Leveraging Synergistic Solubility in the Development of a Direct Isolation Process for Nemtabrutinib

We report the process development for the active pharmaceutical ingredient (API) step of the commercial manufacturing route to nemtabrutinib (MK-1026), a reversible Bruton’s Tyrosine Kinase (BTK) inhibitor currently under investigation for the treatment of several hematological malignancies. Signifi...

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Published inOrganic process research & development Vol. 27; no. 4; pp. 659 - 668
Main Authors Chen, Yonggang, Iuzzolino, Luca, Burgess, Samantha A., Chung, Cheol K., Corry, James, Crawford, Morgan, Desmond, Richard, Guetschow, Erik, Hartmanshenn, Clara, Kuhl, Nadine, Liu, Zhu, Luo, Hanlin, McQuilken, Alison C., Newman, Justin A., Ren, Hong, Thaisrivongs, David A., Wang, Zhixun, Sirota, Eric
Format Journal Article
LanguageEnglish
Published American Chemical Society 21.04.2023
Subjects
impurity crystallization kinetics
crystallization
SNAr
API
BTK inhibitor
synergistic solubility
polish filtration
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Abstract We report the process development for the active pharmaceutical ingredient (API) step of the commercial manufacturing route to nemtabrutinib (MK-1026), a reversible Bruton’s Tyrosine Kinase (BTK) inhibitor currently under investigation for the treatment of several hematological malignancies. Significant improvements on process efficiency were achieved by a direct isolation process leveraging optimal reaction conditions and synergistic API solubility in an ethanol/water system. In combination with additional robustness improvements on impurity control, an efficient, practical, and scalable synthesis of nemtabrutinib was developed.
AbstractList We report the process development for the active pharmaceutical ingredient (API) step of the commercial manufacturing route to nemtabrutinib (MK-1026), a reversible Bruton’s Tyrosine Kinase (BTK) inhibitor currently under investigation for the treatment of several hematological malignancies. Significant improvements on process efficiency were achieved by a direct isolation process leveraging optimal reaction conditions and synergistic API solubility in an ethanol/water system. In combination with additional robustness improvements on impurity control, an efficient, practical, and scalable synthesis of nemtabrutinib was developed.
Author Ren, Hong
Iuzzolino, Luca
Chung, Cheol K.
Burgess, Samantha A.
Kuhl, Nadine
Liu, Zhu
Corry, James
Luo, Hanlin
Newman, Justin A.
Thaisrivongs, David A.
Wang, Zhixun
Desmond, Richard
Hartmanshenn, Clara
McQuilken, Alison C.
Crawford, Morgan
Chen, Yonggang
Guetschow, Erik
Sirota, Eric
AuthorAffiliation Merck & Co., Inc
Department of Analytical Research & Development
Department of Process Research & Development
Department of Modeling & Informatics
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Cites_doi 10.1039/D2GC04117K
10.1021/ac60210a051
10.1158/2159-8290.CD-17-1409
10.1016/j.crgsc.2022.100324
10.1016/B978-0-12-386537-3.00008-3
10.1016/S0378-5173(98)00205-1
10.1080/15298668891379792
10.1016/j.yrtph.2020.104858
10.1021/op034165e
10.1016/j.semcancer.2010.08.004
10.1182/blood-2013-07-515361
10.3390/molecules26237411
10.1021/acs.oprd.9b00077
10.1016/S0378-5173(00)00653-0
10.1021/acs.chemrev.5b00484
10.1080/15428119691015197
10.1039/C6GC00611F
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Keywords impurity crystallization kinetics
crystallization
SNAr
API
BTK inhibitor
synergistic solubility
polish filtration
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References ref17/cit17
ref10/cit10
ref3/cit3
ref9/cit9b
ref9/cit9a
ref12/cit12
ref15/cit15
ref16/cit16
ref13/cit13
ref14/cit14
Anderson N. G. (ref6/cit6) 2012
ref5/cit5
ref7/cit7b
ref2/cit2
ref7/cit7a
ref1/cit1a
ref4/cit4
ref1/cit1b
References_xml – ident: ref14/cit14
  doi: 10.1039/D2GC04117K
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  doi: 10.1021/ac60210a051
– ident: ref3/cit3
  doi: 10.1158/2159-8290.CD-17-1409
– ident: ref5/cit5
  doi: 10.1016/j.crgsc.2022.100324
– start-page: 209
  volume-title: Practical Process Research and Development
  year: 2012
  ident: ref6/cit6
  doi: 10.1016/B978-0-12-386537-3.00008-3
  contributor:
    fullname: Anderson N. G.
– ident: ref17/cit17
  doi: 10.1016/S0378-5173(98)00205-1
– ident: ref4/cit4
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  doi: 10.1080/15298668891379792
– ident: ref9/cit9a
  doi: 10.1016/j.yrtph.2020.104858
– ident: ref10/cit10
  doi: 10.1021/op034165e
– ident: ref1/cit1a
  doi: 10.1016/j.semcancer.2010.08.004
– ident: ref1/cit1b
  doi: 10.1182/blood-2013-07-515361
– ident: ref2/cit2
  doi: 10.3390/molecules26237411
– ident: ref12/cit12
  doi: 10.1021/acs.oprd.9b00077
– ident: ref15/cit15
  doi: 10.1016/S0378-5173(00)00653-0
– ident: ref16/cit16
  doi: 10.1021/acs.chemrev.5b00484
– ident: ref7/cit7b
  doi: 10.1080/15428119691015197
– ident: ref9/cit9b
  doi: 10.1039/C6GC00611F
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Title Leveraging Synergistic Solubility in the Development of a Direct Isolation Process for Nemtabrutinib
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