Development of a scaleable process for the synthesis of a next-generation statin

Organic Process Research and Development

Volumn 14, Issue 2, 2010, Pages 441-458

  Hobson, Lindsay A ^a   Akiti, Otute ^a   Deshmukh, Subodh S ^b   Harper, Shannon ^a   Katipally, Kishta ^a   Lai, Chiajen J ^a   Livingston, Robert C ^c   Lo, Ehrlic ^a   Miller, Michael M ^a   Ramakrishnan, Srividya ^a   Shen, Lifen ^a   Spink, Jan ^d   Tummala, Srinivas ^a   Wei, Chenkou ^a   Yamamoto, Kana ^e   Young, John ^a   Parsons Jr , Rodney L ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b WYETH RESEARCH   (United States)

^c GILEAD SCIENCES   (United States)

^d Johnson and Johnson   (United States)

^e UNIVERSITY OF TOLEDO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 77950165580     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op100010n     Document Type: Article

References (34)

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23. Interestingly, removal of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) from the reaction does not prevent the formation of this impurity. In fact, it seems as though the alcohol, aldehyde, and acid all afford this late-eluting impurity upon treatment with bleach and KBr in CH2Cl2. A mechanistic understanding for these processes is still being developed. It should be noted that, although this putative halide is an impurity in the oxidation of 18, its overall abundance is significantly low when employing the conditions developed. The crystallization conditions used to isolate 9 have also been shown to purge most, if not all, of this side product.
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27. In addition to these optimization studies, a great deal of effort was placed on finding a alternative isolation/crystallization possibility in order to avoid the solvent swap from EtOAc to IPA. After a subsequent screen of solvents and anti-solvents, a crystallization mixture of EtOAc/ heptane was chosen for further refinement and development. Solubility of 9 was mapped at different temperatures and various solvent compositions, and 3:1 heptane/EtOAc was chosen as a potential crystallization solvent mixture. Although this provided a crystallization directly from the reaction solvent, an easier filtration due to the larger granular crystals generated, and improved drying efficiency, the recovery was plagued with issues during discharge from the reactor (i.e., a semi-stickiness of the resulting solid or possible nucleation/ crystallization on the walls of the vessel). Diminished yields (63 M% for 1:1 heptane/EtOAc; 73-79 M% for 3:1 heptane/EtOAc) due to material loss and inherent solubility of 9 were also observed. Further exploration into temperature effects on the crystallization, different ramping protocols, temperature cycling variants, and seeding regimes were found to be successful and to dramatically reduce the amount of fines present in the final solid. These improvements furnished very large granular crystals and an increased yield (9: 92 M%, 100 wt%).
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