Development of a multikilogram synthesis of a chiral epoxide precursor to a CCR1 antagonist. Use of in situ monitoring for informed optimisation via fragile intermediates

Organic Process Research and Development

Volumn 14, Issue 1, 2010, Pages 72-84

  Ange, Debra ^a   Booker, James E M ^a   Pedge, Nicholas ^a   Sinclair, Rhona ^a   Sleigh, Chris ^b   Štefinović, Marijan ^a   Vaz, Luis Manuel ^a   Way, Edward ^a  

^a Process Research and Development   (United Kingdom)

^b ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 77149154975     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op900172t     Document Type: Article

References (37)

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10. -1.
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23. The excess of 12 remained in the toluene layer.
24. Glacial acetic acid was preferred to concentrated HCl, as the solution was buffered at pH 6 and would not lead to the formation of HF which would be detrimental on glass-lined reactors in the plant.
25. Analysis for the end of reaction was an issue on large scale. Multiple analyses of the same analytical samples were not reproducible. The samples in solution would discolour and degrade upon storage.
26. This agglomeration was attributed to the low solubility of 18 in isopropyl acetate, leading to partial precipitation.
27. Four bars pressure, 0.0025 equiv Pd, 11% vessel fill, 600 rpm.
28. One bar pressure, 0.025 equiv Pd, 66% vessel fill, 400 rpm.
29. From the transesterification of 20 and the transesterification of isopropyl acetate with sodium methoxide.
30. When addition was carried out at -5 °C, the reaction mixture solidified.
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33. The catalyst used JM18MA was acidic pH 3.5. Use of similar catalyst JM18 with a pH 6.4 with or without base did not give similar uptake under similar reaction conditions.
34. In spite of an 83% solution yield of 2, the isolated yield was only 33%, and the material lost to the liquors was only14%.
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36. 4, molecular sieves.
37. Five volumes of THF, 14% area of 32 by HPLC. Ten volumes of THF, 5% area of 32 by HPLC.