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Optimization of the Manufacturing Route to PF-610355 (2): Synthesis of the API Stéphane Content, Thomas Dupont, Nicolas M. Fédou, Radoslav Penchev, Julian D. Smith, Flavien Susanne, Christopher Stoneley, and Steven J. R. Twiddle* Chemical Research and Development, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, U.K., CT13 9NJ ABSTRACT: PF-610355 is a novel inhaled β-2 adrenoreceptor agonist. Process development of the final intermediate and the API are discussed with emphasis on the control of physical properties and subsequent isolations. This includes development of a constant volume distillation and evaluation of Nutsche filtration, agitated filter drying, and centrifugation to prevent particle attrition. The optimized process employed to manufacture 100 kg of the API is described.

1. INTRODUCTION Respiratory diseases such as asthma and chronic obstructive pulmonary disorder (COPD) are highly prevalent and affect millions of people across the globe. Common treatments include β-adrenoreceptor agonist inhalers, antimuscarinic inhalers, steroid inhalers, or combination treatments. Current marketed β-adrenoreceptor agonists salmeterol and formoterol possess a duration of action which is adequate for twice-daily administration.1 A key focus area has been the identification and development of long acting β-2 adrenoreceptor agonists (LABAs) which would provide a single daily dose through a dry powder inhaler device. A summary of the discovery and synthesis of a range of β-2 adrenoreceptor agonists culminating in the identification of PF-610355 as a clinical candidate has recently been published.1 The candidate has now progressed through the development phases with publications documenting the enabling chemistry2 and alternative route investigations.3 This paper documents the development work performed to afford a synthetic process suitable for commercial scale manufacture. The focus of the present article is the synthesis of the API from intermediate 5 and the alkyl bromide 6.

Although the preliminary commercial route had provided the desired material of high purity, on commencing development work a number of areas were identified as targets for further optimization. First, increased reaction understanding was desired to optimize the alkylation reaction of the amine 5 and alkyl bromide 6. There were scale-up concerns surrounding the toxicity, dispensability, and corrosiveness of triethylamine trihydrogen fluoride for the desilylation of the coupled product 7. An alternative reagent was required and, as a consequence, an appropriate workup including the elimination of ammonia. A more controlled and reproducible crystallization of the hemifumarate salt 9 was desired due to observed oiling in the preliminary plant batches. This lack of control over the crystallization resulted in variable filtration times and a limited impurity purge; a separate acetonitrile reslurry step was introduced to provide material of appropriate quality. The final debenzylation step suffered from variability in reaction rate due to the presence of an unknown poison; the introduction of a carbon treatment prior to the reaction had provided a shortterm solution but contributed to an unacceptable yield loss for commercialisation. The crystallization of the API involved a solvent exchange from the hydrogenation solvent system (THF/water) into the antisolvent acetonitrile (MeCN) from which PF-610355 was crystallized. Greater control over this operation was essential to install the API physical properties desired for drug product manufacture and inhaled delivery. 2.2. Synthesis of Intermediate 9. The preliminary synthesis of 9 existed as a three-step telescoped sequence from amine 5 and alkyl bromide 6 involving the aforementioned alkylation, desilylation, and crystallization of the hemifumerate salt prior to a separate acetonitrile reslurry step. The research that culminated in the preliminary commercial route exhaustively investigated conditions for the alkylation which suffered from low reactivity due to the steric hindrance of the amine and alkyl bromide partners. Consequently, elevated temperatures were required to obtain acceptable kinetics leading to the selection of the sodium hydrogen carbonate/n-butyl acetate (NaHCO3/nBuOAc)

2. RESULTS AND DISCUSSION 2.1. Background. Upon the identification of PF-610355 as a clinical candidate, enabling work performed led to the development of a synthetic process which built upon the medicinal chemistry route and developed effective syntheses of key building blocks.2 Although this provided the required quantity of material, the route was considered suboptimum for commercial scale manufacture in terms of processing and yield (36%). Alternative route investigations resulted in the nomination of a preliminary commercial route in which the API was constructed from three starting materials; this process was employed to generate 35 kg of PF-610355 (Scheme 1) to support early clinical development. 3 As the candidate progressed, continual development work was performed on the synthetic process and is discussed herein. As eluded to in the introduction, this paper will focus solely on the late stage of the synthesis of PF-610355 from the isolated intermediate 5 and the externally supplied 6. © 2013 American Chemical Society

Received: November 27, 2012 Published: February 5, 2013 202

dx.doi.org/10.1021/op300342y | Org. Process Res. Dev. 2013, 17, 202−212

Organic Process Research & Development

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Scheme 1. PF-610355 preliminary commercial routea

Reagents and conditions: (a) EDC·HCl, HOBt, Et3N, DCM, 20 °C then THF and 6 aq. washes. (b) ClCH2CN, TFA, 50 °C, then DCM and 4 aq. washes. (c) (i) Thiourea, AcOH, 70 °C then byproduct filtration and 2-MeTHF and aq. washes (NH3); (ii) Crystallization from MeCN, 58%. (d) NaHCO3, nBuOAc, 125 °C then EtOAc and aq. wash. (e) Et3N(HF)3, nBuOAc, EtOAc, MeOH, 20 °C then 2 aq. washes (NH3). (f) Fumaric acid, nBuOAc, MEK, 82%. (g) MeCN, 50 °C, 95%. (h) (i) THF/water, 2 aq. washes (NH3); (ii) H2, Pd/C; (iii) crystallization from MeCN, 77%. (i) MeOH/water, 50 °C, 91%. a

