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Chapter 9

Early and Late Stage Process Development for the Manufacture of Dacomitinib Downloaded by COLUMBIA UNIV on December 12, 2016 | http://pubs.acs.org Publication Date (Web): December 9, 2016 | doi: 10.1021/bk-2016-1239.ch009

Shu Yu1 and Olivier Dirat*,2 1Chemical

Research and Development, Pfizer Global Research and Development, Groton, Connecticut 06340-8156, United States 2Chemical Research and Development, Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, United Kingdom *E-mail: [email protected].

The process chemistry efforts to support the development of dacomitinib, a potent irreversible epidermal growth factor receptor inhibitor designed for the treatment of non-small cell lung cancer, are described. Early development routes that enabled the delivery of the first ten’s of kilograms of API are first discussed, followed by a more detailed account of the development of the commercial route, an efficient three steps with two isolations process using, as a key transformation, a low temperature Dimroth rearrangement. The commercial route has been used in Pfizer’s manufacturing facilities to produce over 800 kg of API in 58% overall yield.

Introduction Dacomitinib is a potent irreversible epidermal growth factor receptor (Pan erbB) inhibitor designed for the treatment of non-small cell lung cancer (NSCLC). The discovery and medicinal chemistry synthesis of dacomitinib were described in the preceding chapter. This chapter will describe the process chemistry efforts to support the pre-clinical studies, clinical development program and the potential commercial requirements.

© 2016 American Chemical Society Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Early Stage Development Process Chemistry Downloaded by COLUMBIA UNIV on December 12, 2016 | http://pubs.acs.org Publication Date (Web): December 9, 2016 | doi: 10.1021/bk-2016-1239.ch009

Evaluation of the Medicinal Chemistry Route Since quality, speed and scalability were the focus of the early stage of development, our work started by evaluating the discovery chemistry route (Scheme 1). The synthesis started with the condensation of 2-amino4-fluorobenzoic acid 2, with amidine acetate 3 to afford intermediate 4. Regioselective nitration gave a mixture of two isomers 5 and 6 in ~5:1 ratio, favoring the desired isomer 5, the undesired isomer 6 being successfully purged during isolation. Treatment of 5 with POCl3 afforded chloro-quinazoline 7, which after nucleophilic aromatic substitution with 8 gave 9. This was followed by a second nucleophilic aromatic substitution with a stronger nucleophile NaOMe under more forcing conditions to give intermediate 10. Nitro reduction afforded arylamine 11, which reacted with acid chloride 13 formed in situ, affording the desired API, dacomitinib 1 (1).

Scheme 1. Medicinal Chemistry Route to Dacomitinib 236 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

A critical evaluation of the discovery route in the laboratory revealed that the synthesis was well designed as all the chemical transformations afforded the desired products in good to excellent yield. However, two major issues existed for the route: •

Downloaded by COLUMBIA UNIV on December 12, 2016 | http://pubs.acs.org Publication Date (Web): December 9, 2016 | doi: 10.1021/bk-2016-1239.ch009

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although the in situ yield for the formation of 9 was good, the isolation of the product was challenging causing extensive loss of product to the mother liquor. the reduction of the nitro group via catalytic hydrogenation was capricious: when the conditions were not controlled perfectly, the hydrogenation could afford a small amount of a des-chloro impurity, which could not be purged in the downstream steps.

The formation of the des-chloro impurity was extremely sensitive to palladium catalysis, as a trace amount of leftover catalyst from the hydrogenator was enough to cause de-chlorination. The product, amine 11, also exhibited poor solubility in organic solvents. A mixture of DME and DMAc was required to enable catalyst removal by solubilizing 11. DMAc was subsequently removed via distillation, which was an undesirable operation. In order to meet the API demand for preclinical and clinical studies, the medicinal chemistry route was adapted to adress the issues identified and allow scale-up.

