Flow Chemistry Approaches Directed at Improving Chemical Synthesis

DOI 10.1515/gps-2013-0029 Green Process Synth 2013; 2: 211–230

Review

Ian R. Baxendale* , Laurens Brocken and Carl J. Mallia Flow chemistry approaches directed at improving chemical synthesis

Abstract: Flow synthesis offers many advantages when to adopt greater levels of automation to facilitate continu- applied to the processing of difficult or dangerous chemi- ous scale-up, whilst being coupled with integrated diag- cal transformations. Furthermore, continuous production nostic capabilities that ensure the highest standards of allows for rapid scale up of reactions without significant quality control for the processes. Downstream post reac- redevelopment of the routes. Importantly, it can also pro- tion clean-up is also a critical development area requir- vide a versatile platform from which to build integrated ing more effective quenching, extraction and work-up multi-step transformations, delivering more advanced methods to facilitate a truly seamless continuous product chemical architectures. The construction of multi-purpose supply chain. micro and meso flow systems, that utilize in-line purifi- In this context, microreactor flow technologies have cation and diagnostic capabilities, creates a scenario several potential advantages for chemical production. of seamless connectivity between sequential steps of a Firstly, the high heat and mass transfer rates possible longer chemical sequence. In this mini perspective, we within mesofluidic systems, allow reactions to be per- will discuss our experience of target orientated multi-step formed under a more extensive range of conditions than synthesis as presented at the recent inaugural meeting of can be achieved with conventional reactors (including LEGOMEDIC at Namar University, Belgium. expanded Δ T and Δ P). Hence, new reaction pathways, deemed too difficult or dangerous to operate in conven- Keywords: automation; flow; meso/micro reactor; solid- tional batch equipment, can be pursued [7 ]. Furthermore, supported reagents; synthesis. the inherent safety characteristics of the technology, also allow for production scale systems comprising of multiple connected reactors giving distributed point-of-use synthe- *Corresponding author: Ian R. Baxendale, Department of Chemistry, sis of chemicals without storage and shipping limitations. Durham University, South Road, Durham, DH1 3LE, UK, e-mail: [email protected] This neatly avoids many issues associated with worker Laurens Brocken and Carl J. Mallia: Department of Chemistry, contact and the use or generation of highly reactive and/ Durham University, South Road, Durham, DH1 3LE, UK or toxic intermediates. In addition, scale-up to production levels by replication of the same microreactor conditions used in the laboratory, can eliminate costly redesign and 1 Introduction pilot plant experiments, thereby shortening the development time from laboratory to final production levels.

The discovery process for small biologically active molecules is changing rapidly, generating an inherent need to conduct synthesis in a more efficient and timely manner 2 Building block synthesis [1 – 5 ]. As the global emphasis towards achieving higher safety standards and more sustainable practices unfolds, To rapidly assemble novel bioactive molecules requires the it is becoming necessary to re-evaluate how chemical syn- implementation of well-planned routes using robust, reli- thesis is conducted [6 ]. Accelerated discovery cycle times able and functional group tolerant chemistries. However, have also placed increasing pressures on the reliability a common bottle neck, that limits even well designed and timeliness of preparative processes. There is, there- routes, is the availability and diversity of individual start- fore, a requirement for new chemical processing tech- ing materials and advanced building blocks. Therefore, a niques that can conduct industrially relevant chemical process for rapid on-demand and in-house manufacture syntheses, faster and in a more directly scalable fashion. of these potentially proprietary components is optimum. Consequently, these chemical processing techniques need Here, flow chemistry can provide a solution.

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A good example of a high yielding transformation, prior to the outlet of the reactor. The sulfonic acid resin which can in practice be problematic to employ, is the acted to sequester in its ionic form any residual aniline Huisgen azide-alkyne copper catalyzed cycloaddition starting material from the flow stream. Additionally it reaction. This reaction represents one of the most facile functioned to degrade and protonate any trimethylsi- reactions in the modern cited “ click chemistry” grouping. lyl azide forming hydrazoic acid. This latter by-product, However, although this reaction reliably yields excellent which is a potentially highly explosive component, was conversions of the triazole adducts, the availability of the scavenged quantitatively by the presence of the amine alkyne and azide precursors is often limited. Both of the base (inorganic azide contamination of the out flow was reactive functional groups, azide and alkyne have the pro- colorimetrically tested for). Consequently, a purified flow pensity to be explosive, unless attached to large molecular stream of the organic azide was produced which could be weight units, meaning transport and storage is often an directed as a stream of starting material into other trans- issue. Therefore, to make effective use of such coupling formations [ 8 , 35 ]. We have also used alternative strategies chemistry, flexible methods of preparing the necessary which make use of azide ion exchange polymers to sub- starting materials, on demand and in sufficient quanti- stitute more reactive alkyl halide groups in flow. Simply ties, are required. taking a column of the appropriately loaded azide resin We and others have shown that it is possible to syn- and passing a flow stream of the substrate through under thesize a wide range of azide building blocks in flow using heated reaction conditions, can be used to yield the azide various substitution chemistries [8 – 15 ]. For example, product. This approach has been used to great effect in readily available aniline starting materials can be trans- our total synthesis in flow of the natural product oxomari- formed into their aryl azide counterparts via an intermedi- tidine (1 ) where substitution of an alkyl bromide was con- ate diazonium species prepared by reaction with tert -butyl ducted to prepare the corresponding azide for use in a key nitrate. Substitution of the intermediate diazo group using Staudinger aza-Wittig coupling reaction ( Scheme 2 ) [ 36 ]. an azide nucleophile generated in situ from trimethylsilyl We have also used flow chemistry for the preparation azide, rapidly furnishes the desired azide product through of acetylenes in flow via the Seyferth-Gilbert homologa- loss of nitrogen gas [16 ]. In our flow process, we further tion of an aldehyde using the Bestmann-Ohira reagent utilized a combination of immobilized reagents to perform ( Scheme 3 ) [ 37 ]. A flow stream of the corresponding alde- in-line quenching and scavenging of by-products (Scheme 1) hyde along with the Bestmann-Ohira reagent were com- [ 17 – 34 ]. A cartridge containing a packed bed of a sulfonic bined with a secondary stream containing the base, potas- acid resin followed by a trialkyl amine base was attached sium tert -butoxide, and progressed into a heated flow

