Molecular Complexity as a Driver for Chemical Process Innovation in

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Perspective

Molecular Complexity as a Driver for Chemical Process Innovation in the Pharmaceutical Industry Seb Caille, Sheng Cui, Margaret M. Faul, Steven M Mennen, Jason S. Tedrow, and Shawn D. Walker J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 27 Mar 2019 Downloaded from http://pubs.acs.org on March 27, 2019

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The Journal of Organic Chemistry

Molecular Complexity as a Driver for Chemical Process Innovation in the Pharmaceutical Industry Seb Caille, Sheng Cui, Margaret M. Faul,* Steven M. Mennen, Jason S. Tedrow, Shawn D. Walker*

#

Process Development, Amgen Inc., 360 Binney St., Cambridge, MA 02142 and One Amgen Center Drive, Thousand Oaks, CA 91320. #

Author to whom correspondence should be addressed.

ABSTRACT: A perspective of our work in the development of innovative synthetic methods within the discipline of Process Research and Development is presented. Through an overview of some of the programs that we have worked on during the last decade, we have selected cases studies to illustrate the challenges faced in development of robust chemical processes for molecules on multi-kilogram scale.

The examples have been selected to demonstrate the

innovative chemistry being developed within our laboratories with a focus on fragment design, asymmetric synthesis, new synthetic reagents and the methods that have allowed us to deliver cost effective syntheses under reduced timelines in an increasingly competitive environment. The technical challenges are presented in the context of molecule complexity, that while increasing in the portfolio of small molecules being developed, inspires us to deliver new solutions. Overall, our

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goal is to highlight the exciting work that can be done within our field to support the discovery and delivery of medicines to patients.

KEYWORDS: Process development, molecular complexity, drug substance attributes, fragment design, atom efficiency, product quality, reactive intermediates, safety, ozonolysis, throughput, CH arylation, A -phos, catalysis, robust and reproducible. ta

Introduction


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The molecular complexity of synthetic drug candidates developed at Amgen has continued to rise over the past decade. This trend is consistent with the hypothesis by drug developers that small molecule structural complexity may be correlated to more desirable attributes including (1) enhanced

protein

binding

selectivity;

1

(2)

increased

solubility

via

disruption

of

planarity/symmetry; and (3) higher success rates during drug discovery and development. 2

3,4,5,6,7

Evaluation of the Amgen portfolio against structural complexity (Figure 1) mapped the molecules into the categories of high, medium or low complexity based upon increased content of sp 3

hybridized atoms, molecular weight, number of synthetic steps, stereogenic centers and rings.

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However, molecular complexity paints only a partial picture of the challenges faced by process chemists developing manufacturing routes for new chemical entities (NCEs). To develop cost effective and robust syntheses the process chemist needs to adapt their strategic approach for each program based on the complexity, phase of development, therapeutic area, and business priorities to enable speed to clinic and market, with significantly shortened cycle times, in an increasingly competitive global marketplace. Accordingly, there is a clear need for development of new chemical technology to address the gaps in synthetic capabilities revealed by a modern small molecule portfolio. This includes the need for new, robust and selective processes that are amenable to scale-up (i.e. do not require cryogenic reaction conditions, are safe, cost-effective, use low catalyst loadings etc.) and that can be rapidly transferred from the lab to the plant across a global manufacturing network. Ultimately, this work allows process chemists to deliver new chemical entities in high purity (>99%) to support formulation development, clinical trials and drug delivery to patients.


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Figure 1: Complexity index of Amgen synthetic molecules.

To exemplify the considerable advances in process chemistry under this evolving paradigm, in this volume of the Journal of Organic Chemistry dedicated to “Excellence in Industrial Organic Synthesis, 2019”, we will highlight the innovative approaches applied across our portfolio to address these factors. Our goal is not to describe the total synthesis of each molecule but to highlight the unique attributes of their chemical structure that contributes to its complexity (Table 1), the challenges that were encountered in the first-generation process used to supply the drug substance for Phase 1 and the innovative chemistry that we developed to simplify the synthesis and deliver a viable commercial process. Table 1: Comparison of DS Complexity to Attributes for Amgen Portfolioa Amgen Molecule

DS Complexityb

DS MW 650

Steps from RMs to DSc 6 8 3 6 12

DS Rings

DS Stereocenters

3 3 4 6 3

1 1 4 0 4

DS Synthesis Types L L C C L


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AM-5262 17 X 16 6 3 C AMG 138 17 X 24 4 3 C Hydroxyethyl 18 X 21 5 3 C amines AMG 176 21 X 43 6 6 C DS = Drug Substance, RM = Raw Material, API SM = Active Pharmaceutial Ingredient Starting Material, C = convergent, L = linear For DS Complexity index calculation methodology see Ref. 8 (including Supporting Information) Average number of steps from raw materials to DS. The number of steps for each case study is the sum of the steps to make each API SM and the steps from the (first) API SM to the DS. a

b c

Results and Discussion Process chemistry is an exciting research field at the interface of discovery chemistry and manufacturing that is accountable for the commercial process development of new chemical entities (NCEs) through partnership across the disciplines of synthetic organic chemistry, chemical engineering and manufacturing. In early development, the synthetic route received from our medicinal chemistry colleagues is often quickly refined to deliver the initial kilogram quantities of drug substance to support the first-in-human clinical trials. At this stage the process chemist is normally on the critical path, and given the high attrition rate in early development, the initial goal is to ensure that the route is phase appropriate and can be rapidly and safely scaled-up to deliver drug substance for clinical studies. However, as the molecule advances into Phase 2 and 3 clinical trials, where hundreds of kilograms of drug substance may be required, the focus turns to designing the ideal synthesis and then developing a robust and reproducible commercial process. At this stage, overall efficiency, cost, reduction in the number of critical process parameters, elimination of chromatography and solvent exchanges, simplicity of manufacturing operations, and environmental impact become the key process development drivers. In this perspective we will focus on the following key challenges regularly encountered by the process chemist: 1. Fragment design


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2. Atom efficiency 3. Control of product quality through new reagent development 4. Safety 5. Development of common building blocks Using this framework, we will present case studies that demonstrate how we have been able to develop state of the art synthetic methods and advance the industrial organic chemistry required to bring new medicines to patients. Fragment Design One of our first approaches in designing a molecule is to understand how best to build it given the large number of potential routes. Beta-secretase inhibitors, targets of significance not only at Amgen but across the industry, have a variety of different chemotypes being explored in both pre-clinical and clinical settings. Amgen’s first-generation inhibitors toward beta-secretase were based upon the hydroxyethyl amine isostere (Scheme 1) present in many HIV protease 9

inhibitors. As typical of this series, compound 6, with a complexity index of 19, possesses three non-contiguous stereocenters and a complex azachroman structure containing a spirocylic cyclobutane. These molecules were very challenging to prepare with the discovery route, which relied on a precarious reductive amination of the unstable alpha-alkoxy aldehyde 2 and azachromyl amine fragment 4. While several grams were prepared with this disconnection strategy, chromatography was required to separate decomposition products from aldehyde 2, and to separate diastereomers that were generated from competitive epimerization during the reaction. Therefore, given its propensity for undesired reactivity, the goal of our route selection effort was to eliminate


6

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the alpha-alkoxy aldehyde, identify scalable fragments and develop reliable chemistry including design of crystalline intermediates to control the final impurity profile of 6.

Scheme 1: Discovery route to the hydroxyethyl amine isostere.

Our approach was to simplify the disconnection strategy while keeping the critical coupling surrounding the central secondary amine. We disconnected the molecule into two equal sized fragments and envisioned an approach whereby an electrophilic 7 was tethered to the azachromylamine 4 via a cleavable linker. While similar approaches had been utilized by Das and others for simple amine couplings via oxazolidinone formation, there were no previous reports of 10

its utility in a complex fragment coupling as presented here.


