Process development toward the pilot scale synthesis of the piperidine-based cocaine analogue and potent dopamine and norepinephrine reuptake inhibitor CTDP 31,446

Organic Process Research and Development

Volumn 10, Issue 5, 2006, Pages 914-920

  Mobele, Bingidimi I ^a   Kinahan, Taryn ^a   Ulysse, Luckner G ^a   Gagnier, Steven V ^a   Ironside, Michael D ^a   Knox, Graham S ^a   Mohammadi, Farahnaz ^a  

^a ALBANY MOLECULAR RESEARCH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 33750133220     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op060114g     Document Type: Article

References (18)

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9. Kozikowski, A. P.; Araldi, G. L.; Boja, J.; Meil, W. M.; Johnson, K. M.; Flippen-Anderson, J. L.; George, C.; Saiah, E. J. Med. Chem. 1998, 41, 1962.
10. (a) Crowe, D.; Ward, N.; Wells, A. S. World Patent WO 01/29032.
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13. (a) Ecija, M.; Diez, A.; Rubiralta, M.; Casamitjana, N.; Kogan, M. J.; Giralt, E. J. Org. Chem. 2003, 68, 9541.
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15. The isolation and purification of (±)-6-trans via crystallization entailed the following chemical and process steps: (a) treatment of the crude extracts from the Grignard reaction with sodium methoxide after solvent exchange into methanol to maximize the amount of (±)-6-trans upon thermodynamic epimerization of the cis isomer, (b) conversion of crude (±)-6-trans into the corresponding HCl salt in methanol and crystallization, and (c) regeneration of the free base by treatment of the salt with aqueous base and extraction. Only a modest 33% yield was achieved under these conditions. Overall, the number of steps required for generating material of suitable purity for a direct resolution of (+)-6-trans presented no obvious throughput advantage compared to the isolation and elaboration of the (±)-6-cis isomer.
16. At the inception of the process development work and concurrently with the optimization of the Grignard reaction, several resolving agents were evaluated for their ability to provide a direct resolution of (±)-6-trans. These included (-)-dibenzoyl-L-tartaric acid, (S)-(+)-mandelic acid, L-(+)-tartaric acid, di-p-toluoyl-L-tartaric acid, D-(+)-malic acid, dipivaloyl-L-tartaric acid, (S)-(-)-2-pyrrolidone-5-carboxylic acid, (1S)-(+)-10-camphorsulfonic acid, and D-(-)-quinic acid. Most of these resolving agents provided low to no enantiomeric enhancement in pilot screening experiments in a variety of solvents, to the exception of di-p-toluoyl-L- tartaric acid, which afforded 31% ee and 29% ee in methyl isobutyl ketone (MIBK) and ethyl acetate, respectively, using 1 molar equiv of the resolving agent. The chiral purity could be increased up to 71% ee using substoichiometric amounts of di-p-toluoyl-L-tartaric acid, albeit with a lower mass recovery. Due to time constraints, however, further optimization of the direct resolution of (±)-6-trans was not pursued, and efforts focused instead on streamlining the resolution of (±)-6-cis.
17. For a review on the stereochemistry of kinetic protonation of enolates in cyclic systems, see: Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263.
18. Based on the amount of (±)-6-cis isomer present in the quenched reaction mixture, approximately 70-75% of the theoretical amount was isolated in a single crop.