Route scouting and optimization of a potent sulfoximine-based inverse agonist of RORγt

Article abstract of DOI:10.1016/j.tet.2018.08.043

During our research looking for novel inverse agonists of RORγt, we identified a potent sulfoximine-based modulator as one of our pre-clinical candidates for the topical treatment for psoriasis. Herein, we describe the various routes we evaluated during the lead generation and optimization phases and the final route chosen for scale-up to deliver the first 100 g of API.

Full text of DOI:10.1016/j.tet.2018.08.043

Accepted Manuscript
Route scouting and optimization of a potent sulfoximine-based inverse agonist of
RORγt
Guillaume Lafitte, Veronique Parnet, Romain Pierre, Catherine Raffin, Rodolphe
Vatinel, Branislav Musicki, Loic Tomas, Claire Bouix-Peter, Gilles Ouvry, Sebastien
Daver, Jean-Marie Arlabosse, Jean-Guy Boiteau, Thibaud Gerfaud, Craig S. Harris
PII:
S0040-4020(18)31025-1
10.1016/j.tet.2018.08.043
TET 29763
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 July 2018
Revised Date: 16 August 2018
Accepted Date: 23 August 2018
Please cite this article as: Lafitte G, Parnet V, Pierre R, Raffin C, Vatinel R, Musicki B, Tomas L, Bouix-
Peter C, Ouvry G, Daver S, Arlabosse J-M, Boiteau J-G, Gerfaud T, Harris CS, Route scouting and
optimization of a potent sulfoximine-based inverse agonist of RORγt, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.08.043.
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Route scouting and optimization of a
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potent sulfoximine-based inverse agonist of RORγt
Guillaume Lafitte, Veronique Parnet, Romain Pierre, Catherine Raffin, Rudolphe Vatinel, Branislav
Musicki, Loic Tomas, Claire Bouix-Peter, Gilles Ouvry, Sebastien Daver, Jean-Marie Arlabosse, Jean-
Guy Boiteau, Thibaud Gerfaud, Craig S. Harris
Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France

1
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Tetrahedron
journal homepage: www.elsevier.com
Route scouting and optimization of a potent sulfoximine-based inverse agonist of
RORγt
Guillaume Lafitte, Veronique Parnet, Romain Pierre, Catherine Raffin, Rodolphe Vatinel, Branislav
Musicki, Loic Tomas, Claire Bouix-Peter, Gilles Ouvry, Sebastien Daver, Jean-Marie Arlabosse, Jean-Guy
Boiteau, Thibaud Gerfaud , Craig S. Harris
Nestlé Skin Health R&D, 2400 Route de Colles, 06410 Biot, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
During our research looking for novel inverse agonists of RORγt, we identified a potent
sulfoximine-based modulator as one of our pre-clinical candidates for the topical treatment for
psoriasis. Herein, we describe the various routes we evaluated during the lead generation and
optimization phases and the final route chosen for scale-up to deliver the first 100 g of API.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
RORγt inverse agonist
Psoriasis
Sulfoximine
SNAr
Route scouting
Corresponding author. Tel.: +33 4 93 95 70 42; fax: +33 4 93 95 70 71; e-mail: craig.harris@galderma.com
Corresponding author. Tel.: +33 4 92 38 30 87; fax: +33 4 93 95 70 71; e-mail: thibaud.gerfaud@galderma.com

2
1. Introduction
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Psoriasis is a chronic autoimmune disease characterized by thick, red and scaly lesions that affects 2% of the population worldwide.1
Psoriasis, among other autoimmune diseases, is believed to be caused by pro-inflammatory cytokines IL-17 produced by differentiated
pathogenic T-helper 17 cells (TH-17).2 With a direct impact on the IL-17 pathway, RORγ is a highly sought after target for the
treatment of autoimmune disease and in particular of psoriasis.2 Proof of concept was achieved with Vitae’s VTP43742 and several
molecules have now followed suit in clinic.3
In recent communications, we described the design and synthesis of a novel class of bis(aryl) sulfonamide-based RORγt inverse
agonists.4-5 During our SAR (structure-activity relationship) and SPR (structure-property relationship) investigation, sulfoximine 1 was
identified as a key molecule to target. The sulfoximine motif has attracted much attention in drug discovery with kinase inhibitors
Roniciclib, Atuveciclib (BAY 1143572) and Ceralasertib (AZD 6738) under clinical evaluation.6 In our specific case, the sulfoximine
residue, a recognized alcohol bioisostere,5,7 was identified as part of a broader exploration to introduce hydrophilicity to one of GSK’s
lead compounds (Figure 1).8 Retrosynthetic analysis of 1 drove us to consider 2 approaches: 1) a linear, convergent route whereby the
sulfoximine would be introduced at the end of the sequence preceded by sulfonamide coupling from commercially-available sulfonyl
chloride 6 and aniline 5 followed by aryl methyl ether deprotection, alkylation and Pd-catalysed thioether formation; and 2) a much
more appealing divergent route allowing variation of the key vector of interest at the end of the route via SNAr or PGM (platinum group
metal) catalysis preceded by sulfoximine formation, sulfonamide coupling requiring access to unknown sulfonyl chloride 9 that we
anticipated to be achievable through a 4-step approach starting from 10.
Figure 1. Retrosynthetic analysis of racemic sulfoximine target 1
2. Results and discussion
2.1. Medicinal chemistry: vector exploration
Our first successful route to 1 focused on a linear convergent approach starting from commercially-available 3-bromo-4-
methoxybenzenesulfonyl chloride (6). Coupling with aniline 5 afforded 4 followed by revelation of the phenol moiety through
dealkylation of the aryl methyl ether using thiophenolate to afford 11.9 Alkylation of phenol derivative 11 with 4-
(bromomethyl)tetrahydro-2H-pyran afforded 12. Transformation to thioether 2 was achieved in a respectable 67% isolated yield using
palladium catalysis.10 Finally, transformation to sulfoximine 1 was achieved via first transformation to sulfoxide 13 followed by
rhodium-catalyzed sulfoximine formation using trifluoroacetamide as the imine source as described by Bolm and co-workers (Scheme
1).11