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Our optimized synthesis started with acylation of amine 4 which was accomplished by reaction with carbonate 7. Full conversion was achieved in 18 hours and the crude reaction stream was then treated with potassium tert-amylate to deliver oxazolidinone 9 in 93% yield. Attempts to isolate the Boc-protected oxazolidinone were unsuccessful, so after a simple aqueous workup and solvent exchange to n-BuOH, the Boc-protecting group was removed with HCl and the salt 10 was crystallized via addition of n-BuOAc. Over three steps, the free amine was isolated in 90% yield with high purity (>99%) (Scheme 2). Simple hydrolysis of the oxazolidinone with potassium hydroxide in ethanol, followed by solvent exchange and tris-HCl salt formation led to the desired penultimate in 93% yield and high purity (>99%).

Scheme 2: Optimized templated synthesis of hydroxyethyl amine 511

Prior to this work there had been no demonstration of this coupling approach to prepare the hydroxyethyl amine isostere. With several other molecules containing this fragment in


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Amgen’s medicinal chemistry laboratories, development of a robust synthesis was critical to supplying discovery research as well as defining a synthesis that could be employed for large scale production. This synthesis was transferred to our external network to support further development and supply, thus allowing our internal scientists to focus on further innovative work required to advance the portfolio, a strategy routinely employed within the process development organization. Atom Efficiency The objective of a program entering early development is to advance molecules rapidly into the first-in-human clinical studies and generate sufficient data to justify further investment in the program. Because of the time constraints, early process development often prioritizes speed to clinic and quality of the final product. In this context, an asymmetric synthesis providing a single enantiomer is often not achieved in time for the first drug substance delivery and alternative approaches including classical resolutions or simulated moving bed (SMB) chromatography may be leveraged instead. These methods inherently generate inefficiencies with respect to atom economy, cost, and throughput; however, they allow expedient access to the clinic and deferral of investment in commercial process development until there is greater confidence in the target. In this section we will focus on the novelty and breadth of asymmetric methods that were developed to achieve the goal of robust and chromatography-free routes for commercial manufacture.

Asymmetric Synthesis of Chiral 2-Amino Thiazolones: AMG 221, an inhibitor of 11-β12

hydroxysteroid dehydrogenase type 1 (11-β-HSD1), was pursued as a potential therapeutic agent 13

for the treatment of type 2 diabetes (Figure 2). The molecule was identified as medium complexity, with a complexity index of 11, having a total of four stereogenic centers and four rings. From a


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synthetic perspective, it displays interesting structural features including a chiral dialkylsubstituted 2-aminothiazolone ring. While several methods for the assembly of achiral 2-aminothiazolones have been described, the synthesis of their chiral counterparts has received little attention. In fact, 14

preparation of enantiomerically pure tertiary thiols or thioethers also represent a major synthetic challenge and few suitable asymmetric methods are available for their synthesis.

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Figure 2: Structure of the 11-β-HSD1 inhibitor AMG 221

Chiral chromatography was employed to deliver the initial batches of AMG 221 in early development. Two synthetic routes were subsequently designed by the process chemists and compared to prepare AMG 221 as a single diastereomer for clinical and commercial supplies. Both routes started with thiourea 11 which was available via classical resolution of the corresponding amine. The first approach (Scheme 3) involved two steps starting with the preparation of 16

thiazolone 12 as a mixture of epimers from 11 by treatment with 2-bromopropionic acid. Thiazolone 12 was subsequently deprotonated with chiral base 13 (2.2 equivalents) in the 17

presence of tetramethylethylenediamine (TMEDA) at low temperature and the resultant anion alkylated with isopropyl chloride to provide AMG 221 in 95/5 diastereomeric ratio. The transformation also could tolerate alternative substitution at the 2-amino position.

18

The

diastereomeric ratio of AMG 221 was upgraded through salt formation with methane sulfonic acid. Following salt break and crystallization, AMG 221 was isolated in 64% yield from 11 and >99.5:0.5 diastereomeric ratio.


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Scheme 3: Two-Step Preparation of AMG 221 using Chiral Base 13

An alternative approach was developed which entailed the preparation of AMG 221 in a single pot from 11. Hydroxy-acid 14 (77% ee) was reacted with N-(chloromethylene)-N19

methylmethanaminium methyl chlorophosphite (15) to afford salt 16 which was not isolated but treated directly with thiourea 11 and diisopropylethylamine to afford AMG 221 in 73% yield and 84:16 diastereomeric ratio. In the presence of diisopropylethylamine and thiourea 11, this 20

intermediate is converted to AMG 221. Intermediate 18 is proposed to account for the doubleinversion stereochemical outcome observed in this transformation (Scheme 4). The diastereomeric ratio could be upgraded using methane sulfonic acid, thus enabling the manufacture of AMG 221 in a single step from 11 (55-60% yield) without the use of stoichiometric amounts of chiral base 3.


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Scheme 4: One-step preparation of AMG 221 from hydroxy-acid 14. The synthetic route shown represents a highly convergent access to AMG 221 including four crystallizations and a three-step longest linear-sequence while showcasing a novel stereoselective preparation of 2-aminothiazolone rings. The route features the coupling of two chiral building blocks of molecular complexity, thus enabling maximum manufacturing throughput upon implementation in the plant. Access to chiral β-alkynyl acids via asymmetric conjugate alkynylation of Meldrum’s acid derived acceptors: GPR40 is a G-protein-coupled receptor, primarily expressed in pancreatic 21

islets β-cells that can modulate several metabolic defects when activated. Agonists of GPR40 present low risk of hypoglycemia and have been under investigation by a number of groups, including Amgen, as potential clinical drug candidates for the treatment of diabetes. Several of Amgen’s GPR40 agonists possess a fatty acid-like head group tethered to a functionalized biaryl tail as exemplified by AMG 837 (Figure 3). This target provided fertile ground for the 22

development of new asymmetric alkynylation methods as it required the construction of a synthetically challenging β-alkynyl acid stereogenic center.


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Figure 3: GPR40 receptor agonist AMG 837.

Although AMG 837 was a moderate complexity target, with a complexity index of 10, it had challenging physiochemical properties due to its soap-like fatty acid structure and the 23

technical difficulty of stereoselectively incorporating an alkyne moiety. Our early clinical supplies of this molecule (>20 kg) were produced via a convergent 9-step route with coupling of two key fragments, the chiral β-alkynyl ester 21 and biaryl bromide 22 (Scheme 5).

Scheme 5: Original process to prepare AMG 837.


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The target β-alkynyl acid 19 was prepared in 35% yield via the classical resolution of (±)19 with the chiral amine (1S, 2R)-1-amino-2-indanol 20. Fischer esterification of 19, followed by phenol alkylation with biaryl bromide 22 and hydrolysis of the coupled product, provided AMG 837 in ~25% overall yield. Although this process was suitable for early clinical development, the use of a resolution step limited the overall yield of the process, and a more efficient enantioselective route was desired. Based on our experience with Meldrum’s acid-derived acceptors, we were intrigued by the possibility of employing these substrates in an asymmetric process. These activated olefins are attractive substrates for conjugate addition processes since they can be readily prepared in one step by Knoevenagel condensation of Meldrum’s acid with aldehydes, exist as a single geometric isomer and are typically crystalline. Furthermore, the corresponding conjugate addition products can be readily hydrolyzed to b-alkynyl acids in high yield. However, at the time of this work few practical asymmetric conjugate alkynylation methods existed, and those that did required bulky, electronically activated silyl- or phenyl-acetylenes, high catalyst loadings and expensive ligands.

