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Thomson N.M.,Pfizer | Seibert K.D.,Eli Lilly and Company | Tummala S.,Bristol Myers Squibb | Bordawekar S.,Process Research and Development | And 4 more authors.
Organic Process Research and Development | Year: 2015

A number of strategies have been employed within the pharmaceutical industry in order to mitigate the risk of applying design space boundaries developed on the laboratory scale to commercial drug substance manufacturing. The following communication presents a number of case histories from members of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), with the aim of exemplifying strategies used to confirm applicability of design spaces developed on the laboratory scale. The strategies presented have a common aim of ensuring that appropriate quality standards are developed, maintained, and enhanced during the product lifecycle whilst delivering rapid and cost-effective mechanisms for drug substance commercialization. © 2014 American Chemical Society.

Liu Z.,Merck And Co. | Yasuda N.,Merck And Co. | Simeone M.,Chemical Process Development and Commercialization | Reamer R.A.,Merck And Co.
Journal of Organic Chemistry | Year: 2014

A highly efficient TMSI-mediated deprotection and direct isolation method to obtain zwitterionic compounds from the corresponding N-Boc derivatives has been developed. This method has been demonstrated in the final deprotection/isolation of the β-lactamase inhibitor MK-7655 as a part of its manufacturing process. Further application of this process toward other zwitterionic compounds, such as dipeptides and tripeptides, has been successfully developed. Furthermore, a catalytic version of this transformation has been demonstrated in the presence of BSA or BSTFA. © 2014 American Chemical Society.

Chung J.Y.L.,Merck And Co. | Zhong Y.-L.,Merck And Co. | Maloney K.M.,Merck And Co. | Reamer R.A.,Merck And Co. | And 7 more authors.
Organic Letters | Year: 2014

An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described. © 2014 American Chemical Society.

Thomson N.M.,Pfizer | Singer R.,Pfizer | Seibert K.D.,Eli Lilly and Company | Luciani C.V.,Eli Lilly and Company | And 5 more authors.
Organic Process Research and Development | Year: 2015

A series of case histories from IQ consortium member companies are presented in order to exemplify many of the different elements of drug substance control strategies that are required in order to ensure process performance and product quality. Control through process, method, and/or model design can combine to form a holistic control strategy that effectively manages risk and assures quality for the patient. A typical drug substance control strategy overview is presented, along with a number of detailed case histories that aim to demonstrate the use of process design and the development of methods and modeling to ensure control of critical quality attributes where appropriate, whether in the final drug substance or through upstream controls. © 2015 American Chemical Society.

Miller S.P.,Merck And Co. | Zhong Y.-L.,Merck And Co. | Liu Z.,Merck And Co. | Simeone M.,Chemical Process Development and Commercialization | And 5 more authors.
Organic Letters | Year: 2014

Compound 1, a potent and irreversible inhibitor of β-lactamases, is in clinical trials with β-lactam antibiotics for the treatment of serious and antibiotic-resistant bacterial infections. A short, scalable, and cost-effective route for the production of this densely functionalized polycyclic molecule is described. © 2013 American Chemical Society.

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