Process development and scale-up of a selective α1- adrenoceptor antagonist

Organic Process Research and Development

Volumn 9, Issue 1, 2005, Pages 80-87

  Connolly, Terrence J ^a   Matchett, Michael ^a   Sarma, Keshab ^a  

^a ROCHE BIOSCIENCE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA 1 ADRENERGIC RECEPTOR BLOCKING AGENT; RO 3203546; UNCLASSIFIED DRUG;

ARTICLE; DRUG ACTIVITY; DRUG DETERMINATION; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; PROCESS DESIGN; SCALE UP;

EID: 13844255095     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op0498114     Document Type: Article

References (29)

1. Caine, M.; Raz, S. Br. J. Urol. 1976, 48, 255-263.
2. Schwinn, D. A.; Lomasney, J. W.; Lorenz, W.; Szklut, P. J.; Fremeau, R. T.; Taqny-Feng, T. L.; Caron, m. G.; Lefkowitz, R. J.; Cotecchia, S. J. Biol. Chem. 1990, 265, 8183-8189.
3. Schwinn, D. A.; Johnston, G. L.; Page, S. O.; Mosley, M. J.; Wilson, K. H.; Worman, N. P.; Cambell, S.; Roock, M. O.; Furness, L. M.; Parry-Smith, D. J.; Peter, B.; Beiley, D. S. J. Pharmacol. Exp. Ther. 1995, 272, 134-142.
4. Becker, C. K.; Caroon, J. M.; Melville, C. R.; Padilla, F.; Pfister, J. R.; Zhang, X. WO 02/053558 A1, 2002.
5. Compound 2 is commercially available in small quantities from Acros and SAF.
6. Compound 8 is commercially available from Acros, Lancaster, and SAF.
7. OSHA PEL: 100 ppm, Ullmann's Encyclopedia of Industrial Chemicals 2004, John Wiley and Sons: DOI: 10.1002/14356007.a08_545.
8. TLV-TWA: 5 ppm, Ullmann's Encyclopedia of Industrial Chemicals 2004, John Wiley and Sons: DOI: 10.1002/14356007.a10_101.
9. See ref 5.
10. Formamidine hydrochloride is hygroscopic.
11. See Q3C Guidelines for Residual Solvents at www.ich.org for permitted daily exposures.
12. Scalone, M.; Waldmeier, P. Org. Process Res. Dev. 2003, 7, 418-425.
13. Experiments in the lab have shown that using diisopropylethylamine in place of triethylamine results in a significantly faster alkylation. The reaction is complete within a few hours compared to the 12-18 h required when triethylamine was used as the scavenging base. These observations have not been tested in a pilot plant.
14. Experiments in the lab have shown that a related salt, diisopropylethylamine hydrobromide, may be conveniently removed by adding water and separating out the aqueous layer. Although some diester 11 was extracted into the aqueous layer, using a minimal amount of water and essentially salting out the aqueous layer with the hydrobromide salt of diisopropylethylamine minimized these losses. This process improvement has not been verified on scale. If this process variant is used, then drying the toluene stock solution prior to adding base is necessary to ensure high yields in the Dieckmann reaction. The presence of water complicates the reaction by consuming KTA and facilitating hydrolysis of the ester functional groups.
15. Laboratory-scale stress tests have shown that overstripping the toluene at this stage results in a lower purity of 2. At this point, the reaction mixture was either diluted with toluene, and the distillation continued until the ethanol was removed, or diluted with heptane.
16. The addition of heptane caused the crystals of 2 to agglomerate. Although the particle size of the crystals did not appear to increase, the agglomerated solid filtered much faster.
17. Experiments in the lab have shown that the hydrochloride salt can be formed by adding ethanol or 2-propanol to the reaction mixture followed by the addition of chlorotrimethylsilane. This avoids having to remove the ethanol, thereby decreasing the cycle time and avoiding a distillation that is not robust to overstripping the solvent. The use of gaseous hydrogen chloride in our pilot plant facility is complicated by the Santa Clara Toxic Gas Ordinance (Ordinance No. NS-517.44, Code of Santa Clara, Division B11, Chapter X).
18. Large-scale reactions are typically followed using HPLC. Partial generation of the methyl ester of 2 from methanol and sodium methoxide would require that both esters be identified as starting materials and be followed during the in-process analysis.
19. Significant emulsions formed during the aqueous workup in the absence of potassium phosphate, whereas solids precipitated in the presence of only potassium phosphate.
20. The insoluble impurity was quinazolindione 13, which was the result of overhydrolysis of 7. It is unknown if the generation of this impurity is solvent related, but it is suspected that its generation was related to the large excess of base used by discovery chemists.
21. Degussa offers formamidine acetate in 80 kg drums at $30/kg.
22. Levin, D. Org. Process Res. Dev. 1997, 1, 182.
23. An agitated filter dryer was used for this filtration because the cake will pull away from the walls of the filter.
24. On this scale, the addition of potassium hydroxide required 2.5 h.
25. The organic solutions were transferred as room allowed to the 200 L reactor, leaving a headspace for solvent distillation.
26. The particle size of the precipitate is quite small, and the filtration is slow on Nutsche type filters.
27. Hess, H.-J.; Cronin, T. H.; Scriabine, A. J. Med. Chem. 1968, 11, 130-136.
28. This mixture was heated at ca. 50°C until the solids dissolved (ca. 1 h).
29. This reactor had been previously verified to be free of particulate. All liquid streams entering this system entered via a polishing filter.