3
Scheme 1. Route A: First route to our racemic sulfoximine target 1. Reagents and conditions: a) pyridine, THF, r.t., 65%; b)
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thiophenol, Cs2CO3, DMF, 100 °C, 80%; c) Cs2CO3, DMF, 80 °C, 87%; d) Pd2dba3, Xantphos, CH3SNa, DIPEA, 1,4-dioxane, r.t., 67%;
e) mCPBA, DCM, r.t., 63%; f) Trifluoroacetamide, Rh2(OAc)2, MgO, PhI(OAc)2, DCM, 40 °C; g) K2CO3, MeOH, r.t., 30%
Encouraged by the in vitro activity of racemic 1,5 we decided to focus on building our SAR knowledge by exploring the vector from C-
4 (diversification point 3) and assessing the activity of the individual enantiomers. To prepare our key sulfonyl chloride building block
(9),12 we targeted 2-bromo-5-nitroaniline (10) as the starting material. Formation of thiocyanate 14 through diazotisation13 followed by
reduction14 and in situ alkylation of the thiol moiety with dimethylsulfate15 afforded thioether 15. Reduction, followed by a second
diazotisation step16 afforded our key sulfonyl chloride building block 9 which was in turn coupled with aniline 5 to afford sulfonamide
16. Unfortunately, from sulfoxide 17, we achieved a very poor conversion to sulfoximine 8 employing the rhodium catalyzed
methodology11 that we used previously which could be explained by the presence of the bromine atom that both lowers nucleophilicity
of the thioether moiety compared to sulfoxide 13 and creates considerable steric hindrance. However, inversion of the steps, by
formation of sulfilimine 18 followed by oxidation17 and cleavage of the trifluoracetamide moiety afforded an acceptable overall yield of
our key library precursor 8 with two orthogonal diversification points (Scheme 2).
Scheme 2. Route B: Route to sulfoximine building block 8. Reagents and conditions: a) NaNO2, KSCN, CuSCN, 0 °C-r.t., 2 h, 63%; b)
NaOH (aq), NaBH4, Me2SO4, 2 h, 84%; c) Fe(s), NH4Cl, MeOH-H2O (2:1), reflux, 2 h, 53%; d) NaNO2, SO2 in AcOH, CuCl2, -10 °C-
r.t., 46%; e) pyridine, THF, r.t., 16 h, 78%; f) mCPBA, DCM, r.t., 30 min., 75%; g) trifluoroacetamide, Rh2(OAc)2, MgO, PhI(OAc)2,
DCM, r.t., 48 h; h) K2CO3, MeOH, r.t., 11%; i) NaH, trifluoroacetamide, 1,3-dibromo-5,5-dimethylhydantoin, THF, 0 °C-r.t., 2 h, 73%;
j) K2CO3, mCPBA, 0 °C-r.t., 16 h, 54%.
Scheme 3. Route C: Alternative unoptimized route to sulfoximine building block 8. Reagents and conditions: a) ClSO3H, 0 °C-150 °C,
6 h, 78%; b) pyridine, THF, r.t., 16 h, 80%; c) PPh3, toluene, 90 °C, 10 min. quant.; d) MeI, K2CO3, DMF, r.t., 20 min., 64%; e) NaH,
trifluoroacetamide, 1,3-dibromo-5,5-dimethylhydantoin, THF, 0 °C-r.t., 2 h, 73%; f) K2CO3, mCPBA, 0 °C-r.t., 16 h, 54%
While our route to our sulfoximine building block 8 furnished the project with gram quantities of 8, the sequence was very long with
two sensitive Sandmeyer steps to control and afforded an overall yield of just 13% to sulfonyl chloride 9 and 4% to 8. Moreover, the
alkyl group of the sulfoximine moiety (diversification point 1) was fixed early on in the sequence thus limiting diversity (Scheme 2).

4
Going forwards in the project, we explored a safer, quicker and more versatile route starting from commercially-available 4-
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bromobenzenesulfonyl chloride (19) whereby the key step concerned the differentiation of bis(sulfonylchloride) intermediate 20 to
access 21 (Scheme 3). Briefly, careful chlorosulfonylation afforded 20 in excellent yield that can also be prepared directly from
bromobenzene.7 Despite the generally surprising absence of literature supporting the differentiation of the two chlorosulfonyl groups of
20, we envisioned that the steric hindrance of the C-2 bromine atom and our hindered secondary aniline motif should increase our
chances of obtaining 21 with high regioselectivity. To our delight, through careful dropwise addition of aniline 5 to 20, the desired
sulfonamide regioisomer 21 was obtained in 80% isolated yield with only traces of the undesired regioisomer. From here, reduction of
21 to the versatile and stable thiophenol intermediate 22 was achieved in quantitative yield using triphenylphosphine18 permitting late
stage variation of the alkyl vector of the sulfoximine moiety (diversification point 1). To complete the sequence, we employed the
sulfoximine protocol described in Scheme 2 and were able to prepare 8 in a much improved overall yield of 15% over 6 steps (Scheme
3).
With these routes in hand, we gained access to larger quantities of intermediate 8 to study SARs from C-4. Although SNAr reactions on
haloarenes with unprotected sulfoximines at the ortho position have not yet been reported and there is only one reference at the para
position with a fluorine atom as the leaving group,19 we preferred to explore the SNAr option first owing to the ease of preparing large
libraries compared to palladium or copper catalyzed processes.20 From our model experiments using an excess of (tetrahydro-2H-pyran-
4-yl)methanamine as the nucleophile, product was observed using the most reactive p-fluoro derivative albeit in poor yield and
conversion (entry 1). While we also expected a very poor reaction with bromide substrate having a deactivating SMe group at C-3
(entry 2), we were surprised to observe only trace amounts of substituted product with an unprotected sulfoximine group at C-3 (entry
3). However and to our delight, using intermediate 8 as the substrate, the desired product 23 was afforded in 93% isolated yield at just
room temperature (entry 4, Table 1).
Table 1. SNAr trials on 8 and related structural motifs
NH2
R1
R2
R1
X
R2
see Table 1
HN
O
O
Entry Compound
X
R1
H
R2
Conditions
Yield %
45
1a
-
F
70 °C, 3 d
2b
-
Br
MeS-*
150 °C
traces
3b
4b
-
Br MeNH(O)S-*
Br MeNH(O)S-*
H
180 °C
r.t.
traces
93%
23
a a 3-fold of excess of amine in DMF (5 volumes) was used; b amine used as solvent
O
S
O
S
HN
O
O
S
HN
O
HN
O
S
S
S
N
N
N
O
O
O
a, b
O
Br
O
O
O
8
24 (fraction 1)
(RORy GAL4 IC50 = 26 nM)
25 (fraction 2)
(RORy GAL4 IC50 = 45 nM)
Scheme 4. Preparation of enantiomers of 1. Reagents and conditions: a) (tetrahydro-2H-pyran-4-yl)methanol, NaH, DMF, r.t., 16 h,
84%; b) a solution of 20 mg / mL was purified by stack-injection using SFC chromatography to afford 24 (35.4%) and 25 (37.3%)