Figure 1. Impact of base selection on alkylation reaction to form 7 (% area of 7) in nBuOAc at reflux. Red (6 h), yellow (12 h), and green (18h).

base/solvent combination at reflux (125 °C). For commercial scale production, an alternative solvent was desirable to allow a lower reaction temperature and more efficient solvent removal through distillation. Although a range of alternative base/ solvent systems did impart the desired conversion, the reaction

rates were slower than the original conditions (Figure 1). Note that the rapid initial reaction rate afforded by 1-methylimidazole in the screening study could not be replicated during further laboratory investigations. 203



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It was decided to proceed with the existing conditions focusing attention on optimization through increased reaction understanding. It was confirmed that the alkylation follows an SN2 mechanism with the reaction being first-order with respect to both the amine 5 and the bromide 6. Thus the reaction rate could be increased by increasing the equivalency of the bromide; however, this also resulted in the formation of the acetophenone impurity 11 from excess 6. Formation of 11 proceeds via a rate-limiting elimination of hydrogen bromide (HBr) followed by a fast desilylation (Scheme 2). The impurity Scheme 2. Undesirable side reaction of 6

proved problematic to purge downstream, which, combined with the increased cost of a higher charge of 6, resulted in the use of the amine and bromide in a molar ratio of 1:1.05. As the transformation employs NaHCO3, an insoluble inorganic base, there were concerns over potential mass transfer issues on scale-up particularly considering the 3 L/kg volume of organic solvent. The reaction was close to zero-order with respect to NaHCO3 and thus a minor contributor to the reaction rate (2 equiv were employed). It was concluded that the reaction is not under mass transfer control, neither intraparticle mass transfer nor liquid−solid mass transfer. Upon reaction completion the inorganics were removed through a single water wash after cooling the reaction solution to 25 °C and diluting the concentrated reaction mixture with ethyl acetate (EtOAc). Thus at the end of the process the coupled product 7 existed as a solution in nBuOAc/EtOAc as was the case for the preliminary commercial route. The inherited conditions for the desilylation involved treatment of the telescoped solution with triethylamine trihydrogenfluoride (Et3N·(HF)3) after dilution with methanol (MeOH) to avoid alcohol 8 oiling from solution as the reaction progressed. Although the reaction afforded the desired product in 3 h at ambient temperature, the long-term use of Et3N·(HF)3 was undesirable due to concerns over reagent toxicity, dispensability, and corrosiveness. An initial screen of acidic conditions based on the current literature4 identified that the tert-butyldimethylsilyl (TBS) protecting group is relatively stable to mild conditions. Desilylation required either a strong acid at ambient temperature or weaker acid in a refluxing solvent, further evidence for the steric congestion illustrated by the harsh conditions required for alkylation. Consequently an acidic desilylation was dismissed due to significantly longer reaction times, high acid equivalency (which would also impact the throughput of the reaction workup), and potential robustness issues. Attention was focused toward alternative sources of fluoride, primarily tetraalkylammonium salts (Figure 2). Initial experiments showed low levels of conversion; however, buffering the basicity with acetic acid5 afforded a dramatic increase in reaction rates and also provided a cleaner impurity profile. Increasing the reaction temperature (50 °C) reduced the reaction time to just 2 h longer than the original Et3N·(HF)3 conditions. Tetraethylammonium fluoride (TEAF) was selected as the desilylation reagent based on a lack of corrosiveness (allowing the use of a glass lined vessel), a simplified aqueous workup,

Figure 2. Desilylation of 8 to afford 7: impact of reagent on reaction rate. TBAF = tetrabutylammonium fluoride; TEAF = tetraethylammonium fluoride; TMAF = tetramethylammonium fluoride.

and commercial availability. Use of ammonia to quench the desilylation was undesirable due to the required management of the resulting waste stream. Alternative bases were assessed resulting in the use of 1 M aq. potassium carbonate (K2CO3). There was, however, an issue with the formation of a single impurity during the quench (Scheme 3). The species was identified as possessing the same mass and molecular formula as the reaction starting material, but the location of the TBS group was the phenolic oxygen, 13. Its formation was linked to the pH of the K2CO3 wash and hence the formation of the phenolate 12. Although the silylating species has yet to be conclusively identified, there is literature precedence that alkoxides react selectively at the silicon atom with silyl acetates potentially formed in situ.6 Fate and purge investigations showed the impurity 13 to be unstable when stirred in the presence of ethanol (the crystallization solvent) forming the desired alcohol 8; consequently it was not considered a threat to the quality of the isolated intermediate. The inherited isolation of 8, as the hemifumarate salt 9, from a solution of nBuOAc/2-butanone (MEK) had been developed after exhaustive investigations of alternative salt forms. Unfortunately the process still suffered from significant issues including oiling of the fumaric acid and oiling of the product 9. This lack of control over the crystallization resulted in batch variability with regards to processing and quality. Impurity purges were poor, particularly the excess of alkyl bromide 6, necessitating the introduction of an acetonitrile reslurry (Scheme 1). Efforts were focused on developing a controlled crystallization to provide material with improved processability and of superior purity to allow the removal of the formal reslurry step. An initial re-evaluation of the free base 8 and potential salt forms confirmed that fumaric acid was the only viable option for the crystallization. Solubility studies of the salt 9 identified the solvents methanol (MeOH), tetrahydrofuran (THF), and ethanol (EtOH) as having acceptable solubility. However EtOH showed a favorable temperature dependence demonstrating a 5-fold increase in solubility when raising the temperature from 25 to 50 °C. Direct comparison of the recrystallization using proposed solvents showed that the use of 204



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Scheme 3. Undesirable side reaction of 8a

a

Reagents and conditions: (a) Et4NF (1.1 equiv), AcOH (2.0 equiv), MeOH, EtOAc, 50 °C. (b) (i) 1 M K2CO3 wash; (ii) water wash. (c) EtOH.

