Stereoretentive Etherification of an Î±-Aryl-Î²-amino Alcohol Using a

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Stereoretentive Etherification of an #-aryl-#-amino-alcohol using a Selective Aziridinium Ring Opening for the Synthesis of AZD7594 Angus Erland McMillan, Alan Steven, Ian W. Ashworth, Alexander K. Mullen, Lai Chun Chan, Maria Rita Galan Espinosa, Michael John Pilling, Steven Anthony Raw, and Martin F. Jones J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01062 • Publication Date (Web): 19 Jun 2018 Downloaded from http://pubs.acs.org on June 19, 2018

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The Journal of Organic Chemistry

Stereoretentive Etherification of an α-aryl-β-amino-alcohol using a Selective Aziridinium Ring-Opening for the Synthesis of AZD7594 Angus E. McMillan,†* Alan Steven,‡ Ian W. Ashworth,‡ Alexander K. Mullen,‡* Lai C. Chan,‡ Maria Rita Galan Espinosa,‡ Michael J. Pilling,‡ Steven A. Raw‡ and Martin F. Jones‡ †

Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093 Zürich, Switzerland

[email protected] ‡

Global Chemical Development, Pharmaceutical Development, AstraZeneca, Macclesfield Campus, Macclesfield, SK10 2NA, U.K. [email protected]

ABSTRACT: A selective aziridinium ring-opening was used to etherify an α-aryl-β-amino-alcohol with stereochemical retention. This transformation was achieved in a biphasic system to address phenoxide solubility and the formation of a sulfonate ester impurity. The protecting group strategy was directed by a stability study of the activated α-aryl-β-amino-alcohol in this system. Process analytical techniques were used to establish reaction understanding and mixing on large scale was modelled in silico. The process provided a selective and efficient method of preparing the non-steroidal, inhaled selective glucocorticoid receptor modulator, AZD7594.

INTRODUCTION AZD7594 (1) is a non-steroidal, inhaled selective glucocorticoid receptor modulator (i-SGRM) under development as a once daily treatment of asthma with a secondary indication for the treatment of chronic obstructive pulmonary disease.1 A route was required for the commercial manufacture of this active pharmaceutical ingredient. In order to develop a highly convergent synthesis of AZD7594, an efficient and selective method of aryl etherification using the readily accessible αaryl-β-amino-alcohol 3 was required (Scheme 1).2 Scheme 1. Retrosynthetic disconnection of AZD7594

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The aryl etherification of an α-aryl-β-amino-alcohol affords a structural motif which is present in several biologically active compounds such as: related drug candidate AZD5423 (5),3 scytalone dehydratase inhibitor 64 and natural products 7-95 (Figure 1). Efficient methodologies for assembly of this motif are therefore welcome.

Figure 1. AZD5423 (5), scytalone dehydratase inhibitor (6), discarine C (7) D (8) and miryathine A (9).

There are currently two strategies for the aryl etherification of α-aryl-β-amino-alcohols: arylations which form the aryl ether bond and alkylations which make the alkyl ether connection (Scheme 2). A commonly utilized approach to the arylation strategy is a copper catalyzed coupling of an α-aryl-β-aminoalcohol (10) with an aryl halide.6 Etherification can also be achieved from similar substrates using an SNAr reaction but this approach is limited in its scope due to the electronic requirements of the aryl halide.7 Both these methods are stereoretentive with respect to the α-aryl-β-amino-alcohol. Scheme 2. Approaches to etherifying α-aryl-β-aminoalcohols

When considering the formation of the alkyl ether bond by means of an intermolecular alcohol displacement with a phenol, a competing intramolecular cyclization must be contended with. Under Mitsunobu conditions,8 compounds such as 10 cyclize to afford an aziridine (14).9 Approaches which facilitate an intermolecular alcohol displacement include protecting the amine as a carbamate (11) and out-competing the cyclization with a large excess (20 eq.) of the phenol.10 An alternative strategy to facilitating direct displacement involves the use of a cyclic sulfamidate (12) which can be formed by oxidizing the cyclization product of 11 and thionyl chloride.11 N-methyl derivatives of 12 have been shown to undergo ring-opening with phenols, therefore compounds such as 12 may enable access to 13.12 Both the Mitsunobu and cyclic sulfamidate approaches react via direct displacement which results in stereochemical inversion. By cyclizing analogues of 10 to aziridines 14 and 15 then ringopening with a phenol, α-aryl-β-amino-alcohols can be etheri-

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fied with retention (through double inversion) of stereochemistry. The ring-opening of non-activated aziridines (14) with phenols is known with less functionalized molecules13 however, this approach is unprecedented in the case of aziridines derived from α-aryl-β-amino-alcohols. More commonly, aziridines are activated as a phosphon- or sulfon-amide (15) prior to ring-opening. This approach has been successfully used to etherify optically active α-aryl-β-amino-alcohols.14 In the case of AZD7594, stereoretentive approaches are favored as they utilize stereoisomer 3 which is accessible from an anti-selective asymmetric Henry reaction15 or in high stereochemical purity from (S)-alanine.2 The copper-catalyzed arylation method was employed in the divergent synthesis which led to the discovery of AZD7594, however, the transformation was low yielding and required chromatography, making the approach unsuitable for large scale production.16 Accordingly, efforts were initially focused on previously established stereoretentive etherification methods, primarily aziridine ringopenings.