Enabling of the Medicinal Chemistry Route for Scale-Up Since large amounts of intermediate 5 were readily available, the initial process development work started from 5. The formation of intermediate 9 was initially performed as a telescoped process but later found to be better executed in two separate steps. In the telescoped process, the isolated yield was modest, often in the 50-60% range due to product losses to the mother liquor. It soon became clear that the culprit was toluene, as even relatively small amounts resulted in large losses. The formation of intermediate 7 in the absence of toluene was therefore sought. It was found that 5 could also be chlorinated with 6 equivalents of SOCl2, and gratifyingly, when n-heptane was added to the mixture at the end of reaction, the desired product 7 crystallized, affording a direct drop process. The isolated 7 underwent nucleophilic aromatic substitution smoothly with amine 8, to afford 9 in excellent isolated yield. The two-step process was successfully performed in the pilot plant on a 70 kg scale. The displacement of the fluoride with methoxide proceeded smoothly, however the filtration was very slow due to the presence of small particles. This problem was solved by ripening the particles with heat-cool cycles. As the catalytic hydrogenation of 10 suffered from a number of issues (vide supra, undesired de-chlorination and solubility of product), alternative conditions were sought. Platinum catalysts proved to be a good alternative to palladium catalysts as they provided much lower ratio of the undesired de-chlorination. Profiling of the reaction indicated that the reaction occurred in two stages: 237

Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


• •

a fast reduction of the nitro group to hydroxylamine 14. a slower reduction of the hydroxylamine 14 to amine 11 (Figure 1).

The slow second stage was detrimental, as long reaction times increased the risk of des-chloro impurity formation. A broad screen of solvents revealed that methanol was a good solvent for this reduction as the reaction could be complete within an hour. The low solubility of amine 11 in methanol did not allow for the possibility of catalyst removal by filtration. Through extensive experimentation, it was discovered that a mixed solvent system that contained 70% THF and 30% methanol could achieve fast hydrogenation and keep the product in solution for catalyst removal via a hot filtration. In combination with vigorous vessel cleaning, the process was successfully implemented in the pilot plant and produced 32 kg of 11 in 94% yield.

Figure 1. Nitro reduction reaction profiling.

Compound 11 contains two nucleophilic nitrogens, and owing to the differences in the stereoelectronic effects, the nitrogen at the 6-position was more reactive towards acylation, affording the desired API. The final amide coupling reaction performed well when a two-vessel process was used. The acid chloride 13 was prepared in one vessel and added into a THF solution of amine 11 in a second vessel. The two-vessel process ensured that the concentration of 238 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


acid chloride 13 was low at all stages of the amide formation reaction, thereby minimizing the chances of bis-amide formation. This modified medicinal chemistry route was successfully executed three times in the pilot plant (Scheme 2). As the clinical program continued to show promise, alternative, more efficient routes were investigated.

Scheme 2. Modified Medicinal Chemistry Route

N-Arylation Route to Dacomitinib Oxidation state and functional group manipulations are inefficient operations as they typically do not add structural complexity. The N-arylation route shown in Scheme 3 introduces the nitrogen at the 6-position at the correct oxidation state (hence no need for a nitro reduction); the methoxy group was also introduced through the starting material thereby not requiring functional group manipulations. Finally, the new starting material 15 was commercially available, whereas the previous starting material 5 required in-house preparation from 2 in 2 steps and 59% yield (Scheme 1) Iodination of 15 using NIS produced 16 in excellent yield and regioselectivity, however, the by-product succinimide was hard to remove when dichloromethane was employed as solvent (2). However when 2-methoxy-ethanol was used as the solvent, the iodination performed equally well to give 16 and provided an excellent purge of succinimide during the isolation of 17. Accordingly, the two steps were telescoped without isolating 16. Condensation of 16 with amidine acetate 3 yielded intermediate 17, which crystallized from the reaction mixture affording a direct drop process. The chlorination of 17 was best performed in a mixture of toluene and acetonitrile. This mixture of solvents also performed well during the nucleophilic aromatic substitution leading to 19. The resulting telescoped process from 17 to 19 achieved greater than 95% yield over two steps. At this point, the stage was set for the pivotal palladium catalyzed N-arylation (3). 239



