[NH2:1][CH2:2][CH2:3][N:4]([C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=2[N:14]=1)[CH2:5][CH2:6][C:7](=O)[CH3:8].C([O-])(=O)C.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:12]2[O:11][C:10]([N:4]3[CH2:5][CH2:6][CH:7]([CH3:8])[NH:1][CH2:2][CH2:3]3)=[N:14][C:13]=2[CH:15]=1Bis-MSA adduct 12 (17.19 kg, 36.27 mol), sodium acetate (2.97 kg, 36.3 mol) and DCM (152 kg, 115 L) were charged to a vessel. The resulting slurry was cooled to 15° C. and acetic acid (26.8 kg, this was the amount required for dissolution of the salt) was added maintaining an internal temperature below 20° C. The batch was cooled to 15° C. and Na(OAc)3BH (9.25 kg, 43.6 mol) was charged via a glove bag over 30 min maintaining an internal temperature below 20° C. The resulting solution was aged for 30 min at 20° C., HPLC analysis showed the reaction to be complete. The batch was then cooled to 10° C., 2N HCl (38.80 kg) was added and the resulting solution was aged for 30 min at 10° C. The mixture was then adjusted to pH 9 using 5 N NaOH maintaining an internal temperature below 20° C. Once at pH 9 the layers were allowed to separate and the organic lower layer was ran off into a clean drum. DCM (76.2 kg, 57.5 L) was then added to the aqueous phase, the layers were mixed, allowed to separate, then the lower layer was combined with the previous organics (this step was repeated but HPLC of the third DCM layer showed that this was unnecessary as it only contained 12.5 g of rac-11 by assay). The combined DCM fractions were then charged to a 160 liter vessel and distilled to approximately 20 L (˜1 volume of DCM). THF (44 kg) was charged to the vessel and the resulting stream was discharged into a clean drum and stored in the cold room prior to the next step in the reaction sequence. The final solution was found to contain 9.4 kg of rac-14. This stream was sufficiently pure to be used directly in the subsequent resolution.
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