Kilo-Scale Synthesis of the Dinucleotide DNA Methyltransferase Inhibitor Guadecitabine

Johnson, Matthew; Chidambaram, Ramakrishnan; Davar, Nipun; Madsen, Christian; Sanghvi, Yogesh S.; Short, Robert

doi:10.1021/acs.oprd.4c00072

Cited by 1 publication

(1 citation statement)

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“…High purity (>99%) compound 2 was isolated via appropriate solvent washings, precipitation, and final crystallization. The assembly of top fragment decitabine amidite 1 and its conjugation to 2 is described in the following article …”

Section: Introductionmentioning

confidence: 99%

Development of a Kilogram-Scale Manufacturing Route for Bis-Tac-dG: Essential Building-Block for Guadecitabine

Wani,

Banerjee,

Davar

et al. 2024

Org. Process Res. Dev.

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Guadecitabine (SGI-110) is a dinucleotide that is a prodrug of decitabine. The dinucleotide contains decitabine (top fragment) and 2′-deoxyguanosine (9; dG; bottom fragment) connected via a 3′ → 5′ phosphodiester bond. The manufacturing process of guadecitabine requires a large quantity of N 2 , 3′-O-(4-tert-butylphenoxyacetyl)-protected dG (2; Bis-Tac-dG) to incorporate the bottom fragment. The protected 2 being a critical starting material of the dinucleotide imposes stringent quality requirements for its synthesis and isolation. Presented herein is the development work leading to a practical and scalable route for compound 2 starting from commercial dG. Salient features of the approach included one-pot protection of 5′-OH group of N 2 -Tac-dG (3) with 4,4′-dimethoxytrityl (DMT) group followed by 3′-O-Tac protection furnishing fully protected dG 8, thus reducing the cycle time with fewer isolation steps and lowering the solvent usage. Subsequently, cleavage of DMT group from 8 utilizing NaIO 4 enabled a mild, highly selective, and robust route to produce high purity (>99%) Bis-Tac-dG on kilogram-scale. The structure and origin of major impurities were determined by comparison with reference standards and carefully controlled to an acceptable level in compound 2. The improved synthesis was scaled to prepare multiple ∼60 kg batches of 2 to supply all clinical studies up to phase III.

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Section: Introductionmentioning

confidence: 99%