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Importantly, synthetically useful yields and

enantioselectivities have not yet been achieved in enantioselective conjugate alkynylation of esterderived acceptors with aliphatic alkyne nucleophiles such as propyne. To address this gap, we initiated an extensive research program that ultimately led us to evaluate chiral zinc reagents for conjugate alkynylations. Extensive screening of potential chiral ligands demonstrated that Znalkynylide species prepared by the treatment of MeCºCMgCl with a zinc alkoxide (generated from Me Zn and two equivalents of a chiral amino alcohol), provided the most promising results. Tuning 2

the structure of the zincate by altering the chiral ligand, achiral additive, and counterion (Figure 4) further improved both the enantioselectivity and yield. A marked counterion effect was observed and the use of MeCºCMgCl proved superior to MgBr or Li counterions. As expected, the selection


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of chiral amino alcohol had a dramatic effect on the enantioselectivity and cinchonidine was found to be the most selective ligand. However, the selectivity and rate could also be tuned by using different achiral additives. While a variety of alcohols and carboxylic acids offered comparable enantioselectivity and yield, trifluoroethanol was selected due to its low cost and easy removal by distillation during workup.

Figure 4: Zincate design parameters

This enantioselective conjugate alkynylation mediated by the optimized chiral zincate allowed us to establish a concise 5-step second-generation process that provided AMG 837 in 68% overall yield. As shown in Scheme 6, a fully elaborated olefin acceptor was prepared from 22, phydroxybenzaldehyde 24 and Meldrum’s acid in 92% yield. The olefin 25 was subjected to our optimized chiral zincate mediated alkynylation procedure affording 26 in 97% assay yield and 89% ee. Crystallization from acetone/water provided optically pure (>99% ee) 26 in 82% yield. Notably, the cinchonidine was a recyclable ligand as it could be recovered from the aqueous layer in 95% yield by simple pH adjustment and filtration. Sequential decarboxylation and sodium salt formation concluded the second-generation synthesis of AMG 837. Relative to the earlier racemic 25


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synthesis, the cost of goods for the enantioselective process was lowered by more than 60% and the overall yield increased from 25% to 68%.

Scheme 6: Asymmetric synthesis of AMG 837.

The scope and generality of the enantioselective conjugate alkynylation reaction were also investigated. As summarized in Figure 5, a wide range of functional groups including nitriles, ketones and carbonates were well tolerated. Ortho-substituted arene acceptors were suitable substrates although (rac)-Mosher acid instead of trifluoroethanol was the better additive in some cases. The process was also suitable for heterocyclic substrates, and a wide variety of Znalkynylides, including those possessing both aliphatic and aromatic groups could be employed in the conjugate addition process. Remarkably, even the smallest alkynyl nucleophile derived from acetylene afforded good enantioselectivity and yield. Importantly, all the starting materials and


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products examined were crystalline solids, allowing simple isolations (no chromatography) and chiral purity upgrades via crystallization.

Figure 5: Selected examples of substrate scope for the asymmetric alkynylation process

Preparation of tertiary benzylic stereocenters via phenol-directed hydrogenation: The GPR40 full agonist, AM-5262, possesses both a chiral cyclopropyl acid head group and a biaryl tail bearing a tertiary benzylic carbon center (Figure 6). Since the chiral biaryl moiety 27 was also 26

present in several other GPR40 agonists in our portfolio, efforts were focused on devising a general synthetic approach to the key tertiary benzylic fragment 28.


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. Figure 6: Structure and retrosynthesis of AM-5262.

The original synthesis of the chiral building block 28 involved five linear steps followed by chiral chromatography to afford the target ester in 12% overall yield (Scheme 7).

Scheme 7: Original synthesis of key tertiary benzylic fragment 28. However, it was envisioned that 28 could potentially be prepared from olefin 36 via development of a new enantioselective hydrogenation process. In this improved route, a direct Grignard addition to 1,1-dimethylcyclopentanone followed by tertiary alcohol elimination would


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quickly provide the requisite olefin. Since 1,1-dimethylcyclopentanone (30) was difficult to source in the desired quantity and quality, we first devised an efficient route to prepare this ketone from isobutyronitrile in three steps. Next, a functionalized aryl Grignard reagent was generated from 27

iodide 37 (R = Me) via a step-wise procedure that involved treatment of 37 with 1 equivalent of MeMgCl to deprotonate the phenol, followed by 1 equivalent of i-PrMgCl to affect the desired Mg-I exchange. Due to the known propensity of cyclic ketones, particularly sterically hindered αsubstituted ketones, to undergo enolization rather than carbonyl addition reactions, lanthanide chloride was added to promote the desired 1,2-addition. Use of other salt additives, particularly 28

lithium isopropoxide, further enhanced the Grignard addition. To suppress other possible side reactions (like competing Grignard addition to the ester), the bulkiness of the ester function was increased and was shown to enhance yield as well. Accordingly, under the optimized conditions, overall addition yields were 50-71% for the isopropyl and t-butyl esters (Scheme 8).

Scheme 8: La-mediated 1,2-addition to a hindered ketone. Acid mediated elimination proceeded smoothly to generate the precursor alkenes for asymmetric hydrogenation screening. A large collection of ligands was evaluated for the rhodiumcatalyzed asymmetric hydrogenation using 5 mol% Rh(COD) BF catalyst, and Josiphos SLJ-2102

4

1 provided the highest enantiomeric excess (83%). In the presence of Et N (5 mol %), the catalyst 3

loading could be further reduced from 5% to 0.1% Rh and the hydrogenation ee increased to 99%.


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In this case, the crude product 28 could be crystallized to further upgrade the product purity to 99.5% ee (Scheme 9). Importantly, control experiments showed that the presence of the phenol function was essential for obtaining enantioselectively in the process, with low ee (~10%) and slower conversations observed for substrates lacking the adjacent phenol moiety.

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Scheme 9: Optimized asymmetric hydrogenation process to generate the key tertiary benzylic fragment of AM -5262.

To further explore the potential of our phenol-directed hydrogenation process, a series of substituted styrenes was prepared and shown to be broadly applicable to the new process (Figure 7). As an improvement to the earlier Ir(P-N) catalyst systems, this methodology accommodated trisubstituted olefins in various E/Z mixtures, thus readily enabling an enantioselective synthesis of the urinary incontinence drug, tolterodine.

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Figure 7: Scope of the phenol-directed enantioselective hydrogenation. Ultimately, development of this new asymmetric method allowed us to replace the lengthy original preparation of cyclopentanone 28 (requiring chiral chromatography and proceeding in 12% overall yield) with a chromatography-free asymmetric route to 28 (and related esters) in >65% yield. Our work on ortho phenol-directed hydrogenations also inspired several related reports demonstrating the use of ortho aniline, carboxyl and chloro directing groups. In addition, 31

our procedure for the convenient preparation of tetrahydrofuran solutions of LaCl ·2LiCl was 3

described in the Encyclopedia of Reagents for Organic Synthesis to be widely available for the benefit of the synthetic community.

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A chemoenzymatic approach to introduce chirality: AMG 176, an inhibitor of Mcl-1 for the treatment of hematological malignancies, represents one of the most complex molecules in our portfolio. AMG 176 has a complexity index of 21, due to the presence of six non-contiguous


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stereocenters and six rings, including fragments derived from the spirocyclic N,O-anthranilic acid 39, chiral sulfonamide 41 and the trans-substituted cyclobutane 40, as represented in our retrosynthetic strategy (Scheme 10). These fragments and their assembly into the final drug substance required over 40 synthetic steps and presented a number of unique challenges, including the development of enabling chemistry as well as the logistics of managing a complex supply chain. Access to large quantities of the chiral cyclobutane 40 proved to be particularly difficult, and synthetic studies on this fragment inspired the development of a novel chemoenzymatic approach.