N3 O N3 N3 I MeO

MeO N3 86% 91% 92% 86%

N3 N N O H N R 1) H 3 3 2 SO3 Cl N3

2) NMe2 - TMS N3 Cl MeCN 12 91% 94% 94% 85% N 10 min., Scavenging 3 N3 NO ° N3 O 90 C OMe F3C CF3 89% 93% 95%

N3 CN N3

NO2 Br 87% 93%

Scheme 1 Flow aryl azide preparation including scavenger purification.

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NMe N HO 3 3 HO 1)

Br N HO 20 equiv., 70°C 3 100% conv. n CH3CN : THF (1:1) PhP( -Bu)2

N 20 equiv. MeO 1) rt, 2) 55°C NMe3RuO4 OH OMe O

MeO MeO 2) Flow OMe 10 equiv., rt. 10% Pd/C, THF OMe hydrogenation THF 100% conv.

O HO 80°C HO CH Cl PIFA 2 2 MeO N N Chip CH Cl H MeO 2 2 MeO MeO N O CF3 CF O O 3 OMe OMe O F3C O CF3

O NMe3OH MeO H N ° MeO 35 C 1

MeOH : H2O (4:1)

Scheme 2 Synthesis of the natural product oxomaritidine.

coil. The flow stream upon exiting the reactor coil was other reaction components, giving a superior overall yield then directed into a cartridge of immobilized benzylamine when compared to the stepwise process. to remove excess aldehyde, followed by a sulfonic acid Furthermore, adopting these approaches allows resin to quench the base and protonate any phosphoric archived protocols to be quickly reloaded and transposed residues. Finally, a dimethylamine resin column was used into other reaction sequences, to create new classes of to remove the acidic impurities. The resulting acetylene building blocks. This can be aptly demonstrated by the product could then be collected in high yield and purity utilization of the previously described aryl azide reaction for further use. It should be noted that a small modifica- ( Scheme 1 ), where the product can be reproduced and tion to the sequence was necessary for nitrogen-contain- the flow stream routed into a new amino triazole forming ing starting materials, where the sulfonic acid resin was reaction (Scheme 5) [8 , 35 ]. In this way, it is possible to substituted for an alumina packed cartridge to avoid establish a library of reactor configurations and parame- capture of the newly formed product during the work-up. ters which can be readily applied for repetition of existing Another advantage of flow chemistry is that once reactions, or insertion into new reaction arrangements. a targeted sequence has been exemplified, it is possible A significant benefit of this approach to working is that to take the individual step and incorporate it with other the devised chemistry is less reliant on human experi- sequential steps into more elaborate and integrated pro- mental recording and interpretation. The majority of the cesses. In this way, multi-step reactions can be run in a reaction parameters (e.g., ΔT, Δ P, time) can be captured planned and automated fashion. For example, the fully and monitored by the reactor platform which can then functional triazole can be assembled by plugging together repeat the exact sequence including heating ramp rates the individual steps as discussed above ( Scheme 4 ) [ 37 ]. and injection times with absolute precision. This increase This scheme also involves an additional TEMPO oxidation in automation enhances accuracy and reduces user vari- of the benzylic alcohol to generate the aldehyde as part of ation and human error. It should, however, be implic- the flow process. This is conducted in the presence of the itly highlighted that this does not negate the need for a

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O O O P R H Me OMe NH H 1.3-1.5 equiv. OMe 2 SO3 N2 1 equiv. ° KOtBu in MeOH 70 C 30 min., H 1.2 equiv. 100°C R NMe2

H H H H

Cl NO2 MeO2C NO2 81% volatile 77% 84%

H H H H O

O Br Ph 65% 73% 79% 82%

OMe H N H H N N CI N CI Me *78% *64% *71%

Scheme 3 Seyferth-Gilbert homologation. *Required alternative procedure as described in the main body text. well-trained chemist as part of the process, but instead production, especially as part of a telescoped production frees up valuable time for creative thinking and advanced pathway. Often, when conducting batch chemistry a par- experimentation, as opposed to conducting repetitive and ticular chemical step or occurrence of an intermediate labor intensive manual operations. along the planned synthetic route will necessitate either a work-around or the devising of a new route, to avoid issues of potential toxicity and/or explosive or extreme exo- thermic behavior [ 38 , 39 ]. As well as this being less than 3 Reactive intermediates optimum in terms of chemical strategy and efficiency, it can also represent a significant time and cost implication Another aspect where flow chemistry offers a major advan- for reworking the route. Obviously, obviating the inher- tage is in the area of reactive and dangerous intermediate ent danger associated with such chemistry by decreasing

Me Me

N3 O N O O SO3 P F Me OMe Me Me S OMe 2 equiv. N2 + NMe CuI N NH 1 equiv. OH 2. H 2 MeCN, 60°C Ph 2 equiv. t KO Bu 45 min in MeOH 100°C N N N NMe2 SO3H NH2 Ph 55% yield 70°C by crystalization F

Scheme 4 Multi-step triazole synthesis using an integrated flow reactor.

