A Combined High-Throughput Screening and Reaction Profiling

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A Combined High-Throughput Screening and Reaction Profiling Approach Toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol David C. Leitch, Thomas F. Greene, Roisin O'Keeffe, Thomas Lovelace, Jeremiah D Powers, and Andrew D. Searle Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00261 • Publication Date (Web): 19 Oct 2017 Downloaded from http://pubs.acs.org on October 20, 2017

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Organic Process Research & Development

A Combined High-Throughput Screening and Reaction Profiling Approach Toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol David C. Leitch,*,†,‡ Thomas F. Greene,§ Roisin O’Keeffe,§ Thomas C. Lovelace,‡ Jeremiah D. Powers,‡ and Andrew D. Searleǁ †

Chemical Catalysis Group, API Chemistry, GlaxoSmithKline, King of Prussia PA. ‡Catalysis

Center of Excellence, GlaxoSmithKline, Research Triangle Park, NC. §Global Manufacturing and Supply, GlaxoSmithKline, Cork, Ireland. ǁGlobal Manufacturing and Supply, GlaxoSmithKline, Stevenage, UK.

ACS Paragon Plus Environment

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Table of Contents artwork. Legacy Two-St ep Route OH

OH

OH

NaBH4 O Ph

N H

Salbut amol

OH

OH

OH

Pd/C, H2 HO Ph

HO N

HN

Cl Pd/C, Pt/C, H 2, mild acid

Dir ect, Telescoped Pr ocess


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KEYWORDS. Salbutamol, hydrogenation, high-throughput screening, tandem catalysis.

ABSTRACT. A combined high-throughput screening and reaction profiling approach to the telescoping of two reductions in the synthesis of Salbutamol is described. Optimization studies revealed the beneficial effect of mildly acidic conditions, and the use of water as a co-solvent. Persistent formation of deoxygenated impurities using a Pd/C catalyst led to the initiation of reaction profiling studies, which revealed that the ketone intermediate formed after rapid debenzylation is the sole source of deoxygenated impurities, indicating that more rapid ketone hydrogenation should minimize this deoxygenation. A dual catalyst approach based on these insights has been developed, with both Pd/Pt and Ru/Pt catalyst systems as more selective than Pd-only systems. Based on reaction profiles that indicate the deoxygenation side reaction is first-order in the concentration of debenzylated ketone intermediate, Pt catalysts for rapid and selective ketone hydrogenation were paired with Pd and Ru catalysts known to perform selective debenzylation.

Optimization of these dual catalyst processes led to conditions that were

demonstrated on 20 g scale to prepare Salbutamol in 49% isolated yield after recrystallization.


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Introduction. Salbutamol (or albuterol, 3), a potent and short acting β2-adrenergic agonist, is a vital medicine for the treatment of bronchospasm resulting from a number of conditions, including asthma and COPD.1 First described in the 1960s,2 Salbutamol is still widely used, and remains among the most prescribed and highest volume medicines worldwide. Because of its continued status as a vital medicine, improvements in synthetic efficiency are important to drive down production costs and reduce waste generation, which will continue to ensure patient access into the future.

As a result, many research groups have reported racemic and enantioselective

syntheses of 3.3 Part of an existing synthetic route to Salbutamol is shown in Scheme 1, highlighting the final steps.3a,b reduction

Transformation of the tertiary amino ketone 1 into 3 is achieved by a two-step sequence

involving

NaBH4

mediated

ketone

reduction

and

Pd-catalyzed

hydrogenolysis of the benzyl protecting group; the overall yield for this two-step process is ~55%. While straightforward, both of these reductions could, in principle, be telescoped into a single, one-pot catalytic hydrogenation step. Replacement of the hydride reduction with a catalytic step would be especially advantageous; in addition to elimination of stoichiometric NaBH4, the current work-up and isolation protocol for the ketone reduction requires multiple laborious liquid-liquid extractions to completely remove inorganic byproducts. Salmeterol, a structurally similar β2-adrenergic agonist can be made using such a tandem reduction strategy with a dual Pd / Pt catalyst.4


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Scheme 1. Synthesis of Salbutamol, with targetted tandem hydrogenation in blue.

