A morpholine-free process amenable convergent synthesis of apixaban: a potent factor Xa inhibitor

Nevuluri, Narasimha Rao; Rapolu, Rajesh Kumar; Iqbal, Javed; Kandagatla, Bhaskar; Sen, Saikat; Dahanukar, Vilas H.; Oruganti, Srinivas

doi:10.1007/s00706-017-1920-1

“…In the last section of this work we advance a much simpler computational method based on the Borda count positional voting procedure [32,33]. We illustrate the results of all three ranking methods on 6 industrial plans to apixaban [34][35][36][37][38][39] shown in Figure 2 and discuss the merits and limitations of each method. Specifically, we show that the Borda count method yields the same ranking results as the poset method using simpler and faster computation, but are different from the results of the inferior VMR method.…”

Section: Part 2 -Synthesis Treementioning

confidence: 99%

Aiming for a standardized protocol for preparing a process green synthesis report and for ranking multiple synthesis plans to a common target product

Andraos¹

2019

Green Processing and Synthesis

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This paper proposes a standardized format for the preparation of process green synthesis reports that can be applied to chemical syntheses of active pharmaceutical ingredients (APIs) of importance to the pharmaceutical industry. Such a report is comprised of the following eight sections: a synthesis scheme, a synthesis tree, radial pentagons and step E-factor breakdowns for each reaction step, a tabular summary of key material efficiency step and overall metrics for a synthesis plan, a mass process block diagram, an energy consumption audit based on heating and cooling reaction and auxiliary solvents, a summary of environmental and safety-hazard impacts based on organic solvent consumption using the Rowan solvent greenness index, and a cycle time process schedule. Illustrative examples of process green synthesis reports are given for the following pharmaceuticals: 5-HT2B and 5-HT7 receptors antagonist (Astellas Pharma), brivanib (Bristol-Myers Squibb), and orexin receptor agonist (Merck). Methods of ranking synthesis plans to a common target product are also discussed using 6 industrial synthesis plans of apixaban (Bristol-Myers Squibb) as a working example. The Borda count method is suggested as a facile and reliable computational method for ranking multiple synthesis plans to a common target product using the following 4 attributes obtained from a process green synthesis report: process mass intensity, mass of sacrificial reagents used per kg of product, input enthalpic energy for solvents, and Rowan solvent greenness index for organic solvents.

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“…This mathematical evidence therefore shows that step E-factors for a linear plan are not additive. Close examination of equation (7) shows that each of the E-factor parameters is defined with respect to different product masses. Now, if we define the overall mass of waste produced in a linear synthesis plan as the difference between the sum of masses of all input materials used in all reaction steps and the sum of masses of all products produced along the way as shown in equation ( 8)…”

Section: E-factor and Pmimentioning

confidence: 99%

“…We evaluated the material efficiency of various literature-documented syntheses of the blood anti-coagulant apixaban 1 as a demonstration of the mathematical relationships presented in this work. Six synthesis plans were considered including two from Bristol-Myers Squibb [3,4], one from an academic lab in China [5], and three from generic drug companies [6][7][8]. All of them follow the same convergent synthesis strategy as evidenced by the common target bond mapping shown in Figure 1…”

Section: Application To Syntheses Of Apixabanmentioning

confidence: 99%

“…We begin by showing the derivation of each method and supply mathematical evidence supporting the connections between the relevant metrics. Next, we illustrate the computation of those metrics for published synthesis plans to the blood anti-coagulant pharmaceutical apixaban 1 [3][4][5][6][7][8] since this was chosen as a showcase example by the pharmaceutical industry for achieving a "green" synthesis [9]. Finally, we show how these metrics may be used for ranking the published plans with respect to material efficiency.…”

mentioning

confidence: 99%

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Relationships Between Step and Cumulative PMI and E-factors: Implications on Estimating Material Efficiency With Respect to Charting Synthesis Optimization Strategies

Andraos¹

2018

Preprint

0

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This report describes mathematical relationships between step and cumulative process mass intensities (PMIs) for synthesis plans, and analogous parameters applied to Efactors. It is shown that both step E-factors and step PMIs are not additive for synthesis plans. It is also shown that a recursive calculation of cumulative PMIs from step PMIs is a rapid method of determining overall PMIs for synthesis plans, though cumulative PMIs are not sufficiently informative as step PMIs or step E-factors to identify bottlenecks in synthesis plans. Illustrations on the use of these metrics to track the material efficiency of published synthesis plans for the pharmaceutical, apixaban, are given as a template example. Advantages and disadvantages of each metric are discussed. A general algorithm to select the most promising candidate synthesis plans considered at the design stage for a given molecular target that most likely satisfy “green” material efficiency criteria is also presented.

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“…In the last section of this work we advance a much simpler computational method based on the Borda count positional voting procedure [32,33]. We illustrate the results of all three ranking methods on 6 industrial plans to apixaban [34][35][36][37][38][39] shown in Figure 2 and discuss the merits and limitations of each method. Specifically, we show that the Borda count method yields the same ranking results as the poset method using simpler and faster computation, but are different from the results of the inferior VMR method.…”

Section: Introductionmentioning

confidence: 99%

Aiming for a Standardized Protocol for Preparing a Process Green Synthesis Report and for Ranking Multiple Synthesis Plans to a Common Target Product

Andraos¹

2019

Preprint

0

View full text Add to dashboard Cite

This paper proposes a standardized format for the preparation of process green synthesis reports that can be applied to chemical syntheses of active pharmaceutical ingredients (APIs) of importance to the pharmaceutical industry. Such a report is comprised of the following eight sections: a synthesis scheme, a synthesis tree, radial pentagons and step E-factor breakdowns for each reaction step, a tabular summary of key material efficiency step and overall metrics for a synthesis plan, a mass process block diagram, an energy consumption audit based on heating and cooling reaction and auxiliary solvents, a summary of environmental and safety-hazard impacts based on organic solvent consumption using the Rowan solvent greenness index, and a cycle time process schedule. Illustrative examples of process green synthesis reports are given for the following pharmaceuticals: 5-HT2B and 5-HT7 receptors antagonist (Astellas Pharma), brivanib (Bristol-Myers Squibb), and orexin receptor agonist (Merck). Methods of ranking synthesis plans to a common target product are also discussed using 6 industrial synthesis plans of apixaban (Bristol-Myers Squibb) as a working example. The Borda count method is suggested as a facile and reliable computational method for ranking multiple synthesis plans to a common target product using the following 4 attributes obtained from a process green synthesis report: process mass intensity, mass of sacrificial reagents used per kg of product, input enthalpic energy for solvents, and Rowan solvent greenness index for organic solvents.

show abstract

A morpholine-free process amenable convergent synthesis of apixaban: a potent factor Xa inhibitor

Cited by 11 publications

References 8 publications

Aiming for a standardized protocol for preparing a process green synthesis report and for ranking multiple synthesis plans to a common target product

Aiming for a standardized protocol for preparing a process green synthesis report and for ranking multiple synthesis plans to a common target product

Relationships Between Step and Cumulative PMI and E-factors: Implications on Estimating Material Efficiency With Respect to Charting Synthesis Optimization Strategies

Aiming for a Standardized Protocol for Preparing a Process Green Synthesis Report and for Ranking Multiple Synthesis Plans to a Common Target Product

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