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ArNH2 + TMSN3 (1:1) MeCN 1) SO3H NC CN

2) NMe MeCN 2 NMe3 BPR CN 100 psi N 12 N NH2 rt. 60°C N 10 ml CH Cl Ar 2 2 70°C 1.0 ml/min tBuONO NC CN MeCN MeCN

Scheme 5 Concerted formation of amino triazole products in flow.

the associated risks is a far better solution, thus allowing silica gel plug to trap inorganic salts. This simple, yet very the chemistry to be safely progressed. Microreactor tech- effective modification immediately renders the flow output nology has been shown to very effectively address many free from HF and other inorganic fluoride contamination. of the safety concerns associated with high risk chemis- This eliminates high risk user exposure for this versatile, tries, mainly through reduction in reactive volumes (small but previously potentially dangerous reaction sequence, reactor volumes) and increased containment (sealed thereby expanding the scope of chemistry available to reactor systems) [40 – 47 ]. Additionally, the manufactur- the bench chemist. Taking advantage of this increased ing concept of “ make-and-use ” where the potentially safety and extending its scope, DAST has also been used problematic chemical is generated and then immediately to promote cyclodehydration of amido alcohols to furnish consumed in a subsequent step, thereby furnishing a oxazoline structures in flow (Scheme 7) [52 , 53 ]. This has more stable and easily handled product, further directly been used to synthesize both natural products and as part increases the safety profile of the process. of a sequence leading to chiral ligands for use in catalysis. We have conducted several examples of reactions Alternatively, the electrophilic fluorinating species which fall under this general categorization of classically 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane problematic to run, or previously thought of as “ forbid- ditetrafluoroborate (Selectfluor) can be used to induce den chemistries ” , when considered as batch based proce- α -fluorination ( Scheme 8 ) of an activated carbonyl or dures [ 7 ]. As an illustration, fluorination chemistry with a nitrile [ 49 – 51 ]. It has also been used to promote a fluoro- reagent such as diethylamino sulfur trifluoride (DAST) pro- Ritter reaction of a series of olefinic substrates (Scheme 9). vides rapid access to many chemical structures with modi- This demonstrates the practicality and versatility of using fied pharmacokinetic profiles, by replacement of alcohols flow reactors which can allow the running of different or carbonyls units with mono or gem difluoro groups, chemistries on the same reactor platform, with only minor respectively. Whilst this reagent is extremely effective, it modifications. has a number of drawbacks, such as it is volatile, reacts Acyl azides are another class of useful, but poten- violently with water and readily undergoes dismutation to tially high risk intermediates. They have found particu-

SF4 and (Et 2 N)2 SF2 when heated to temperatures in excess lar utility in the Curtius rearrangement, which converts of 90° C [48 ]. Another issue that arises is that the products a carboxylic acid moiety into the corresponding amino are formed with concurrent release of hazardous hydro- group. Classically, an acid chloride would be treated with fluoric acid. Fortunately, in flow, it is possible to incorpo- an azide source [ 12 , 54 , 55 ] to effect this transformation, rate a direct in-line work-up, to facilitate a flow scheme but improved reagents such as diphenylphosphoryl azide where inorganic fluoride and excess starting material and (DPPA) are able to convert the parent carboxylic acid by-products are systematically extracted from the liquid directly to a protected amine [13 ]. This chemistry has been stream and sequestered onto a solid matrix (Scheme 6) shown to be highly amenable to flow synthesis, allowing [49 – 51 ]. Such a scavenger process does not need to be us to prepare a wide range of materials using immobilized highly complex to enhance the processing capabilities, as reagents, to facilitate the work-up of the product stream illustrated in the above chemistry by the expedient appli- (Scheme 10). Following rearrangement, the intermedi- cation of a calcium carbonate packed hydrofluoric acid ate generated isocyanate in our procedure was immedi- (HF) quenching column, immediately followed by a small ately intercepted by an in situ nucleophile (an alcohol or

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R1 R2

CH2Cl2 CaCO3 SiO2 F F

R1 R2

CH Cl CFC 2 2 70°C

SF N 3

DAST Fluorination products derived from alcohols

N F F F I F N Cl TrO F Cl NO2 73% 97% 87% 83% 92% OMe O F F N F O O NO 2 F 83% 88% 80% 83% Fluorination products derived from carbonyls Cl F F F F F N N MeO O F F O N F F N Cl O H 86% F 75% 75% 71% 83%

F F F F N N N F O O N F F Cl CN O N F O2N 87% 96% 89% N 94% OMe

Scheme 6 Fluorination chemistry performed using diethylamino sulfur trifluoride (DAST) in flow.

N F3S O DAST MeO OH

MeO + CDI CH2Cl2 OH 50 min., 25 min., ° ° O 110 C 75 C H2N 1) SO H 1 3 O HCl + Et3N 2 2) NMe2

CaCO3 SiO2 Cl R = iPr R = tBu R= Ph O N O O O MeO N N N 75–90% O R R MeO 90%

Scheme 7 Activation and cyclization of β -amino alcohols to form oxazoles.