Scheme 10: Structure and retrosynthesis of AMG 176.

As shown in Scheme 11, the initial discovery route presented a variety of problems including the use of expensive starting materials, low overall yield and the lack of crystalline intermediates to control product quality.


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Scheme 11: Original route to prepare trans cyclobutane aldehyde 40.

Early engagement with our discovery colleagues revealed that the silyl protecting group was not required and any number of alternative protecting groups could be used that were tolerant of the oxidation and reductive amination conditions. Thus, we introduced an acetate protecting group, to reveal a simple, yet effective path to generate an appropriately functionalized fragment from relatively simple starting material (cyclobutane anhydride 51). Desymmetrization of the diacetate 48 via enzymatic hydrolysis or acylation was precedented in the literature, albeit on 33

small scale, and provided additional support for this approach.

Accordingly, reduction of

anhydride 51 with lithium aluminum anhydride and acylation of the product diol provided the diacetate 48 in 54% yield and provided us with the requisite substrate to test the key enzymatic desymmetrization step (Scheme 12). Recapitulation of the literature conditions with PPL (derived from pigs) afforded clean diacylation in 90% yield and 95% ee. Quick evaluation of other enzymes led to the finding that amanolipase from pseudomonas fluorescens cleanly afforded the desired monoacetate in 95% yield and >99% ee. Additionally, moving away from an animal-derived enzyme to pseudomonas mitigated transmissible spongiform risks downstream. The enzymatic conditions required neutral pH for optimum performance and therefore continuous pH adjustment


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(with NaOH) was needed. However, this proved challenging to scale up due to the high risk of over addition and decomposition of the product. Simple replacement of sodium hydroxide with a sodium citrate buffer kept the pH in constant range (centered at pH 7) over the course of the reaction and prevented erosion of selectivity.

Scheme 12: Optimized Enzymatic Desymmetrization of Diacetate 48

The desired monoacetate 49 could be isolated from the reaction mixture via extraction but this material proved to be an oil with limited stability. Erosion of enantioselectivity from 99% to 90% at ambient temperature over 17 days limited processing time for this intermediate so we chose to telescope it directly into the next step. Oxidation to the cis-aldehyde most readily accomplished under mild conditions with catalytic TEMPO and iodobenzene diacetate (Scheme 13). The crude 34

reaction mixture was then treated directly with iPr NEt at ambient temperature to arrive at a ratio 2

of 12:1 trans:cis isomers. Additional time or stronger base was not effective at increasing the trans:cis ratio and iPr NEt provided an appropriate balance of reaction rate and purity of the crude 2

aldehyde stream with 79% yield from the diacetate to aldehyde 53. Given that the cyclobutane aldehyde fragment 53 was a key intermediate in the synthesis of AMG 176, there was a strong desire to control the quality of the material and provide a sufficient shelf-life for transport and storage. Additionally, the intermediates after the anhydride were all carried forward as oils, so the sequence lacked a critical control point via a crystallization to purge


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impurities. Attempts at preparing crystalline derivatives such as a bisulfite adduct or semicarbazone were met with amorphous materials or challenging methods to break the adducts. Following the method of Katriztky, we discovered that the corresponding benzotriazole adduct 35

was a highly crystalline and well behaved solid. Simply treating the crude reaction mixture of the aldehyde with benzotriazole in MTBE afforded a crystalline adduct 54 in 95% yield. Importantly, the adduct was isolated in excellent purity: 98 wt%, >99% ee and >99:1 trans:cis. Additionally, the adduct was a bench stable crystalline solid which could be stored for months without degradation (Scheme 13).

Scheme 13: Synthesis of CBTA 54 from 1,2-cyclobutane dicarboxylic acid

Overall the chemoenzymatic route shortened the process from twelve to six steps and incorporated two crystallization control points including a critical stabilization of the aldehyde fragment as a benzotriazole adduct. The overall yield of the process was improved three-fold to 33% starting from a readily available cyclobutane dicarboxylic acid. Key to this route was simplification of the stereochemical determining step by using a scalable enzymatic


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desymmetrization of a prochiral diacetate. The improved synthesis of this fragment could then be transferred to a contract manufacturing organization which allowed the team to focus on internal development of the reminder of the complex synthesis of AMG 176. Reduction of complexity is not only a motivator for innovation, but back integration of new technology into discovery research is also a key enabler in the transition of these molecules into development. In this case, the new chemistry to the cyclobutane fragment simplified the process, reduced costs and secured supply for scale-up as well as eliminating bottlenecks for both the discovery and development teams. Development of a Dynamic Kinetic Resolution: Our final resolution example involves the development of a crystallization-induced dynamic resolution (CIDR) for the preparation of 36

diarylmethylamines as applied to the synthesis of our anti-migraine drug candidate AMG 333 37

(Scheme 14). Although this molecule was identified as a relatively low complexity target, with a complexity index of 9, the diarylmethylamine core present in AMG 333 is a fragment commonly found in pharmaceutical products. In the first-generation process, addition of Grignard 58 to Ellman aldimine 57 was used to set the stereochemistry of the chiral amine, where the observed sense of stereo-induction was consistent with literature models for substrates bearing coordinating substituents with the pyridine ring influencing the reaction outcome. A solvent screen revealed 38

that replacing THF with 2-MeTHF increased the stereoselectivity from 80:20 dr to 91:9 dr while allowing the use of higher temperatures (up to –10 °C) to avoid cryogenic (–78 °C) conditions. However, chromatography on silica gel was required to isolate the desired sulfinamide product 59 in >99:1 dr. While the use of Ellman’s sulfinamide-based chiral auxiliary was suitable to supply AMG 333 for early clinical development, the high levels of undesired diastereomer formed and need for chromatography made this process unattractive for commercial use. Accordingly, route-


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scouting efforts were conducted to develop a more cost-efficient and practical approach to the chiral amine core of AMG 333.

Scheme 14: First-generation process to AMG 333.

Among numerous methods for the synthesis of chiral amines evaluated, crystallizationinduced dynamic resolution (CIDR) was identified as a particularly attractive approach due to the facile synthesis of racemic amine starting materials, low cost and ready availability of resolving agents, straightforward isolation of the crystalline products, and high yields. Route-scouting efforts for the synthesis of the chiral amine were aided by the knowledge that chiral purity could be further upgraded in the downstream process by crystallization of later intermediates as well as the final drug substance. Two key criteria must be satisfied for the design of a successful CIDR: (1) the development of a crystallization system that resolves the molecule; and (2) conditions that allow its simultaneous epimerization. During process development, these two conditions may be developed independently; however, the most critical and challenging design element involves the


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combination of these individual components such that the two processes can proceed effectively in one pot with practical efficiency. Toward the development of this resolution method for AMG 333, a variety of chiral acid resolving agents and solvent systems were investigated with a highthroughput screening platform. These experiments identified L-dibenzoyl tartaric acid (L-DBTA) as the optimal resolving acid in a mixture of MeCN/water (95:5) affording the DBTA salt 62 in 39% yield with 90% de (Scheme 15).

Scheme 15: Classical resolution of racemic amine 61 to provide (S)-amine•L-DBTA 62.

