An Efficient Synthesis of Darunavir Substantially Free from Impurities: Synthesis and Characterization of Novel Impurities

Rapolu, Rajesh Kumar; Areveli, Srinivas; Raju, V. V. N. K. V. Prasada; Srinivasu, Navuluri; Chavali, Murthy; Mulakayala, Naveen

doi:10.1002/slct.201803825

Cited by 11 publications

(14 citation statements)

References 19 publications

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“…To confirm this, we have isolated these two compounds using preparative HPLC after the stress conditions. The two impurities were analyzed using several analytical methods, such as 1 H NMR, 13 C NMR, and mass spectrometry. For the VHA impurity, we have used 2D NMR [heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond correlation (HMBC)] to confirm the structure.…”

Section: Identification/detection Of Unknown Impuritiesmentioning

confidence: 99%

“…The reaction went smoothly to result in only one product, which matches with the more polar peak present in the HPLC chromatogram of the stressed sample. Further, to confirm this impurity, we analyzed this sample using 1 H NMR and 13 C NMR to confirm the structure of venetoclax N-oxide.…”

Section: Identification/detection Of Unknown Impuritiesmentioning

confidence: 99%

“…In this paper, we subjected venetoclax for oxidative stress using a 10% hydrogen peroxide solution. We obtained two major impurities (Figure ) during the stress conditions, and these two impurities were thoroughly characterized to identify their structure owing to our interest toward the identification of unknown impurities and API impurities. − …”

Section: Introductionmentioning

confidence: 99%

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Identification, Synthesis, and Characterization of Potential Oxidative Impurities of Venetoclax: Application of Meisenheimer Rearrangement

Vaddamanu,

Goswami,

Nandipati

et al. 2023

ACS Omega

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Venetoclax is a potent BCL-2 inhibitor that is used for the treatment of several blood cancers. During the oxidative stress degradation of venetoclax, we observed the formation of two potential impurities at levels of about 8−10%, which have similar molecular weights. The two impurities were isolated and identified as 4- (3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (((3-nitro-4-(((tetrahydro-2H-pyran-4-yl))benzamide (venetoclax hydroxylamine impurity, VHA). To confirm these two compounds, we have synthesized each impurity individually and analyzed it by high-performance liquid chromatography, mass spectrometry, 1 H NMR, 13 C NMR, and 2D NMR. VNO was synthesized by the oxidation of venetoclax using m-CPBA in dichloromethane to get the required N-oxide impurity. After the confirmation of the VNO impurity, the VNO impurity was heated with water at reflux in a sealed tube for 36 h to get the VHA impurity of about 6−8% after 36 h. After thorough analysis, it was confirmed that venetoclax Noxide undergoes [1,2] Meisenheimer rearrangement to form the venetoclax hydroxylamine impurity. These two impurities may be relevant reference standards in manufacturing venetoclax Active Pharmaceutical Ingredient (API) (or) tablets.

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Section: Identification/detection Of Unknown Impuritiesmentioning

confidence: 99%

Section: Identification/detection Of Unknown Impuritiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification, Synthesis, and Characterization of Potential Oxidative Impurities of Venetoclax: Application of Meisenheimer Rearrangement

Vaddamanu,

Goswami,

Nandipati

et al. 2023

ACS Omega

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“…These impurities after liquid chromatography–mass spectrometry (LC–MS) analysis were identified as N -((3-(4-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-1 H -pyrazol-1-yl)-5-oxotetrahydrofuran-3-yl)methyl)ethane sulfonamide (lactone impurity, BCL), 2-(3-(4-(7 H -[4,7′-bipyrrolo[2,3- d ]pyrimidin]-4′-yl)-1 H -pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (dimer impurity, BCD), and 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-1 H -pyrazol-1-yl)azetidin-3-yl) acetonitrile (hydroxymethyl impurity, BHM) (Figure ). Due to our interest toward the synthesis and identification of API impurities, we wish to report the synthesis and structural illustration of three major impurities of baricitinib obtained during the synthesis of baricitinib in this article. − …”

Section: Introductionmentioning

confidence: 99%

Identification, Synthesis, and Characterization of Novel Baricitinib Impurities

Vaddamanu

Goswami

Reddy³

et al. 2023

ACS Omega

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Baricitinib is a novel active pharmaceutical ingredient used in the treatment of rheumatoid arthritis, and it acts as an inhibitor of Janus kinase. During the synthesis of baricitinib, three unknown impurities were identified in several batches between 0.10 and 0.15% using high-performance liquid chromatography. The unknown compounds were isolated and identified as N-((3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-5-oxotetrahydrofuran-3-yl)methyl)ethane sulfonamide (lactone impurity, BCL), 2-(3-(4-(7H-[4,7′-bipyrrolo[2,3-d]pyrimidin]-4′-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (dimer impurity, BCD), and 2-(1-(ethylsulfonyl)-3-(4-(7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl) acetonitrile (hydroxymethyl, BHM). These compounds were synthesized and confirmed against the isolated samples. The structures of all the three impurities were confirmed by extensive analysis of 1H NMR, 13C NMR, and mass spectrometry. The lactone impurity formation was explained by a plausible mechanism. The outcome of this study was very useful for scientists working in process as well as in formulation development. To synthesize highly pure baricitinib drug substance, these impurities can be used as reference standards due to their potential importance.

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“…Due to continuous interest in the development of API and API impurities by our laboratory [10][11][12], we wish to report the easy and convenient method for the synthesis of pimavaserin in this article. Thus, our efforts in achieving an environmental friendly, step-wise and one-pot synthetic process for pimavanserin via three different intermediates (isothiocyanate, urea and N-formyl) was described under green conditions.…”

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confidence: 99%