Development of scalable syntheses of selective PI3K inhibitors

Organic Process Research and Development

Volumn 15, Issue 3, 2011, Pages 556-564

  Huang, Qinhua ^a   Richardson, Paul F ^a   Sach, Neal W ^a   Zhu, Jinjiang ^a   Liu, Kevin K C ^a   Smith, Graham L ^a   Bowles, Daniel M ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HIGH THROUGHPUT EXPERIMENTATION; SCALABLE SYNTHESIS; SUZUKI COUPLINGS; TITLE COMPOUNDS;

COLUMN CHROMATOGRAPHY;

EXPERIMENTAL REACTORS;

EID: 79957451449     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op100286g     Document Type: Article

References (35)

1. Nuss, J. M.; Tsuhako, A. L.; Anand, N. K. Annu. Rep. Med. Chem. 2009, 44, 339-356
2. For examples of recently reported potent compounds containing 2-aminothiophene cores, see: Renou, C. C. WO/2009/094224 A1, 2009.
3. Lethu, S.; Ginisty, M.; Bosc, D.; Dubois, J. J. Med. Chem. 2009, 52, 6205-6208
4. Castano Mansanet, A. M.; Dominguez-Manzanares, E.; Escribano, A. M.; Fernandez, M. C.; Hornback, W. J.; Jimenez-Aguado, A. M.; Tromiczak, E. G.; Wu, Z.; Zarrinmayeh, H.; Zimmerman, D. M. WO/2005/070916 A1, 2005.
5. Cardin, D. P.; Gaulin, J. L.; Greenspan, P. D.; Vyskocil, S.; Xu, T.; Renou, C. C. WO/2009/154741 A1, 2009.
6. Starting material 2,4-dichloroacetophenone was available from Aldrich at 31/25 g, and malononitrile was purchased from Aldrich at 68/500 g.
7. Gust, R.; Burgemeister, T.; Mannschreck, A.; Schönenberger, H. J. Med. Chem. 1990, 33, 2535-2544
8. Lautens, M.; Schmid, G. A.; Chau, A. J. Org. Chem. 2002, 67, 8043-8053
9. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36, 333-345
10. For a review on the synthesis of tetrasubstituted thiophenes, see: Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36, 333-345
11. Sommen, G.; Comel, A.; Kirsh, G. Synthesis 2003, 735-741
12. Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber 1966, 99, 94-100
13. For a review, see: Merkushev, E. B. Synthesis 1988, 923-937
14. While the synthesis of ester 10 was previously reported in ref 2c, our chemistry was carried out in a relatively large scale, and procedures described herein were modified to enable scale-up.
15. 2 procedure has potential risk if oxygen is liberated in the flammable solvent during reaction.
16. For the replacement of NaH with other bases, such as NaOEt and KOH, see: Yu, S.-Y.; Cai, Y.-X. Synth. Commun. 2003, 33, 3989-3995
17. Ryan, G.; Mettler, H. P.; Previdoli, F. EP508353 A1, 1992
18. Zhao, W.; Wang, S.; Wang, W.; Li, Z. Xuaxue Shiji 2000, 22, 376
19. DSC and ARC analysis of reaction mixtures and raw materials, as applicable, indicated that in all but one case the desired reactions could be carried out in a dose-controlled manner at a temperature more than 100 °C under any significant exothermic onset. Exothermic additions were found to be dose-controlled; however, it should be noted that further extensive calorimetric studies should be required before this process could be considered for further scale-up in a plant setting. DSC onsets for reaction mixtures of interest: step 1 alkylation, 224 °C (190 J/g); step 2 condensation, 205 °C (142 J/g), step 3 Sandmeyer, 119 °C (342 J/g); step 4 oxidation, 184 °C (213 J/g); step 5 morpholine addition, 221 °C (148 J/g).
20. Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358-3368
21. Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461-1473
22. Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544-4568
23. Higginson, P. D.; Sach, N. W. Org. Process Res. Dev. 2004, 8, 1009-1014
24. As the Pd catalysts (0.1 M in toluene) and bases (1.0 M aqueous solution) were prepared and utilized as solutions, identical amounts of water and toluene were incorporated for all the screening conditions. The screening reactions were carried out under highly dilute conditions; thus, the conditions were slightly modified on the concentration and ratio of solvents for 1 g condition validation and scale-up synthesis.
25. For a reference describing the efficiency of use Si-thiol resin to remove palladium, see: Flahive, E. J.; Ewanicki, B. L.; Sach, N. W.; O'Neill-Slawecki, S. A.; Stankovic, N. S.; Yu, S.; Guinness, S. M.; Dunn, J. Org. Process Res. Dev. 2008, 12, 637-645
26. 2 and 3.0 equiv of CsF were used (also see Experimental Section for detail).
27. 3 in various solvents has been briefly investigated. The reactions proceeded very slowly at elevated temperature using pressure vessels. However, longer reaction time and higher reaction temperatures led to decomposition of both the starting materials and products, while the reaction was difficult to achieve good conversion.
28. We observed a ∼ 25 °C exotherm on 5-g scale.
29. 2 chemistry further. It is likely that the number of equivalents of hydrazine could be further reduced with additional studies.
30. 2 was purged in the aqueous sidestream.
31. The acetate salt was avoided by using HCl with a direct-drop product isolation.
32. The largest scales that this reaction was run are 25 g, 14 g, and 50 g for compounds 1, 2 and 3, respectively. No further scale-up was carried out because our PI3K project was held. The materials obtained from this method are pure enough for animal studies.
33. As with any transformation, attempts to scale this chemistry further should be met with additional calorimetric scrutiny. DSC analysis of steps 7-10 indicated that all transformations except step 9 were carried out at more than 100 °C under any significant exothermic onset. DSC onsets for reaction mixtures of interest: step 7 saponification, 230 °C (120 J/g); step 8 amide formation, 244 °C (524 J/g); step 9 condensation, 179 °C [122 J/g, DMA-DMF has an onset of 255 °C (255 J/g)]; step 10 triazole formation, 169 °C [697 J/g, hydrazine hydrate has an onset of 180 °C (2334 J/g)].
34. While several intermediates leading to compounds 1 and 2 were concentrated to dryness (see experimental description), workup and purification of intermediates 5c, 13c, 4c, and 14c were demonstrated in such a manner that we believe a successful plant campaign could be realized with minor additional process development work, such as solvent exchanges in place of concentrations to dryness.
35. Determined by atomic absorption, the synthesized Suzuki product 5c contained <50 ppm palladium.