Concise synthesis of a selective α1-adrenoceptor antagonist

Organic Process Research and Development

Volumn 10, Issue 3, 2006, Pages 391-397

  Connolly, Terrence J ^a,b   Matchett, Michael ^a   McGarry, Patrick ^a   Sukhtankar, Sunil ^a   Zhu, Jiang ^a  

^a ROCHE BIOSCIENCE   (United States)

^b Celera ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 33745745674     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op050122h     Document Type: Article

References (23)

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7. Connolly, T. J.; Keitz, P. F.; Lee, E. K.; Li, J.; Lopez-Apia, F. J.; McGarry, P. F.; Melville, C. R.; Nitzan, D.; O'Yang, C.; Padilla, F.; Weinhardt, K. K. WO 2005005395, 2005.
8. Connolly, T. J.; McGarry, P.; Sukhtankar, S. Green Chem. 2005, 7, 586-589, 2005.
9. Eleven kilograms of product with an LOD of 38% was isolated. Drying trials indicated that decomposition of the product would occur when the water-wet cake was dried at elevated temperatures.
10. Connolly, T. J.; Matchett, M.; Sarma, K. Org. Process Res. Dev. 2005, 9, 80-87.
11. Connolly, T. J.; Constantinescu, A.; Lane, T. S.; Matchett, M.; McGarry, P.; Paperna, M. Org. Process Res. Dev. 2005, 9, 837-842.
12. When triethylamine was employed as the base in the coupling reaction of 2 and 4 and the same reaction conditions were used, the product cake did contain triethylamine hydrochloride. Increasing the water charge was not examined since throughput was already starting to suffer at 15 L/kg 4.
13. The presence of 10 in 2 was not verified.
14. Johnstone, R. A. W.; Wilby, A. H.; Entwistle, I. D. Chem. Rev. 1985, 85, 129-170.
15. Although all hydrogenations involving a metal catalyst on an insoluble support are heterogeneous, this mixture was termed "extreme" because neither the starting material nor the product was entirely soluble in the reaction mixture. The reduction process involved partial solubility of the starting material and precipitation of the product.
16. Interestingly, compound 13 decomposed to 8 in the presence of TFA. Initial analysis by HPLC that used TFA to modify the mobile phase seemed to indicate that the forward reaction had stalled. Analysis of the reaction by TLC indicated the absence of starting material and the presence of a nonpolar impurity, later identified as 13.
17. Sforza, S.; Dossena, A.; Corradini, R.; Virgili, E.; Marchelli, R. Tetrahedron Lett. 1998, 39, 711-714.
18. Bredereck, H.; Gompper, R.; Klemm, K.; Rempfer, H. Chem. Ber. 1959, 92, 837.
19. -1 (See Merenyi, R. Iminium Salts in Organic Chemistry, Part 1. Advances in Organic Chemistry; John Wiley: New York, 1979; Vol. 9, Chapter 2, pp 23-106.
20. At this scale, 4.1 kg of acetic acid was required.
21. Caution! This reaction is exothermic. At this scale, a 7 °C temperature rise was observed over 40 min.
22. At this scale, the addition required 30 min with 5 °C aqueous glycol circulating through the reactor jacket.
23. It is important that the pH remain above 8 for at least 30 min after the pH adjustment. The pH had a tendency to drift lower following initial adjustments into the specified pH range.