Modulating the pKa of an α-amine stereocenter by formation of the corresponding iminium ion has proven to be an effective strategy for the racemization of amino acids and related α-amino carbonyl compounds. To identify a suitable iminium ion in this setting, kinetic studies of the catalytic racemization of optically enriched (S)-amine 61 in MeCN/water were performed (Figure 8). Notably, substitution of the resolving acid L-DBTA with acetic acid rendered the system homogeneous and allowed an accurate comparison of racemization rates. Screening a range of aldehyde catalysts led to the identification of formaldehyde as the optimal additive to promote racemization within a reasonable time. The preponderance of literature evidence illustrates that use of electron-deficient aryl aldehydes are best for the racemization of a stereocenter adjacent to an amine functional group; however, despite this precedence, a range of aryl aldehydes proved less


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effective than formaldehyde at epimerizing (S)-amine 61. Less sterically-encumbered alkyl aldehydes such as butyraldehyde and trifluoro acetaldehyde were also not suitable for this purpose. Therefore, to the best of our knowledge, this study represented the first example of diarylmethylamine epimerization by activation as an iminium ion and the use of formaldehyde in this context.

Figure 8: Racemization (%ee) of (S)-amine 61 versus time (h) for a range of aldehyde additives.

After further optimization, it was found that the racemization rate proved particularly sensitive to the agitation method, where the use of overhead stirrers equipped with stir paddles resulted in extended reaction times and stalling of the chiral resolution compared to the use of a magnetic stir bar. We attributed the increased resolution efficiency to attrition-enhanced dissolution, i.e., particle-size reduction by mechanical grinding with a magnetic stir bar.

39


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Considering options for large-scale manufacture of this material, as an analogy to stir-bar based grinding we introduced a wet-milling operation into the resolution process to ensure adequate particle size reduction. Thus, to a solution of rac-amine 61 in MeCN/water (95:5) was charged L40

DBTA (0.05 equiv) then HCHO (10 mol %) at 20 °C. Upon formation of the slurry, wet milling was commenced, the reaction temperature was increased to 60 °C, and a solution of L-DBTA (1.05 equiv) in MeCN/water (95:5) was added. The slurry was further aged at 60 °C with continuous wet milling and monitored via HPLC to track the chiral purity of the resultant crystalline solid. After 10 h, the reaction mixture was cooled to room temperature and filtered to provide (S)amine•L-DBTA 62 in 83% yield with 91% de.

Scheme 16: Classical resolution of racemic amine 61 to provide (S)-amine•L-DBTA 62.

Efforts to evaluate the scope of this CIDR process provided key insights into the epimerization pathway. A selection of benzylic amines was subjected to the reaction conditions with catalytic formaldehyde in the presence of acetic acid at 65 °C (Figure 9). Diarylmethylamine 64, which differs only by the absence of electron-withdrawing groups on the aryl substituents, underwent rapid racemization in the presence of formaldehyde in agreement with the results obtained for amine 61. In contrast, amine 65, which is isoelectronic with amine 61 but differs only in the position of the pyridine nitrogen, did not racemize under identical conditions. Substrates 66


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and 67, lacking a pyridine ring or aryl substituent, respectively, also did not racemize. These data demonstrate that both the presence and position of the pyridine nitrogen is a critical component of the racemization mechanism.

Figure 9: Effect of substrate structure on the extent of racemization.

The geometric requirement of the pyridine nitrogen combined with the unique role of formaldehyde prompted us to consider a different mechanism than that traditionally proposed for epimerization of an amine via iminium ion formation (Scheme 17).

41

We postulated that

nucleophilic addition of an appropriately-positioned pyridine nitrogen could result in aminal formation followed by tautomerization and dearomatization to form intermediate 69.

42

This

pathway accounts for the increased rate of racemization observed with formaldehyde relative to other aldehydes investigated as the iminium ion derived from formaldehyde is several orders of magnitude more electrophilic than that derived from benzaldehyde.

43


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Scheme 17: Proposed mechanism for racemization via iminium ion formation.

This unique approach to the synthesis of diarylmethylamines highlights the application of a novel CIDR process to pharmaceutically relevant chiral amines and underscores the value of leveraging mechanistic knowledge to develop reliable processes. By combining our understanding of both chemical and physical processes, including implementation of wet milling for attrition-enhanced dynamic resolution, a scalable process was achieved.

Control of product quality through new reagent development In process development it is at times possible to shorten the preparation of drug candidates by developing a new reagent that renders a key transformation more robust and thus potentially eliminating several synthetic intermediates from the route. A good example of this approach was demonstrated in our synthesis of AMG 232, an inhibitor of the p53-MDM2 protein-protein 44

interaction being evaluated for the treatment of various forms of cancer. 45

AMG 232 is a molecule of high complexity, with a complexity index of 14, which incorporates three rings and four stereogenic centers. The drug candidate possesses a denselyfunctionalized δ-lactam ring bearing two polar side-chains. An efficient 12-step process was


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developed to manufacture this drug substance for commercialization (Scheme 18), starting with 46

the preparation of δ-lactone 73.

47

Dynamic kinetic resolution of keto-ester 71 and

diastereoselective alkylation of the anion of δ-lactone 73 were used to construct the three ring stereogenic centers. Alkylation of the anion of 73 resulted in stereoselective formation of 74 in accordance with precedents for similar transformations with cis-5,6-disubstituted δ-lactone starting materials providing C3 trans-alkylated products. After formation of the δ-lactam ring, a 48

creative solution had to be devised to install the two polar side-chains of the molecule. A relatively inert terminal alkene had to be utilized to prepare the carboxylic acid moiety of AMG 232 to enable carrying out the preceding transformations under orthogonal reaction conditions. This prompted the development of an ozonolysis-Pinnick tandem transformation as the last steps of the synthesis.

Scheme 18: Synthesis of AMG 232. The first-generation synthesis of sulfone 76 was lengthy requiring its preparation from 75 via treatment with sodium hydroxide followed by: (i) derivatization of the primary alcohol function as a leaving group, (ii) displacement using isopropyl thiol, a reagent with severe stench concerns for plant applications, and (iii) oxidation of the resultant thioether to the corresponding sulfone,


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which necessitated forcing conditions. A one-pot access to 76 via opening of oxoiminium ion 75 with an isopropylsulfinate salt seemed far more attractive to install this polar side-chain. Sodium 49

isopropylsulfinate proved successful for synthesis of 76 at elevated temperature while also providing alcohol 78 as a side-product. Consequently, the mechanism of this transformation was further examined. Diastereomeric sulfinate esters 77 are formed as kinetic products in the preparation of sulfone 76 from 75. The sulfinate esters (77) convert to 76 at elevated temperature via the intermediacy of 75 (Scheme 19). Residual water in the corresponding reaction mixture is 50

problematic as it causes the formation of 78. Isopropylsulfinic acid was prepared via reaction of isopropyl magnesium chloride with sulfur dioxide followed by an aqueous hydrochloric acid quench. Azeotropic removal of water from isopropylsulfinic acid did not represent a viable longterm process due to the propensity of this material to undergo disproportionation upon drying.

51

Scheme 19: Intermediates and side-products generated during the preparation of 76.


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As a result, a novel calcium isopropylsulfinate dihydrate salt 79 was developed to enable a robust process to prepare 76 from 75 (Scheme 20). The calcium salt (79) was prepared via reactive 52

crystallization upon treatment of isopropyl sulfinic acid with calcium acetate and was isolated as a dihydrate. Azeotropic drying of 79 was performed in toluene (with no degradation) as part of 53

the process to prepare 76. After solvent exchange to DMAc, the mixture was heated at 120 °C to complete the transformation and sulfone 76 was isolated by crystallization after an aqueous workup.

Scheme 20: Manufacture of Sulfone 76 using the calcium salt of Isopropylsulfinic acid (79). The development of novel reagents such as 79 serves to reduce the number of synthetic steps necessary for the preparation of clinical candidates by successfully enabling key transformations which lacked robustness using previously available reagents. This enables control of the cost of goods and increase throughput for late-stage manufacturing for linear synthetic routes.