RESULTS AND DISCUSSION AZIRIDINE BASED ETHERIFICATION Aziridine 19 was prepared from 3 using a modified Wenker synthesis (Scheme 3).17 Heating an equimolar mixture of 19 and 4 in tert-amyl alcohol to 160 °C in a sealed microwave reactor resulted in complete consumption of 19 after 8 hours. The yield of this reaction was limited by the formation of a range of N-alkylated oligomers of 20, identified from the ion extracted chromatogram. It was thought that compound 23 may represent an aziridine analogue which would not undergo N-alkylation. Activation of 21 with methanesulfonyl chloride resulted in O-cyclization to afford oxazoline 22. The desired N-cyclization product (23) was not detected; however, it was unclear whether this species could be accessed via an alternative route. When 19 was treated with 2,2-difluoropropanoyl chloride, only 22 was isolated, indicating that the N-acyl-aziridine 23 readily underwent a Heine reaction to produce 22.18 Attempts to ring-open oxazoline 22 in a productive manner were unfruitful. N-Nosyl protection of 3 presented an attractive option as this approach has successfully been used with a related substrate14 and as the subsequent deprotection was expected to be facile.19 Activating 16 through mesylation and treatment with an aqueous solution of the lithium salt of 4 afforded the desired aryl ether 18 in low yield. Examination of the ion extracted chromatogram at reaction completion revealed the presence of an isomeric impurity. Characterization by NMR spectroscopy revealed that this impurity (24) was not in fact a diastereomer, but material in which the C4 of indazole 4 had been alkylated. It proved straightforward to remove the p-nosyl group from 18 to reveal 19, however as with the other aziridine approaches investigated, issues with the etherification step made this route unfavorable. Scheme 3. Aziridine approaches to etherification


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The Journal of Organic Chemistry an AZD7594 precursor. From the aziridine studies, it was noted that 4, had particularly low solubility in organic solvents, with the exception of polar aprotics. The use of polar aprotics in manufacture is not desirable due to the difficulties associated with solvent removal and their potential toxicities.22 It was anticipated that 4 would exhibit high aqueous solubility as a phenoxide anion and so a biphasic system using an aqueous hydroxide solution for the aziridinium coupling was sought. Compounds 25 and 26 were readily prepared by N-alkylation and isolated as their hydrochloride salts. An investigation into the mesylation then hydrolysis of these compounds was then conducted (Scheme 4). Scheme 4. Preparation, mesylation and hydrolysis of Nalkyl-α-aryl-β-amino-alcohols

a) NsCl, 2-MeTHF, DIPEA b) MsCl, TEA, 2-MeTHF c) DBU, 4, DMF d) 1-octanethiol, 2-MeTHF, nBu4NBr, aq. LiOH e) T3P, 2, TEA, DCM f) i) ClSO3H, MeCN f) ii) NaOH, PhMe g) 4, tert-amyl alcohol 160 °C h) 2, T3P, DCM, TEA i) MsCl, TEA, 2-MeTHF j) 2,2-difluoropropanoyl-chloride, TEA, PhMe k) 4, tert-amyl alcohol, 160 °C

AZIRIDINIUM BASED ETHERIFICATION As previously established stereoretentive etherification methods proved ineffective, the ring-opening of an aziridinium species derived from 3 was considered. Aziridinium ions are known to be versatile electrophiles, reacting with a range of nucleophiles in a regio- and stereo-specific manner.20 The formation and ring-opening of aziridinium ions with phenols has been used as a strategy in macrocycle formation.21 Selection of a suitable N-alkyl group would enable the product of an aziridinium ring-opening reaction to be deprotected, affording

a) i) RBr, K2CO3, MeCN a) ii) HCl b) MsCl, TEA, 2-MeTHF c) aq. NaOH d) EtOH

The mesylation of 26 was monitored with in situ attenuated total reflectance fourier transformed infrared (ATR-FTIR) spectroscopy (absorption at 1232 cm-1 assigned to 28) and high pressure liquid chromatography (HPLC) using an ethanol quench of the active species to afford a measurable surrogate, 32 (Figure 2). These methods gave consistent reaction profiles, validating the use of ethanol quenching in further reaction monitoring. Solutions of 27 and 28 in 2methyltetrahydrofuran were prepared and then treated with sodium hydroxide. Hydrolysis was seen to return the initial diastereomers of 25 and 26, indicating that hydrolysis occurred via aziridinium ions 29 and 30 rather than directly through mesylates 27 and 28 (Scheme 4). This observation is consistent with previous reports23 and supported the notion that etherification could be achieved with stereochemical retention.



Figure 2. Reaction monitoring from the mesylation of 26 using ATR-FTIR and HPLC. Reaction carried out at 0 °C with a dump charge of 2.3 eq. of MsCl. The initial concentration of 26 was 0.113 mmol/mL of 2-MeTHF.

ATR-FTIR spectroscopy was also used to observe the consumption and quenching of methanesulfonyl chloride (absorption at 1177 cm-1). An excess of methanesulfonyl chloride was required to achieve complete mesylation of 25 and 26 in desirable solvent systems. If the excess of this reagent is not quenched, it reacts with phenol 4 to produce a potentially genotoxic sulfonate ester, 33 (Figure 3).24 Water washes did not prove effective at quenching the excess methanesulfonyl chloride, however, addition of an aqueous sodium hydroxide solution (2 mol/L) provided rapid and complete hydrolysis, adding further utility to the choice of a biphasic reaction media.

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Figure 4. Hydrolysis study of 27 and 28 (assessed using quenching to surrogates 31 and 32) in a 1.16 : 1 mixture of 2-MeTHF and 2.0 M NaOH at 0 °C. Initial concentration of 25 and 26 (used to synthesis 27 and 28) was 0.075 mmol/mL of 2-MeTHF.

The reaction is expected to be an extractive process in which the partition of the mesylates from the organic phase into the aqueous phase is coupled with their subsequent cyclization to the aziridinium ions 29 and 30, which then rapidly hydrolyze (Scheme 5). Fitting the profile for the level of 27 remaining (analysed as 31) to first order kinetics gave a reasonable fit with an observed rate constant of kobs, = 3.1×10-2 min-1.27 A similar analysis of the rate of loss of 28 (analysed as 32) assuming first order kinetics gave a significantly lower rate constant of 1.2×10-3 min-1 implying that the hydrolysis of 27 is 25 times faster than 28. Scheme 5. Proposed mechanistic scheme for the extractive hydrolysis of 27 and 28

Figure 3. An impurity formed by reaction of 4 with excess methanesulfonyl chloride.

To enable the quenching of residual methanesulfonyl chloride with sodium hydroxide on large scale, a hydrolysis resistant mesylate species was required. Accordingly, a stability study of 27 and 28 was conducted. This experiment was carried out in an Mettler Toledo EasyMax102 reactor to allow the mixing rate and temperature to be controlled accurately for extended periods of time.25 An equimolar solution of 27 and 28 was prepared in 2-methyltetrahydrofuran, washed with water and then combined with aqueous sodium hydroxide (2 mol/L, 11 eq.) at 0 °C. Samples were taken using a Mettler Toledo EasySampler1210 to enable consistent sampling of a biphasic mixture.26 These aliquots were quenched with ethanol to afford 31 and 32 which were then analysed by HPLC using the internal standard (IS) biphenyl ether. Figure 4, derived from the normalized area counts, shows that 27 hydrolyses significantly faster than 28.