5
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Using 8 as our diversification point, we prepared a very large library of final compounds through SNAr reaction with alcohol, amine and
thiol based nucleophiles in order to thoroughly explore the SARs from vector C-4 while retaining the sulfoximine motif in place.
However, despite the large number of final compounds evaluated (>100 final compounds), no improvement over our original hit was
made. Going forwards in the program, we decided to exploit this strategy to prepare 1 in large quantity in order to separate the
enantiomers and compare their individual activity in vitro and in vivo. From this head-to-head property evaluation, the only significant
difference observed between the first eluting fraction (24) and the second eluting fraction (25) was in potency.5 Enantiomer 24 was ~2
fold more potent, therefore, we selected 24 for chemical development with no knowledge of its absolute configuration (Scheme 4).
2.2. Chemical development of the clinical candidate
In order to start early formulation activities and pursue the biological evaluation of the candidate, larger quantities of drug substance
were required. At that point it became critical to determine its chirality (Figure 2). Isolation of the least active enantiomer (25) by chiral
HPLC followed by salt formation with (1R)-(−)-10-camphorsulfonic acid21 allowed for single crystal X-Ray diffraction and attribution
of the R configuration to the sulfoximine stereocenter. Chiral resolution of the racemate with chiral sulfonic acids was attempted but
was unsuccessful.
Figure 2. X-Ray of least active enantiomer 25.camphorsulfonate
Route A was not really appealing for several reasons: 6 and 4-(bromomethyl)tetrahydropyran (3) are not commercially available on
large scale, use of thiophenol and sodium methanethiolate is not preferred on scale and final sulfoximine installation was low yielding.
To meet the project’s timelines, early stage process development activities were initiated to ensure a smooth scale-up of second
generation route B. Scale-up of the first steps proved complicated: conversion of 10 to 14 involved energetic intermediates and
purification of 14 was difficult, rendering chromatography impossible to overcome. On scale the reaction was not robust with important
batch to batch yield variations. Thiocyanate reduction and alkylation scaled up smoothly but involved toxic reagents. Nitro reduction
followed by the second diazotization was also cumbersome involving once again highly energetic intermediates along with lack of
robustness. Several campaigns at 100 g scale were necessary to furnish ultimately 500 g of 9.
Most of our efforts were turned toward the last steps of the synthesis focusing mainly on the improvement of intermediate isolation and
purification and on a robust and scalable introduction of the sulfoximine moiety. Aniline 5 is not commercially available on large scale
and was prepared by reductive amination and isolated in high yield and purity as a hydrochloride salt. From 5.HCl, a convenient
coupling process with 9 was devised. The 2 solids were suspended in acetonitrile at 50 °C and coupling occurred smoothly upon DIPEA
(N,N-diisopropylethylamine) addition. After addition of 1N aqueous HCl, the product crystallized out and was collected by filtration
before being recrystallized (wet) in pure i-PrOH. 16 was obtained in good yield and high purity at >300 g scale. Sulfoximine formation
was challenging on large scale. Formation of trifluoroacetyl sulfilimine 18 could be scaled up with minimal modifications (NaH
replaced with safer n-HexLi) but concomitant sulfoxide formation (15-18% depending on batches) could not be avoided.
Recrystallization from iPrOH:water was necessary to eliminate this impurity, reducing the overall yield to 71% at 50 g scale. Further
oxidation of the trifluoroacetyl sulfilimine to the corresponding sulfoximine was not an easy task. Among all oxidants tested (mCPBA,
H2O2, Oxone, KMnO4, NaOCl, RuCl3…), only Ru based oxidation systems were able to deliver the sulfoximine as the major product.
However, high amounts of RuCl3 (up to 30 mol%) and 4 to 6 equivalents of co-oxidant were required, with conversion stalling at ~70%.
This prompted us to investigate other sulfilimines and preliminary experiments rapidly showed that oxidation of cyanosulfilimine to
cyanosulfoximine were much cleaner and higher yielding.22 Ru based oxidation systems were once again affording the best reaction
profiles and after complete optimization of the 2 steps, a convenient and scalable access to the cyanosulfoximine 27 was devised
(Scheme 5). 16 was converted to the cyanosulfilimine 27 using cyanamide with NBS as oxidant and potassium tert-butoxide as base in
a THF-MeOH mixture. 27 crystallized out of the reaction mixture upon addition of an aqueous sodium metabisulfite solution and was
easily isolated in high yield and high purity (89% yield, >97% purity at 500g scale). Oxidation of 27 to cyanosulfoximine 28 was
performed in a DCM-MeCN-water mixture with RuCl3 (2 mol%) and periodic acid as a co-oxidant. Complete conversion was reached
within two hours and after workup and solvent switch to a mixture of iPrOH-DIE-acetone, cyanosulfoximine 28 crystallized and was
isolated in 82% yield and >96% purity at 500 g scale. For a more efficient process, remaining steps (cyano moiety hydrolysis and SNAr)
were combined. Upon treatment with TFA in wet DCM,23 crude cyanosulfilimine 27 was converted to the crystalline and easily isolated
urea 29. Concomitant urea hydrolysis and SNAr were achieved by treating the crude urea with 4-(hydroxymethyl)tetrahydropyran and
cesium carbonate in 1,4-dioxane under reflux. After completion of the reaction and base filtration, the final product 1 was crystallized
out of the reaction mixture as a tosylate salt, enabling a very efficient impurity purging. Free-basing was achieved readily from 2-
methyltetrahydrofuran/aq. NaOH and after a solvent switch to acetone-TBME, 1 was crystallized and isolated in good yield and high
purity (72% yield, >98% purity, 400 g scale).

6
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Scheme 5. Route D: Optimized route to deliver 100 g of 24. Reagents and conditions: a) NaNO2, KSCN, CuSCN, 0 °C-r.t., 2 h, 50%;
b) NaOH (aq), NaBH4, Me2SO4, 2 h, 50%; c) Fe(s), NH4Cl, MeOH-H2O (2:1), reflux, 2 h, 82%; d) NaNO2, SO2 in AcOH, CuCl2, -10
°C-r.t., 30%; e) Isobutyraldehyde, NaBH(OAc)3, TBME, 23°C, 18 h then 3M HCl in CPME, 75%; f) DIPEA, MeCN then 1N HCl; g)
iPrOH, 89% over 2 steps; h) Cyanamide, NBS, t-BuOK, MeOH-THF (2:1), 89%; i) RuCl3 (1.5 mol%), H5IO6, DCM-MeCN-H2O
(2:2:1); j) iPrOH, acetone, DIE, 93% over 2 steps; k) TFA, DCM-H2O (40:1), 85%; l) Cs2CO3, 1,4-dioxane, reflux, 24 h then p-TsOH,
acetone; m) NaOH (aq), 2-methyltetrahydrofuran-H2O, 70%; n) chiral HPLC, chiralpack AD
While scaling up this route, the search for a more viable approach for larger scale production was pursued. We focused on the following
criteria: 1) shorter sequence; 2) readily available and cheap starting materials; and 3) possible earlier separation of the enantiomers.
Route C, involving the two chlorosulfonyl group differentiation (Scheme 3) was briefly explored but while well suited for small scale
production, the anticipated low stability of 20 and the harsh reaction conditions of its formation were not suitable for large scale
production.24 A good compromise was found using the synthetic pathway described in Scheme 6 and demonstrated on mg scale. 2-
Hydroxythioanisole (30), a cheap and readily available compound,25 can be reacted with 4-(hydroxymethyl)tetrahydropyran under
Mitsunobu conditions to deliver 31 in high yield. Conducting the reaction in toluene with DEAD/PPh3 as the activating agent allowed
easy removal of all by-products without chromatography: Ph3PO was removed by addition of MgCl2 to the reaction mixture triggering
the formation of an insoluble MgCl2-Ph3PO complex26 and reduced DEAD could be removed by crystallization upon heptane addition.
Cyanosulfilimine formation using the previously optimized conditions worked in 55% yield after crystallization albeit on small scale.
Oxidation of 32 to the corresponding cyanosulfoximine under Ru catalysis worked well, furnishing 33 in 40% yield (not optimized).
When 33 was treated with chlorosulfonic acid, a clean and fully regioselective chlorosulfonylation at C5 took place. The crude
sulfonylchloride was directly engaged in a coupling step with 5.HCl delivering 34 in 40% yield over 2 steps. Access to 1 could then be
completed by converting cyanosulfoximine into the corresponding trifluoroacetamide using TFAA followed by hydrolysis with K2CO3
in MeOH. A lot of development work still remains to optimize and ensure complete robustness but this novel approach reduces the
longest linear sequence to only 6 steps and circumvents the use of expensive starting materials. It also offers interesting possibilities
such as earlier enantiomers separation by chiral HPLC on cyanosulfoximine 33 or a possible enantioselective version by conducting a
chiral oxidation of sulfide 31 to the corresponding sulfoxide followed by imination using Bolm’s method.11