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Safety One of the most challenging reactions performed on large scale is ozonolysis and during our portfolio advancement we have faced this challenge multiple times. Ozonolysis reactions present several challenges which are particularly demanding to safely execute, especially at large scale. These include: (i) the requirement to use an oxygen rich atmosphere to generate ozone is 54

an inherent flammability risk; (ii) the Criegee mechanism for ozonolysis generates several high energy intermediates which present a risk for thermal decomposition; (iii) environmental controls require the excess ozone to be destroyed and not released into the environment; and (iv) prevention of ozone exposure to personnel is a critical worker safety issue which ultimately means reaction endpoints may need to be determined without collecting in-process samples. A demonstration of how we have been able to successfully execute batch ozonolysis is highlighted in our synthesis of AMG 138, a BACE inhibitor that is a highly stereochemically congested target with high complexity as represented by the complexity index of 17. In early development AMG 138 was 55

prepared in 20 steps and while several synthetic challenges existed, including a particularly difficult resolution of diastereomeric salts to avoid chromatographic separation, we will focus here on the design and execution of a safe ozonolysis process that was scaled from grams to multikilogram scale (Scheme 21). In addition to the typical challenges with an ozonolysis process, the resulting aldehyde intermediate was prone to epimerization which required surgical precision to quench the process. Intermediate styrene 80 was a key intermediate to form the [3.2.1] bridgedbicyclic warhead of AMG 138 and progression of the synthesis required ozonolysis. As shown in Scheme 21, the ozonolysis process was designed to drive the primary ozonide 81 to methoxy hydroperoxide 82, and most importantly to avoid the secondary ozonide, which can be difficult to


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reduce. Based on the work of Kula and coworkers, the presence of a participating solvent 56

(methanol) and a temperature above –78 °C can drive the intermediates from the primary ozonide to the more readily reduced methoxy hydroperoxide 82.

Scheme 21: Ozonolysis and reduction process to deliver primary alcohol 83.

Because of the challenges in implementing ozonolysis reactions, the proper design of a safe ozonolysis process is critical at lab scale. The first issue was to design a generic process that insures a flammable environment is not generated. Generation of ozone was never conducted with pure oxygen, but instead diluted with nitrogen, to stay below a maximum 5% oxygen concentration. By diluting the oxygen content of the reactor with nitrogen, having a reaction 57

temperature of –30 °C (or higher) and a participating protic solvent we were able to ensure several of the issues with batch ozonolysis were addressed. These techniques are now routinely used at Amgen across all scales when ozonolysis is required and with dispersion of the ozone mixture performed by either a gas dispersion tube or with the placement of the gas input line next to the agitator to promote good mixing (Figure 10).


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Figure 10: General equipment setup for ozone process, scrubber employed for production scale

One additional challenge for plant scale runs is to safely determine reaction endpoint without exposing workers to ozone. Based on the assumption that the high reactivity of ozone will ensure its consumption in the presence of olefin 80, we hypothesized that upon detection of excess ozone in the reactor headspace, the reaction would be complete. To understand if this is an acceptable plant control strategy we first tested this hypothesis on 5 L scale wherein ReactIR was used to follow reaction conversion and an ozone detector was placed at the effluent vent of the reactor to detect when ozone was present in the headspace. As shown on lab scale, ReactIR indicated the generation of intermediate 82 and the simultaneous consumption of 80 (Figure 11) and during this time ozone was not detected in the headspace. At approximately 440 min the ReactIR trend plateaued (indicating full conversion), and ozone was detected in the gas effluent at low ppm levels. The generation of ozone was then halted, and the reactor was purged with nitrogen gas. At this point a traditional in-process sample could be safely pulled from the batch to confirm reaction completion.


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Figure 11: Normalized ReactIR trends from 5 L ozone process, Legend (È) = 80; (n) = 82.

The key learnings from these pilot studies were critical to the safe transfer of the process from the lab to a plant which did not have ReactIR capabilities. Using all the process design controls described above, and the aid of an explosion-proof ozone detector and an ozone scrubber, the process was executed several times on 20 kg scale. As can be seen in the production facility 58

ozone trace, during the first part of the process, ozone was continuously consumed via reaction with the olefin and was not detected in the gas stream exiting the reactor (Figure 12). Once ozone was confirmed to be present in the effluent gas, the ozone generation was ceased, and the reaction was purged with nitrogen for safe sampling in the plant. Off-line HPLC analysis was then used to confirm completion of the ozonolysis portion of the process.


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Figure 12: Inline analysis of production scale ozonolysis. Legend (Ð) ozone production in kg; (l) analysis of unconsumed ozone at reactor exit in kg/h.

Due to their efficiency and atom economy, ozonolysis reactions and our ability to successfully perform them on large scale is important. For batch reactions, the techniques developed for AMG 138 are valuable and reproducible and have been applied to several other cases across the portfolio. Recently, additional approaches to the development of continuous ozonolysis reactions have been reported which will provide further opportunities to perform these reactions safely on scale.

59

Development of Common Building Blocks While we have demonstrated many of the challenges that need to be addressed in the development of commercial processes for our NCEs, at times we also need to develop new methods to synthesize core fragments and building blocks within the portfolio. These methods often provide more efficient and rapid access to key intermediates or starting materials and at reduced cost. To demonstrate the breadth of research and innovative approaches developed in our laboratories to address this need we will describe three methods of broad impact.


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Synthesis

of

Functionalized

Pyridines

via

Highly

Regioselective

N-Oxide

Rearrangements: Substituted pyridines, particularly 2-aminopyrdyl and halogenated derivatives 60,61

are common building blocks / motifs in several compounds in the pharmaceutical industry.

62

Typical routes to these differentially substituted pyridine derivatives derive from already substituted pyridines. During our development of a commercial process we came upon the need to generate 2-aminopyridine derivatives which were differentially substituted at the 3 and 5 positions. These derivatives could either be arrived at from the aminopyridine itself or a halogenated derivative (Scheme 22).

Scheme 22. Synthetic strategy surrounding synthesis of N-aryl-3,5-substituded-2-pyridine amine 86.

Typical methods to generate pyridines of this substitution pattern include SnAr or metalcatalyzed cross-coupling reactions of differentially functionalized pyridine substrates. However, these complex starting materials can be challenging to source as single regioisomers. The previous synthesis of the 2-aminopyridine started with 5-bromo-3-nitropicolinonitrile which was an expensive starting material and two steps of the synthesis involve conversion of the nitrile into an amine. We identified that an attractive alternative route to either derivative would be from selective functionalization of a pyridine-N-oxide which could be easily prepared from 3,5-dibromopyridine-


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N-oxide (Scheme 23). Functionalization of N-oxides into halopyridines is well precedented with a variety of activators ranging from POX , SOX and SO Cl . However, fewer reports exist for 63

3

64 2

2

65 2

N-based nucleophiles, and few regioselective reactions of differentially substituted pyridine N66

oxides have been reported.

Scheme 23: Entry into 2-halo or 2-aminopyridines via regioselective N-Oxide rearrangement

We initially set out screening conditions to selectively install an appropriate ammonia surrogate into an electronically differentiated pyridine-N-oxide utilizing an appropriate activating agent. Knowing that Ts O is an effective activator of N-oxides toward tert-butylamine addition

67c

2

we chose to start with similar conditions, but with the ammonia surrogates saccharin, diethyl-N68

(Boc)phosphoramidite, and phthalimide (Figure 13). Fortunately, as an initial hit, we found that saccharin delivered high conversion of the substrate and afforded promising regioselectivity.