25, 27, 29 R = allyl, 26, 28, 30 R = Bn, KP1 partition coefficient for 27/28, k the rate constant for aziridinium ion formation, KP2 partition coefficient for 25/26

This difference in reactivity is somewhat surprising considering the structural similarity of 25 and 26. However, the extractive nature of the reaction means that the partition of 27 and 28


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into the aqueous phase is coupled with their hydrolysis reactions. Therefore, differences in the partition coefficients (KP1) of 27 and 28 will be reflected in the observed rate constants. An estimate of the relative partition behavior of 27 and 28 was obtained by calculating and comparing their cLogP values.28,29 The calculated values of 3.56 and 5.38 for 27 and 28 suggests that the partition of 27 into water will be favored relative to 28 by a factor of approximately 50. A more system specific30 prediction of the partition coefficients of 27 and 28 between 2-methyltetrahydrofuran and water using COSMOtherm31 gave log KP values of 4.7 and 6.6, which show a similar relative difference. The magnitude of the difference in the partition coefficients of 27 and 28 is consistent with it being responsible for the greater hydrolytic stability of 28 relative to 27. This investigation supported the idea that 28 in 2methyltetrahydrofuran could be washed with a hydroxide solution to quench excess methanesulfonyl chloride prior to the addition of 4 without significant hydrolysis. With 28 selected as a suitable intermediate, the cyclization and ring-opening to afford 34 was trialed (Scheme 6). Phenol 4 was found to exhibit high solubility in aqueous lithium hydroxide, enabling it to be conveniently dosed and purged. The washing of 28 in 2-methyltetrahydrofuran with aqueous sodium hydroxide prior to addition of 4, proved effective at preventing the formation of impurity 33. The etherification of 26 was successfully achieved with complete conversion and high selectivity. No C4 coupling occurred, however, a small quantity (2 area%) of material identified from the ion extracted chromatogram as being consistent with the N-alkylation of 34 was observed. Scheme 6. Etherification of 28 with 4

a) i) MsCl, TEA, 2-MeTHF a) ii) H2O a) iii) NaOH b) 4 (1.10 eq.) in 5 w/w LiOH at 0 °C

To gain further reaction understanding, the coupling of 28 and 4 was monitored using attenuated total reflectance ultraviolet (ATR-UV) spectroscopy. A decreasing trend in the absorbance at 352 nm, ascribed to the anion generated by the deprotonation of 4 at oxygen, was clearly visible in the data (Figure 5). Fitting the entire data set for consumption of 4 (352 nm) to first order kinetics gave a relatively poor fit as the initial portion of the profile shows a linear decrease in absorbance with time.32 A possible explanation of this behavior is that the experiment was operated under conditions that were on the boundary between the reaction being under mass transport and chemical rate control.33 In the early portion of the reaction the cyclization of 28 to give 30 consumed 28 faster than it could be replenished by transfer from the 2-methyltetrahydrofuran phase, meaning that the transport of 28 between the phases at least partially controlled the rate of formation of 30 and hence disappearance of 4. Discarding the first 10000 seconds of the profile data resulted in a good fit to first order kinetics with a rate constant of 8.1×10-3 min-1, suggesting that the later stages of the reaction were under chemical rate control.

Figure 5. Monitoring the consumption of 4 with ATR-UV spectroscopy in a 1.14: 1 mixture of 2-MeTHF and 5% w/w LiOH at 0°C. The initial concentration of 4 was 0.139 mmol/mL of LiOH.

The observed first order kinetics for the coupling of 28 with 4 are consistent with the hypothesis that the reaction proceeds via the rate limiting formation of an aziridinium ion (Scheme 7). A slow reaction between 30 and 4 would give rise to second order kinetics and the formation of the aziridinium ion is prerequisite of the observed stereoselective formation of 34. The first order kinetics obtained for the consumption of 4 in the later stages of the reaction suggest that 4 is effective at outcompeting water and hydroxide, as a deviation from first order kinetics would be expected if this were not the case. Analysis of the 2-methyltetrahydrofuran phase has ruled out the transfer of significant levels of 4 into this phase, meaning that it is unlikely that the formation of 34 occurs in the 2-methyltetrahydrofuran phase. Combining this learning leads to an extractive reaction model for the formation of 34 by the coupling of 28 and 4, which proceeds through rate limiting formation of aziridinium ion 30. Scheme 7. Proposed mechanistic scheme for the formation of 34 via an extractive reaction involving an aziridinium ion intermediate

KP1 partition coefficient for 28, k the rate constant for aziridinium ion formation, KP2 partition coefficient for 34.



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When operating under chemical rate control the partition of 28 should be at equilibrium meaning that the reaction kinetics should be described by Equation 1, where k is the rate constant for the cyclization of 28 in the water rich phase and KP is the partition coefficient for 28. Comparing the rate constant for the consumption of 28 when reacting with 4 in the biphasic system (8.1×10-3 min-1) with its rate of hydrolysis, (1.2×10-3 min-1) shows the coupling reaction to be slightly faster. As the rate controlling process in both cases is the formation of 30 the rate constants should be similar if the conditions are similar. The observed difference is believed to arise from the use of lithium rather than sodium hydroxide. This gives rise to a differing salting out effect and therefore modifies KP.34 (1)35