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O EWG R

MeCN SO H NMe 3 2 O EWG R F CFC MeCN ° Cl 100–120 C O F N NC F H O Cl N O NH F N 2BF4 O F MeO O OEt Selectfluor® 90% 82% 93% l C O O O O O CF3 OEt F F F F 89% 82% 83%

Scheme 8 Electrophilic α -fluorination using Selectfluor in flow.

NHAc NHAc NHAc the context of a target driven multi-step synthesis, aimed at the delivery of advanced chemical structures such as F F active pharmaceutical ingredients (APIs) [56 – 66 ]. As most F Cl pharmaceutical syntheses typically require between 8 97% 86% 83% and 10 chemical transformations (this is often somewhat F OH NHAc reduced to 5/6 steps when analogue/library syntheses are F F being conducted), excluding protecting group manipula- NHAc tions, to realize the target molecule, this is a good founda- F tion from which to explore the advantages of flow chem- 86% 96% 91% istry. We have generated a flow protocol for the synthesis of imatinib, the API of the Novartis block buster antican- Scheme 9 Product prepared via a Fluoro-Ritter reaction in flow. cer therapeutic Gleevec (imatinib mesylate), including a series of analogues ( Scheme 11 ) [ 67 ]. This molecule also amine), to furnish carbonates or carbamates as the final highlights a difference in planning and thinking between products. It is worth highlighting that in this sequence, the original batch based routes [68 , 69 ] and the flow the final product could be isolated without recourse to based synthesis. The batch preparative routes had been any further purification. This demonstrates the syner- originally optimized to provide intermediates of low solu- gistic effect of employing flow synthesis in combination bility, which facilitate isolation and purification through with immobilized reagents, for improved product output. sequences of precipitation, crystallization and filtration. In this way, by extending and integrating additional steps However, this is inherently counterproductive for a flow that each generate clean product flows, it is possible to approach where solubility is a prerequisite. Furthermore, prepare more complex molecular architectures through we aimed to create a route which would allow each of multi-step transformations. the three main fragments to be exchanged to address maximum variation in subsequent analogue synthesis. This requires additional planning to build flexibility into the sequence where this desired diversity can be easily 4 Synthesis of drug substances introduced. Again, prior consideration of the generated intermediates, and any potential by-products that may The true potential of flow chemistry as an enabling tech- arise, is critical and should be addressed prior to embark- nology can really only be fully appreciated when seen in ing on the synthesis. Consequently, the extensive profiling

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O PhO P N3 SO3H NMe2 PhO H N Nuc MeCN R

Et3N O O + Nuc CFC ° R OH 100–120 C

Br H Cl H H N OEt H MeO N O N O N O O2S N N O O O O

95% 86% 75% 88% O O Me H O Cl N N N H HN O N EtO OEt O N N O H O O N N N N NH CF3 EtO 95% 75% 78% 77% 86% N H H O O MeO N O N OEt N N O N OMe O O H H MeO N 85% 79% 87% 73% F O H H O O N O N N O MeO H N OEt NH O H N MeO 91% 84% 91% 89% O

H HN OEt H N N O MeO N OEt H N O O O N Br O N O2N 81% 85%N 84% 89%

H H N O O N OtBu O2S O N O NH O H O N N O MeO N O H O 87% 92% 76% 89% Br

Scheme 10 Curtius rearrangement using diphenylphosphoryl azide (DPPA) in flow.

of the reaction in terms of its purity profile is more closely into a pre-charged vial containing a dimethylformamide analogous to process chemistry than traditional Medicinal (DMF) solution of N - methylpiperazine (other secondary Chemistry, even at the development stage. So, although amines could be used) by an automatic fraction collector more time consuming in the planning stage, having a triggered by a UV detector. This collection process facili- greater understanding of the chemistry, does then enable tated an automated solvent exchange from the highly vola- a smoother up scaling and more rapid optimization of the tile dichloromethane (DCM) used for the first step to the route. more polar DMF required for further processing. A simple The continuous flow synthesis of imatinib commences heating plate was used to raise the temperature of the vial with a coupling between an acid chloride and an aniline of collected solution to 50°C and a purge flow of nitrogen component, each of which can be easily varied (Scheme 11). gas was used to encourage evaporation of the volatile DCM. The resulting amide product stream was worked up by After a predetermined time, the resulting DMF solution was elution through a mixed bed column containing both an automatically re-injected into the second stage reactor. The acidic and basic resin, followed by a short plug of silica. stream was passed through a column of calcium carbon- The purified output stream was then directly collected ate maintained at 80°C, then scavenged with immobilized

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O Cl (1 equiv.) DIPEA (1.1 equiv.) SO3H Exhaust CH2Cl2 NMe2 BPR SiO2 N2 100 psi UV

10 ml CH Cl 2 2 rt HNR'R'' (2 equiv.) DMF R Br Fraction Collector/ Autosampler

(1 equiv.) NH2

BPR SO3H NCO CaCO3 100 psi Waste ° then Capture of 80 C intermediate 2 R Br R' R'' N

HN DBU 2 R O H N R' R'' R''' N 1,4-dioxane/tBuOH (2:1) 2.5 ml BPR SO3H 250 psi HN