Scheme 3. N-Arylation Route to Dacomitinib

High throughput screening was used to rapidly evaluate palladium sources, ligands, bases and solvents. The combination of Pd2(dba)3, Xantphos, the dual bases Cs2CO3/Hunig’s base and mixed solvents toluene/water afforded the desired API efficiently in 75% isolated yield. The crude API prepared this way contained varying amounts of residual palladium. However, activated carbon and 1,1,2,2-tetramethylethylenediamine (TMEDA) treatment allowed consistent reduction of the palladium content to 100 L/kg) owing to the insolubility of intermediates 10 and 11. For this reason, this route was deemed not optimal for commercial manufacture and therefore was not pursued further.

Scheme 5. Approaches to Dacomitinib Using a Dimroth Rearrangement

Route B started with a nitro reduction which proceeded very well in high yields. The Dimroth rearrangement on the aniline 24 proceeded smoothly with 71% yield at 55 °C, again within one hour. The amide bond formation also proceeded well. Similarly to route A, the aniline quinazoline intermediate 11 was very insoluble and required processing volumes greater than 100 L/kg and therefore route B was also deemed not optimal. Clearly the later the introduction of the quinazoline ring the more efficient the process would be. 241 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Route C solved the solubility issue as the quinazoline ring was formed in the last step with the amide already installed, which provided increased solubility. Indeed, all intermediates in this sequence had solubilities that require a dilution of less than 10 L/kg. While the first two steps were straightforward, the Dimroth rearrangement initially appeared challenging owing to a thermal side reaction of the product. The formation of lactam 26 had been observed under acidic, basic and/or thermal conditions. Lactam 26 readily hydrolyzed to the corresponding hydroxyl lactam 28 in the presence of water, or reacted with aniline 8 to give compound 27 (Scheme 6). It was therefore crucial to find milder reaction conditions for the Dimroth rearrangement than the typical conditions of refluxing acetic acid. To our delight, the Dimroth rearrangement proceeded smoothly at lower temperatures giving 80% yield at only 30 °C in 16 h. Accordingly, route C was selected as the commercial route to dacomitinib and the process was developed further.

Scheme 6. Side Reactions of Dacomitinib

Development of the Nitro Reduction Step The nitro group reduction reaction performed well with many palladium on carbon catalysts in several solvents. We chose acetonitrile as solvent as it enabled telescoping with the next step. For many aromatic nitro group reductions, the rate limiting step is the final reduction of the hydroxyl amine to aniline. In our case, profiling studies showed that the rate limiting steps were the initial reduction of nitro 23 to nitroso 29 and the reduction of the nitroso 29 to hydroxyl amine 30, the hydroxyl amine 30 being so reactive that it has never been observed during the reaction (Scheme 7, Figure 2). The main side reaction is the reduction of the nitrile which immediately cyclises to form quinazoline 31. This impurity purges readily in the downstream process, so did not pose a concern. 242 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 7. Nitro Reduction Intermediates

Figure 2. Nitro reduction reaction profiling.

Development of the Amide Bond Formation Step The first task was to identify a suitable coupling agent for the amidation reaction between aniline 24 and acid 12. We focused on reagents that do not require a separate activation step to improve efficiency of the manufacturing process (one vessel required and no activation IPC required). After screening 6 reagents (cyanuric chloride, CDMT, DCC, EDC, EEDQ and T3P®) with a range of additives using the acetonitrile solution of aniline 24 obtained after nitro reduction, propanephosphonic acid anhydride (T3P®) was clearly the reagent of choice for this transformation. T3P® was also conveniently available as a solution in acetonitrile. Acid 12 was isolated as an HCl salt, so one equivalent of a non nucleophilic base was required for the reaction. Pyridine-derived bases (pyridine and 2,6-lutidine) gave superior impurity profiles compared with aliphatic amines (Hunig’s base and triethylamine), carbonates and alkoxides. Therefore, 2,6-lutidine was selected as base (Scheme 8), and the reaction was profiled (Figure 3). 243