!" #,%&

()*+ !" #,%&

As the coupling of 28 and 4 is an example of an extractive reaction, its performance has the potential to be affected by mass transfer as previously described. To address concerns over the mixing of a biphasic system on plant scale, the modeling tool DynoChem was used to scale the power per unit mass used by the impeller of a 2 L vessel up to a 1000 L vessel.36 The reaction was seen to perform well with an impeller speed of 250 rpm in a 2 L reactor. This corresponded to a 71 rpm impeller speed on a 1000 L vessel with an operating range of 55-110 rpm. The DynoChem results also indicated that the droplet size would be decreased on large scale providing a positive effect on mass transport. It was therefore concluded that mixing on plant scale was feasible, however, further work would be required when selecting a specific reactor for manufactures. Compound 34 is an amorphous solid, accordingly, a telescope into the deprotection step was developed (Scheme 8). After the washing of 28 in 2-methyltetrahydrofuran with water and sodium hydroxide, 4 was introduced in a solution of sodium hydroxide rather than lithium hydroxide. This was seen not to decrease the quality of the material produced and improved the manufacturability of the process. Compound 34 underwent a reductive debenzylation to afford 20 which was isolated from a reactive crystallisation with 2-furoic acid. The isolation of this salt created a point of control, providing efficient purging of the previously mentioned N-alkylation impurity of 34. The final amide coupling to afford AZD7594 (1) was then achieved using CDI. The absolute stereochemistry of 1 was confirmed using a chiral HPLC method, validated against all eight stereoisomers. The undesired enantiomer did not exceed the limit of detection (0.05 area%) representing an enantiomeric excess of >99.9% and the measurement of diasteromeric excess (99.3% de) was consistent with the output material from the etherification (99.4% de). Scheme 8. Process description diagram for the etherification process and amide coupling

a) MsCl, TEA, 2-MeTHF b) H2O c) NaOH d) 4 in NaOH e) H2 Pd/C, TFA f) filter, aq. K2CO3 g) 2-furoic acid h) 2, CDI, TEA, 2MeTHF

CONCLUSIONS Previously established stereoretentive methods of etherifying α-aryl-β-amino-alcohols were found to be unsuitable for the manufacture of AZD7594, instead a double inversion approach using an aziridinium species was successfully developed. N-Alkylation of an α-aryl-β-amino-alcohol was used to introduce readily removable protecting groups. A biphasic system was utilized to eliminate issues with phenol solubility and the formation of a potential genotoxic impurity. Protecting group selection was directed with a stability study of the dibenzyl and diallyl mesylate intermediates which found their hydrolysis rate constants in this system to be 1.2×10-3 min-1 and 3.1×10-2 min-1 respectively. Calculation of clogP values indicated that dibenzyl protection provided a hydrolysis resistant mesylate species as a result of a partitioning effect. A high yielding and diastereoselective process using phenoxide ring-opening of an aziridinium ion for etherification was developed and studied using ATR-UV. In silico modeling of mixing showed that the process would not be negatively impacted by scaling effects. The identification of this aziridinium ring-opening strategy allowed the development and implementation of a selective and scalable manufacturing route concept for AZD7594.

EXPERIMENTAL SECTION General. NMR spectra were recorded on Bruker instruments with tetramethylsilane (TMS) as internal reference. Chemical shifts are


Page 7 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


expressed in ppm (δ) relative to TMS, coupling constants (J) are in Hz. Infrared spectra were recorded with diamond ATR sampling on an FTIR spectrometer using powdered samples. DSC and melting point data were acquired on a Q2000-2339 from TA Instruments. TGA data were acquired on a TGA Q5000 from TA Instruments. High resolution mass spectra were recorded using positive ion electrospray ionization on a QTOF coupled to a Waters UPLC. Compounds 3 and 4 were prepared according to previous reports.2,16 Unless stated otherwise, commercial grade materials were used. 3-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)-N((R)-tetrahydrofuran-3-yl)benzamide (1). Compound 20 (3.41 g, 93.5 mass%, 5.09 mmol) was dissolved in an aqueous solution of potassium carbonate (100 mL, 200 mmol, 2 mol/L) and extracted in 2-methyltetrahydrofuran (100 mL). The organic phase was washed with sodium chloride solution (2 x 25 mL, 20 mass%) and concentrated to afford a white foam. Carbonyldiimidazole (1.79 g, 11.0 mmol) and 2-methyltetrahydrofuran (30 mL) were added to an 80 mL jacketed vessel. The slurry was stirred at 22 °C then heated to 42 °C. 2,2-Difluoropropanoic acid (22.56 g, 97 mass%, 22 mmol) was dissolved in 2-methyltetrahydrofuran (10 mL) and added over 2.5 h using a syringe pump. The reaction was cooled to 25 °C and triethylamine (0.8 mL, 6 mmol) was added. The previously isolated white foam was dissolved in 2-methyltetrahydrofuran (13 mL) and added. After 1 h, water (20 mL) and MeCN (10 mL) were added. Two phases formed, the organic phase was collected and then the aqueous layer was washed with 2-methyltetrahydrofuran (2 x 10 mL). The organic phases were combined and concentrated under reduced pressure to afford an oil. This oil was then dissolved in refluxing MeCN (45 mL). After cooling, a crystalline solid formed and was collected by filtration. The white solid was then dried in a vacuum oven at 45 °C for 18 hours to afford 1 (2.75 g, 96.2 mass%, 4.36 mmol, 86%); m.p. 178.7 °C; 1H NMR (500 MHz, d6-DMSO, 27 °C) δ 8.71 (d, J = 6.5 Hz, 1H), 8.67 (d, J = 8.7 Hz, 1H), 8.23 (d, J = 0.7 Hz, 1H), 8.18 (dd, J = 1.8, 1.8 Hz, 1H), 7.88−7.84 (m, 2H), 7.76 (d, J = 9.2 Hz, 1H), 7.64 (dd, J = 7.9, 7.9 Hz, 1H), 7.20 (dd, J = 9.2, 2.4 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.88−6.85 (m, 2H), 6.82−6.78 (m, 1H), 5.17 (d, J = 6.8 Hz, 1H), 4.48 (ddddd, J = 7.8, 6.5, 6.4, 4.5, 4.3 Hz, 1H), 4.21−4.12 (m, 5H), 3.89−3.82 (m, 2H), 3.71 (ddd, J = 8.1, 8.1, 5.9 Hz, 1H), 3.61 (dd, J = 8.9, 4.3 Hz, 1H), 2.19−2.11 (m, 1H), 1.97−1.90 (m, 1H), 1.54 (t, J = 19.5 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H); 13 C NMR (125 MHz, d6-DMSO, 27 °C) δ 165.6, 163.0 (t, J = 29.1 Hz), 153.0, 143.0, 142.9, 139.7, 135.8, 135.4, 134.0, 131.5, 129.6, 125.6, 125.3, 124.3, 120.6, 120.0, 119.7, 116.9, 115.5, 117.1 (t, J = 248.2 Hz), 111.6, 104.2, 81.1, 72.3, 66.5, 64.0, 64.0, 50.4, 50.1, 31.8, 21.0 (t, J = 25.4 Hz), 15.8; IR (ATR sampling) 3280, 1671, 1633, 1541, 1501, 1284, 1190, 1149, 1052, 952, 834, 805, 728, 636, 575, 501 cm-1; HRMS (ESI) m/z: [M+Na]+ calcd. for C32H32F2N4O6Na 629.2188, found 629.2198. N-[(1S,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1methyl-ethyl]-4-nitro-benzenesulfonamide (16). A solution of compound 3 (3.00 g, 99.0 mass%, 12.1 mmol) and 4nitrobenzenesulfonyl chloride (2.98 g, 13.4 mmol) in anhydrous 2methyltetrahydrofuran (20.6 g) was prepared under nitrogen at 20 °C. The reaction was cooled to –5 °C before triethylamine (3.71 g, 36.6 mmol) was added dropwise. The yellow slurry was stirred for a further 4 h before water (30 mL) was added. The layers were separated and the organic layer washed again with water (30 mL) and then saturated sodium chloride solution (30 g, 50 mass%). The aqueous fractions were combined and back-extracted with more 2methyltetrahydrofuran (30 g). The combined 2methyltetrahydrofuran fractions were dried (magnesium sulfate) and concentrated to a residue which was recrystallised from hot 2methyltetrahydrofuran and heptane. After vacuum drying in a 50 °C oven, the yellow solid so produced was determined to be a 2methyltetrahydrofuran solvate of 16 (5.15 g, 80.7 mass%, 10.5 mmol, 87%); DSC endotherm at 78 °C followed by degradation from 230 °C; 1H NMR (500 MHz, d6-DMSO, 27 °C, ansolvate) δ 8.29 (d, J = 9.0 Hz, 2H), 8.03 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 9.0 Hz, 2H), 6.66– 6.57 (m, 3H), 5.37 (d, J = 4.9 Hz, 1H), 4.29 (dd, J = 5.8, 4.9 Hz, 1H), 4.20–4.08 (m, 4H), 3.30 (dqd, J = 8.6, 6.8, 5.8 Hz, 1H), 0.94 (d, J =

