Practical Convergent Laboratory-Scale Synthesis of a CCR5 Receptor Antagonist

Crawford, Jason; Chen, Gang; Carpenter, Bryon E.; Wilson, T.; Ji, Jenny; Skerlj, Renato T.; Bridger, Gary

doi:10.1021/op200259t

Cited by 8 publications

(5 citation statements)

References 22 publications

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“…Since HOBt crystallizes as the hydrate, it is a safer option than the anhydrous material. It has been reported that HOBt containing >10 wt % water becomes desensitized DMF: This reagent has been extensively employed in catalytic amounts for acid chloride formation with SOCl 2 and (COCl) 2 and also in one instance with Vilsmeier reagent.…”

Section: General Concepts In Large-scale Amidationsmentioning

confidence: 99%

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Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Magano

2022

Org. Process Res. Dev.

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This review describes the practical aspects involved in the implementation of large-scale amidations in process chemistry. Coupling reagent, base, additive, and solvent selections are critically analyzed to highlight their pros and cons. Other important factors to be considered on large scale, such as atom economy, cost, safety, and toxicity, are also examined. These concepts are then showcased through selected examples from the literature for the synthesis of active pharmaceutical ingredients.

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Section: General Concepts In Large-scale Amidationsmentioning

confidence: 99%

“…Since HOBt crystallizes as the hydrate, it is a safer option than the anhydrous material. It has been reported that HOBt containing >10 wt % water becomes desensitized …”

Section: General Concepts In Large-scale Amidationsmentioning

confidence: 99%

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Magano

2022

Org. Process Res. Dev.

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“…Among them, ethyl acetate exhibited the best performance, and the product 3 ab was obtained in 85 % yield (entry 14). Moreover, no additional improvement in yield was observed by increasing or decreasing reaction temperature (entries [17][18]. Ultimately, we sought to further improve the yield by adjusting the equivalent ratio of substrates and base, and the results indicated that the optimal ratio of 1 a/2 b/K 2 CO 3 was 1.5 : 1 : 2, and the cycloadduct 3 ab could be isolated with a 90 % yield being obtained (entry 20).…”

Section: Resultsmentioning

confidence: 99%

“…The N-alkoxy-(4-nitrophenyl)-carbamates 1 were synthesized according to the known literature procedure 18 . The N-sulfonyl azaheptafulvenes 2 were prepared by the reported procedure 6 .…”

Section: Methodsmentioning

confidence: 99%

[8+2]‐Cycloaddition Reaction of Carbamates and N‐Sulfonyl azaheptafulvenes

Wang,

Liu,

et al. 2023

ChemistrySelect

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The base‐mediated higher‐order [8+2]‐cycloaddition reaction of carbamates with N‐sulfonyl azaheptafulvenes has been successfully developed, providing a facile access to a series of highly functionalized cycloheptatriene‐fused imidazolidin‐2‐one derivatives in 52–95 % yields. This reaction features transition‐metal free, simple operation, and mild reaction conditions. Additionally, this transformation can also be utilized to modify some natural isolates.

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“…The advanced intermediate 8 , prepared by reductive amination of 3-aminomethyl thiophene 7 with ketone 6 , was used to prepare the analogues 2a – r . Nitrile reduction of enantiomerically pure 5 , under Raney-Ni-catalyzed hydrogenation conditions followed by Boc protection of the amine afforded 6 in good yield. Installation of the amide moiety was readily accomplished using standard peptide coupling procedures, whereas the urea moiety was installed using commercially available isocyanates or amines.…”

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confidence: 99%

Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication

Skerlj¹,

Bridger²,

Zhou³

et al. 2012

ACS Med. Chem. Lett.

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A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels. KEYWORDS: HIV-1, hERG, CCR5, chemokine receptor Recently, we reported 5 on the identification of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amides (1) as a novel class of CCR5 antagonists that exhibited potent inhibition of R5 HIV-1 (BaL) replication in PBMC (Figure 1). These compounds were identified based on our initial redesign efforts of Schering C. 6 Although these compounds met most of the criteria for further development, they were found to have a significant hERG liability (also reported by the GSK 7 and Pfizer 8 groups), which we sought to mitigate by reducing the lipophilicity through the design of compounds 2 (Figure 1). The antiviral activity was used to determine a structure−activity relationship (SAR), and it was measured utilizing the R5 HIV-1 PBMC assay. 9 In addition, we also utilized a gp120/CCR5 cell fusion assay 10 as a first pass screen to select compounds for antiviral screening since the fusion data were found to be a reliable predictor of antiviral activity.On the basis of the recognition that compound 1a containing an anilino nitrogen (R 1 = phenyl) had potent antiviral activity, we reasoned that the most expedient way to address the hERG liability was to replace the substituted phenyl group on the left had side with an amide or urea that would reduce the lipophilicity 11 as measured by cLog P. Initially, the 4-methyl pyridine moiety on the top left-hand side was retained, but these compounds were substantially less potent than the corresponding thiophene analogues, 5 so the thiophene moiety was utilized for further optimization (Table 1). For example, comparison of the tetrahydropyranyl esters 1b and 2b showed that the thiophene 2b provided a 44-fold enhancement in potency as compared to the 4-methyl pyridine 1b based on CCR5 fusion inhibition. Similarly, comparison of the pyridinyl ureas 1c and 2c showed a 130-fold increase in potency for 2c as compared to the 4-methyl pyridine 1c.Several amide analogues of compound 2 were prepared (Table 2). Aside from maintaining antiviral potency, the important properties that were measured to distinguish the analogues was fusion inhibition shift in the presence of α-1-acid glycoprotein (AGP), human plasma protein binding, and hERG inhibition based on % inhibition and/or IC 50 . The simple methyl amide 2d containing the optimum 2-chloro-4,6-

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Practical Convergent Laboratory-Scale Synthesis of a CCR5 Receptor Antagonist

Abstract: An efficient laboratory-scale synthesis has been developed for the selective CCR5 antagonist 1. The convergent route has a longest linear sequence of nine steps (15 steps overall), and has overall yields of 18–25%. The route has enabled the preparation of 550 g of 1.

Cited by 8 publications

References 22 publications

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

[8+2]‐Cycloaddition Reaction of Carbamates and N‐Sulfonyl azaheptafulvenes

Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication

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