Figure 3. Process flow diagram illustrating the crystallization of 9.

EtOH afforded self-nucleation at 65 °C leading to a high recovery (90%) of a filterable solid which did not suffer from the oiling issues observed for MEK. Moving on from recrystallizations, formation of the hemifumarate salt 9 was evaluated in EtOH. An addition of solid fumaric acid to the free base 8 at 65 °C resulted in gumming, not dissimilar to the oiling observed for the MEK process. This appeared to be dependent on the concentration of the crystallization solution but could also be prevented through seeding with the desired product. The solubility of fumaric acid in EtOH was a limiting factor and thus a solution was charged rather than the solid; the solution required a concentration of 5 L/kg of EtOH with respect to the starting material 5. The addition of a seed to the free base solution did not result in dissolution; consequently the seed was present when supersaturation was achieved upon

completion of the addition of the fumaric acid solution and induced crystallization. Further crystallization trials identified a target solution concentration of 14 L/kg (wrt starting material 5) prior to seeding and fumaric acid addition. This ensured a more robust process with no oiling or gumming and provided a high recovery of material with consistent and improved filtration times. PXRD data confirmed that the material isolated from the EtOH solutions was the same form as the product of the original MEK isolation procedure. Conditions had been identified for the crystallization which involved a target solution of 8 in 14 L/kg (wrt starting material 5) of EtOH. At the end of the reaction workup the free base 8 existed as a solution in EtOAc, nBuOAc, and MeOH. A process needed to be designed that allowed an efficient solvent exchange to generate the desired EtOH solution (Figure 3). 205



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Scheme 4. Telescoped sequence for the synthesis of 9a

Reagents and conditions: (a) (i) NaHCO3 (2.0 equiv), nBuOAc, 125 °C; (ii) EtOAc and aq. wash. (b) (i) Et4NF (1.1 equiv), AcOH (2.0 equiv), MeOH, 50 °C; (ii) 2 aq. washes. (c) (i) Fumaric acid (0.5 equiv), EtOH; (ii) EtOAc, 50 °C, 83%. a

reagents for the desilylation (Et4NF/AcOH) also transferred successfully on scale-up. Although Et4NF could be sourced, the material is highly hygroscopic which complicated the quantity and method of charging. Controlling the impurity 13 proved an additional challenge when performed in the pilot plant and required a strict process to be defined. Its formation was limited by defining the 1 M K2CO3 wash contact time to 15 min. The conversion of any 13 to the desired product 8 was ensured by specifying a 5 h stir time after the EtOH dilution prior to the distillative solvent exchange so that, on completion of the operation, levels of NMT 0.05% were obtained. The aforementioned distillation demonstrated a remarkable level of consistency to afford an average EtOH content of 84.5% across different vessel sizes and was consistent with the laboratory studies (Table 1). This ensured that, on reaching

A distillative approach was explored, and it was identified that reduced pressure distillation operations were required to maintain the solution of 8 below 30 °C and minimize degradation. Furthermore, an initial EtOH charge was required to maintain a solution during any initial concentration. Computer modeling software was employed to chart the changing solvent composition under a range of different scenarios to identify the most efficient and robust process.7 This afforded a protocol involving the initial dilution before two concentration−dilution cycles performed at reduced pressure. This prediction was probed through laboratory investigations. Upon completion of the solvent exchange cycles, a solution consisting of an EtOH content of approximately 84% w/w was consistently afforded with the remainder primarily as nBuOAc. This resulted in a solvent system with approximately 90% w/w EtOH of the required concentration consistently being achieved at the point of crystallization (i.e., after the addition of the fumaric acid solution). In the presence of the seed the hemifumarate salt 9 could be crystallized from this solution with no oiling phase to allow isolation, with improved filtration times and in high yields (80−85%) for the three-step telescoped sequence. Although a more robust and controlled crystallization was introduced, the material still possessed levels of the starting materials 5 and 6 and the acetophenone fate product 11, which were greater than desired. In order to streamline the process, it was believed that a simple reslurry of the wet cake could be performed using the agitated filter drier (AFD) on scale-up to replace the formal reslurry step. The use of EtOH, EtOAc, and the existing MeCN were evaluated at 50 °C. Unlike the free base 8, the hemifumarate salt did not suffer from the degradation observed which resulted in the distillations being performed at reduced pressure. The use of EtOAc (already present in the step) allowed a reduced solvent quantity to be employed while also providing an improved impurity purge and an increased recovery (Scheme 4). The process outlined above was transferred to the pilot plant and implemented to produce 220 kg of 9. The alkylation reaction performed as expected with no deviations from the developed process and proved to be robust. The alternative