Based on this established tandem reduction for synthesis of Salmeterol, we reasoned that a similar strategy could improve the efficiency of Salbutamol synthesis. Herein we describe our efforts to discover an optimal catalyst system, elucidate the various reaction pathways in this tandem hydrogenation reaction, and to use these insights to develp a robust, scalable process that delivers Salbutamol base 3 with equal or superior yield and purity to the current two-step method. In order to achieve this, we applied a combined high-throughput screening and reaction profiling approach to reaction space exploration. As a result of these small-scale studies, this tandem reduction sequence using a Pt/Pd dual catalyst system was demonstrated on 20 g scale with 49% isolated yield after recrystallization.

Results and Discussion.


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The effect of acidity on reaction outcome. In order to rapidly explore the major factors in this tandem hydrogenation reaction, a statistically-driven high-throughput screening approach was enacted. As part of the preliminary analytical work, we carried out synthesis of markers for the various anticipated intermediates and byproducts. Since debenzylation of 1 is rapid relative to ketone hydrogenation (vide infra), the preparation of 2° aminoketone 5 was attempted by subjecting 1 to 1 atmosphere of H2 with a 5% Pd/C catalyst at room temperature in ethanol solvent. After only one hour, 1 was completely consumed, giving a mixture of four products as judged by HPLC analysis.

LC/MS data enabled characterization of this mixture, which

contained compounds 3-6 (Scheme 2, top pathway); these included the desired Salbutamol base (3), as well as the deoxygenated compound (4) and the respective ketone products (5 and 6). Deoxygenation of benzylic alcohols is an unfortunately common reaction of heterogeneous hydrogenation catalysts.5 This uncontrolled reactivity was attributed to the fact that the equivalent of acid in 1 was not neutralized prior to hydrogenation. Subsequent work to prepare a pure sample of 3 followed the two step borohydride reduction, hydrogenolysis process from Scheme 1.

In this case,

debenzylation of 2 was extremely slow under analogous conditions (1 atmosphere H2, 5% Pd/C, room temperature). Addition of one equivalent of acetic acid led to a dramatically accelerated reaction, with no observed formation of the desoxy compound 4 (Scheme 2, bottom). From these simple experiments, it is clear that the acidity of the reaction medium is a major factor in all three types of hydrogenation: the desired debenzylation and ketone reduction, as well as the undesired deoxygenation.


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Scheme 2. Acid strength effects on hydrogenation.

High-throughput screening. Based on the observation of a pronounced acid effect in our preliminary experiments, several rounds of high-throughput screening were designed to modulate acid strength, through both base and solvent identity, as well as investigate the importance of catalyst type. A library containing ~200 heterogeneous catalysts was employed for this purpose. Because Pd/C alone is capable of effecting both debenzylation and ketone hydrogenation, initial screening focused on developing a single-catalyst system for conversion of 1 to 3. H2 pressure was 2-4 barg, and temperature fixed at 30 °C.6 Several key insights were gleaned from these screens, which sought to simultaneously maximize the amount of Salbutamol (3) formed, and minimize the degree of deoxygenation to form 4 and 6. First, that a variety of Pd-based catalysts are effective for dual reduction with