6.8 Hz, 3H); 13C NMR (125.7 MHz, d6-DMSO, 27 °C, ansolvate) δ 149.1, 147.5, 142.7, 142.2, 136.1, 127.8 (2C), 124.3 (2C), 119.2, 116.4, 114.9, 74.6, 64.0 (2C), 55.6, 16.5; IR (ATR sampling) 1523, 1503, 1346, 1305, 1282, 1161, 852, 736, 608 cm−1; HRMS (ESI) m/z: [M+Na]+ calcd. for C17H18N2O7SNa 417.0732, found 417.0692. 3-[5-[(1R,2S)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(4nitrophenyl)sulfonylamino]propoxy]indazol-1-yl]-N-[(3R)tetrahydrofuran-3-yl]benzamide (18). A solution of compound 16 (100 mg, 80.7 mass%, 0.205 mmol) and triethylamine (113 µL, 0.811 mmol) in dry 2methyltetrahydrofuran (0.82 mL) was prepared under a nitrogen atmosphere and with magnetic stirring. After cooling in an ice bath, methanesulfonyl chloride (31.7 µL, 0.410 mmol) was added dropwise. After 1 h in the ice bath, the flask was stored in a freezer overnight. The slurry was filtered through a cotton wool plug, and washed with an equal volume of water to afford a solution. A solution of (R)-3-(5-hydroxy-1H-indazol-1-yl)-N-(tetrahydrofuran-3yl)benzamide 4 (78 mg of 85 mass%, 0.21 mmol) and DBU (93.6 mg, 0.615 mmol) in undried 2-methyltetrahydrofuran (1 mL) and DMF (0.40 mL) was prepared. This mixture was filtered through a cotton wool plug and added to the first solution which was being stirred in an ice bath. The light brown homogeneous solution was allowed to warm to 20 °C as the ice melted. The reaction mixture was diluted to 10 mL with 2-methyltetrahydrofuran and washed with 0.5 M sodium hydroxide solution (2 x 10 mL). The organic phase was concentrated to a residue which was recrystallised from hot isopropanol so as to afford an isopropanolate of 18 sodium (57.0 mg, 94 mass%, 0.074 mmol, 36%). This material was amorphous and did not melt according to DSC analysis; 1H NMR (d6-DMSO, 400 MHz, 27 °C, ansolvate) δ 8.72 (d, J = 6.5 Hz, 1H), 8.17 (dd, J = 3.7,1.9 Hz, 1H), 8.14– 8.12 (m, 3H), 7.91–7.86 (m, 4H), 7.70 (d, J = 9.2 Hz, 1H), 7.65 (dd, J = 7.9, 7.9 Hz, 1H), 7.10 (dd, J = 9.2, 2.4 Hz, 1H), 6.84 (d, J=2.3 Hz, 1H), 6.70–6.68 (m, 3H), 4.95 (d, J = 4.8 Hz, 1H), 4.48 (ddddd, J = 7.9, 6.5, 6.4, 4.5, 4.4 Hz, 1H), 4.17–4.15 (m, 4H), 3.89–3.83 (m, 2H), 3.72 (ddd, J = 8.2, 8.0, 5.8 Hz, 1H), 3.61 (dd, J = 9.1, 4.4 Hz, 1H), 3.60 (qd, J = 6.7, 4.8 Hz, 1H), 2.17 (dddd, J = 12.6, 7.9, 7.9, 7.9 Hz, 1H), 1.94 (dddd, J = 12.6, 7.5, 5.8, 4.5 Hz, 1H), 1.08 (d, J = 6.7 Hz, 3H). 13C NMR (d6-DMSO, 125.7 MHz, 27 °C, ansolvate) δ 165.7, 152.7, 148.6, 143.0, 142.8, 139.7, 135.8, 135.2, 133.8, 131.1, 129.6, 127.6 (2C), 125.4, 125.2, 124.3, 124.1 (2C), 119.9, 119.4, 116.9, 115.1, 111.4, 103.5, 81.3, 72.3, 66.5, 63.9, 63.9, 55.0, 50.4, 31.8. 16.2; IR (ATR sampling) 1527, 1503, 1347, 1306, 1285, 1158,1090, 1065, 853, 736, 685, 610 cm-1; HRMS (ESI) m/z: [M+H]+ calcd. for C35H34N5O9S 700.2077, found 700.2097. (2S,3S)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-methylaziridine (19). Compound 3 (6.00 g, 99.0 mass%, 24.2 mmol) and acetonitrile (120 mL) were changed to a 250 mL round bottom flask. The slurry was cooled to 0 °C using an ice bath. While stirring, chlorosulfonic acid (2.11 mL, 31.7 mmol) was charged dropwise. After 30 mins, the reaction was allowed to warm to room temperature. A white precipitate formed and was collected by using a Buchner filter. The white solid was then transferred to a 500 mL round bottom flask. Toluene (120 mL) was charged and the slurry was cooled to 0 °C using an ice bath. Sodium hydroxide (100 mL, 6 mol/L, 0.6 mol) was added and the reaction left to return to 22 °C. After 16 h, the phases were separated. The aqueous layer was washed with toluene (40 mL) and the organic phases combined, then washed with water (3 x 40 mL). The organic phase was dried over magnesium sulfate and concentrated under reduced pressure to afford 19 as a transparent oil (4.05 g, 93 mass%, 20 mmol, 81% yield). 1H NMR (500 MHz, CDCl3, 27 °C): δ 6.79 (d, J = 8.2 Hz, 1H), 6.75−6.64 (m, 2H), 4.20−4.18 (m, 4H), 2.53 (br s, 1H), 2.03 (br s, 1H), 1.31 (d, J = 4.21 Hz, 3H), 0.53 (br s, 1H); 13 C NMR (126 MHz, CDCl3, 27 °C) δ 143.0, 142.0, 133.3, 118.0, 116.6, 113.7, 63.8, 63.7, 39.4, 36.0, 19.0; IR (ATR sampling) 2980, 1589, 1509, 1282, 1203, 1065, 812, 730 cm-1; HRMS (ESI) m/z: [M+H]+ calcd. for C11H14NO2 192.1025 found 192.1023. (R)-tetrahydrofuran-3-yl-3-(5-((1R,2S)-2-amino-1-(2,3dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1yl)benzoate furan-2-carboxylate (20).