Scheme 8. Amidation Reaction Scheme

The reaction profiling led to interesting observations on the side reactions. Firstly, the most prevalent impurity (1,4-adduct 34) formed very rapidly at the start of the reaction. We initially thought that a 1,4 addition of aniline 24 onto the α,β-unsaturated amide was occurring. However we have failed to form any trace of adduct 34 after examining many conditions to react the product with aniline 24. We serendipitously observed that if the cis-acid 37 was used instead of the trans-acid 12, it formed adduct 34 exclusively under the reaction conditions, which led us to postulate the mechanism shown in Scheme 9. Adduct 34 can be envisaged to form via activation of cis-acid 37 to form a highly reactive electophile 38 (the trans-acid cannot form the ring) that reacts with aniline 24 to form ketene 39. This in turn also reacts with aniline 24 to form adduct 34. The postulated mechanism fits with observed levels of 34 and the reaction profiling, but we have not been able to obtain proof of the existence of the reactive intermediates (38 and 39).

Scheme 9. Postulated Mechanism of Formation of Adduct 34

The rate of formation of bis-amide 35 was particularly intriguing as its levels keep increasing, even past reaction completion. The hydrolysis of the formamidine group was ruled out as the root cause as the levels of aniline 33 remained constant throughout the reaction. The formation of aniline 36, where the formamidine group has been replaced by an amide, led us to speculate the mechanism shown in Scheme 10 where the formamidine nitrogen in 24 is first acylated and the resulting formanidinium species 40 is transferred by the attack of another molecule of starting material 24. An indirect proof of this mechanism was obtained by submitting pure amide product 25 to the reaction conditions and observing elevated levels of bis-amide 35. This minor side reaction pathway explains the constant growth of the bis-amide 35 impurity post reaction completion. 244 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 3. Amidation reaction profiling.

Scheme 10. Postulated Mechanism for the Formation of Bis-amide 35 245 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 4. Amidation processes.

The initial work-up and isolation process was extremely simple as a direct drop after quench with an aqueous solution of sodium hydroxide. This provided an efficient process from nitro 23 to amide 25 with no solvent changes, distillations or phase separations. Upon scale up, this process proved to be problematic owing to two issues: 246 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

•


•

At the start of the quench operation the reaction mixture was exposed to aqueous conditions at low pH which led to the hydrolysis of the formamidine group. The pH swing-induced crystallization lacked robustness and led to a poor purge of impurities and inorganics.

Accordingly, a new quench, work-up, and crystallization processes were designed. To suppress the instability of 25 under aqueous acidic conditions, a reverse quench was implemented whereby the reaction mixture was added into a basic aqueous solution of sodium hydroxide. To improve the robustness of the crystallization, a seeded cooling crystallization from a mixture of acetonitrile and toluene was designed. The quench and crystallization operations were linked by an aqueous work-up using toluene. The new process, whilst requiring more unit operations, proved to be very robust on scale up and delivered significantly pure product (Table 1). A flow diagram comparing the initial and the new processes and the corresponding isolated solids is shown in Figure 4.