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good selectivity, without the need for added Pt. In many cases, complete conversion can be achieved in as little as 3 hours. Second, that the base used to partially neutralize the HCl salt 1 is critical to achieving high reactivity and selectivity. Strong bases (KOH) induce slow or no hydrogenation, while very weak bases (KOTFA, KH2PO4) promote significant deoxygenation, to the point where in some cases 4 is the major product of the reaction. Organic nitrogen bases (pyridine, N,N-dimethylaniline) reduce reactivity, presumably by reversible inhibition through coordination to Pd sites at the catalyst surface.7 Sodium and potassium acetate (acetic acid pKa = 4.76, aqueous) were identified as desirable bases in terms of both reactivity and selectivity. Third, polar, protic solvents are preferred, with the general reactivity order MeOH > EtOH > iPrOH. Finally, under optimal conditions, the amount of deoxygenation products tracks very closely to the amount of 3 produced, consistently 4-7% when using NaOAc or KOAc. With an effective solvent/base combination identified, we subjected our entire catalyst library to the reaction conditions in an effort to find catalysts that would exhibit decreased deoxygenation relative to standard 5-10% Pd/C systems. From these data, the ~200 catalysts were categorized based on the reactivity observed.6 Unsurprisingly for a library this large and diverse, nearly half of the catalysts achieved 89% 3. In addition to several Pd/C systems, Pd catalysts with alternate supports such as BaSO4, Al2O3, and CaCO3 performed particularly well. These non-carbon supports generally have much lower surface area, leading to lower activity relative to Pd/C;8 however, a reduction in activity could result in greater selectivity. From these ~200 catalysts, ten were chosen for further study (Table 1).

Table 1. Ten standout catalysts from library screen.

Entry Catalyst

1 (%)a

3 (%)a

Mass 5 4+6 Balance (%)a (%)a (%)a

1

5% Pd/C; E196 R/Wb

0.0

91.2

0.0

5.4

96.6

2

5% Pd/C; E213 R/Db

0.0

89.4

3.7

2.8

95.9

3

5% Pd/Al2O3; 5R325c

0.0

92.7

0.0

5.5

98.2

4

5% Pd/CaCO3; 5R405c,d

3.3

87.8

0.0

5.2

96.3

5

5% Pd/BaSO4; 5R29Ac,d

2.1

89.6

0.0

5.0

96.7

6

2% Pd/SiO2-Al2O3; 2R31c

0.0

9.5

83.7

0.0

93.2

7

5% Ru/C; H105 RA/Wb

49.3

0.8

43.3

0.0

93.4

8

5% Ru/Al2O3; 5R698c

23.4

0.9

70.1

0.0

94.4

9

5% Ru, 0.25% Pd/C; 5R611c

31.3

0.6

59.4

0.0

91.3

10

5% Pd/C; E101 NE/Wb

3.0

88.0

0.6

5.9

97.5

a

%Area from HPLC (210 nm), corrected for response factor vs. 3: 1: 1.6; 4: 1.0; 5: 1.2; 6: 1.2. Remaining mass balance is comprised of multiple low-level impurities that were not individually quantified. bEvonik. cJohnson Matthey. d20 wt% catalyst used.


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The effect of water. As shown in Table 1, despite achieving excellent reactivity with a number of systems, levels of the desoxy impurities 4 and 6 were still rather high in reactions that proceeded to completion. As the telescoped hydrogenation would be the penultimate stage of the API synthesis, further reducing the amount of these impurities was desired. As catalyst identity had been fully explored, we then turned to base identity as a method to modulate reactivity and selectivity. While there are countless conjugate bases of organic acids that would provide an appropriate and tunable range of pKa values close to that of acetic acid, use of such bases was deemed undesirable due to the additional costs and purification steps that could result; instead, we investigated solvent composition. We had already established the reactivity order MeOH > EtOH > iPrOH, and the importance of reaction medium acidity provides one possible rationale for these observations: pKa values decrease in more polar media, meaning that the overall [H+] in MeOH is higher than in iPrOH for the same acid.9 Thus, we investigated the effect of using water as a co-solvent with IMS (Industrial Methylated Spirits: 5% MeOH in EtOH) in varying ratios for eight of the catalysts from Table 1.9b Two representative plots of product distribution versus volume of water added are shown in Figure 1, for the Ru and Pd catalysts from Table 1, entries 8 and 10 respectively.