A solution of compound 34 in 2-methyltetrahydrofuran (5.95 g of 9.2 mass%, 0.79 mmol), TFA (1.6 mmol) and Pd/C 5R395 (Johnson Matthey 5% Pd on charcoal 5.05 %wt Pd when dry, 55.0 %moisture, 219 mg ‘as is’) was hydrogenolysed for 12 h at 50 °C, 60 psig and 300 rpm in the cell of an Biotage® Endeavor™. The reaction mixture was passed through a short pad of Celite®, washing through with an equal volume of 2-methyltetrahydrofuran. The filtrate was washed with potassium carbonate solution (5 mL of 2 M) and the organic phase concentrated to a residue. This was suspended in 2methyltetrahydrofuran (10 mL), filtered so as to remove inorganics and the filtrate treated with a solution of 2-furoic acid (177 mg, 1.58 mmol) in 2-methyltetrahydrofuran (3 mL). A slurry rapidly formed and was collected by filtration before being washed with 2methyltetrahydrofuran (2 x 2 mL) and dried in a vacuum oven to afford 20 (454.4 mg, 0.67 mmol, 84 %); mp 199 °C; 1H NMR (500 MHz, d6-DMSO+TFA, 27 °C) δ 8.77 (d, J = 6.5 Hz, 1H), 8.22 (s, 1H), 8.20 (dd, J = 1.8, 1.7, 1H), 7.88 (dd, J = 7.9, 1.7 Hz, 1H), 7.88 (dd, J = 7.9, 1.8 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.65 (dd, J = 7.9, 7.9 Hz, 1H), 7.60 (dd, J = 1.7, 0.8 Hz, 1H, 2-furoate), 7.30 (dd, J = 9.2, 2.3 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.92–6.84 (m, 3H), 6.76 (dd, J = 3.2, 0.8 Hz, 1H, 2-furoate), 6.45 (dd, J = 3.2, 1.7 Hz, 1H, 2furoate), 5.60 (d, J = 3.5 Hz, 1H), 4.49 (ddddd, J = 7.8, 6.5, 6.4, 4.5, 4.3 Hz, 1H), 4.20 (1H, s, 4H), 3.89–3.83 (m, 2H), 3.71 (ddd, J = 8.1, 8.1, 5.9 Hz, 1H), 3.62 (dd, J = 9.0, 4.3 Hz, 1H), 3.55 (qd, J = 6.7, 3.6 Hz, 1H), 2.16 (dddd, J = 12.7, 8.1, 7.8, 7.8, 1H), 1.95 (dddd, J = 12.5, 7.5, 5.9, 5.7 Hz, 1H), 1.19 (d, J = 6.7 Hz, 3H) (NH3+ missing). 13C NMR (125 MHz, d6-DMSO, 27 °C) δ 165.7, 162.2, 152.6, 151.8 (2furoate), 143.3 (2-furoate), 143.3, 143.1 (2-furoate), 139.7, 135.8, 135.4, 134.1, 130.1, 129.7, 125.5, 125.3, 124.3, 120.6, 120.2, 119.5, 117.2, 115.4, 112.5 (2-furoate), 111.5, 111.0 (2-furoate), 104.5, 79.7, 72.3, 66.6, 64.0, 64.0, 51.2, 50.5, 31.8, 13.5; IR (ATR) 1581, 1572, 1504, 1346, 1310, 1283, 1160, 1061, 923, 795, 755 cm-1; HRMS (ESI) m/z: [M−C5H4O3+Na]+ calcd. for C29H30N4O5Na 537.2114, found 537.2111. N-((1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1hydroxypropan-2-yl)-2,2-difluoropropanamide (21). Compound 3 (0.505 g, 99.0 mass%, 2.04 mmol), 2,2difluoropropanoic acid (0.46 g, 4.2 mmol) and dichloromethane (5.05 mL) were charged to a 25 mL EasyMax tube. The reaction was cooled to 0 °C and N,N-diisopropylethylamine (1.7 mL, 12 mmol) was added. After stirring for 10 mins, T3P (1.82 mL, 3.05 mmol, 50 mass% in ethyl acetate) was added. After 1 h at 0 °C, the reaction was heated to 22 °C then DCM (5 mL) and water (5 mL) were added. The phases were separated and the organic layer was washed with a sat. aq. NaHCO3 solution (2 x 5 mL) then water (5 mL). After concentrating the organic phase to 3 mL under reduced pressure, a white precipitate formed and was collected by filtration. This solid was transferred to a petri dish and dried in a vacuum oven at 40 °C for 72 h to afford 21 (0.592 g, 93.0 mass%, 1.83 mmol, 90%); m.p. 155.5 °C; 1H NMR (500 MHz, DMSO-d6, 27 °C) δ 8.31 (d, J = 8.6 Hz, 1H), 6.79−6.74 (m, 3H), 5.39 (br s, 1H), 4.42 (d, J = 6.6 Hz, 1H), 4.20−4.16 (m, 4H), 3.84 (dq, J = 6.6, 6.6 Hz, 1H), 1.55 (t, J = 19.5 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) δ 162.7 (t, J = 28.8 Hz), 142.6, 142.1, 136.4, 119.1, 116.2, 117.3 (t, J = 247.5 Hz), 115.0, 73.74, 64.0, 63.9, 50.7, 24.4 (t, J = 25.4 Hz), 15.3; IR (ATR sampling) 3290, 1672, 1552, 1512, 1292, 1195, 1159, 1052, 936, 816, 739 cm-1; HRMS (ESI) m/z: [M+Na]+ calcd. for C14H17F2NO4Na 324.1023, found 324.1022. (4S,5S)-2-(1,1-difluoroethyl)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6yl)-4-methyl-4,5-dihydrooxazole (22). Compound 21 (100 mg, 93 mass%, 0.31 mmol), 2methyltetrahydrofuran (2 mL) and triethylamine (0.18 mL, 1.3 mmol) were charged to a 25 mL reaction vial. The solution was cooled to 0 °C and methane-sulfonyl chloride (0.04 mL, 0.5 mmol), was added dropwise. The reaction was stirred at 0 °C for 1 h before being heated to 25 °C. After 1 h, the reaction was diluted with ethyl acetate (2 mL) and washed with water (3 x 2 mL). The organic layer was then concentrated under reduced pressure to afford a crude oil which was then purified by flash silica chromatography (1:4 ethyl acetate : n-heptane) to afford 22 as a transparent oil (82 mg, 88.0 mass%, 0.25 mmol,

