Efficient syntheses of AZD4407 via thioether formation by nucleophilic attack of organometallic species on sulphur

Organic Process Research and Development

Volumn 9, Issue 5, 2005, Pages 555-569

  Alcaraz, Marie Lyne ^a   Atkinson, Stéphanie ^a   Cornwall, Philip ^a   Foster, Alison C ^a   Gill, Duncan M ^a   Humphries, Lesley A ^a,b   Keegan, Philip S ^a   Kemp, Richard ^a   Merifield, Eric ^a   Nixon, Robert A ^a   Noble, Allison J ^a   O'Beirne, Darren ^a,c   Patel, Zakariya M ^a   Perkins, Jacob ^a   Rowan, Paul ^a   Sadler, Paul ^a   Singleton, John T ^a   Tornos, James ^a   Watts, Andrew J ^a   Woodland, Ian A ^a  

^a ASTRAZENECA   (United Kingdom)

^b GLAXOSMITHKLINE   (United Kingdom)

^c Schering Plough (Avondale) Co   (Ireland)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 26444521686     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op0500483     Document Type: Article

References (47)

1. Hutton, J.; Jones, A. D.; Lee, S. A.; Martin, D. M. G.; Meyrick, B. R.; Patel, I.; Peardon, R. F.; Powell, L. Org. Process Res. Dev. 1997, 1, 61.
2. Bird, T. G. C.; Ple, P.; Crawley, G. C.; Large, M. S. EP 623614 B1, 1994.
3. Atkinson, S.; Tornos, J. WO 2003051862 A1.
4. Holt, R. A.; Rigby, S. R.; Waterson, D. WO 9719185 A1.
5. Crawley, G. C.; Briggs, M. T. J. Org. Chem. 1995, 60, 4264.
6. Haslegrave, J. A.; Jones, J. B. J. Am. Chem. Soc. 1982, 104, 4666.
7. Hetero Diels - Alder approaches to a dihydropyranone have been reported: Unni, A. K.; Takenaka, N.; Yamamoto, H.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 1336.
8. Mitsuda, M.; Hasegawa, J. GB 2304339 A1.
9. A related method for the synthesis of similar pyranone precursors has also been recently reported: Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91.
10. Rieke, R. D.; Seung-Hoi, K.; Xiaoming, W. J. Org. Chem. 1997, 62, 6921.
11. Jayasuriya, N.; Kagan, J. Heterocycles 1986, 24, 2261.
12. Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. WO 9951609 A1.
13. Abarbri, M.; Dehmel, F.; Knochel, P. Tetrahedron Lett. 1999, 40, 7449.
14. Trécourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Quéguiner, G.; Tetrahedron Lett. 1999, 40, 4339.
15. Trécourt, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.; Quéguiner, G. Tetrahedron 2000, 56, 1349.
16. Martin, G. J.; Mechin, B.; Leroux, Y.; Paulmier, C.; Meunier, J. C. J. Organomet. Chem. 1974, 67, 327.
17. The synthesis of pyranone 12 by an intramolecular Prins cyclisation between 3-buten-1-ol and acetaldehyde is reversible and can go back either to the same starting materials or to formaldehyde and 4-penten-2-ol. The latter will undergo a Prins reaction with acetaldehyde to generate 2,6-dimethylpyran-4- ol.
18. Wiped-film evaporation (WFE) was briefly investigated as a technique for the purification of the mixture of TMS ethers 15 and 16. Results on a small scale demonstrated the feasibility of this technique since the purified mixture of 15 and 16 with an assay of around 100% by HPLC was produced via a 2-stage process. The first stage of this process distilled off residual 3-bromothiophene with the bulk of the toluene at 55°C/1- 3 mbara. In the second stage, the product itself was distilled at 110°C/1 mbara. This process resulted in the 3-bromothiophene level being reduced from as much as 7% w/w to 0.5% w/w. However, this additional level of purification was not found to be necessary.
19. Sawada, T.; Fuerst, D. E.; Wood, J. L. Tetrahedron Lett. 2003, 44, 4919.
20. Moody, C. J.; Miah, S.; Slawin, A. M. Z.; Mansfield, D. J.; Richards, I. C. Tetrahedron 1998, 54, 9689.
21. Esses-Reiter, K.; Reiter, J. J. Heterocycl. Chem. 2000, 37, 927.
22. Deberly, A.; Bourdais, J. J. Heterocycl. Chem. 1977, 14, 781.
23. Yamada, S.; Yaguchi, S.; Matsuda, K. Tetrahedron Lett. 2002, 43, 647.
24. The cost of hexyllithium at the time this work was done was approximately the same as n-butyllithium on a w/w basis; therefore in terms of molar amounts, hexyllithium was only slightly more expensive.
25. If this route had been selected for longer-term supply of AZD4407, recovery and recycling of the thiolate from the aqueous phase by oxidation to disulphide 23 would have been considered.
26. One issue concerning the use of toluene in the final stage of the process is the level of benzene in the final product, and until we had more information on the amount in the dried product, a grade of low-benzene toluene was chosen for this stage. A change in the risk phrases for toluene published recently may have necessitated a change of solvent for this recrystallisation. This change was made as a result of the 29th ATP to EU Directive 67/ 548/EEC.
27. Pakulski, Z.; Pierożyński, D.; Zamojski, A. Tetrahedron 1994, 50, 2975.
28. Toste, F. D.; De Stefano, V.; Still, I. W. J. Synth. Commum. 1995, 25, 1277.