Table 1. Comparison of Initial and Final Amidation Processes Assay

Yield

Residue on Ignition (ROI)

Phosphorous content (ppm)

Initial process

87-91%

63-71%

0.4-1.8%

1500-10000

Final process

95-96%

73-77%

0.10-0.18%

200-300

Development of the Dimroth Rearrangement Reaction A successful Dimroth rearrangement was unlikely to be feasible for this reaction as both starting material 25 and product 1 are unstable towards high temperatures, and typical Dimroth rearrangement conditions are refluxing acetic acid. We therefore focused on identifying low temperature conditions for this reaction. A wide range of acids was screened at 30 °C in acetonitrile at high concentrations. This screen identified salicylic and acetic acid as the best compromise between conversion and impurity formation. Cost and simplicity of operations led us to select acetic acid. A solvent screen performed with several concentrations identified that neat acetic acid was optimal. Balancing impractically long reaction time when low temperatures were used with impurity generation at higher temperatures, a compromise was found at 30 °C using two equivalents of aniline 8 to increase the reaction rate (Scheme 11). Compounds 25 and 43 were observed during the reaction while compound 42 was not during reaction profiling experiments. This indicated that the rate limiting steps are both the initial formamidine exchange and the rearrangement itself, since 25 will be converted slowly to 42 which itself will be converted quickly to 43 but 43 will rearrange slowly to product. 247



Scheme 11. Dimroth Rearrangement Reaction

The initial work-up and isolation process was simple and consisted of the addition of IPA followed by a pH induced crystallization via the addition of an aqueous solution of sodium hydroxide. The yield was excellent (85%) and this process performed well on pilot scale (20 kg), but calculations predicted that filtration time on commercial equipment could take up to 10 days, which was unacceptable. The root cause for this slow filtration could be the physical properties of the solid, the viscosity of the solvent, or a combination of both. To answer this question, we tested typical small particles of 1 in the filtration, alongside a slurry made of the typical solvent composition with engineered large particles of 1 (Figure 5). Both filtrations were equally slow, pointing to the solvent system being the root cause for the slow filtration.

Figure 5. Particles tested in the filtration. 248 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The work-up and isolation process was therefore re-designed to avoid filtration of a viscous aqueous/organic mixture. An extractive process was sought using 2-MeTHF as organic solvent. The poor solubility of dacomitinib 1 in 2-MeTHF led to volumeous dilutions and volume swing as the reaction was performed in low volumes of acetic acid. We next examined a work-up where the volume of 2-MeTHF was capped at 10 L/kg and studied the addition of sodium hydroxide carefully. This showed that two liquid phases were observed until less than 5.7 equivalents of acetic acid remained. Between 5.7 equivalents and 2 equivalents, a three liquid phase system existed and below 2 equivalents the product 1 precipitated. We therefore designed a process that partially quenched acetic acid, leaving enough acetic acid in the system to ensure a two phase system with the product still in solution. The phases were then separated. The remaining acetic acid needed to be quenched to allow the product to crystallize. To achieve this, an organic base in conjunction with acetonitrile was used in order to keep the mixture monophasic. Several tertiary amines were investigated and all performed well. The lipophilicity of the amine appeared to correlate with yield loss as liquid amines appeared to be acting as solvents as well as bases (Table 2). To balance yield, boiling point of the amine and cost, we selected triethylamine as the organic base.

Table 2. Tertiary Amines Screening for Work-Up Me2NEt

Et2NMe

Et3N

Et2N(i-Pr)

nBu2NEt

Log P

0.7

1.1

1.5

2.4

4.6

Boiling point

36 °C

64 °C

89 °C

105 °C

181 °C

Yield

82%

80%

77%

69%

48%

With a practical extractive process in place, we were able to design a robust seeded crystallization that delivered a fast filtration (Figure 6). Whilst the yield range was slightly lowered to 75-80% from 80-85%, it was worth the trade for the improvement on the purge of inorganic and organic impurities. Finally, a dramatic improvement in predicted filtration time on commercial equipment from ten days to 14 h was realized (Table 3).

249 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 6. Dimroth rearrangement processes.