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Figure 1. Plot of % area (HPLC, 210 nm, corrected for response factor vs. 3) versus water content for the hydrogenation of 1 with 5% Pd/C (E101 NE/W, top) and 5% Ru/Al2O3 (5R698, bottom). Clearly, increasing water content has a dramatic effect on reactivity, leading to much higher conversions to 3 in the case of 5% Pd/C (Figure 1, top), and 5 in the case of 5% Ru/Al2O3 (Figure 1, bottom). Each of the eight catalysts behaves differently in this experiment; however, one striking commonality is that all of the systems operate better with some amount of added water. On average, an IMS:water ratio of about 1:1 appears optimal; this is likely due to a compromise between increasing acid strength and maintaining the solubilities of 1 and the various intermediates. While water clearly has a positive effect on reactivity, its influence on


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selectivity is not as pronounced. In several cases, as the water content is increased, the total area of all impurities observed by HPLC-UV/Vis decreases; however, the total amount of desoxy impurities (4 + 6) remains effectively constant. Reaction Profiling of Pd-catalyzed hydrogenation.

The consistent formation of small

amounts of deoxygenated compounds 4/6 under a wide range of conditions prompted a mechanistic investigation of the hydrogenation process through reaction progress analysis. Time-course plots of the concentrations of 1-6 were generated by HPLC analysis of aliquots withdrawn from the reaction mixture while maintaining stirring under an atmosphere of H2 (mesitylene was used as an internal standard). Initially, the hydrogenation of 1 (1.0 g) with a lower loading of 5% Pd/C E101 NE/W (20 mg, 2 wt% versus 1) was studied in order to determine if less catalyst could be used upon scale-up. Following the progress of this reaction reveals rapid debenzylation of 1 to give ketone 5, with a zero-order dependence on [1] (kobs = 5.51 x 10-3 M min-1; Figure 2). This is likely due to both very rapid amine debenzylation, and the low H2 pressure used for these experiments (1 atm); stir-rate studies to assess mass-transport effects were not explored. Under these conditions, further reduction of 5 to give 3 is not observed, even over extended reaction times. While this result is disappointing, deoxygenation to 4 or 6 is also not observed; thus, a low-loading of Pd could be used as a selective debenzylation component in a dual-catalyst process if a suitable ketone hydrogenation system could be identified (vide infra).


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Figure 2. Plot of normalized concentration versus time (using mesitylene as internal standard), for the hydrogenation of 1 at 30 °C and 2 wt% charge of 5% Pd/C, clearly showing zero-order dependence on [1] for the debenzylation reaction.

In order to collect reaction progress data on the entire hydrogenation process, a higher loading of 5% Pd/C (10 wt% versus 1) was used under analogous reaction conditions; the time-course profiles and various expansions are shown in Figure 3. Several key insights have resulted from this single experiment. First, debenzylation is again rapid and zero-order in [1] (Figure 3, top right), with a rate of 7.66 x 10-5 M min-1; the similar rates observed for debenzylation using 2 wt% and 10 wt% catalyst loadings are consistent with mass-transport limited kinetics for the debenzylation. Second, ketone hydrogenation does not occur until debenzylation is complete. This completely step-wise reactivity can be explained by the much slower initial rate of ketone hydrogenation (6.08 x 10-4 M min-1), which is an order of magnitude less than debenzylation. Alternatively, the starting material 1 may be more strongly bound to the catalyst surface than intermediate 5, which would result in negligible rates of ketone hydrogenation until all of bound 1 is consumed. Third, the rate dependence on [3] for ketone hydrogenation is slightly less than first order, with the reaction proceeding too quickly at high conversion for simple exponential


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decay (Figure 3, bottom left). Fitting the first 1.5 half-lives of [3] to a first-order mechanism gives good correlation, while the overall reaction order appears to be complex, and empirically is ~0.8 by double-ln plot analysis.6 This non-integer overall order could be due to changing acidity over the course of the reaction (since the system is not strictly buffered, and the pKa values of 1H+, 3-H+, and 5-H+ are not exactly the same), and/or substrate-inhibition of the ketone hydrogenation process. This latter possibility could result from catalyst surface saturation by adsorbed 5, with dissociation of 5 required to reveal Pd sites for H2 activation.