O 5 ml 10 ml t 32% isolated yield 1,4-dioxane/ BuOH (2:1) 150°C N 3 R'''NH2 ( ) Imatinib Pd cat. (4) R = CH3 R''' = t 3 NN NaO Bu H2O Me N 1,4-dioxane/tBuOH (2:1) NH 2 R' N = CH3 NH R'' N NN Pd 2 H3C OCH3 Cl CH3

i Pr OCH3

iPr Cat. 4 iPr OMe

Scheme 11 Flow route used to prepare imatinib related analogues. isocyanate to remove the excess N -methylpiperazine. The subsequent Buchwald-Hartwig coupling with heterocyclic flow was then directed into a further column containing material 3, using the BrettPhos Pd precatalyst ( 4 ), at an ele- silica-immobilized sulfonic acid, to conduct a catch-and- vated temperature of 150°C. A water stream was combined release purification (capture of 2 ). The intermediate 2 towards the exit of the reactor, which aided dissolution of was then released from the silica supported sulfonic acid sodium bromide precipitate formed during the coupling. by elution with a 1,8-diazabicycloundec-7-ene/sodium Finally, the reactor output was concentrated in vacuo and tert-butoxide (DBU)/( t BuONa) solution directly into a loaded onto a silica Samplet cartridge for automated flash

Brought to you by | University of Durham Authenticated | 129.234.252.65 Download Date | 7/1/13 3:02 PM 220 I.R. Baxendale et al.: Flow chemistry chromatography, to give the desired product in 32% yield immobilized thiourea removed the palladium salts. The in better than 95% purity. freshly prepared ynone products could be isolated in Also, by modification of the input fragments, we moderate to high yield (41 – 95%) and excellent purity, fol- were able to demonstrate that a small derivative library lowing only evaporation of the solvent. However, without could be synthesized, in which a new unique structure intermediate isolation, they could be further elaborated could be prepared every approximately 12 h under auto- by combination with an additional input stream con- mated control (Scheme 12). In addition to supplying taining a nucleophile, such as a hydrazine or guanidine commercial fragment sets to the system, we were also derivative. By uniting the flow streams and heating the able to supplement the structural diversity by incorpo- resultant mixture, the corresponding heterocycles could rating heterocyclic scaffolds prepared in a convergent be directly prepared as a single linked flow sequence. This manner on a second flow platform. This involved the also allowed us to exemplify another attractive feature of synthesis and further condensation reaction of ynone this mode of processing, which was the ability to split the intermediates to generate the corresponding pyrimi- main product stream with each of these new flow tribu- dines (Scheme 13). taries being directed towards different product outcomes Using palladium catalysis, an acid chloride and acety- by varying the subsequently introduced condensation lene (which can be made as described earlier) are induced agents ( Scheme 14 ). to undergo a Sonogashira coupling to yield the unified With the growing number of reported syntheses, flow ynones (Scheme 13) [70 ]. To generate a flow process, a chemistry is slowly gaining acceptance as a very versa- solution of the acid chloride and acetylene were combined tile tool for performing many different types of chemis- with a stream containing a catalytic amount of palladium try [71 ]. Even within our own laboratory, we have already i (II) acetate and H ü nig ’ s ( Pr2 NEt) base. The united flow was demonstrated it can be used to prepare a wide range of heated at 100° C for 30 min in a tubular coil reactor and the chemical structures including quite complex natural output purified by passage through a series of four differ- products (Scheme 15) [72 – 83 ]. However, in order to utilize ent solid reagents and scavengers. First, a polyol resin was the full capacity of flow chemistry, it is imperative that used to remove the excess acid chloride (1.2 equiv. used) we gain better insights into the active chemical transfor- then a column of calcium carbonate trapped the hydro- mation occurring within the reactors, in real-time, so as chloric acid formed during the reaction and deprotonated to make immediate informed modifications to reaction the ammonium salts. The resultant H ü nig ’ s free base was parameters enhancing and accelerating optimization trapped on a sulfonic acid resin and finally a column of and increasing process quality control.

O H CF3 N H N N O N N N N H N N N N N N N HN HN HN N O N O N O 24% 24% 28% N N N H H N N H N N N N N N N N N N HN HN N HN O N O N O 25% F 26% 29% N N N F H H H N N N N N N N N N N N HN N O HN HN

N O O O 35% 31% 33%

Scheme 12 Examples of imatinib analogues prepared in flow.

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OH N OH H2NNHR'' H or Pd(OAc)2 (1 mol%) OH i HO NH ( Pr)2 NEt (1.2 HNO equiv.) OH O 3 O H2N NH2 R NaOH (1.1 equiv.) S R Cl EtOH : H O (1:1) 40 min., R' 2 + 100°C N NH2 R' H

Water 30 min., SO H MgSO4 100–130°C NH2 3 NN Liquid/Liquid Extractor (FLLEX) Catch and R R' NH3 in release MeOH/DCM Aqueous output

N N N N S N N N N

MeO 78% 65% 74% 53%

NH2 H N H NN N N N N N

86% 69% 62% 74% Br

NH NH H 2 NH 2 N 2 N NN NN NN

71% 57% 61% S 64% Br NO2 OMe

O NH N NH N NH 2 H N NH 2 2 N EtO 2 NN N N N OMe OMe N

MeO MeO 87% 77% 79% 90% N 83% F

Scheme 13 Preparation of ynones and elaboration to their heterocyclic derivatives.