Table 1. Solvent composition for post-distillative solvent exchange for five pilot plant batches solvent composition % w/wa

a

batch

nBuOAc

EtOAc

water

MeOH

EtOH

1 2 3 4 5

12.4 12.7 13.7 13.6 14.0

0.8 0.9 2.6 0.8 0.6

0.6 0.5 0.6 0.6 0.6

0.0 0.0 0.0 0.0 0.0

86.2 85.9 81.5 84.9 83.9

Determined by 1H NMR and Karl Fischer analysis.

supersaturation after the addition of the fumaric acid solution, the desired solvent composition 90% w/w EtOH was achieved. After filtration of the resulting slurry, the AFD reslurry operation performed as expected and was demonstrated as an appropriate replacement for a formal reslurry step reducing the cycle time. Intermediate 9 was isolated in an average yield of 83%, and the purity was consistent with laboratory findings. 2.3. Synthesis of PF-610355. The conversion of the final isolated intermediate 9 to PF-610355 involved an initial salt break prior to hydrogenolysis to remove the benzyl protecting group yielding the API. As discussed there was the desire to 206



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remove ammonia from the process, increase the hydrogenation understanding, and identify an unknown poison which had resulted in the introduction of a carbon treatment. The selection of alternative solvent systems was limited by substrate solubility and that the optimum solvent for the hydrogenation had been identified as THF/water (9:1 v/v, 20 L/kg), with initial work focused on the salt break. A screen of aqueous base solutions were compared on the following criteria; phase separation, the quantity of fumaric acid remaining in the organic phase, and loss of 8 to the aqueous waste layer. The use of 1 M K2CO3 was shown to be superior to those tested. The original half saturated brine wash was maintained to remove any residual fumaric acid, mitigate the risk of carryover of inorganic salts and provide control over the THF/water ratio. A Karl Fisher IPC was introduced to quantify the water content and allow an additional water charge and to ensure the desired solvent composition prior to the debenzylation. As presented above, the hydrogenation had been preceded by a carbon treatment to ensure reaction completion due to early batches stalling during the hydrogenation. Its introduction afforded consistency in the reaction through the removal of an unknown impurity(s). However, a mass balance study showed the treatment was responsible for a 10−15% yield loss in the step and hence was a costly and unacceptable operation. The solvent and catalyst for the hydrogenation had been identified previously and were considered optimum; the catalyst, 5% Pd/ C, is a 50% wet catalyst, and the loading was uncorrected. The catalyst loading initially appeared to be batch dependent with carbon treatment allowing an approximate reduction in catalyst loading of 5% w/w. However, the development of the upstream processing afforded intermediate 9 which did not suffer from the variation and presumably did not contain the poison thus allowing a consistent catalyst charge of 10% w/w to be made. During the development it became apparent that the hydrogen pressure did not impact the reaction rate which would be expected even under mass transfer control. This suggested the reaction followed Langmuir−Hinshelwood kinetics in which adsorption of the substrate molecule to the catalyst surface is the rate-determining step. If the pressure is too high, retardation of the reaction rate can be observed due to saturation of the catalyst surface; the reaction was subjected to a hydrogen pressure of 50 psi. Initial trials of the final step sporadically afforded batches which contained elevated levels of palladium in the API, the source identified as the hydrogenolysis catalyst. A high level of leaching was detected under the hydrogenation conditions, probably existing as Pd(0) and/or nanoparticulates, which appeared to be recaptured at the end of the reaction. Leaching was also shown to occur when the catalyst slurry was exposed to air upon reaction completion. Note that the assessment of palladium levels was made using a combination of ICP-MS and HPLC.8 The complexity and combination of events led to the conclusion that to achieve process robustness, palladium removal rather than prevention would be required. A study of the latest literature identified a number of approaches which could be investigated; these included filtrations, carbon treatments, and scavenger resins.9 It became apparent that palladium levels could be reduced by over 50% simply through the introduction of speck-free filtration using a microfilter after the initial catalyst removal (Table 2). Although this removed the insoluble palladium clusters, a complete purge could not be achieved due to palladium remaining in solution. The use of a carbon treatment

Table 2. Assessment of palladium removal techniques approach

description

Pd level/ppma

% Pd removed

none filtration filtration filtration filtration filtration filtration resin resin resin resin

reference 5 μm 1 μm 0.45 μm 0.20 μm 0.10 μm 0.02 μm Smopex 110 Purolite S-920 MP-TMT Quadrapure TU

26 17 18 12 12 12 12 1 2 1 2

0 35 31 54 54 54 54 96 92 96 92

a

Determined by ICP-MS of PF-610355 after concentration from solution post-filtration/resin treatment.