Figure 3. Top left: full plot of normalized concentration versus time for the hydrogenation of 1 at 30 °C and 10 wt% charge of 5% Pd/C. Top right: expansion of debenzylation of 1 to give 5. Bottom left: expansion of hydrogenation of 5 to give 3. Bottom right: expansion of


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deoxygenation products, showing that all deoxygenation occurs from 5, with 3 stable under the reaction conditions. Finally, and perhaps most importantly, the formation of 4 and 6 only occurs from deoxygenation of the ketone intermediate (Figure 3, bottom right). Compound 4 is formed by hydrogenation of the ketone in 6, and not by direct deoxygenation of 3; in fact, compound 3 is very stable under the reaction conditions, with no increase in deoxygenation observed over a reaction time of more than 30 hours. We note that this result is not consistent with previous observations that electron-donating groups on the aryl ring accelerate deoxygenation,5a whereas in our case, converting an electron-withdrawing ketone into an electron-donating benzyl alcohol shuts down deoxygenation activity. This is a significant result, as the risk of over-reduction under these conditions once the reaction is complete is negligible. In addition, the rate of the deoxygenation process clearly depends on [5], so it should be possible to minimize deoxygenation through rapid ketone hydrogenation. Scheme 3 summarizes the possible and observed pathways deduced.


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Scheme 3. Possible and observed reaction pathways in the Pd-catalyzed hydrogenation of 1, with non-operative pathways in grey.

Because of the possibility of substrate-inhibition in the conversion of 5 to 3, and the need to more rapidly consume 5 to reduce deoxygenation, the hydrogenation of 1 was carried out at 55 °C and monitored over time. If desorption of 5 from the catalyst surface is necessary to effect reduction, increasing reaction temperature should further increase the reaction rate by shifting the adsorption/desorption equilibrium toward desorption, and thus decreasing inhibition. Increasing temperature will also shift the acid/base equilibria to increase acidity, which should also result in a faster reaction. Comparing the initial rates of ketone hydrogenation at 30 °C and 55 °C reveals a greater than 8-fold increase, and a switch in reaction order from nearly first-order in [5] to effectively zero-order in [5] (Figure 4). This means that the elementary steps of ketone hydrogenation have increased in rate such that the reaction is now hydrogen-limited, likely


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resulting from mass-transfer limitations. Rather than reaching completion in ~10 hours at 30 °C, conversion to 3 is now complete in only one hour. Unfortunately, the degree of deoxygenation is slightly worse under these conditions, with 4 at 9% by HPLC, even though the initial rate of deoxygenation is only 1.4x faster than at 30 °C.

This is because deoxygenation has also

switched to zero-order in [5], and therefore the ratio of 3 to 4+6 simply depends on the relative initial rates of ketone reduction and deoxygenation, rather than the concentration dependences observed at lower temperature. This is a key observation for further reaction development, in that an increase in reaction temperature must be accompanied by an increase in H2 pressure to avoid global mass-transfer limited kinetics. Finally, despite the more forcing conditions, 3 is still stable toward deoxygenation, with all deoxygenation occuring from intermediate 5.

Figure 4. Left: full plot of normalized concentration versus time for the hydrogenation of 1 at 55 °C, showing zero-order dependence on [5] for ketone reduction. Right: expansion of deoxygenation products, showing zero-order dependence on [5], and that all deoxygenation still occurs from 5. Development of a dual catalyst system.

One method to further decrease the rate of

deoxygenation is to employ a dual-catalyst process.

This system would ideally exhibit

orthogonal reactivity: one catalyst should have low enough activity to only achieve


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debenzylation, and the second catalyst should be able to reduce the ketone while minimizing deoxygenation pathways. Based on the data collected in the comprehensive catalyst library screen, several promising candidates were investigated. From the reaction profiling experiments, it was apparent that reducing the loading of 5% Pd/C to 2 wt% would achieve selective debenzylation; low-loading 1% Pd/C catalysts also appeared promising, as did the 5% Ru/Al2O3 system. In order to identify suitable ketone hydrogenation catalysts, a series of high-throughput screens were designed to evaluate 48 Pt-based catalysts alongside several Pd- and Ru-based debenzylation systems.