5 Reaction monitoring with in-line over bulk solution characteristics (high surface to volume reactor ratio) and improved mixing coefficients. As a con- diagnostics tinuous flow process is by definition a dynamic environment, it is possible to effect rapid changes in reaction Working within a flow domain is not directly comparable parameters leading to immediate downstream changes to conducting the same reaction in batch. Many additional in the reactor output. Therefore, utilizing real-time analy- factors contribute to the altered reaction environment, sis of flow processes allows the rapid harvesting of large such as the increased governance of surface phenomenon amounts of data regarding multiple reaction parameters

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Ph 20 min., Input 1 Input 2 100°C OMe N N

MeO 60% 30 min., N N 100°C Ph

O MeO OMe 87%

OMe N Ph MeO OMe

Ph MeO OMe 20 min., 88% ° 120 C O I

MeO O Ph Input 4 Input 3 20 min., 100°C 71%

Scheme 14 Divergent chemical synthesis by stream splitting.

that can then be usefully employed to optimize the trans- transient or reactive intermediates [88 , 89 ]. We have used formation [ 84 – 87 ]. Qualitative spectral data can be easily this diagnostic tool to help evolve a flow route to various acquired using adjustable wavelength photodiode detec- butane-2,3-diacetals (BDAs) which are key polyol fragments tors (or similar spectrometers) placed as in-line analysis used in the synthesis of numerous natural products [ 90 , 91]. cells. Other diagnostic devices can also be used to report The developed flow approach allowed the BDA units to be on reaction progress, e.g., impedance measurements, prepared generally in much higher yields and with greater Raman spectroscopy, near or React IR, fluorescence meas- reproducibility than the equivalent batch processes. Spe- urements and various in-line bioassays. Alternatively, or cifically, the BDA protected tartrate was generated in multi- in addition, automated sampling techniques can be used gram quantities from a mixed stream of dimethyl-l -tar- to divert aliquots of reaction media into auxiliary moni- trate, trimethyl orthoformate and butane-2,3-dione under toring equipment, allowing standard LCMS or GCMS to be acid catalysis using catalytic camphorsulfonic acid (CSA) assimilated into the system. ( Scheme 16 ). It was discovered that when the dimethyl- One device we have found particularly useful has been l -tartrate and trimethyl orthoformate were premixed, rapid a ReactIR flow cell which can be easily positioned at any formation of an intermediate diacetal occurred, which was point throughout the reactor to interrogate a flow stream observed using the ReactIR flow cell (Scheme 17). This in real-time, including monitoring for the presence of proved to be an important observation and optimization of

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Polypeptides [82] Casein Kinase Inhibitors library [77] Aminopyrrolidines [78] N Me F Ph H2N O O N CO2Me H N N N OEt MeN N Ph O N N N H H O Me O δ -opioid Receptor Agonist [76] 5HT1B Antagonist [75] P2X7 Antagonist library O O MeO Et2N H N O F N NH H O O N O N OH O HN N N H Me Meclinertant SR 48692 [74] Zolpidem [72] Grossamide [81]

OH O MeO HO O N HN O O N N MeO HO H N N N H O MeO O N N Cl OMe Thiazole library [79] Guanadine library [80] Oxazole library [83] OH O Cl F Ph N EtO N H N N N AcO S O F HN F C N O 3 O Me Ph O O Ph O N CF3 O O OH OEt (-)-Hennoxazole A [73] OMe O Me Me N H N OMe O Me Me

Scheme 15 A range of other targeted structures achieved using multi-step flow synthesis. the breakdown of this reactive relay species increased the volatiles was required in order to isolate the product in a yield of the protected diol. In this sequence, the product crystalline form. This newly synthesized BDA-protected stream was again conveniently purified using a sequence tartrate was further modified in a two-step transformation, of immobilized scavengers to remove any remaining butan- first to furnish an unsaturated system by treatment with a edione and CSA catalyst, a process which could also be strong base lithium diisopropylamide (LDA) in the presence confirmed using the ReactIR flow cell to monitor for dis- of iodine, then through a selective hydrogenation using the appearance of these materials. A periodate resin was then H-cube Midi system (Rh on alumina catalyst) to yield the employed to perform a rapid glycol cleavage of the residual corresponding meso reduced form in quantitative conver- tartrate ester, to generate volatile by-products that could sion ( Scheme 18 ). Here again, application of the ReactIR then be easily removed. As a result, only evaporation of the proved valuable in optimizing the process.

OH NH MeO2C 2 NMe3 IO4 CO2Me OMe + CH(OMe) IR MeO C OH 3 flow cell 2 O MeO2C O O 70 min., 78% OMe CSA + 90°C O

Scheme 16 Flow synthesis of butane-2,3-diacetal (BDA) protected tartrate.

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MeO MeO MeO MeO

MeO2C CO2Me OH OMe

MeO2C O O MeO2C OMe

CH(OMe)3

02:10:00 02:15:00 02:20:00 02:25:00 O

Scheme 17 Mettler Toledo ReactIR Flow Cell and processed output.

A more challenging sequence, based upon this same yielding the lactone. Reaction clean-up was then affected general protection strategy, was investigated involving by passage of the flow stream through a sulfonic acid the preparation of a BDA protected glycolate (Scheme 19). resin, to scavenge the morpholine then an immobilized Utilizing conditions similar to those used to protect the thiourea matrix to sequester any leached osmium. Finally, tartrate above ( Scheme 16 ), enantiomerically pure chloro- isolation of the pure lactone product involved only solvent propanediol was first converted to the bis -acetal without evaporation. racemization. The resulting primary chloride substituted These examples clearly indicate that flow approaches product was then treated with a strong base (KO t Bu) to assisted by in-line purification and real-time reaction promote elimination to the exo-alkene. It was gratifying monitoring can significantly improve existing processes. to discover that this new flow procedure consistently pro- However, they can also help to automate and regulate new duced a high quality product, in an improved ratio of 24:1, sequences. We recently required an approach to repeatedly exo:endo, compared to variable ratios of between 15:1 and prepare quantities of various coumarin-8-carbaldehydes 5:1 as achieved in batch. The final oxidative cleavage of as selective IRE1-binders for investigations of mRNA splic- the double bond was conducted with a combination of ing [ 92 , 93 ]. Having ready access to the freshly prepared Osmium EnCat and immobilized periodate in the pres- substrate was very beneficial for biological investigations, ence of morpholine N -oxide as a solution-phase reoxidant as this aldehyde tended to undergo auto oxidation upon