69

Additionally, the saccharin adduct could be deprotected cleanly in aqueous HCl at 80 °C. Further optimization found tosyl chloride to be equally competent in the reaction with the choice of nucleophile having a strong impact to the regioselectivity. While diethyl-N-(tertbutoxycarbonyl)phosphoramidate afforded the highest regioselectivity of those nucleophiles


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examined (>17:1) the cost of this reagent left saccharin (11:1) as the obvious choice to further develop.

Figure 13: Effect of Nucleophile on Amination Regioselectivity with Ts2O and 3-Br-5-OMepyridine N-Oxide

With optimized conditions in hand we examined several electronically differentiated pyridine N-oxides in the regioselective amination reaction (Figure 14) and found that substitution is favored ortho to the aryl oxy substituent and regio-selectivity is highly influenced by altering the electronics of the substituents. Of the substrates examined, there was a clear trend toward amination ortho to the electron releasing substituent and para to the electron withdrawing substituent. Even modestly differentiated 3-thiopyridyl-5-pyridyl oxy showed a strong preference to amination adjacent to the oxygen substituent.


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Figure 14: Representative substrate scope for regioselective amination reaction of Pyridine NOxides with TsCl and saccharin.

In a similar vein to the regioselective amination, we were equally interested in exploring regioselective halogenation in generation of 2-chloro-3,5-disubstituted pyridines (Scheme 24). Typical halogenation conditions of pyridine N-oxides are often quite harsh which can be challenging when working with energetic substrates. A screen of a variety of reagents (POCl , 3

PCl , SO Cl , SOCl , NCS and oxalyl chloride with a variety of bases (triethylamine, 5

2

2

2

diisopropylethylamine, DBU, 2,6-lutidine, pyridine) showed distinct interplay between the base and activating agent. Gratifyingly, the combination of oxalyl chloride and triethylamine delivered 76% yield and >99:1 regioselectivity favoring the 92 isomer (Scheme 24). Surprisingly, this


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reaction occurred under much milder conditions (0 °C, CH Cl ) than expected for typical 2

2

halogenation. The reaction could even be run as low as -70 °C and the substrate was rapidly consumed with full conversion achieved upon completion of the oxalyl chloride addition.

Scheme 24: Regioselective Chlorination of Pyridine N-Oxide 91.

With an optimized set of conditions in hand, we set out to understand the generality and scope of this reaction and found that a variety of electronically differentiated pyridine N-oxides afforded high yields and in almost every case nearly perfect regioselectivity (Figure 15).

Figure 15: Scope of chlorination on pyridine-N-oxides.

Given the exceptionally mild conditions and highly regioselective chlorination with oxalyl chloride, we reasoned by extension, we could access the 2-bromopyridines by substitution of


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oxalyl bromide. Compared to chlorinations, there are fewer reports of practical regioselective brominations. Indeed, running the halogenation under identical conditions, but replacing oxalyl chloride with oxalyl bromide, the bromination reaction performed equally well. Interestingly, when the bromination was run in dichloromethane, a mixture of chloro and bromo products was formed (1:3 Cl:Br). Control experiment with oxalyl chloride in dibromomethane showed a near equal ratio of chloro to bromo pyridine (1.2:1 Cl:Br) indicating that both the solvent as well as the activating agent are potential sources of the halogen. Further computational studies have pointed to a deprotonated ylide-like intermediate involved in halogen capture. In total, we developed two 70

novel methodologies to access differentially 3,5-disbustituted 2-amino or 2-halo pyridines via a highly selective N-oxide rearrangement. This allowed access to the highly valuable building blocks from inexpensive and readily available 3,5-dibromopyridine N-oxide rather than more highly functionalized starting materials.

Development of a general C-H arylation method: As part of a development program to prepare functionalized benzothiazole and thiazolopyridine S1P agonists, exemplified by 96 and AMG 369 1

(Figure 16), we became interested in new, general methods to arylate the 2-position across this class of molecules.

71

Figure 16. Benzothiazole and thiazolopyridine agonists of S1P

1


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Scheme 25: Development of a general C-H arylation method

Although these targets had moderate complexity scores due to the lack of stereocenters (e.g. AMG 369 complexity index = 11), the 2-aryl substituted benzothiazole / thiazolopyridine cores required step-wise procedures to construct (Scheme 25). Although applications of transition-metalcatalyzed direct C-H arylations had begun to emerge at the time, industrial use of these methods remained challenging due to the requirements for high catalyst loadings, use of strong bases, and harsh reaction conditions. To address these challenges, extensive screening was conducted and 72

resulted in the identification of a highly efficient Pd/Cu cocatalytic system for the C-H arylation reaction. Specifically, an air-stable [(t-Bu) PCl] PdCl (PXPd) complex (0.25 mol%) in 2

2

2

combination with Cu(Xantphos)I (1 mol %) provided an excellent cocatalyst system in the presence of Cs CO to provide high yields of the desired arylation products (Figure 17).

73

2

3

Interestingly, at the same loading, neither the Pd or Cu catalyst could individually catalyze the CH arylation reaction. The new catalytic system was shown to be general for the cross-coupling of a broad range of heteroarenes and aryl halides including electron-poor or electron-rich aryl bromides containing trifluoromethyl, vinyl, ester, or aldehyde groups as well as pyridinyl rings.


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Activated aryl chlorides also provided good conversion to the desired products. Phenyl triflate showed good reactivity, but the corresponding reaction with iodobenzene was more sluggish, affording a moderate yield. Electron rich benzothiazoles were found to be more reactive than their electron-poor counterparts and both benzoxazole and N-methylbenzoimidazole were successfully arylated under these conditions as well. Ultimately, this co-catalytic process proved to be remarkably robust and we successfully performed this chemistry on multi-kilogram scale in our facilities to supply the S1P program. 1

Figure 17: Pd/Cu Cocatalytic System for Direct Arylation of Heteroarenes

A -Phos - a novel catalyst for efficient Suzuki-Miyaura cross-coupling reactions of ta

heteroatom-substituted heteroaryl chlorides: The ability to perform cross-coupling reactions on 74

scale is a key transformation required in the process chemist’s toolkit. During the development of AMG 517, a potent and selective TRPV1 (VR-1) inhibitor for the potential treatment of neuropathic pain and osteoarthritis, a sequence of selective C-O and C-C bond forming steps on 75

a dichloropyrimidine core 101 was required (Scheme 26). However, the late stage Suzuki-Miyaura


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coupling proved to be particularly difficult due to slow reaction kinetics (necessitating high catalyst loadings) and competitive cleavage of the acetate group under the reaction conditions which reduced yield and required a tedious purification.

Scheme 26: Structure and retrosynthesis of AMG 517.

