Process Development and Synthesis of Birinapant: Large Scale Preparation and Acid-Mediated Dimerization of the Key Indole Intermediate

Deng, Yunkun; Xie, Qiuzhe; LaPorte, Matthew G.; Chasnoff, Anna T. A.; Mortensen, Mark A.; Patra, Debasis; Putrelo, Seth A.; Antonovich, Robert S.; Chen, Hong; Yan, Jun; Cooper, Amiel G.; Rippin, Susan R.; Alexander, Matthew D.; Kumar, Pavan Tirunahari; Hendi, Mukta S.; Lee, Yu‐Hua; Haimowitz, Thomas; Condon, Stephen M.

doi:10.1021/acs.oprd.5b00390

Cited by 10 publications

(14 citation statements)

References 29 publications

(46 reference statements)

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“…In addition to the required product 26 , the des-fluoro product 27 was also obtained in 1.0–1.5% quantities. Compound 27 could not be removed by recrystallization and was carried though to subsequent steps . The use of HBr/HOAc as alternative to hydrogenation for removal of the carbobenzyloxy groups avoided the problem. , …”

Section: Impurity Occurrence In Crystallizations In Process Chemistrymentioning

confidence: 99%

“…Compound 27 could not be removed by recrystallization and was carried though to subsequent steps . The use of HBr/HOAc as alternative to hydrogenation for removal of the carbobenzyloxy groups avoided the problem. , …”

Section: Impurity Occurrence In Crystallizations In Process Chemistrymentioning

confidence: 99%

“…Compound 27 could not be removed by recrystallization and was carried though to subsequent steps. 34 The use of HBr/HOAc as alternative to hydrogenation for removal of the carbobenzyloxy groups avoided the problem. 34,35 During process development for the manufacture of palbociclip, a Heck coupling step to obtain the intermediate 29 gave rise to impurities 30, 31, 32, and 33 (Scheme 7).…”

Section: Impurity Occurrence In Crystallizations In Process Chemistrymentioning

confidence: 99%

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Impurity Occurrence and Removal in Crystalline Products from Process Reactions

Moynihan

Horgan

2017

Org. Process Res. Dev.

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The behavior of impurities when subjected to crystallizations, and related processes such as recrystallization and reslurrying, has been reviewed with a particular focus on the years 2000−2015, but also including significant cases from outside that period. Small molecule pharmaceuticals and similar small organic molecules are included but not biomolecules, inorganics, or minerals. Phase impurities are only covered when a phase transformation is involved with the management of an impurity. Introductory examples illustrating some general features of crystallization as a method of purification are presented, as well as approaches to quantifying the effectiveness of purification. The review classifies cases based on the behavior of the specific impurities covered. The classes of behavior observed are the removal by washing, recrystallization, or reslurrying (Class I), impurities not being removed by these operations (Class II), and impurities which are removed in conjunction with a phase transformation (Class III). Examples of each of these types of behavior are presented, with many processes producing impurities which fall into more than one of these classes. Studies on the inclusion of extraneous molecules into crystalline materials are also covered. These particularly include the incorporation of compounds as solid solutions, but also eutectic formation and inclusion at surfaces during crystal growth. The relationship between types of impurities and behavior during processing is also examined.

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Section: Impurity Occurrence In Crystallizations In Process Chemistrymentioning

confidence: 99%

Section: Impurity Occurrence In Crystallizations In Process Chemistrymentioning

confidence: 99%

Section: Impurity Occurrence In Crystallizations In Process Chemistrymentioning

confidence: 99%

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Impurity Occurrence and Removal in Crystalline Products from Process Reactions

Moynihan

Horgan

2017

Org. Process Res. Dev.

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“…[8][9][10][11][12][13][14] Crystallisations do not always decrease the level of specic impurities to an acceptable level. [15][16][17][18][19][20][21][22][23] In such cases, knowledge of the location or locations of impurities within batches of crystalline material can be important in designing a strategy for the management of specic impurities. The distribution of a specic impurity within a multi-particle batch of crystalline solid may not necessarily be uniform or localised, and in general it would be best to assume that the concentration of impurities can vary both within individual particles and from particle to particle.…”

Section: Introductionmentioning

confidence: 99%

Stepwise dissolution and composition determination of samples of multiple crystals using a dissolution medium containing aqueous alcohol and fluorocarbon phases

Moynihan

Armstrong

2019

RSC Adv.