Examining various reaction conditions, including solvent and base

identity, revealed that these dual catalyst systems operate best under the same general conditions as the Pd-only process, namely 1:1 IMS/water solvent, and KOAc as the base. This is a key outcome, as development of many tandem catalyst systems are plagued by incompatibilities and reaction rates that are not well-matched.10 Another key observation is that the Pt-catalysts investigated appear to perform ketone hydrogenation much more efficiently after Ndebenzylation. Control experiments with only Pt-catalysts under analogous conditions gave modest conversion of 1 to the alcohol 2 (~15-20%), with minimal formation of 3 by debenzylation; in contrast, many dual catalyst systems achieve complete conversion to 3 in the same length of time.6 Data from several high-throughput screens were collated, and ten stand-out Pt-based catalysts were chosen for further investigation. Table 2 details the results of pairing these ten Pt systems with a 1% Pd/C catalyst under the previously optimized conditions. Clearly, these dual catalyst systems exhibit superior selectivity to the Pd-only reactions: typical desoxy content with the Pdonly system was 4-7%, whereas with a dual Pd/Pt system, as low as 1.2% deoxygenation can be


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achieved. In addition to dual Pd/Pt systems, we also investigated use of the aforementioned 5% Ru/Al2O3 catalyst as the debenzylation component. To the best of our knowledge, Ru-based catalysts are not reported to be applicable to selective N–Bn hydrogenolysis; however, this particular catalyst works well, even at modest H2 pressure. While control experiments revealed that debenzylation with 5% Ru/Al2O3 does not occur at 1 atmosphere H2, increasing to only 1.5 barg enables catalysis. hydrogenation of 1.

Table 3 outlines the results of tandem Ru/Pt catalysis for the

Once again, the levels of deoxygenation are lower than for Pd-only

reactions, though not as low as for the Pd/Pt systems (Table 2); however, the ruthenium screening results were obtained at lower H2 pressure, which may lead to lower selectivity. Table 2. HTS results for dual Pd/Pt catalyst systems.

Entry Pt Catalyst

3 5 4+6 1 (%)a (%)a (%)a (%)a

Mass Balance (%)a

1

5% Pt/C; F105 N/Wb

0.0

91.2

1.5

2.8

95.5

2

5% Pt/C; F1015 RE/Wb

0.0

89.0

2.7

2.4

94.1

3

5% Pt/Al2O3; 5R94c

0.0

94.1

1.7

2.0

97.8

4

3% Pt/C; B103032-3d

0.0

90.3

2.1

2.6

95.0

5

1% Pt/C; 1.5R199c

0.2

91.2

1.2

1.2

93.8

6

5% Pt/C; 78-1611e

0.3

91.1

1.6

2.5

95.5

7

1% Pt/C; 38313f

0.0

92.9

0.9

1.7

95.5

8

3% Pt/C; 38317f

0.0

93.2

1.0

1.9

96.1


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9

1% Pt/C; F1525 KT/Wb

0.0

91.0

2.3

1.3

94.6

10

5% Pt/C; F101KYA/Wb

0.0

93.8

0.9

2.1

96.8

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a

%Area from HPLC (210 nm), corrected for response factor vs. 3: 1: 1.6; 4: 1.0; 5: 1.2; 6: 1.2. Remaining mass balance is comprised of multiple low-level impurities that were not individually quantified. bEvonik. cJohnson Matthey UK. dJohnson Matthey US. eStrem. fAlfa Aesar. Table 3. HTS results for dual Ru/Pt catalyst systems.

