-l-ol is expected to be a new route for the production of (S)-Duloxetine. 

Similar enantioseparation processes applying the solvent switch have been reported for the enantioseparation of racemic l-phenyl-2-(4-methylphenyl)ethyl-amine and 2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl)-2,3-dihydro-l,5-benzothiazepin-4(5H)-one with enantiopure mandelic acid [34]. 

Huang, D., Huang, K., Chen, S., Liu, S., Yu, J. (2008). Enantioseparation of racemic a-cyclohexyl-mandelic acid across hoUow fiber supported hquid membrane. J. Brazilian Chem. Soc., 19, 557-62. 

CyDs have been used as major chiral mobile phase additives (CMPAs) for enantio-separations in HPLC. The first application of 8-CyD as a CMPA in combination with an achiral reversed-phase material for HPLC enantioseparations was reported by Sybilska and co-workers in 1982 [27]. These authors could achieve partial resolution of the enantiomers of mandelic acid and derivatives. The CMPA method played an important role in HPLC enantioseparations before the development of effective chiral stationary phases (CSPs) but is now rarely used. The major disadvantage of this technique, together with difficulties associated with the isolation of resolved enantiomers, is the rather large consumption of chiral selector. 

The enantioseparation of ten mandelic acid derivatives was done using reverse phase HPLC with hydroxypropyl-j3-cyclodextrin or sulfobutyl ether-j3-cyclodextrin as chiral mobile phase additives (43). The mandelic acid derivatives are shown in Figure 1.16. 

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