was deemed undesirable due to the associated yield loss observed when performed previously prior to hydrogenation, and so attention was focused on screening scavenger resins. Evaluation of the resins focused on palladium removal, API stability to the nucleophilic functional groups, processing, and commercial availability. As presented in Table 2, a significant Pd purge was observed in all cases; however, the resin selected was Quadrapure TU. This possesses a thiourea pendent (3.0− 3.5 mol/kg) with an optimal charge of 25% w/w. Significantly, studies showed that there was no leaching of the thiourea from the resin scaffold. The combined strategy of the 0.2 μm in-line filter and Quadrapure TU treatment ensured all API plant batches met the specification for palladium content (NMT 10 ppm). The crystallization of PF-610355 involved distillation, exchanging the hydrogenation solvent system THF/water (20% w/w) for the antisolvent MeCN. Typically, the solution was concentrated under reduced pressure to 9 L/kg prior to dilution with 5 L/kg of MeCN. Atmospheric distillation followed in which the distilled volume was replaced by an equal aliquot of 5 L/kg MeCN. This operation was conducted 7 to 8 times to ensure the replacement of the THF/water mixture to a final composition of >99% of MeCN as measured by the boiling point (bp ≥80 °C). The isolated API was then subjected to MeOH/water reslurry which provided a purity upgrade through the purge of thermal degradation byproducts. Unfortunately early scale-up batches showed a high degree of variability over a range of physical properties; this is illustrated by the particle size distribution data for six pilot plant runs performed in two different reactors (Figure 4). Some of these batches resulted in an API with physical properties unsuitable for further drug product processing. The crystallization of PF-610355 was highly significant, as it set the quality attributes such as purity, crystal habit, and particle size distribution. Tight control of the physical properties is critical for inhaled treatments, and hence tight control over the crystallization process was essential.10 The crystallization approach lacked robustness at the critical stages; generation of supersaturation, nucleation, crystal growth, and agglomeration were impacted by process parameters (for example antisolvent addition rate, antisolvent temperature, etc.) that were not routinely and precisely controlled between runs and across different reactors. In order to impart an appropriate level of control over the API crystallisation, a defined and controlled evolution of supersaturation was required. This is typically achieved through a cooling 207



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Figure 4. Particle size distribution of pilot plant batches crystallized using the aliquot-based process.

the model and dependent on the batch size and vessel employed. This process was introduced as a separate recrystallisation step, as this allowed greater control over the starting solution in terms of solvent composition and concentration. The newly designed constant feed process was implemented in the pilot plant using two different material streams and two different sized reactors (250 L, 600 L) to probe the level of robustness. Analysis of the process showed the nucleation events occurred predictably and reproducibly with similar output physical properties regardless of the input batch. The particle size distribution for six batches is presented (Figure 6) and highlights the high level of reproducibility and robustness of the new crystallization process across the scale. In the previous process API isolation was followed by a reslurry in MeOH/water to purge thermal degradation impurities formed during the distillation procedure. This operation was still required after the constant feed distillation, but it was believed that this could be performed in the AFD as demonstrated in the isolation of 9. This tactic was evaluated and generated PF-610355 with the required purity; however there was a significant impact on the physical properties. Scanning electron microscopy (SEM) illustrated that the particles, the growth of which was carefully controlled in the crystallization, suffered severe attrition during the isolation process. Sample analysis identified that the particles were maintained through the reslurry operation (Figure 7a). Attrition was shown to occur during the drying in phase in which the damp cake was agitated. This not only afforded smaller primary particles but also resulted in their subsequent agglomeration (Figure 7b). The API produced from this isolation technique would not be suitable for drug product manufacture. Isolation on a Nutsche filter before tray drying circumvented the issue of mechanical agitation and thus particle attrition, but

crystallization with the content temperature as an easily and accurately controlled process parameter. Due to the limited solubility of PF-610355, supersaturation control had to be achieved by controlling the evolution of the solvent composition over the course of the distillation. It was envisioned that the continuous addition of MeCN antisolvent to the distilling mixture at approximately the same rate as the distillation rate should enable the bulk volume, and hence concentration, to remain constant, allowing a more gradual change in solubility (Figure 5).

Figure 5. Theoretical comparison of the change in solubility for the aliquot (dashed line) and constant feed (solid line) processes.

Utilizing thermodynamic principles and software modeling, the desired crystallization was designed and a constant feed protocol prepared.11 The distillation was controlled by three parameters: (1) ΔT (ΔT = Tj − Tr), (2) the MeCN addition rate, and (3) time (the distillation/addition time required to reach the desired composition). The set values were defined by 208



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Figure 6. Particle size distribution of pilot plant batches crystallized using the constant volume process.

reduction in solvent content prior to drying (in a pan drier) allowed a significant reduction in drying times, and the agitation of the dry material afforded minimal particle attrition (Scheme 5).

3. CONCLUSION A new process for the synthesis of PF-610355 from intermediate 5 has been developed that overcomes many of the issues associated with the original process. Optimization of the synthesis of intermediate 9 afforded alternative reagents (Et4NF/AcOH) for the desilylation which were more amenable to commercial scale manufacture. The introduction of a seeded crystallization process from an alternative solvent, EtOH, provided greater control and reproducibility to generate material which filtered much more rapidly. Performing a purity upgrade through a reslurry on the AFD significantly reduced the cycle time. The process was employed to produce 220 kg of 9 in an average yield of 83%. The focus of the conversion of the final isolated intermediate 9 to the API was to provide material of the appropriate quality for inhaled delivery. Greater robustness was achieved in the debenzylation through increased reaction understanding and the improved upstream processing. Physical properties were a critical quality attribute of PF610355. A constant feed distillative solvent exchange process was designed as a distinct recrystallization step and implemented on scale to consistently afford material of the desired properties. Also key to achieving this was the isolation and drying strategy employed. The use of centrifugation as the filtration technique minimized particle attrition during the agitated drying phase. Implementation of the new final steps afforded 100 kg of PF-610355 in 71% yield from 9.