OMe

MeO2C OO MeO2C SO H NMe S O 2 + LDA 3 [ 3]2 2 3 OMe OMe MeO2C OO MeO C rt. 2 OMe 65% I2

H-Cube MidiTM OMe OMe MeO2C MeO2C O OO O MeO2C

MeO2C OMe OMe Rh/Al2O2 Quant.

MeOH, 60 bar, 40°C

Scheme 18 Flow derivatization of a butane-2,3-diacetal (BDA)-protected tartrate.

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HO OH NH 2 OMe + CH(OMe) 95% 3 81% OMe O Cl O O OO 120 min., OMe CSA + 90°C OMe KOtBu O 60 min., NMO 70°C

NMe3 IO4 S + OMe N NH2 SO3H OsEnCat H OO O 85% OMe

Scheme 19 Synthesis of butane-2,3-diacetal (BDA) protected glycolate.

storage. One particular route to this molecule is depicted could be recycled. The entire loading procedure could in Scheme 20 below. The synthesis provides clean, easily be run in an automated manner using Gilson Unipoint isolated material, and can be reproducibly run. Further- control software. more, the operation of the reactor can be performed by Once each column had been fully loaded and cleaned numerous people, as much of the sequence is automated. (10 in total), a modified set-up was used for the O -allyla- This significantly increases access times to these com- tion and linked Claisen rearrangement process. The feed pounds when scheduling time allocation in a busy syn- line for the coumarin loaded columns was switched to thesis laboratory. deliver a solution of allyl bromide in NMP. Upon allyla- The selected route is based upon a key Claisen rear- tion, the coumarin material was released from the solid rangement reaction, which in high regioselectivity forms phase and passed through a scavenging step (an amine the required carbon functionality at position 8. As a start- resin) to sequester any co-eluting allyl bromide. Real- ing point, we elected to utilize readily available 7-hydroxy- time monitoring of the reaction stream using the UV/Vis coumarin, as isolation of this material was readily achieved device enables automatic succession to a new phenoxide at scale from our previous acetic acid flow procedure by cartridge, when the signal intensity received by the detec- direct induced precipitation by dilution of the output tor falls below a pre-prescribed absorption threshold (also stream with water [93 ]. The first step of the sequence triggering simultaneous exchange of the amine scavenger involved the allylation of the phenolic group with allyl column). This allows an automatic and essentially seam- bromide, which was conducted in N -methyl-2-pyrrolidone less transition between the different reactor cartridges. (NMP) in the presence of an immobilized carbonate base. The reaction flow stream containing intermediate 6 was To conduct this reaction, a bulk solution of the 7-hydroxy- next relayed into a stainless steel flow reactor and heated coumarin in NMP was eluted through a series of capture at 235° C, promoting the Claisen sigmatropic rearrange- cartridges (each was 40 mm internal diameter (id.) 75 mm ment. At this stage, the Claisen product 7 is recaptured depth, containing ~200 mmol loadable carbonate base). onto a second ion exchange resin, supported tetraal- A high concentration and flow rate were used for this kylammonium hydroxide. This simplifies the isolation rapid and efficient ion exchange process, where the phe- of the alkylated coumarin product from the high boiling nolic component 5 was trapped upon the resin following point NMP solvent, as well as enabling its separation from deprotonation. An automated valve network was set up any residual non-Claisen rearranged intermediate (2.5 – to exchange between the different columns, as the resin 4%). Following washing of the column with tetrahydro- became saturated by the substrate. Breakthrough of the furan (THF) (flushing all the NMP solvent away), release coumarin was easily monitored for by an in-line UV/Vis from the resin could be affected by passing a 1.5% (v/v) detector using a threshold based voltage to trigger switch- trifluoroacetic acid (TFA) in THF solution through the ing to the next column for loading. During this loading column. The released material could be isolated directly phase, a second HPLC pump (pure NMP solvent delivery) by solvent evaporation in a pure form. Alternatively, the enabled sequential washing of the newly loaded column, isomerization of the double bond leading to the conju- thereby eluting any non-bound starting material which gated analogue 8 could be achieved using an immobilized

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HO O O 1.0 ml/min 1.0 ml/min Wide bore S 0.15 M THF residence tube 8 N NH2 H T-piece HO O O

H O Argon Vent 92%

Ozone 500 ml/min

generator 0.5 bar Oxygen 10 port value NMP

HO O O 1.33 M NMP 2 NEt3 CO3 2

Data acquisition and control Waste UV-Vis Load 10 port valve

Br 1.15 equiv. NMP Data acquisition 10 port valve and control

NEt3 A B C D E

O OO 5

NH2

UV-Vis

NEt3OH 235°C 1 57 min. O OO 6 10 port 2 BPR valve 100 psi 3 10 port Wash Waste 4 valve THF Release (then TFA 5 1.5% sol. THF)

