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. 2023 Mar 2;8(10):9583-9591.
doi: 10.1021/acsomega.3c00100. eCollection 2023 Mar 14.

Identification, Synthesis, and Characterization of Novel Baricitinib Impurities

Guruswamy Vaddamanu  1   2 , Anandarup Goswami  1 , N Ravi Sekhar Reddy  2 , Katam Reddy Vinod Kumar Reddy  2 , Naveen Mulakayala  2
Affiliations

Identification, Synthesis, and Characterization of Novel Baricitinib Impurities

Guruswamy Vaddamanu et al. ACS Omega. .

Abstract

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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structure of baricitinib.
Scheme 1
Scheme 1. Chemical Synthesis of Baricitinib
Figure 2
Figure 2
Chemical structures of reported baricitinib impurities.
Figure 3
Figure 3
Three new impurities identified during the process development of baricitinib.
Figure 4
Figure 4
1H NMR spectrum of BCL impurity in DMSO-d6.
Figure 5
Figure 5
HSQC spectrum of BCL impurity in DMSO-d6.
Figure 6
Figure 6
HMBC spectrum of BCL impurity in DMSO-d6.
Figure 7
Figure 7
1H NMR spectrum of BCD impurity in DMSO-d6.
Figure 8
Figure 8
1H NMR spectrum of the BHM impurity in DMSO-d6.
Figure 9
Figure 9
Plausible mechanism for the formation of BCL impurity.
Figure 10
Figure 10
1H NMR spectrum of intermediate-1 in DMSO-d6.
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