Table 3. Comparison of the Dimroth Rearrangement Processes Yield

Total impurities

Filtration K value

Predicted filtration speed

Initial process

80-85%

1.2-1.6%

700

10 days

Final process

75-80%

NMT 0.050.07%

70

14 h Actual: Less than 10 h



Conclusion Several processes were developed during the project lifecycle to meet the clinical and projected commercial demands. The initial medicinal chemistry route was significantly improved to enable the delivery of the first tens of kilos of API by changing reagents, solvents and conditions. The N-arylation route was developed to avoid oxidation state and functional group manipulations, but was ruled out based on economic and practical considerations. Finally, an efficient three-step, two-isolation process has been developed to manufacture dacomitinib on commercial scale. The commercial process comprises of a nitro group reduction reaction telescoped with an amidation reaction, followed by a Dimroth rearrangement to install the quinazoline ring motif. Key to the development of this process was the ability to perform the Dimroth rearrangement under unprecedented low temperature conditions, which provided a practical operating window for the desired reaction without the degradation of starting material and product. Extractive work-ups followed by seeded controlled crystallizations for the two isolations were critical to ensure high purity and fast filtrations. Finally, the use of acetonitrile in steps 1 and 2 allowed an efficient telescope between the hydrogenation of the nitro group and the amidation reaction. The commercial route has been used in Pfizer’s manufacturing facility and produced over 800 kg of API to date in 58% overall yield (Scheme 12).

Scheme 12. The Commercial Process to Dacomitinib



Acknowledgments The authors would like to thank Mark Barrila, Weiling Cai, Juan Colberg, Mark Delude, Shane Eisenbeis, Kevin Girard, Arun Ghosh, Mark Maloney, Jason Mustakis, Mike Waldo and Greg Withbroe for their contributions to the early development part of this project; Ruth Boetzel, Claudio Brunelli, Ciaran Byrne, Steve Challenger, Yaling Cheng, Steve Collins, Doug Critcher, Rob Crook, Andrew Davidson, Niamh Dennehy, Andrew Derrick, Stuart Field, Andy Fowler, Denise Harris, Mike Hawksworth, Dave Henderson, James Hogbin, Ricky Jones, Phil Levett, Neil McDowall, Ivan Marziano, Jinu Mathew, Suju Mathew, Phil Peach, Sam Prior, Chris Stoneley, Roman Szucs, Steve Twiddle, Steve Yeo and David Walker for their contributions to the late development part of this project. Special thanks to David Daniels, Rob Singer, Karen Sutherland and Steve Twiddle for proof reading the manuscript.

References 1.

2. 3. 4.

5. 6. 7.

Smaill, J. B.; Gonzales, A. J.; Spicer, J. A.; Lee, H.; Reed, J.; Sexton, K.; Althaus, I. W.; Zhu, T.; Black, S. L.; Blaser, A.; Delaney, A.; Denny, W. A.; Ellis, P. A.; Fakhaury, S.; Harvey, P. J.; Hook, K.; McCarthy, F. O. J.; Palmer, B. D.; Rivault, F.; Schlosser, K.; Spoon, T.; Thompson, A. M.; Trachet, E.; Winters, R. T.; Tecle, H.; Bridges, A. J. Med. Chem. Submitted for publication. Arnold, L. D.; Sobolov-Jaynes, S. B. Eur. Pat. Appl. 1998, 837063. Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043–6048. Flahive, E. J.; Ewanicki, B. L.; Sach, N. W.; O’Neill-Slawecki, S. A.; Stankovic, N. S.; Yu, S.; Guinness, S. M.; Dunn, J. Org. Proc. Res. Dev. 2008, 12, 637–645. Chandregowda, V.; Rao, G. V.; Reddy, G. C. Org. Proc. Res. Dev. 2007, 11, 813–816. For the synthesis of erlotinib: Asgari, D.; Aghanejad, A.; Mojarrad, J. S. Bull. Korean Chem. Soc. 2011, 32, 909–914. Foucourt, A.; Dubouilh-Benard, C.; Chosson, E.; Corbiere, C.; Buquet, C.; Iannelli, M.; Leblond, B.; Marsais, F.; Besson, T. Tetrahedron 2010, 66, 4495–4502.


Early and Late Stage Process Development for the ... - ACS Publications

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