7
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Scheme 6. Route E: Last generation route towards racemic 1. Reagents and conditions: a) PPh3, DEAD, toluene; b) MgCl2, heptane-
toluene, 92% over 2 steps; c) Cyanamide, NBS, t-BuOK, MeOH-THF (2:1), 55%; d) RuCl3 (1.5 mol%), H5IO6, DCM-MeCN-H2O
(2:2:1), 40%; e) HSO3Cl, DCM, 0°C; f) DIPEA, DCM, 40% over 2 steps; g) TFAA, DCM; h) K2CO3, MeOH, 75%.
3. Conclusion
In conclusion, we have developed five novel racemic routes (A,B,C,D and E) to a potent sulfoximine-based RORγt inverse agonist.
For exploratory medicinal chemistry, diversity-orientated routes B and C were particularly appealing as they facilitated late stage
variation, particularly from our key exploratory vector C-4 but also from S and N of the sulfoximine moiety.5 Out of the three routes
explored during the medicinal chemistry phase, Route B was retained and further optimised to deliver the first 100 g of our lead
candidate 24. Further route scouting led to the discovery of Route E, a much more efficient and convergent 6-step route offering
potential avenues to develop an enantioselective approach that is under investigation in our laboratories.
column: IA 5ꢀm x 4.6 x 250mm; flow rate= 4.0 mL/min; co-
solvent: EtOH 35%; isocratic conditions.
4. Experimental
4.1. General methods
4.2. Route A: First route to racemic sulfoximine target 1
1H NMR spectra were recorded on a BRUKER Biospin
AVANCE 400 spectrometer. Chemical shifts are reported as δ
values downfield from internal TMS in appropriate organic
solutions. The abbreviations used for explaining the multiplicities
were as follows: s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet, br = broad. High resolution mass (ESI HRMS) was
recorded on a Thermofisher Q Exactive™ Hybrid Quadrupole-
Orbitrap™ Mass Spectrometer. The relative purity and the mass
of the products were confirmed by UPLC-MS (220 nm to 420
nm) on a Waters acquity uplc photodiode array detector system
using the following conditions: Column, BEH C18 50*2.1 mm;
1.8 µm; Solvent A, water 0.1% formic acid or water ammonium
carbonate 2 g/l; Solvent B, CH3CN; flow rate, 0.8 ml/min; run
time, 2.2 min; gradient, from 5 to 95% solvent B; mass detector,
Waters SQ detector. For route D, in process controls were
performed using the previously described HPLC-MS conditions
and relative purity was assessed by HPLC on an Agilent system
using the following parameters: column Acquity BEH C18 1.7
µm 2.1*150 mm, flow rate= 0.8 mL/min, 14.0 min runs, solvent
system: MeCN+0.1% HCOOH, H2O +0.1% HCOOH, gradient:
10% to 35% MeCN from 0 to 10 min, and 35% to 95% from 10
to 14 min. All compounds for routes A, B and C were purified by
LC/MS on a waters Autopurification system using the following
conditions unless otherwise stated: Column, Xbridge C18
150*30mm, 5µm; Solvent A, water 0.1% formic acid or water
ammonium carbonate 2 g/l; Solvent B, CH3CN; flow rate, 50
ml/min; run time, 10 or 15 min; with adapted isocratic elution
mode; mass detector, Waters ZQ detector. Enantiomeric purity
was determined by chiral SFC under the following conditions:
4.2.1. 4-Ethyl-N-isobutylaniline (5)
To a stirred solution of 4-ethylaniline (94.8 mL, 0.76 mol), was
added iso-butyraldehyde (63.3 mL, 0.69 mol) in THF (1.0 L) and
the reaction mixture was stirred at 2-methyltetrahydrofuran
temperature for 30 minutes, cooled to 0 °C and NaBH(OAc)3
(162 g, 0.76 mol) was added portionwise while keeping the
temperature below 25 °C. The reaction mixture was stirred at
room temperature for 16 h, quenched with water (100 mL) and
extracted with EtOAc (2 x 200 mL). The organic phases were
combined, washed with brine (100 mL), dried over MgSO4 and
concentrated to dryness to afford a pale brown residue. The
residue was purified by flash chromatography eluting with
heptane-DCM (0-100%) to afford the title compound (5, 111 g,
90%) as
a pale orange oil: UPLC-MS (tR=1.10 min,
purity=100%), ESI m/z 179.20 (M+H)+; H NMR (DMSO-d6) δ
0.91 (d, J=6.6 Hz, 6H), 1.10 (t, J=7.6 Hz, 3H), 1.80 (m, 1H),
2.42 (q, J=7.6 Hz, 2H), 2.77 (dd, J=6.7, 5.5 Hz, 2H), 5.35 (t,
J=5.7 Hz, 1H), 6.40 – 6.56 (m, 2H), 6.77 – 7.01 (m, 2H).
1
4.2.2. 3-Bromo-N-(4-ethylphenyl)-N-isobutyl-4-methoxy-
benzenesulfonamide (4)
3-Bromo-4-methoxy-benzenesulfonyl chloride (4.83 g, 16.9
mmol) was added portionwise to a stirred solution of 4-ethyl-N-
isobutylaniline (5, 3.00 g, 16.9 mmol) and pyridine (8.19 mL,
102 mmol) in THF (60 mL). The reaction mixture was stirred at
r.t. for 5 h, quenched with water (10 mL) and extracted with
EtOAc (2 x 30 mL). The organic phases were combined, washed
with 1.0 M HCl (aq) (10 ml), brine (10 mL), dried over MgSO4