Entry Pt Catalyst

Mass 1 3 5 4 + 6 Balance (%)a (%)a (%)a (%)a (%)a

1

5% Pt/C; F105 N/Wb

0.0

89.0

0.8

3.6

93.4

2

5% Pt/C; F1015 RE/Wb

0.0

89.2

0.5

4.0

93.7

3

5% Pt/Al2O3; 5R94c

0.0

93.6

0.5

3.5

97.6

4

3% Pt/C; B103032-3d

0.5

89.3

1.2

3.0

94.0

5

1% Pt/C; 1.5R199c

1.1

88.9

2.0

2.7

94.7

6

5% Pt/C; 78-1611e

3.5

82.8

4.9

3.4

94.6

7

1% Pt/C; 38313f

2.2

87.3

3.2

1.9

94.6

8

3% Pt/C; 38317f

2.4

86.6

3.1

2.4

94.5

9

1% Pt/C; F1525 KT/Wb

1.4

71.0

20.3

2.3

95.0

10

5% Pt/C; F101KYA/Wb

1.6

89.1

2.2

2.6

95.5

a

%Area from HPLC (210 nm), corrected for response factor vs. 3: 1: 1.6; 4: 1.0; 5: 1.2; 6: 1.2. Remaining mass balance is comprised of multiple low-level impurities that were not individually quantified. bEvonik. cJohnson Matthey UK. dJohnson Matthey US. eStrem. fAlfa Aesar.


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Scale-up and isolation. Once this detailed picture of the hydrogenation pathways and catalyst suitability was obtained through high-throughput experimentation and small-scale reaction profiling experiments, our efforts shifted to scale this chemistry and develop a process to isolate and purify 3. During the course of process optimization, it became apparent that removal of the inorganic salt impurities would be a considerable challenge. KCl has non-negligible solubility in ethanol/water mixtures;11 thus, use of even modest IMS/water ratios during the reaction severely complicates isolation.

Furthermore, upon neutralization to generate the free base of 3, an

equivalent of KOAc is generated, which has significant solubility even in water-free ethanol.12 Ordinarily, salts could be removed by water washes; however, 3 is very water-soluble, even in its neutral form. Thus, alternate reaction conditions are required for a feasible process. Using the insights gained as a result of high-throughput screening and mechanistic studies, we evaluated substoichiometric inorganic carbonate bases to achieve a similar reaction acidity to that using KOAc, and used IMS as the sole reaction solvent. Because the absence of water was anticipated to dramatically reduce the reaction rate, the temperature was raised to 45 °C, and catalyst loadings increased to compensate. Based on the reaction progress data from Figure 4, even a small temperature increase should lead to a substantial rate increase. Table 4 summarizes the key results from these experiments, with 0.25 equivalents of K2CO3 as the optimal base. While the reactions do not reach complete conversion in 10 hours, the selectivity is increased, with ~1% deoxygenation observed. It should be noted that while these reactions do not have water as a co-solvent, there is undoubtedly some water present as a result of acid neutralization, and as part of the catalysts (supplied as 50% w/w water).


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Page 22 of 30

Table 4. Substoichiometric K2CO3 as a base.

Entry Catalysts

1 3 5 4+6 (%)a (%)a (%)a (%)a

Mass Balance (%)a

0.2

76.0

19.1

1.4

96.7

1.1

90.1

4.9

1.0

97.1

6.8

57.9

30.8

0.6

96.1

6.3

84.8

3.9

0.5

95.5

1% Pd/C; 38293b 1

5% Pt/Al2O3; 5R94c 1% Pd/C; 38293b

2

3% Pt/C; 38317b 5% Ru/Al2O3; 5R698c

3

5% Pt/Al2O3; 5R94c 5% Ru/Al2O3; 5R698c

4

3% Pt/C; 38317b a

%Area from HPLC (210 nm), corrected for response factor vs. 3: 1: 1.6; 4: 1.0; 5: 1.2; 6: 1.2. Remaining mass balance is comprised of multiple low-level impurities that were not individually quantified. bAlfa Aesar. cJohnson Matthey UK.

With confidence that a “water-free” reaction would still progress with a reasonable rate, we scaled-up the conditions from Table 4, entry 2 for a 20 g demonstration run (eq. 1). The hydrogenation was performed for 23 hours in order to ensure complete conversion of 1. Upon


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reaction completion, the catalyst mixture and inorganic salts were removed by a simple filtration. Recrystallization of the resulting crude product from an IMS/EtOAc system afforded 3 in 49% isolated yield, with

A Combined High-Throughput Screening and Reaction Profiling

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