Figure 7. SEM images illustrating PF-610355 particle attrition through agitated drying. (a) SEM of PF-610355 MeOH/water damp cake. (b) SEM of PF-610355 dried product.

this was deemed to be unviable for commercial scale manufacture based on projected volumes. Different drying regimes were defined for the AFD. These included extended blow through and strictly controlled agitation, but significantly extended drying times along with attrition ruled out this approach. The level of attrition was linked to the solvent composition of the damp cake when agitation commenced; the PF-610355 cake after filtration was shown to contain ∼60% w/ w of solvent (determined by LoD). Rheometry data suggested that to minimize attrition the solvent content had to be reduced to less than 50% w/w to reduce the sheer stresses exerted on the particles during agitation. The use of centrifugation was evaluated, as it was believed that the G force exerted on the damp cake would reduce the solvent content to a level at which agitation could be performed without attrition. Trial batches were performed in the lab which suggested that this mode of isolation would afford a cake with a significantly lower solvent content. Transfer to the pilot plant utilized a centrifuge/pan drier equipment train. Filtration afforded a damp cake with a reduced solvent content of ∼38% w/w; significantly the material could be efficiently peeled from the centrifuge basket with no attrition and existed as a free-flowing solid. The 209



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Scheme 5. API synthesis and isolationa

Reagents and conditions: (a) (i) THF, 2 aq. washes; (ii) Pd/C, H2 (50 psi), 20 °C; (iii) Quadrapure TU (25%w/w); (iv) Crystallization from MeCN; (v) MeOH/water (9:1); 80%. (b) Strip and replace from THF/water to MeCN, 94%. (c) MeOH/water (9:1), 95%.

a

4. EXPERIMENTAL SECTION General. The starting material 5 was prepared in-house, and 6 was synthesized by external vendors following a procedure developed and supplied by Pfizer. All reagents and solvents were used as received from commercial suppliers. 1H NMR was performed using either a Bruker Avance III spectrometer at 600 MHz or a Bruker Ultrashield Plus spectrometer at 400 MHz. 13 C NMR was performed using either a Bruker Avance III spectrometer at 150 MHz or a Bruker Ultrashield Plus spectrometer at 100 MHz. Mass spectrometry was performed on a Bruker MaXis QTOF under positive ion conditions. Combustion analyses were performed by Warwick Analytical Service, University of Warwick Science Park, The Venture Centre, Sir William Lyons Road, Coventry, UK, CV4 7EZ. (R)-2-(3-{2-[2-(4-Benzyloxy-3-methanesulfonamidophenyl)-2-hydroxyethylamino]-2-methylpropyl}phenyl)-N-[(4′-hydroxybiphenyl-3-yl)methyl]-acetamide Hemifumarate 9. (2-[3-(2-Amino-2-methylpropyl)phenyl]N-[(4′-hydroxybiphenyl-3-yl)methyl]acetamide 5 (50.0 kg, 129 mol), ((R)-N-{2-benzyloxy-5-[2-bromo-1-(tertbutyldimethylsiloxy)ethyl]phenyl}methanesulfonamide 6 (69.5 kg, 135 mol), and sodium bicarbonate (21.7 kg, 258 mol) were added to a reactor containing n-butyl acetate (500 L). The resulting slurry was heated to reflux temperature, and n-butyl acetate (350 L) was removed from the mixture by distillation at atmospheric pressure.12 The concentrated reaction mixture was heated at reflux for 35 h. The reaction was cooled to 20−25 °C, diluted with ethyl acetate (500 L), and washed with water (500 L). The n-butyl acetate/ethyl acetate solution was diluted with methanol (150 L). Acetic acid (14.8 L, 258 mol) was added in one portion at 22 °C followed by tetraethylammonium fluoride hydrate (28.8 kg, 142 mol; water content was determined by Karl Fischer analysis, and the charge was adjusted accordingly). The reaction mixture was heated to 50 °C and was maintained at this temperature for 5 h. The reaction was cooled to 20 °C, quenched by the addition of aqueous 1 M potassium carbonate solution (450 L) at 20 °C, and the resulting biphasic mixture was stirred for 15 min. The phases were separated, and the organic phase was washed with water (200 L). To the organic