8
and concentrated to dryness to afford an orange residue. The
acetone)palladium (0) (0.53 g, 0.92 mmol) and sodium
ACCEPTED MANUSCRIPT
crude product was purified by flash chromatography eluting with
heptane-EtOAc (0-20%) to afford the title compound (4.69 g,
65%) as a white solid: UPLC-MS (tR=1.51 min, purity=100%),
methanethiolate (0.35 g, 5.06 mmol) in 1,4-dioxane (23.5 mL)
purged with argon, was added 4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene (0.21 g, 0.37 mmol). The reaction mixture was
heated at 90 °C for 16 h, cooled to r.t. and divided between water
(10 mL) and EtOAc (50 mL). The organic phase was collected,
washed with brine (2 x 5 mL), dried (MgSO4) and concentrated
to dryness. The residue was purified by flash chromatography
eluting with heptane-EtOAc (0-30%) to afford the title compound
(1.75 g, 59%) as a pale yellow solid: UPLC-MS (tR=1.48 min,
1
ESI m/z 426.10 / 429.08 (M+H)+; H NMR (CDCl3) δ 7.77 (d,
J=2.2 Hz, 1H), 7.50 (dd, J=8.6, 2.2 Hz, 1H), 7.23 – 7.11 (m,
2H), 7.02 – 6.95 (m, 2H), 6.92 (d, J=8.6 Hz, 1H), 3.98 (s, 3H),
3.30 (d, J=7.4 Hz, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.69 – 1.56 (m,
1H), 1.26 (t, J=7.6 Hz, 3H), 0.93 (d, J=6.7 Hz, 6H); 13C NMR
(101 MHz, DMSO-d6) δ 158.8, 143.6, 136.5, 131.7, 130.6, 128.9,
128.3, 112.8, 110.9, 57.1, 57.0, 27.7, 26.4, 19.7, 15.4.
purity=100%), ESI m/z 478.23 (M+H)+; H NMR (400 MHz,
1
CDCl3) δ 7.31 (dd, J=8.5, 2.2 Hz, 1H), 7.09 – 7.00 (m, 2H), 6.93
– 6.86 (m, 2H), 6.73 (d, J=8.5 Hz, 1H), 4.01 – 3.90 (m, 2H), 3.86
(d, J=6.4 Hz, 2H), 3.40 (m, 2H), 3.18 (dd, J=7.3, 5.3 Hz, 2H),
2.56 (q, J=7.6 Hz, 2H), 2.16 (s, 3H), 1.73 (m, 2H), 1.49
(overlapping s and m, 3H), 1.30 – 1.02 (m, 3H), 0.83 (d, J=6.8,
6H).
4.2.3. 3-Bromo-N-(4-ethylphenyl)-4-hydroxy-N-isobutyl-
benzenesulfonamide (11)
To
a stirred suspension of 3-bromo-N-(4-ethyl-phenyl)-N-
isobutyl-4-methoxy-benzenesulfonamide (4, 5.0 g, 11.7 mmol)
and Cs2CO3 (4.58 g, 14.1 mmol) in DMF (100 mL) , was added
thiophenol (1.32 mL, 12.9 mmol). The reaction mixture was
stirred at 100 °C, treated with a saturated aqueous solution of
sodium sulfite and dlitued with EtOAc (100 mL). The reaction
mixture was extracted with EtOAc (2 x 100 ml) and the organic
phases were combined, washed with water (2 x 50 mL), dried
over MgSO4 and concentrated to dryness. The residue was
purified by flash chromatography eluting with heptane-EtOAc
(0-80%) to afford the title compound (3.87 g, 80%) as a white
solid: UPLC-MS (tR=1.36 min, purity = 100%), ESI m/z 413.96 /
4.2.6. N-(4-Ethylphenyl)-N-isobutyl-3-(methylsulfinyl)-4-
((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (13)
To a stirred solution of
N-(4-ethyl-phenyl)-N-isobutyl-3-
methylsulfanyl-4-(tetrahydro-pyran-4-ylmethoxy)-benzene-
sulfonamide (500 mg 0.73 mmol) in DCM (7.0 mL) at 0 °C, was
added mCPBA (131 mg, 0.59 mmol). The reaction mixture was
stirred at r.t. for 30 minutes, quenched with a 10% (w/v) aqueous
solution of Na2S2O3 and extracted with DCM (20 mL). The
organic phases were washed with 0.1 M NaOH (aq), brine, dried
over MgSO4 and concentrated to dryness. The residue obtained
was purified by flash chromatography eluting with heptane-
EtOAc (0-100%) to afford the title compound (235 mg, 65%) as
a white solid: UPLC-MS (tR=1.32 min, purity=100%), ESI m/z
1
415.82 (M+H)+; H NMR (400 MHz, DMSO-d6) δ 11.44 (br s,
1H), 7.49 (d, J=2.3 Hz, 1H), 7.37 (dd, J=8.6, 2.3 Hz, 1H), 7.26 –
7.15 (m, 2H), 7.06 (d, J=8.6 Hz, 1H), 7.01 – 6.92 (m, 2H), 3.28
(d, J=7.3 Hz, 2H), 2.60 (p, J=7.6 Hz, 2H), 1.40 (m, 1H), 1.18 (t,
J=7.6 Hz, 3H), 0.84 (d, J=6.6 Hz, 6H); 13C NMR (101 MHz,