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“…Biindole 15 is employed in the synthesis of 1. 4,5 Treatment of 15 under modified DMDO-mediated oxidation conditions provided a mixture of hydroxyindolenines 16 and 17 (Scheme 4). As with 2 and 3 (supra), the absolute chemistry at the C3-indole positions of 16 and 17 is unknown and therefore has been assigned arbitrarily.…”

mentioning

confidence: 99%

Electrophilic Oxidation and [1,2]-Rearrangement of the Biindole Core of Birinapant

Deng

Haimowitz

LaPorte

et al. 2016

ACS Med. Chem. Lett.

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Birinapant/TL32711 (1) is a bivalent antagonist of the inhibitor of apoptosis (IAP) family of proteins and was designed to mimic AVPI, the N-terminal tetrapeptide of the second mitochondria-derived activator of caspases (Smac/ DIABLO). Birinapant bound to the BIR3 domains of cIAP1, cIAP2, and XIAP with K i values of 1, 36, and 45 nM, respectively. Birinapant-mediated activation of cIAP1 resulted in cIAP1 autoubiquitylation and degradation and correlated with inhibition of TNF-mediated NF-κB activation, induction of tumor cell death in vitro, and tumor regression in vivo. Birinapant is being evaluated in Phase 1/2 trials for the treatment of cancer and hepatitis B virus (HBV) infection. After one year at accelerated storage conditions, a formulation of 1 afforded four degradants in >0.1% abundance by HPLC analysis. The primary degradants (2 and 3) were formed via oxidation of the biindole core, while the secondary degradants (5 and 6) arose via [1,2]-rearrangement of 3 and 2, respectively. Forced degradation conditions were developed, which allowed the isolation of 2 and 3 in multigram quantities. Novel deuterated analogues of 1 were prepared to determine the site of oxidation, and NMR experiments confirmed the chemical structures of 5 and 6. The de novo synthesis of 2, 3, 5, and 6 confirmed these experimental findings. KEYWORDS: Birinapant, biindole, oxidation, degradation, rearrangement, stability, drug product B irinapant/TL32711 (1) is a small-molecule antagonist of the inhibitor of apoptosis (IAP) family of proteins that is currently in clinical trials for the treatment of cancer and hepatitis B virus (HBV) infection. 1−3 Structurally, 1 contains two N(Me)Ala-Abu-Pro peptide chains attached to a central biindole core ( Figure 1A). 4 The discovery and development of birinapant drug substance has been reported. 4,5 Birinapant drug product (1 DP) is currently manufactured as a sterile-filtered, aqueous formulation, which is administered as an intravenous infusion. As part of an ongoing chemical development program, 1 DP has been evaluated for long-term stability at multiple conditions including 25°C/60% relative humidity (RH) and 40°C /75% RH. In the course of these investigations, partial degradation (>0.1%) of 1 was observed on prolonged storage of 1 DP at the accelerated storage condition of 40°C/75% RH ( Figure 1B). High performance liquid chromatography (HPLC) and mass spectral (MS) analysis of these samples demonstrated that four degradants (i.e., 2, 3, 5, and 6) were formed by the addition of a single oxygen molecule to 1 (i.e., M + 16); degradants arising from the addition of two oxygen molecules (i.e., 4) were observed in lower quantities. 6 In order to gain insight into the degradation process, we prepared each oxidative degradant via forced degradation and then confirmed their structures based on independent synthesis.To generate sufficient quantities of the oxidative degradants, air was bubbled through an aqueous solution of 1 containing 0.1% acetic acid (HOAc) for 7 days thus affording a...

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Process Development and Synthesis of Birinapant: Large Scale Preparation and Acid-Mediated Dimerization of the Key Indole Intermediate

Cited by 10 publications

References 29 publications

Impurity Occurrence and Removal in Crystalline Products from Process Reactions

Impurity Occurrence and Removal in Crystalline Products from Process Reactions

Stepwise dissolution and composition determination of samples of multiple crystals using a dissolution medium containing aqueous alcohol and fluorocarbon phases

Electrophilic Oxidation and [1,2]-Rearrangement of the Biindole Core of Birinapant

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