phase was added absolute ethanol (200 L), and the solution was distilled under reduced pressure to a volume of approximately 400 L. The concentrated solution was diluted with absolute ethanol (350 L). The solution was concentrated under reduced pressure to a volume of approximately 250 L. The concentrate was diluted with absolute ethanol (450 L), and the mixture was heated to 65 °C. Seed crystals of 9 (0.5 kg, 1% w/w) were added to the mixture, and a solution of fumaric acid (7.5 kg, 65 mol) in absolute ethanol (250 L) was added whilst maintaining a temperature of 65 °C. After 1 h the resulting slurry was cooled to 20 °C at 0.23 °C/min, and stirring at this temperature was continued for 3 h. The slurry was filtered, and the solid was washed with absolute ethanol (300 L). The wet filter cake was suspended in ethyl acetate (600 L), and the slurry was heated to 50 °C and agitated for 1 h. The slurry was cooled to 20 °C, and the solid was collected by filtration, washed with ethyl acetate (50 L), and dried at 45 °C under vacuum to obtain 9 as a white solid (82.3 kg, 84.0% yield; 82.6% corrected for H2O content) which contained 0.79% w/w water by Karl Fischer analysis (equivalent to 0.34 mol of water per mol of 9). 1H NMR (600 MHz, d6-DMSO) δ 1.03 (s, 6H), 2.73 (s, 2H), 2.78 (dd, J 11.5 and 9.3 Hz, 1H), 2.89 (m, 4H), 3.46 (m, 2H), 4.31 (d, J = 6 Hz, 2H), 4.68 (dd, J = 9.3 and 3.1 Hz, 1H), 5.17 (s, 2H), 6.51 (s, 1H), 6.84 (m, 2H), 7.04 (d, J = 7.7 Hz, 1H), 7.11 (m, 3H), 7.17 (d, J = 7.6 Hz, 1H), 7.21 (m, 2H), 7.32 (m, 3H), 7.39 (m, 6H), 7.54 (d, J = 7.2 Hz, 2H) and 8.56 (t, J = 6.0 Hz, 1H). 13C NMR (100 MHz, d6-DMSO) δ 24.4, 24.5, 42.2, 42.4, 44.6, 49.1, 55.6, 56.0, 69.8, 70.0, 112.8, 115.7, 124.0, 124.2, 124.3, 124.7, 125.1, 125.6, 126.9, 127.6, 127.6, 127.8, 128.3, 128.6, 128.7, 130.7, 131.2, 135.4, 135.9, 136.0, 136.8, 137.0, 139.9, 140.2, 150.8, 157.2, 168.5, and 170.2. Found: C, 66.85%; H, 6.23%; N, 5.42%. C43H47N3O8S·0.34 H2O requires C, 66.90%; H, 6.22%; N, 5.44%. N-[(4′-Hydroxybiphenyl-3-yl)methyl]-2-(3-{2-[((2R)-2hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide PF-610355. To a suspension of (R)-2-(3-{2-[2-(4-benzyloxy3-methanesulfonamidophenyl)-2-hydroxyethylamino]-2methylpropyl}phenyl)-N-[(4′-hydroxybiphenyl-3-yl)methyl]acetamide hemifumarate 9 (10.0 kg, 13.0 mol) in tetrahy210



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which contained 0.48% w/w water by Karl Fischer analysis (equivalent to 0.17 mol of water per mol of PF-610355). Mp 197−199 °C. 1H NMR (600 MHz, d6-DMSO) δ 0.89 (s, 3H), 0.91 (s, 3H), 2.54 (s, 2H), 2.59−2.68 (m, 2H), 2.89 (s, 3H), 3.44 (s, 2H), 4.31 (d, 2H), 4.42 (dd, 1H), 6.80−8.83 (m, 3H), 6.97−7.02 (m, 2H), 7.08−7.12 (m, 3H), 7.16 (t, 1H), 7.19 (d, 1H), 7.30 (t, 1H), 7.37−7.41 (m, 4H), and 8.50 (t, 1H). 13C NMR (151 MHz, d6-DMSO) δ 26.39, 26.64, 39.85, 42.22, 42.48, 46.36, 50.15, 52.71, 72.00, 115.14, 115.70, 123.76, 124.02, 124.29, 124.38, 124.76, 125.23, 126.49, 127.57, 127.63, 128.40, 128.71, 130.82, 131.13, 135.38, 135.73, 138.43, 139.94, 140.20, 149.76, 157.11, and 170.28. HRMS (ESI): calcd (M + H)+ 618.2632, found 618.2641. Found: C, 65.70%; H, 6.33%; N, 6.71%; S, 5.24%. C34H39N3O6S·0.17H2O requires C, 65.78%; H, 6.39%; N, 6.77%; S, 5.16%.

drofuran (89.6 kg) under an atmosphere of nitrogen was added a solution of potassium carbonate (4.1 kg, 30 mol) in water (30 L), and the mixture was stirred at 20 °C for 35 min. The phases were separated, and the organic phase was washed with a solution of sodium chloride (5.0 kg, 85.6 mol) in water (30 L). The phases were separated, and the organic phase was diluted with tetrahydrofuran (67.2 kg) and water (12 L). To the solution was added 5% palladium on carbon (1.0 kg) followed by a rinse of a mixture of tetrahydrofuran (16 kg) and water (2 L), and the mixture was hydrogenated under 50 psi pressure of hydrogen at 20−25 °C for 13 h. The catalyst was removed by filtration, and the solid was washed with a mixture of tetrahydrofuran (77 kg) and water (10 L). To the combined filtrates was added Quadrapure TU resin (2.5 kg), and the suspension was stirred at 20 °C for 9.5 h. The mixture was filtered, and the solid was washed with a mixture of tetrahydrofuran (20 kg) and water (4 L). The combined filtrates were concentrated by the removal of 233 L of solvent by distillation under vacuum. To the concentrated solution was added acetonitrile (39 kg), and the solution was concentrated by removing 55 L of solvent by distillation under vacuum. To the concentrated solution was added acetonitrile (40 kg), and the solution was concentrated by removing approximately 50 L of solvent by distillation at atmospheric pressure. The concentrated solution was diluted with acetonitrile (39 kg). Concentration of the mixture by removal of approximately 50 L of solvent by distillation at atmospheric pressure followed by dilution with approximately 39 kg of acetonitrile was repeated 6 times until the solvent composition was predominantly acetonitrile and the temperature of the mixture reached 81 °C. The resultant slurry was cooled to 20 to 25 °C over 2.5 h and stirred at this temperature for 5.5 h. The solid was collected by filtration, washed with acetonitrile (2 × 39 kg), and dried at 50 °C under vacuum to give a solid (6.80 kg). A suspension of this solid (6.80 kg) in a mixture of methanol (61 L) and water (7 L) under an atmosphere of nitrogen was heated at 50 °C for 1 h, then cooled to 20 °C, and stirred for 0.5 h at this temperature. The solid was collected by filtration, washed with a mixture of methanol (31 L) and water (3 L) and then with methanol (34 L), and dried at 50 °C in vacuo to give PF610355 as a white solid (6.40 kg, 80%). PF-610355 may be recrystallized using the following procedure. A stirred suspension of PF-610355 (9.42 kg) in a mixture of tetrahydrofuran (81.4 kg) and water (20.3 L) under an atmosphere of nitrogen was heated to reflux to give a clear solution. The mixture was then distilled at a rate of approximately 27 L/h atmospheric pressure for 13 h using a fixed temperature difference between the reactor contents and the reactor’s heated jacket (for the reactor used, this temperature difference was 30 °C). Over the whole course of the distillation, acetonitrile (a total of approximately 350 L) was continuously added to the mixture at a rate of approximately 27 L/h. The resultant slurry was cooled to 20 °C and stirred at this temperature for 4 h, and the solid was collected by filtration. The filter cake was washed with acetonitrile (2 × 37 kg) and dried at 40 °C under vacuum to give a solid (8.86 kg). A stirred suspension of this solid (8.86 kg) in a mixture of methanol (80 L) and water (9 L) under an atmosphere of nitrogen was heated at 50 °C for 70 min. The mixture was cooled to 20 °C and stirred for 140 min. The solid was collected by filtration, washed first with a mixture of methanol (41 L) and water (4 L) and then with methanol (45 L), and dried at 50 °C under vacuum to give PF-610355 (8.38 kg, 89%) as a white solid