DMSO-d6) δ 158.2, 143.5, 136.6, 132.1, 129.0, 128.3, 116.4,
109.4, 57.1, 27.8, 26.4, 19.7, 15.4.
1
494.22 (M+H)+; H NMR (400 MHz, DMSO-d6) δ 7.78 – 7.59
(m, 2H), 7.34 (d, J=8.5 Hz, 1H), 7.26 – 7.11 (d, J=8.4 Hz, 2H),
7.01 – 6.89 (d, J=8.4 Hz, 2H), 4.18 – 3.97 (m, 2H), 3.90 (ddd,
J=11.6, 4.6, 1.9 Hz, 2H), 3.32 (m, 2H), 2.74 (s, 3H), 2.60 (q,
J=7.6 Hz, 2H), 2.05 (m, 1H), 1.65 (m, 2H), 1.51 – 1.26 (m, 3H),
1.18 (t, J=7.6 Hz, 3H), 0.85 (t, J=6.8 Hz, 6H).
4.2.4. 3-Bromo-N-(4-ethylphenyl)-N-isobutyl-4-((tetrahydro-2H-
pyran-4-yl)methoxy)benzenesulfonamide (12)
To
a stirred suspension of 3-bromo-N-(4-ethyl-phenyl)-4-
hydroxy-N-isobutyl-benzenesulfonamide (11, 2.20 g, 5.34 mmol)
and Cs2CO3 (3.48 g, 10.7 mmol) in DMF (44 mL), was added 4-
(bromomethyl)tetrahydropyran (1.15 g, 6.40 mmol). The reaction
mixture was stirred at 80 °C for 16 h, cooled to r.t. and quenched
with water (5.0 mL). The reaction mixture was extracted with
EtOAc (2 x 50 mL) and the organic phases were combined,
washed with a saturated solution of sodium carbonate, brine,
dried over MgSO4 and concentrated to dryness. The residue was
triturated with heptane and the solid obtained was collected by
filtration and dried to a constant weight in a vacuum oven at 40
°C to afford the title compound (2.36 g, 87%) as a white solid:
UPLC-MS (tR=1.52 min, purity=100%), ESI m/z 510.11 / 512.11
4.2.7. N-(4-Ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-
((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (1)
To
a
stirred solution of N-(4-Ethylphenyl)-N-isobutyl-3-
(methylsulfinyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzene-
sulfonamide (230 mg, 0.47 mmol) in DCM (11.5 mL) purged
with argon, was added 2,2,2-trifluoroacetamide (132 mg, 1.16
mmol), rhodium(II) acetate dimer (30.9 mg, 70 µmol),
magnesium oxide (93.9 mg, 2.33 mmol) and iodobenzene
diacetate (285 mg, 0.89 mmol). The reaction mixture was stirred
at r.t. for 16 h, filtered through a pad of Celite® and concentrated
to dryness. The residue was dissolved in MeOH (11.5 mL) and
K2CO3 (322 mg, 2.33 mmol) was added and the reaction mixture
was stirred for 30 minutes. Water (2.5 mL) was added and the
reaction mixture was extracted with EtOAc (2 x 20 mL). The
organic phases were combined, washed with brine, dried over
MgSO4 and concentrated to dryness. The residue was purified by
flash chromatography eluting with DCM-MeOH (0-5%) to afford
the title compound (91.4 mg, 39%) as a white solid: UPLC-MS
1
(M+H)+; H NMR (400 MHz, CDCl3) δ 7.77 (d, J=2.3 Hz, 1H),
7.46 (dd, J=8.6, 2.3 Hz, 1H), 7.21 – 7.09 (m, 2H), 7.04 – 6.93 (m,
2H), 6.87 (d, J=8.6 Hz, 1H), 4.07 (ddd, J=11.6, 5.0, 1.8 Hz, 2H),
3.94 (d, J = 6.4 Hz, 2H), 3.50 (td, J=11.6, 2.1 Hz, 2H), 3.29 (d,
J=7.3 Hz, 2H), 2.67 (q, J=7.6 Hz, 2H), 2.19 (m, 1H), 1.83 (m,
2H), 1.67 – 1.49 (m, 2H), 1.26 (t, J=7.6 Hz, 3H), 0.93 (d, J = 6.6
Hz, 6H).
1
(tR=1.33 min, purity=100%), ESI m/z 509.33 (M+H)+; H NMR
(400 MHz, DMSO-d6) δ 8.00 (d, J=2.4 Hz, 1H), 7.67 (dd, J=8.8,
2.4 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.01
(d, J=8.4 Hz, 2H), 4.41 (s, 1H), 4.11 (m, 2H), 3.96 – 3.83 (m,
2H), 3.39-3.24 (m, 4H), 3.19 (s, 3H), 2.61 (q, J=7.6 Hz, 2H),
2.21 – 2.02 (m, 1H), 1.83 – 1.66 (m, 2H), 1.58 – 1.27 (m, 3H),
1.18 (t, J=7.6 Hz, 3H), 0.86 – 0.84 (d, J=6.4 Hz, 6H); HRMS:
4.2.5. N-(4-Ethylphenyl)-N-isobutyl-3-(methylthio)-4-
((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (2)
To a stirred solution of 3-bromo-N-(4-ethyl-phenyl)-N-isobutyl-
4-(tetrahydro-pyran-4-ylmethoxy)-benzenesulfonamide (12, 2.35
g, 4.60 mmol), DIPEA (2.38 mL, 13.8 mmol), bis(dibenzylidene-