Page 8 of 10

82%). 1H NMR (500 MHz, CDCl3, 27 °C) δ 6.87 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 6.77 (dd, J = 8.3, 2.2 Hz, 1H), 5.00 (d, J = 8.0 Hz, 1H), 4.26−4.22 (m, 4H), 4.12 (dq, J = 8.0, 6.8 Hz, 1H), 1.93 (t, J = 18.8 Hz, 3H), 1.41 (d, J = 6.8 Hz, 3H); 13C NMR (126 MHz, CDCl3, 27 °C) δ 159.4 (t, J = 31.6 Hz), 143.6, 143.4, 131.8, 118.4, 117.3, 115.1 (t, J = 239.3 Hz), 114.4, 88.9, 69.9, 64.0, 63.9, 21.9 (t, J = 25.4 Hz), 20.4; IR (ATR sampling) 2924, 1680, 1591, 1509, 1286, 1204, 1134, 1066, 928, 887, 813, 658 cm-1; HRMS (ESI) m/z: [M+H]+ calcd. for C14H16F2NO3 284.1098, found 284.1088. N-allyl-N-((1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1hydroxypropan-2-yl)prop-2-en-1-aminium chloride (25). Compound 3 (20.25 kg, 96.6 mass%, 79.6 mol), MeCN (120.87 L) and water (60.00 L) were charged to a vessel. After stirring for 0.2 h, potassium carbonate (39.1 kg, 283 mol) was added, the reaction was stirred for 0.25 h then allyl bromide (17.36 L, 200.9 mol) was added. The reaction was stirred at 20 °C for 21 h then water (118 L) was added. The aqueous layer was discarded then toluene (135.64 L) was added. The organic phase was washed with water (2 x 69 L) then heated to 100 °C for 2 h. The solution was cooled to 5 °C and hydrochloric acid (20.86 L, 6.0 mol/L, 140 mol, in isopropyl alcohol) was added. A precipitate formed and was collected by filtration. The filter cake was washed with toluene (9.23 L) and then centrifuge dried to afford compound 25 (22.6 kg, 98.8 mass%, 68.5 mol, 86%); m.p. 180.0 °C; 1H NMR (500 MHz, d6-DMSO, 27 °C) δ 11.53 (s, 1H), 6.92–6.80 (m, 3H), 6.25–6.10 (m, 3H), 5.62–5.42 (m, 5H), 4.29–4.18 (m, 5H), 3.89–3.81 (m 1H), 3.81–3.68 (m, 2H), 3.40–3.33 (m, 1H), 1.07 (d, J = 6.88 Hz, 3H); 13C NMR (125 MHz, d6-DMSO, 27 °C) δ 143.0, 142.5, 135.6, 128.6 (2C), 124.0, 123.9, 118.2, 116.8, 114.3, 68.7, 64.1, 64.0, 62.5, 52.9, 52.0, 5.4; IR (ATR sampling) 3254, 2613, 2527, 1589, 1503, 1296, 1256, 1066, 1052, 922, 802, 574, 540 cm-1; HRMS (ESI) m/z: [M−HCl+H]+ calcd. for C17H24NO3 290.1756, found 290.1747. (1R,2S)-N,N-dibenzyl-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1hydroxypropan-2-aminium chloride (26). Compound 3 (100 g, 93 mass%, 378.51 mmol), potassium carbonate (288 g, 2080 mmol) and acetonitrile (2.5 L) were charged to a vessel. The slurry was stirred at 21 °C for 1.5 h, then benzyl bromide (102 mL, 817 mmol, 95.3 mass%) was added over 1.25 hours. The reaction was then heated to 90 °C for 18 h. Once cooled, the organics were removed by filtration and the mother liquors were concentrated to afford 160 g of an oil. This oil was then taken up in propan-2-ol (500 mL) and heated to 60 °C. With stirring, hydrochloric acid (35 mL, 11.65 mol/L, 410 mmol) was added dropwise over 1 hour. A thick slurry formed, this slurry was cooled to 22 °C and the product collected by filtration. The filtrate was washed with n-heptane (500 mL) and then dried in a vacuum oven at 40 °C for 18 hours to afford 26 (161.65 g, 96.2 mass%, 365.1 mmol, 97%); m.p. 206.2 °C; 1H NMR (500 MHz, d6-DMSO, 27 °C) δ 11.60 (br s, 1H), 7.84 (dd, J = 6.5, 2.9 Hz, 2H), 7.75 (dd, J = 6.5, 3.0 Hz, 2H), 7.40−7.35 (m, 3H), 7.33−7.26 (m, 3H), 6.72–6.62 (m, 3H), 6.22 (br s, 1H), 5.85 (app. s, 1H), 5.04 (dd, J = 13.5, 3.5 Hz, 1H), 4.40 (dd, J = 13.5, 6.8 Hz, 1H), 4.27–4.20 (m, 2H), 4.19–4.17 (m, 4H), 3.23 (app. q, J = 6.8 Hz, 1H), 1.16 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, d6-DMSO, 27 °C) δ 143.0, 142.4, 135.8, 131.4 (2C), 131.1 (2C), 130.6, 130.5, 129.1, 129.1, 128.6 (2C), 128.5 (2C), 118.0, 116.6, 114.1, 68.5, 64.0, 63.9, 62.8, 54.3, 53.5, 5.1; IR (ATR sampling) 3305, 2611, 1590, 1507, 1456, 1286, 1258, 1070, 903, 772, 746, 619, 499 cm-1; HRMS (ESI) m/z: [M−HCl+H]+ calcd. for C25H28NO3 390.2069, found 390.2065. 3-(5-((1R,2S)-2-(dibenzylamino)-1-(2,3dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)-N((R)-tetrahydrofuran-3-yl)benzamide (34). Compound 30 (5.00 g, 96.2 mass%, 11.27 mmol), 2methyltetrahydrofuran (25 mL) and triethylamine (5.82 mL, 41.8 mmol) were charged to a 100 mL reactor. The slurry was stirred at 0 °C for 15 mins, then methanesulfonyl chloride (2.01 mL, 26.0 mmol) was added dropwise. After 1.5 hours, water (25 mL) was added. The slurry became a biphasic solution. The aqueous phase was discarded and the organic phase was washed with water (25 mL) and then stirred with sodium hydroxide (5 mL, 2 mol/L) at 0 °C for 5 mins. A solution of compound 4 (4.15 g, 98 mass%, 12.5 mmol) was dissolved in sodium hydroxide (45 mL, 2 mol/L) and then added at 0 °C.


