From racemic epichlorohydrin to a single enantiomer of the drug timolol maleate

The synthesis for a single enantiomer timolol maleate based on an initial Jacobsen hydrolytic kinetic resolution of racemic epichlorohydrin and on the stereochemistry of the subsequent chemical transformations has been proposed. The feature of this synthesis is that both products of the kinetic resolution, (R)-epichlorohydrin (R)-4 and (S)-3-chloropropane-1,2-diol (S)-5, have been utilized in the synthesis of the target, (S)-timolol. The mirror stereochemical results can be obtained with the use of (R,R)-salen Co(III) catalyst instead of (S,S)-salen Co(III).

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(2R)-1-Chloro-3-(4-morpholin-4-yl-[1,2,5]thiadiazol-3-yloxy)-propan-2-olC9H14ClN3O3SEe = 96% (ee from HPLC)[α]D25 = +6.7 (c 0.9, CHCl3)Initial source of chirality: (R)-EpichlorohydrinAbsolute configuration: (R)

(S)-1-(tert-Butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanolC13H24N4O3SEe = 99% (ee from HPLC)[α]D25 = −4.7 (c 1, CHCl3); [α]43625 = −6.4 (c 1, CHCl3)Initial source of chirality: 4-{4-[(2S)-Oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholineAbsolute configuration: (S)

(S)-1-(tert-Butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol hemimaleate saltC17H28N4O7SEe = 99% (ee from HPLC)[α]D25 = −7.0 (c 4, 1 M aq HCl); [α]43625 = −12.7 (c 4, 1 M aq HCl)Initial source of chirality: 4-{4-[(2S)-Oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholineAbsolute configuration: (S)

4-{4-[(2S)-Oxiran-2-ylmethoxy]-1,2,5-thiadiazol-3-yl}morpholineC9H13N3O3SEe = 99% (ee from HPLC)[α]D25 = +28.9 (c 1.0, CHCl3)Initial source of chirality: (S)-3-(4-Morpholin-4-yl-1,2,5-thiadiazol-3-yloxy)-propane-1,2-diol or (R)-epichlorohydrinAbsolute configuration: (S)

(S)-3-(4-Morpholin-4-yl-[1,2,5]thiadiazol-3-yloxy)-propane-1,2-diolC9H15N3O4SEe = 99.8% (ee from HPLC)[α]D20 = +17.5 (c 1, EtOH)Initial source of chirality: (S)-3-Chloropropane-1,2-diolAbsolute configuration: (S)