Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 May 17;23(5):711-715.
doi: 10.1021/acs.oprd.8b00440. Epub 2019 Mar 28.

A Holistic Approach to Streamlining Pharmaceutical Processes: A Conversation

B Frank Gupton  1 , D Tyler McQuade  1
Affiliations
Review

A Holistic Approach to Streamlining Pharmaceutical Processes: A Conversation

B Frank Gupton et al. Org Process Res Dev. .

Abstract

Nearly 10 years ago, Frank Gupton and I had a chance encounter where we learned that we both had interest in creating efficient routes to generic medicines. Lucky for me, Frank and I began mentoring each other-Frank teaching me wisdom gained from 30 years in industry and I sharing what I knew about the academic world. As some who know Frank will understand, his lessons in some cases seem devilishly obvious and should be chanted daily like a zen koan while others are subtle and complex, requiring many years of reflection. Frank was asked by OPR&D to offer these lessons in a condensed form so that others might learn what I have. Frank and I decided that a transcript of our many conversations condensed into one document might do the trick.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
M4All five-step process to guide us toward our objectives.
Scheme 1
Scheme 1. Final Two Steps Leading from Registered Starting Materials to the Drug Substance Nevirapine; Here We Used Novel Manufacturing Platforms To Achieve Process Intensification
Scheme 2
Scheme 2. Prior to Our M4All Work on Nevirapine, the State-of-the-Art Starting Materials Were Low-Volume, High-Cost Molecules; We Developed an Efficient Approach That in a Few Steps Realizes CAPIC from Acetone
See this image and copyright information in PMC

References

    1. Leng R. B.; Emonds M. V. M.; Hamilton C. T.; Ringer J. W. Holistic Route Selection. Org. Process Res. Dev. 2012, 16, 415–424. 10.1021/op200264t. - DOI

    1. For an example of a system for selecting synthetic routes, see the following three-part series:

    2. Parker J. S.; Moseley J. D. Kepner–Tregoe Decision Analysis as a Tool To Aid Route Selection. Part 1. Org. Process Res. Dev. 2008, 12, 1041–1043. 10.1021/op8000349. - DOI
    3. Moseley J. D.; Brown D.; Firkin C. R.; Jenkin S. L.; Patel B.; Snape E. W. Kepner–Tregoe Decision Analysis as a Tool To Aid Route Selection .Part 2. Application to AZD7545, a PDK Inhibitor. Org. Process Res. Dev. 2008, 12, 1044–1059. 10.1021/op800033c. - DOI
    4. Parker J. S.; Bower J. F.; Murray P. M.; Patel B.; Talavera P. Kepner–Tregoe Decision Analysis as a Tool To Aid Route Selection. Part 3. Application to a Back-Up Series of Compounds in the PDK Project. Org. Process Res. Dev. 2008, 12, 1060–1077. 10.1021/op8000355. - DOI
    1. Verghese J.; Kong C. J.; Rivalti D.; Yu E. C.; Krack R.; Alcázar J.; Manley J. B.; McQuade D. T.; Ahmad S.; Belecki K.; Gupton B. F. Increasing global access to the high-volume HIV drug nevirapine through process intensification. Green Chem. 2017, 19, 2986–2991. 10.1039/C7GC00937B. - DOI
    2. Longstreet A. R.; Rivalti D.; McQuade D. T. Synthesis and Reactivity Profile of Ylidenemalononitrile Enamines and Their Ester Analogs Towards Electrophiles and Nucleophiles. J. Org. Chem. 2015, 80, 8583–8596. 10.1021/acs.joc.5b01169. - DOI - PubMed
    3. Longstreet A. R.; Campbell B. S.; Gupton B. F.; McQuade D. T. Improved Synthesis of Mono- and Disubstituted 2-Halonicotinonitriles from Alkylidene Malononitriles. Org. Lett. 2013, 15, 5298–5301. 10.1021/ol4025265. - DOI - PubMed
    1. Green Chemistry: Research Tools. https://www.acs.org/content/acs/en/greenchemistry/research-innovation/to... (accessed Dec 14, 2018).

    1. For example, see:

    2. Klucznik T.; Mikulak-Klucznik B.; McCormack M. P.; Lima H.; Szymkuc S.; Bhowmick M.; Molga K.; Zhou Y.; Rickershauser L.; Gajewska E. P.; Toutchkine A.; Dittwald P.; Startek M. P.; Kirkovits G. J.; Roszak R.; Adamski A.; Sieredzinska B.; Mrksich M.; Trice S. L. J.; Grzybowski B. A. Efficient Syntheses of Diverse, Medicinally Relevant Targets Planned by Computer and Executed in the Laboratory. Chem. 2018, 4, 522–532. 10.1016/j.chempr.2018.02.002. - DOI
    3. Kaiser D.; Yang J.; Wuitschik G. Using Data Analysis To Evaluate and Compare Chemical Syntheses. Org. Process Res. Dev. 2018, 22, 1222–1235. 10.1021/acs.oprd.8b00199. - DOI