9
(M+H)+ calculated for C25H36N2O5S2 509.20656; found
509.21724.
added and the reaction mixture was allowed to warm to r.t. and
ACCEPTED MANUSCRIPT
stirred for 2 hours. The reaction mixture was extracted with
EtOAc (500 mL). The extract was washed brine, dried over
Na2SO4, concentrated to dryness and purified by flash
chromatography eluting with heptane-EtOAc (0-10%) to afford
the title compound (63 g, 46%) as a white solid: UPLC-MS
(tR=1.02 min, purity=100%), ESI m/z 281.03 / 282.96 (M(-
4.3. Route B: Route to building block 8
4.3.1. 1-Bromo-4-nitro-2-thiocyanatobenzene (14)
2-Bromo-5-nitroaniline (10, 470 g, 2.19 mol) and 6N HCl (4 L)
were stirred at r.t. until a homogeneous paste was obtained.
Sodium nitrite (167.4 g, 2.42 mol) dissolved in H2O (300 mL)
was added dropwise to the paste at 0 °C under an inert
atmosphere. After the addition was complete, the mixture was
stirred for an additional hour at 0 °C then added portionwise to a
solution of KSCN (295 g, 3.03 mol) and CuSCN (259 g, 2.13
mol) in water (1.50 L) at r.t. over a period of 2 hours and the
reaction mixture was stirred overnight. The resulting suspension
was filtered and the solid was washed with DCM (3 x 500 mL).
The filtrate was recuperated and washed with DCM (1000 mL)
and the combined organic extracts were washed with water (200
mL) and dried over MgSO4 and concentrated to dryness to afford
the title compound (352 g, 63%) as a yellow solid that was used
Cl)+OH)-H)-; H NMR (400 MHz, CDCl3) δ 7.77 (m, 1H), 7.62
1
(m, 2H), 2.57 (s, 3H), 13C NMR (101 MHz, DMSO) δ 148.2,
139.6, 132.6, 123.6, 122.5, 121.2, 15.4. HRMS: (M-H)-
calculated for C7H6BrClO2S2 298.8681; found 280.8952 (M(-
Cl)+OH)-H)-.
4.3.5. 4-Bromo-N-(4-ethylphenyl)-N-isobutyl-3-(methylthio)-
benzenesulfonamide (16)
To a stirred solution of 4-ethyl-N-isobutylaniline (5, 5.58 g, 31.5
mmol) and pyridine (15.3 mL, 189 mmol) in THF (190 mL) at
r.t., was added 4-bromo-3-(methylthio)benzenesulfonyl chloride
(9, 10.0 g, 31.5 mmol) in THF (47.5 mL) over 10 minutes. The
reaction mixture was stirred for 16 h at r.t. Water (5 mL) was
added and the reaction mixture was extracted with EtOAc (2 x
200 mL). The organic phases were combined, washed with a
saturated aqueous solution of NH4Cl, brine, dried over MgSO4
and concentrated to dryness to afford the title compound (12.9 g,
92%) as a pale yellow solid that was used without further
purification: UPLC-MS (tR=1.53 min, purity=100%), ESI m/z
443.95 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=8.2
Hz, 1H), 7.26 (dd, J=8.2, 2.0 Hz, 1H), 7.22 (d, J=8.2 Hz, 2H),
7.06 – 7.00 (d, J=8.2 Hz, 2H), 6.98 (d, J=2.0 Hz, 1H), 3.47 –
3.16 (m, 3H), 2.61 (q, J=7.6 Hz, 2H), 2.32 (s, 3H), 1.43 (m, 1H),
1.18 (t, J=7.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 6H); 13C NMR (CDCl3,
101 MHz) δ 144.2, 141.6, 137.8, 136.6, 132.8, 131.2, 128.7,
128.5, 128.4, 128.3, 125.8, 124.9, 123.9, 123.6, 58.3, 57.9, 41.8,
28.4, 26.8, 26.7, 19.8, 15.4, 15.3; HRMS: (M+H)+ calculated
for C6H3BrCl2O4S2 442.0431; found 442.0503.
1
without further purification: MS ESI m/z no ion detected; H
NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.24 (d, J=8.4 Hz, 2H),
7.88 (d, J=8.4 Hz Hz, 1H).
4.3.2. (2-Bromo-5-nitrophenyl)(methyl)sulfane (15)
NaOH (55.4 g, 1.39 mol) was dissolved in a mixture of water
(660 mL) and methanol (3400 mL). 1-Bromo-4-nitro-2-
thiocyanatobenzene (41, 352 g, 1.36 mol) was added under
stirring. After 30 minutes, the reaction mixture was cooled to 0-5
°C and sodium borohydride (25.7 g, 0.68 mol) was added and the
reaction mixture was stirred for a further 30 minutes in an ice
bath. Me2SO4 (176 g, 1.40 mol) was added dropwise and the
resulting mixture was stirred for 30 minutes then at r.t. for 30
minutes. The volatiles were removed and water was added to the
reaction mixture and the product was extracted in diethyl ether
(2.00 L). The extract was washed twice with water (100 mL),
dried over MgSO4 and concentrated to dryness to afford the title
compound (283 g, 84%, purity 65%) that was used in the
following step without further purification: MS ESI m/z no ion
4.3.6. 4-Bromo-N-(4-ethylphenyl)-N-isobutyl-3-(methylsulfinyl)-
benzenesulfonamide (17)
1
detected; H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.82 (d,
To a stirred solution of 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-
(methylthio)-benzenesulfonamide (16, 1.00 g 2.26 mmol) in
DCM (20 mL) at 0 °C, was added mCPBA (0.46 g, 2.03 mmol).
The reaction mixture was stirred at r.t. for 30 minutes, treated
with a 10% w/v aqueous solution of Na2S2O3 and extracted with
DCM (100 mL). The organic phase was washed with 0.1 M
NaOH (aq), brine, dried over MgSO4 and concentrated to
dryness. The crude product was purified by flash
chromatography eluting with heptane-EtOAc (0-100%) to afford
the title compound (784 mg, 76%) as a white solid: LCMS (tR =
J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 1H).
4.3.3. 4-Bromo-3-(methylthio)aniline
Fe (291 g, 5.20 mol) and NH4Cl (223 g, 4.16 mol) were added to
a solution of (2-bromo-5-nitrophenyl)(methyl)sulfane (258 g,
1.04 mol) in a mixture of CH3OH-H2O (2.00 L-1.00 L). The
reaction mixture was heated at refluxed for 2 hours, the
suspension was filtered, concentrated and the residue was
extracted with EtOAc (3 x 1.00 L). The organic layers were
combined, dried over MgSO4, concentrated and purified by flash
chromatography eluting with DCM-MeOH (0-5%) to afford the
title compound as a pale brown solid (120 g, 53 %): MS ESI m/z
1
1.35 min, purity = 100%), ESI m/z 460.04 (M+H)+; H NMR
(400 MHz, DMSO-d6) δ 7.98 (d, J=8.2 Hz, 1H), 7.74 (d, J=2.3
Hz, 1H), 7.66 (dd, J=8.2, 2.3 Hz, 1H), 7.20 (d, J=8.2 Hz, 2H),
7.01 (d, J=8.2 Hz, 2H), 3.44 – 3.20 (m, 2H), 2.79 (s, 3H), 2.60 (p,
J=7.6 Hz, 2H), 1.43 (m, 1H), 1.18 (t, J=7.6 Hz, 3H), 0.86
(overlapping d, J=6.6 Hz, 6H).
1
217 (M+H)+; H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.8 Hz,
1H), 6.45 (s, 1H), 6.34 (m, 1H), 3.70 (br s, 2H), 2.43 (s, 3H).
4.3.4. 4-Bromo-3-(methylthio)benzenesulfonyl chloride (9)
4.3.7. (E)-N-((2-bromo-5-(N-(4-ethylphenyl)-N-
isobutylsulfamoyl)phenyl)(methyl)-λ4-sulfaneylidene)-2,2,2-
trifluoroacetamide (18)
To a solution of concentrated HCl (300 mL) diluted with H2O
(160 mL) was added 4-bromo-3-(methylthio)aniline (100 g, 0.46
mol) and the mixture was cooled to -10 ° C. A solution of NaNO2
(34.8 g, 0.51 mol) in H2O (60 mL) was added and the resulting
slurry was stirred at -10 °C for 20 minutes then poured into a
freshly prepared chilled saturated solution of SO2 in AcOH (1000
mL). A solution of CuCl2 (25.9 g, 0.19 mol) in H2O (60 mL) was
A
solution
of
4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-
(methylsulfinyl)-benzenesulfonamide (12.0 g, 27.1 mmol) and
2,2,2-trifluoroacetamide (4.60 g, 40.7 mmol) in THF (24 mL)
was added to a suspension of 60% NaH (0.98 g, 24.4 mmol) in