Page 9 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


After 16 h at 0 °C, the phases were separated and the organic phase concentrated under reduced pressure to a foam which was then purified using flash silica chromatography (1:3 ethyl acetate : n-heptane) to afford 34 (8.17 g, 92 mass%, 10.8 mmol, 96%) as a white foam. This material was amorphous and did not melt according to DSC analysis; 1H NMR (500 MHz, d6-DMSO, 27 °C) δ 8.73 (d, J = 6.5 Hz, 1H), 8.22 (d, J = 0.8 Hz, 1H), 8.21 (dd, J = 1.8, 1.8 Hz, 1H), 7.90−7.86 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.65 (dd, J = 7.9, 7.9 Hz, 1H), 7.30−7.22 (m, 5H), 7.23−7.18 (m, 7H), 6.80 (d, J = 8.2 Hz, 1H), 6.73−6.68 (m, 2H), 5.52 (d, J = 5.8 Hz, 1H), 4.50 (ddddd, J = 7.8, 6.5, 6.4, 4.5, 4.3 Hz, 1H), 4.27−4.17 (m, 4H), 3.91−3.84 (m, 2H), 3.79−3.70 (m, 3H), 3.65−3.58 (m, 3H), 2.97 (qd, J = 6.7, 5.8 Hz, 1H), 2.22−2.13 (m, 1H), 1.99−1.91 (m, 1H), 1.24 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, d6-DMSO, 27 °C) δ 165.6, 152.8, 143.0, 142.6, 139.9 (2C), 139.7, 135.7, 135.7, 135.2, 133.8, 133.2, 129.6, 128.3 (2C), 128.3 (2C), 128.0 (2C), 128.0 (2C), 126.7 (2C), 125.6, 125.2 124.2 120.5 120.0, 119.8, 116.5, 115.6, 111.4, 103.9, 80.4, 72.2, 66.5, 64.0, 58.2, 53.4 (2C), 50.4, 31.8, 9.2; IR (ATR sampling) 2873, 1587, 1502, 1305, 1284, 1155, 1065, 886, 774, 697, 600, 464 cm-1; HRMS (ESI) m/z: [M+H]+ calcd. for C43H43N4O5 695.3233, found 695.3240.

1 H and 13C NMR spectra for compounds 1, 16, 18-22, 25, 30 and 35. Kinetic analysis, best-fit plots and details of ATR-FTIR and ATR-UV experiments.

ASSOCIATED CONTENT

We would like to thank AstraZeneca for providing an excellent environment for research. We also acknowledge Amand W. Connor for his work in related route design activities and Valerie Loader for the running of the chiral HPLC method.

Supporting Information

AUTHOR INFORMATION Corresponding Authors Angus E. McMillan E-mail: [email protected] ORCID: 0000-0002-8883-1380 Alexander K. Mullen E-mail: [email protected] ORCID: 0000-0001-7475-5543 Funding Source AstraZeneca

ACKNOWLEDGMENT

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Stereoretentive Etherification of an Î±-Aryl-Î²-amino Alcohol Using a

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