Ph2 P NMe2 Ir(H)2(THF)2 PF6 P Ph2

HO OO HO O O 7 8

Scheme 20 Synthetic flow route to coumarin-8-carbaldehyde. version of Felkin’ s iridium catalyst at 60 ° C, although a simple set-up to perform the cleavage step of the alkene long residence time was required [90 , 91]. 8 using an immobilized thiourea as a solid ozonide Having had previous experience performing ozonol- quenching agent. A flow stream of the substrate was ysis reactions in flow [ 94, 95 ] we quickly established a pumped to mix with a continuous gas flow (O2 /O3 ) at a

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T-piece and directed into a plastic tubular reactor with removal of low level contaminants, their viability as a residence time of ~75 s. The reactor output, which re agents or excess sequestering agents generally falls off was comprised of a droplet spray, was collected into a with up scaling. Consequently, classical aqueous extrac- nitrogen blanketed purge vessel where the excess ozone tions must be re-evaluated and modified to fit continuous was eliminated by passing a constant flow of nitrogen processing frameworks. Although several concept designs through the chamber. The expunged solution was con- using semi-permeable membranes and counter-current tinuously pumped from the chamber as it collected extraction methods have been reported, these still need passing through a packed bed cartridge containing an substantial improvements to reach the levels and process- excess of the polymer-supported thiourea. This gave the ing capacity currently available from existing reactors, desired aldehydes in quantitative conversion and 92% thereby avoiding the creation of an artificial bottleneck. isolated yield after solvent removal. Another aspect of flow which has attracted significant In total, this four step sequence involving allyla- attention is the ability to instantly evaluate newly pre- tion, Claisen rearrangement, isomerization and ozonoly- pared compounds, flowing directly from a reactor straight sis, could be used to deliver the desired product in 51% into a bioassay [96 , 97 ]. Linking synthesis sequentially overall yield after crystallization (used to remove the with property assays (physical, chemical or biological) minor regioisomer by-product derived from the alterna- will allow for a fully closed loop discovery and optimi- tive sigmatropic rearrangement). The limiting step of the zation process at a much reduced cost and much higher route was the iridium catalyzed isomerization, although speed (greater throughput) than currently achievable. this could conceivably be performed using parallel reactor This ability to specifically explore chemistry and biology cartridges, thereby increasing the throughput. Despite in an integrated manner, offers tremendous advantages this restriction, it was still possible to preform multi-gram for pharmaceutical and agrochemical research, especially preparations (5 – 20 g). at the early stage of hit-to-lead discovery. As indicated in This and the other examples highlighted starts to the introduction, cycle times to new compounds need to clearly demonstrate the value of flow chemistry as a be as short as possible, therefore, being able to screen development tool in research and scale-up a compound to give an early indicator of its biological potency could save valuable time. This would be particularly beneficial when preparing new discovery libraries, 6 Conclusion: the future of flow by giving rapid evidence to guide the selection of the next suitable compound to be prepared. As a result, a faster chemistry in discovery research and more comprehensive structure-activity relationship (SAR) picture could be systematically constructed, which The complete flow solution tool box is still a future dream would lead to a higher degree of success. This would be for chemists, but significant process is being made to even more profitable if, as well as basic potency evalu- expand the available chemistry and improve reactor ation, additional tests relating to ADME and toxicology designs. Some key areas of developments covering could be run in parallel by splitting the synthesized com- aspects such as improving downstream processing, better pound flow stream. This approach to combined synthesis gas delivery, enhanced pressure regulation (current back and screening could revolutionize the pharmaceutical pressure regulators are limiting due to their potential for and agrochemical research discovery pipelines. With the fouling) and the expansion of self-interrogating Design exponential growth in this area, it is anticipated that this of Experiment software packages, are still required. In will be a plausible alternative way of working within the addition, for translation to larger scale applications, it next 5 years. will be necessary to devise better methods of performing aqueous quenching and extraction. Solid supported Acknowledgements: We would like to acknowledge the reagents, although extremely valuable and cost effective funding and support from the Royal Society (to IRB), Syn- for laboratory based use, do have limitations regard- genta (to CJM), and Unilever (to LB) that has enabled this ing volume and scaling (pressure effects and reactor work to be undertaken. volumes), especially when used as stoichiometric reagents or scavengers at scale. So, although they remain Received April 2, 2013; accepted April 20, 2013; previously published an effective alternative for catalytic processes or for the online May 25, 2013

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Professor Ian R. Baxendale is part of the Chemistry Faculty at Carl J. Mallia was born and raised in the small Mediterranean Durham University and also a Royal Society University Research island of Malta. He attended the University of Malta from where he Fellow. His primary areas of interest are the study and development received his BSc (Hons) degree in Chemistry and Biology in 2011 of advanced chemical synthesis tools and novel processing and his MSc in Chemistry in 2012. He is currently reading for a PhD methodologies for use in scaled synthesis of biologically active at Durham University working on synthesis in flow using gases as compounds. reactants under the supervision of Professor I.R. Baxendale.

Laurens Brocken (1987) started studying Chemistry in 2006 at the Radboud University Nijmegen (The Netherlands) and obtained his BSc in 2010. For his Bachelor internship, he worked with Professor F.P.J.T. Rutjes on the synthesis of hydroxyl substituted pyrolines catalyzed by gold. He continued with his MSc, which he obtained in 2012. His first master internship was under the supervision of Prof. F.P.J.T. Rutjes and FutureChemistry on the feasibility of 18 F-labeling procedures in flow and the development of an efficient and save set up. He then moved to work with Prof. I.R. Baxendale at the University of Cambridge and is currently doing his PhD under his supervision at Durham University.

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