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AUTHOR INFORMATION

Corresponding Author

*E-mail: Steven.Twiddle@pfizer.com. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Stuart Field and John Deering for screening studies; Wilfried Hoffman for Dynochem modeling; Mike Hawksworth for process safety assessments; Andrew Fowler for scale-up support; James MacGregor, Sam Morris, Rutjit Durve, Alex Paget, and Griff Read for analytical support; and Gary Nichols and Barry Aldous for characterization of API physical properties.

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REFERENCES

(1) Glossop, P. A.; Lane, C. A. L.; Price, D. A.; Bunnage, M. E.; Lewthwaite, R. A.; James, K.; Brown, A. D.; Yeadon, M.; PerrosHuguet, C.; Trevethick, M. A.; Clarke, N. P.; Webster, R.; Jones, R. M.; Burrows, J. L.; Feeder, N.; Taylor, S. C. J.; Spence, F. J. J. Med. Chem. 2010, 53, 6640. (2) de Koning, P. D.; Gladwell, I. R.; Moses, I. B.; Panesar, M. S.; Pettman, A. J.; Thomson, N. M. Org. Process Res. Dev. 2011, 15, 1247. (3) de Koning, P. D.; Castro, N.; Gladwell, I. R.; Morrison, N. A.; Moses, I. B.; Panesar, M. S.; Pettman, A. J.; Thomson, N. M. Org. Process Res. Dev. 2011, 15, 1256. (4) (a) Kawai, A.; Hara, O.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1988, 29, 6331. (b) Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch, K. J. Am. Chem. Soc. 1995, 117, 8258. (c) Karimi, B.; Zareyee, D. Tetrahedron Lett. 2005, 46, 4661. (d) Cunico, R. F.; Bedell, L. J. Org. Chem. 1980, 45, 4797. (e) Wetter, H.; Oertle, K. Tetrahedron Lett. 1985, 26, 5515. (5) Höbartner, C.; Rider, R.; Kreutz, C.; Puffer, B.; Lang, K.; Polonskaia, A.; Serganov, A.; Micura, R. J. Am. Chem. Soc. 2005, 127, 12035. (6) Hudrlik, P. F.; Feasley, R. Tetrahedron Lett. 1972, 13, 1781. (7) The software was developed internally and utilizes COSMOtherm calculations. (8) An HPLC technique was developed in-house which centered around the complexation of Pd to afford a species with a quantifiable UV response. (9) (a) Hinchcliffe, A.; Hughes, C.; Pears, D. A.; Pitts, M. R. Org. Process Res. Dev. 2007, 11, 477. (b) Flahive, E. J.; Ewanickie, B. L.; Sach, N. W.; O’Neil-Slawecki, S. A.; Stankovic, N. S.; Yu, S.; Guiness, S. M.; Dunn, J. Org. Process Res. Dev. 2008, 12, 637. (c) Bullock, K. M.; Mitchell, M. B.; Toczko, J. F. Org. Process Res. Dev. 2008, 12, 896. (d) Girgis, M. J.; Kuczynski, L. E.; Berberena, S. M.; Boyd, C. A.; Kubinski, P. L.; Scherholz, M. L.; Drinkwater, D. E.; Shan, X.; Babiak, S.; Lefebvre, B. G. Org. Process Res. Dev. 2008, 12, 1209. 211



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(10) Crowder, T. M.; Rosati, J. A.; Schroeter, J. D.; Hickey, A. J.; Martonen, T. B. Pharm. Res. 2002, 19, 239. (11) A detailed discussion of the modeling and development of distillations will be published in due course. Dynochem 2011, Scale-up Systems, www.scale-up.com, 2011. (12) To ensure a mobile slurry at ambient temperature, 10 L/kg of nBuOAc was required. Heating increased the solubility of 5 to maintain a solution; concentration through distillation afforded a rate increase. For further details, see ref 3.

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