The tendency of such heteroatom containing substrates to deactivate Pd/L catalysts in Suzuki-Miyaura coupling processes is well known and particularly relevant in the pharmaceutical setting where these types of targets are common. Forcing conditions, high catalyst loadings and protection/de-protection strategies are often needed to circumvent these challenges. However, these measures increase cost, slow development times and reduce the scope of Pd-catalyzed crosscouplings for drug discovery and development. Therefore, inspired by AMG 517 and similar examples from our portfolio, we initiated a study to develop new and improved catalysts for the cross-coupling reactions of heteroaryl halides. This work culminated in the development of a simple, air-stable, and comparatively inexpensive series of phosphines, the most notable of which was A -Phos which could be prepared as the corresponding palladium complex, PdCl {PtBu -(pta

2

2

NMe2-Ph)} (Figure 18). 2


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Figure 18: A Phos-Pd Catalyst ta

A -Phos represents a simple, general, and highly active catalyst for the efficient Suzukita

Miyaura cross-coupling reactions of aryl halides including six-membered heteroaryl chlorides

76

with -SR, -NH2, and -OR substituents and five membered heteroaryl halides (Figure 19). The catalyst is versatile (offers many solvent and base choices for process development), highly efficient (low catalyst loadings and high product yields) and can significantly extend the prior substrate scope and utility of Suzuki-Miyaura reactions. Key to the success of this new 77

monodentate phosphine ligand was its resistance to displacement from Pd metal centers by heteroatom-containing reactants as compared to previous state of the art phosphines. As a result, the Pd/AtaPhos catalyst system has found widespread use in both academic and industrial settings.72a


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Figure 19: Selected Scope of Suzuki-Miyaura couplings with A -Phos ta

Conclusion In this perspective we presented a variety of innovative synthetic approaches to demonstrate the excellence in industrial organic chemistry resulting from pharmaceutical process development. We have demonstrated, through case studies, the challenges faced by process chemists and the creativity needed to deliver cost effective, safe, and environmentally friendly processes into the manufacturing environment. As the complexity of our drug candidates increases, new challenges emerge, and the opportunities to add novel methods to the synthetic chemistry


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toolkit continues. Our field of research remains exciting, and the impact of delivering new medicines to patients makes the job immensely rewarding! Author Information Biographies

Margaret Faul is Vice President of Drug Product Technologies at Amgen Inc, in Thousand Oaks, CA where she is responsible to develop the commercial drug product processes for modalities across the Amgen portfolio from preclinical to commercial. Margaret was raised in Dublin, Ireland and received her B.Sc. and M.Sc. degrees from University College Dublin, Ireland. In 1987 she moved to the United States where she received her Ph.D. degree in Synthetic Organic Chemistry from Harvard University with Professor David A. Evans. Margaret has a strong scientific reputation and has invested significantly in supporting external scientific efforts being an author/co-author of more than 150 peer reviewed publications, presentations and patents. Margaret has served as a symposium organizer and session chair for several major process chemistry events and is has been a member of the Editorial boards for Science of Synthesis, Organic Synthesis, Journal of Organic Chemistry and Organic and Biomolecular Chemistry. She has significantly advanced novel technologies across the pharmaceutical industry as chair of the Enabling technologies consortium and Vice Chair of the International Consortium for Innovation


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and Quality in the Pharmaceutical Industry (IQ). Margaret has received numerous awards in recognition of her leadership and mentorship including the Earle B. Barnes Award for Leadership in Chemical Research Management from Dow Chemical Company and the American Chemical Society and a HBA Rising Star Award.

Shawn D. Walker received his B.Sc. in Chemistry from McGill University, and his Ph.D. in Organic Chemistry from the University of British Columbia with Prof. Edward Piers. He subsequently completed post-doctoral research at the Massachusetts Institute of Technology with Prof. Stephen L. Buchwald, before joining Amgen in 2004. He currently serves as Director of Process Development at Amgen in Cambridge, Massachusetts and leads the Synthetic Technologies & Engineering organization.

Acknowledgements The work summarized herein was the collective effort of a talented and dedicated group of process chemists and chemical engineers. We are grateful to have had the opportunity to work with these gifted scientists to bring new medicines to patients.


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Prepared from the corresponding chiral trimethylsilyl cyanohydrin, see Caille, S.; Cui, S.; Hwang, T.-L.; Wang, Xiang ; Faul, M. M. Two Asymmetric Synthesis of AMG 221, an Inhibitor of 11β-Hydroxysteroid Dehydrogenase Type 1. J. Org, Chem. 2009, 74, 3833–3842.

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Engler, T. A.; Wanner, J. Lewis Acid-Directed Cyclocondensation of Piperidone Enol Ethers with 2-Methoxy-4-(N-phenylsulfonyl)-1,4-benzoquinoneimine: A New Regioselective Synthesis of Oxygenated Carbolines. J. Org. Chem. 2000, 65, 2444-2457

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Xiong,

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Convenient

Approaches

to

4-

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Couch, G. D.; Burker, P. J.; Knox, R. J.; Moody, C. J. Synthesis of 2-aryl-6-methyl-5nitroquinoline derivatives as potential prodrug systems for reductive activation. Tetrahedron, 2008, 64, 2816-2823

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(a) Keith, J. J. Org. Chem. One Step Conversion of Heteroaromatic-N-Oxides to ImidazoloHeteroarenes. 2008, 73, 327-330. (b) Keith, J. One-Step Conversion of Azine N-Oxides to α1,2,4-Triazolo-, 1,2,3-Triazolo, Imidazolo-, and Pyrazoloheteroarenes. J. Org. Chem. 2010,


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75, 2722-2725. (c) Yin, J.; Xiang, B.; Huffman, M.; Raab, C.; Davies, I. A General and Efficient 2-Amination of Pyridines and Quinolines. J. Org. Chem. 2007, 72, 4554-4557. 67

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Conditions: 2 equiv Ts2O, 1.3 equiv DBU, 1.1 equiv N-(t-butoxycarbonyl)-PToluenesulfonamide, CH2Cl2 (10 mL/g starting material), 0 °C.

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Regioselectivity 5.8/1 (6 isomer/2 isomer)

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(a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998. (b) Modern Arylation Methods; Ackermann, L., Ed.; Wiley-VCH: Weinheim, Germany, 2009.

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(a) Guram, A. S. 2016 Paul N. Rylander Award Address: Enabling Palladium / PhosphineCatalyzed Cross-Coupling Reactions for Practical Applications. Org. Process Res. Dev. 2016, 20, 1754−1764. (b) Guram, A. S.; Wang, X.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J. New Catalysts for Suzuki-Miyaura Coupling Reactions of HeteroatomSubstituted Heteroaryl Chlorides. J. Org. Chem. 2007, 72, 5104−5112. (c) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.; Reider, P. J. New Air-Stable Catalysts for General and Efficient SuzukiMiyaura Cross-Coupling Reactions of Heteroaryl Chlorides Org. Lett. 2006, 8, 1787−1789. ACS Paragon Plus Environment

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Gavva NR, Bannon AW, Hovland DN Jr, Lehto SG, Klionsky L, Surapaneni S, Immke DC,

Henley C, Arik L, Bak A, Davis J, Ernst N, Hever G, Kuang R, Shi L, Tamir R, Wang J, Wang W, Zajic G, Zhu D, Norman MH, Louis JC, Magal E, Treanor JJ. Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade. J Pharmacol Exp Ther. 2007 23(1), 128-137.

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The development of other catalysts and conditions for general and efficient Suzuki−Miyaura

coupling reactions of heteroatom-substituted heteroaryl chlorides were concurrently reported; see (a) Kudo, N.; Perseghini, M.; Fu, G. C. A Versatile Method for Suzuki Cross-Coupling Reactions of Nitrogen Heterocycles. Angew. Chem., Int. Ed. 2006, 45, 1282−1284. (b) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. A Highly Active Catalyst for Suzuki–Miyaura Cross-Coupling Reactions of Heteroaryl Compounds. Angew. Chem., Int. Ed. 2006, 45, 3484−3488. (c) Billingsley, K.; Buchwald, S. L. Highly Efficient Monophosphine-Based Catalyst for the Palladium-Catalyzed Suzuki−Miyaura Reaction of Heteroaryl Halides and Heteroaryl Boronic Acids and Esters. J. Am. Chem. Soc. 2007, 129, 3358−3366.

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The A -Phos ligand also effectively promotes palladium-catalyzed cross coupling of Grignard ta

and zinc reagents. For an early example see: Woo, J. C. S.; Walker, S. D.; Faul, M. M. Preparation and decarboxylative rearrangement of (Z)-enyne esters. Tetrahedron Letters 2007, 48, 5679–5682. For additional examples see Ref 74a.


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Molecular Complexity as a Driver for Chemical Process Innovation in

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