29. A recently reported procedure describes direct electrophilic thiocyanation of a range of aromatic and heteroaromatic compounds including oxindoles using ammonium thiocyanate and iodine: Yadav, J. S.; Reddy, B. V. S.; Shubashree, S.; Sadashiv, K. Tetrahedron Lett. 2004, 45, 2951.
30. Kice, J. L.; Anderson, J. M.; Pawlowski, N. E. J. Am. Chem. Soc. 1966, 88, 5245.
31. Tyrrell, A. W. R. Tetrahedron Lett. 1985, 26, 1753.
32. Oae, S.; Togo, H. Bull. Chem. Soc. Jpn. 1983, 56, 3802.
33. The reasons for this reduction in yield with increasing temperature were not fully elucidated; however competing attack of the nucleophile at the carbon in the thiocyanate unit was thought possible leading to a 2-cyanothiophene and liberation of oxindole thiolate. This in turn could react as a nucleophile with oxindole thiocyanate forming the symmetrical disulphide 23, significant quantities of which were seen in many of the coupling reactions tried.
34. Ranasinghe, M. G.; Fuchs, P. L. Synth Commun. 1988, 18, 227.
35. Prasad, J. V. N. V. Org. Lett. 2000, 2, 1069.
36. Fujiki, K.; Tanifuji, N.; Sasaki, Y.; Yokoyama, T. Synthesis 2002, 343.
37. Protection of 33 was attempted using TBDMS chloride in the presence of an alkoxide base but without success. Previous attempts at the coupling of 33 without protection using an excess of lithiothiophene 7 had demonstrated that the enolate of 33 was unstable, and this was thought to be the reason protection of the enolate under anionic conditions could not be accomplished.
38. Crawley, G. C.; Briggs, M. T. J. Med. Chem. 1995, 38, 3951.
39. This reaction was also applied to 2,3- and 2,5-dibromothiophene, to determine the fate of impurities in 39. The former was totally unreactive towards Grignard exchange, and the latter gave only the product arising from a single Grignard exchange. An iterated process did give the 2,5-dithioether, but this was found to be extremely sensitive towards acid-catalysed decomposition.
40. iPrMgCl and 36 was only 80% complete after 24 h. The isopropyl sulphide derived from this side reaction was not detectable in crude solutions.
41. Several other solvents were examined for the isolation: IMS (industrial methylated spirit), IPA, THF, acetonitrile, ethyl acetate. IMS gave an excellent recovery, but in one experiment a different, less soluble polymorph was produced. In view of the success and practicality of the toluene procedure, this was not pursued further.
42. By HPLC peak area. The largest impurity was (2S,4S)-AZD4407 at 3.7%, with 38 and the desbromo analogue reduced to 0.3% and 0.5%, respectively.
43. 1H NMR was carried out before acid treatment to demonstrate that the TBDMS-protection had gone to completion.
44. A multiplication factor for the hexyllithium charge to account for reagent consumed by reaction with impurities was determined as follows. Area percentages of impurities undergoing lithiation (thiophene, 3-bromothiophene, pyranone 12, and residual thienyl pyranols 13 and 14) were converted to mole percentages by multiplying each by molecular weight ratios relative to TMS thienyl pyranols 1 (3.07, 1.61, 2.35, 1.36, respectively) and their relative response factors (1.0, 1.7, 1.0, 1.0, respectively). The multiplication factor for the hexyllithium charge was then calculated as 1 + (∑ mol % impurities/total area% 15 and 16).
45. It was found that the product was unstable in the presence of excess aqueous sodium thiosulphate, particularly during a prolonged workup. To generate a more robust process by minimising risk of degradation in the workup, the amount of sodium thiosulphate solution charged was reduced by calculating a slight excess over the amount of excess iodine input over the 1 molar equiv required for reaction. Although this process was not proven on any scale larger than 10 g, the stability of the reaction mixture in the presence of the wash solution over a period of 2 h indicated that no problems with workup were expected on scale-up. This wash regime was preferred over the use of mildly basic aqueous systems which led to emulsion formation.
46. The rationale behind use of this two-phase aqueous organic solvent system was to minimise contact between the product 32 and cyanide, by extraction into the organic phase. Degradation occurred when water alone was used as solvent leading to formation of large amounts of oxindole disulphide by nucleophilic displacement of thiolate from thiocyanate by cyanide, which would then react with thiocyanate to form disulphide and liberate cyanide. It is important to add the toluene before the potassium cyanide, since the reaction is rapid.
47. iPrMgCl and 36 was only 80% complete after 24 h. The isopropyl sulphide derived from this side reaction was not detectable in crude solutions.