10
THF (60 mL) at 0-5 °C over 10 minutes. Next, a solution of 1,3-
dibromo-5,5-dimethylhydantoin (11.6 g, 40.7 mmol) in THF (24
mL) was added while maintaining the temperature at 0-5 °C. The
reaction mixture was allowed to warm to r.t. and stirred for 2 h,
quenched with a 10% w/v aqueous solution of citric acid (5 mL)
and extracted with EtOAc (2 x 100 mL). The organic phases
were combined, washed with brine, dried over MgSO4 and
concentrated to dryness. The residue was triturated in a mixture
of isopropyl ether and the solid was collected by filtration and
dried to a constant weight to afford the title compound (11.0 g,
73%) as a white solid: UPLC-MS (tR=1.40 min, purity=100%),
calculated for C6H3BrCl2O4S2 350.8033; found 332.8320 (M(-
ACCEPTED MANUSCRIP
T
Cl)+OH)-H)-.
4.4.2. 2-Bromo-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-
benzenesulfonyl chloride (21)
A solution of 4-ethyl-N-isobutylaniline (5, 0.43 g, 2.17 mmol)
and pyridine (180 µL, 2.23 mmol) in THF (11.0 mL) at 0 °C was
added dropwise a solution of 4-bromobenzene-1,3-disulfonyl
dichloride (20, 1.00 g, 2.17 mmol) in THF (10 mL) at 0 °C. The
reaction mixture was stirred at r.t. for 20 h, quenched with 1.0 M
HCl (aq) (1 mL) and extracted with EtOAc (30 mL). The organic
phase was washed with water (2 x 5 mL), dried over MgSO4 and
concentrated to dryness. The residue was purified by flash
chromatography eluting with heptane-EtOAc (0-20%) to afford
the title compound (21, 0.86 g, 80%) as an off-white solid:
UPLC-MS (tR=1.49 min, purity=92%), ESI m/z 474.00 / 476.98
(M-(Cl+OH)H)-; 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d,
J=2.3 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.28 (dd, J=8.3, 2.3 Hz,
1H), 7.21 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 3.31 (d,
J=7.2 Hz, 2H), 2.61 (q, J=7.6 Hz, 2H), 1.42 (m, 1H), 1.18 (t,
J=7.6 Hz, 3H), 0.85 (d, J=6.7 Hz, 6H).
ESI m/z 553.07 / 554.97 (M+H)+; H NMR (400 MHz, DMSO-
1
d6) δ 8.12 (d, J=8.4 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H), 7.68 (dd,
J=8.4, 2.2 Hz, 1H), 7.28 – 7.13 (d, J=8.4 Hz, 2H), 7.05 – 6.85 (d,
J=8.4 Hz, 2H), 3.38 – 3.26 (m, 2H), 3.21 (dd, J=12.9, 6.6 Hz,
1H), 3.13 (s, 3H), 2.60 (q, J=7.6 Hz, 2H), 1.51 – 1.33 (m, 1H),
1.17 (t, J=7.6 Hz, 5H), 0.83 (2 d, J=6.6 Hz, 6H); 13C NMR
(CDCl3, 101 MHz) δ 177.4, 144.6, 140.8, 135.7, 134.3, 132.8,
128.8, 128.3, 126.4, 126.2, 58.5, 33.5, 28.3, 26.7, 25.0, 19.6,
15.1.
4.3.8. 4-Bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-
methylsulfonimidoyl)benzenesulfonamide (8)
4.4.3. 4-Bromo-N-(4-ethylphenyl)-N-isobutyl-3-mercapto-benz-
enesulfonamide (22)
Potassium carbonate (8.24 g, 59.6 mmol) was added to (E)-N-((2-
bromo-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)phenyl)-
(methyl)-λ4-sulfaneylidene)-2,2,2-trifluoroacetamide (18, 11.0 g,
19.9 mmol) in MeOH (110 mL) at 0 °C, followed by mCPBA
(6.68 g, 29.8 mmol) while maintaining a temperature of 0-5 °C.
The reaction mixture was allowed to warm to r.t. and was stirred
for 16 h. Water (5 mL) was added and the reaction mixture was
extracted with EtOAc (2 x 100 mL). The organic phases were
combined, washed with brine, dried over MgSO4 and
concentrated to dryness. The residue was triturated with
isopropyl ether and the solid was collected by filtration and dried
to a constant weight to afford the title compound (8, 5.07 g, 54%)
as a white solid: UPLC-MS (tR =1.35 min, purity=100%), ESI
A
solution
of
2-bromo-5-(N-(4-ethylphenyl)-N-isobutyl-
sulfamoyl)benzenesulfonyl chloride (1.50 g, 3.03 mmol) in
toluene (6.00 mL) was added dropwise to a stirred solution of
triphenylphosphine (2.39 g, 9.09 mmol) in toluene (15.0 mL) and
the reaction mixture was heated at 90 °C for 2 h, cooled to r.t.
and concentrated to dryness to afford the title compound (4.30 g,
(contaminated
with
excess
triphenylphospshine
and
triphenylphosphine oxide) as a white solid that was used directly
in the next step without further purification: UP-LCMS (tR=1.51
min, purity=89%), ESI- m/z 426.01 / 428.01 (M-H)-.
4.4.4.
4-Bromo-N-(4-ethylphenyl)-N-isobutyl-3-(methylthio)-
1
m/z 473.01 / 475.01 (M+H)+; H NMR (400 MHz, DMSO-d6) δ
benzenesulfonamide (16)
8.19 (d, J=2.4 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.61 (dd, J=8.3,
2.4 Hz, 1H), 7.29 – 7.14 (d, J=8.3 Hz, 2H), 7.09 – 6.95 (d, J=8.3
Hz, 2H), 4.73 (d, J=1.6 Hz, 1H), 3.33 (m, 2H), 3.26 (s, 3H), 2.61
(q, J=7.6 Hz, 2H), 1.44 (m, 1H), 1.18 (t, J=7.6 Hz, 3H), 0.86 (2
d, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 169.9, 144.2,
140.3, 136.6, 128.5, 128.4, 126.3, 122.4, 110.2, 67.3, 58.1, 48.7,
34.2, 30.6, 28.4, 26.8, 19.9, 15.3. HRMS: (M+H)+ calculated
for C19H25BrN2O3S2 473.04899; found 473.05634.
To a stirred solution of 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-
mercaptobenzenesulfonamide (22, 1.20 g, 2.80 mmol, 1.00 eq.)
in DMF (12 mL) at r.t. was added K2CO3 (0.43 g, 3.08 mmol)
followed by iodomethane (0.26 mL, 4.20 mmol). The reaction
mixture was stirred at r.t. for 20 minutes and water (5 mL) was
added. The reaction mixture was extracted with EtOAc (3 x 20
mL) and the organic phases were combined, washed with brine (3
x 5 mL) and concentrated to dryness. The residue was purified by
flash chromatography eluting with heptane-EtOAc (0-10%) to
afford the title compound (0.79 g, 64%) as a white solid: UPLC-
MS (tR=1.53 min, purity=100%), ESI m/z 441.85 / 443.90
4.4. Route C: Alternative route to sulfoximine building block
8
1
(M+H)+; H NMR (DMSO-d6) δ 7.83 (d, J=8.3 Hz, 1H), 7.26
4.4.1. 4-Bromobenzene-1,3-disulfonyl dichloride (20)
(dd, J=8.3, 2.1 Hz, 1H), 7.24 (d, J=8.3 Hz, 2H), 7.05 (d, J=8.3
Hz, 2H), 6.99 (d, J=2.1 Hz, 1H), 3.30 (m, 2H), 2.61 (q, J=7.6
Hz, 2H), 2.32 (s, 3H), 1.44 (m, 1H), 1.18 (t, J=7.6 Hz, 3H), 0.85
(d, J=6.7 Hz, 6H).
A mixture of 4-bromobenzene sulfonyl chloride (19, 50.0 g, 197
mmol) and chlorosulfonic acid (260 mL, 3.91 mol) was stirred
for 6 h at 150 °C. The reaction mixture was poured slowly in a
1.5 L bath of ice-water [CAUTION: Strongly exothermic]. The
reaction mixture was extracted with DCM (500 mL and 200 mL)
and the organic phases were combined, dried over MgSO4 and
concetrated to dryness. The solid was suspended in a mixture of
EtOAc-heptane (1:10, 330 mL) and the resulting grey precipitate
was collected by filtration and dried to a constant weight to
afford the title compound (20, 54.0 g, 78%) as a grey solid:
UPLC-MS (tR =1.26 min, purity=98%), ESI m/z 332.78 / 334.73
4.5. Exploration of C-4 vector by SNAr
4.5.1. N-(4-Ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-
((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (1)
NaH (60% dispersion in mineral oil, 0.51 g, 12.7 mmol) was
added portionwise to (tetrahydropyran-4-yl)methanol (1.08 g,
9.29 mmol) in DMF (80 mL) at 0 °C followed by 4-bromo-N-(4-
ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)benzene-
sulfonamide (4.00 g, 8.45 mmol). The reaction mixture was
allowed to warm to r.t. and stirred overnight. Water (5 mL) was
added and the reaction mixture was extracted with EtOAc (2 x
1
(M-(Cl+OH)H)-; H NMR (CDCl3) δ 8.81 (d, J=2.0 Hz, 1H),
8.18 (d, J=2.0 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 144.32,
143.90, 138.26, 132.85, 129.04, 129.01. HRMS: (M-H)-

11
100 mL). The organic phases were combined, washed with brine,
dried over MgSO4 and concentrated to dryness. The residue was
purified by flash chromatography eluting with DCM-MeOH (0-
5%) to afford the title compound (1, 3.63 g, 84%) as a white
solid: UPLC-MS (tR=1.32 min, purity=100%), ESI m/z 510.16
(M+H)+; NMR analyses were identical to 1.
MHz) δ 169.87, 144.21, 140.34, 136.64, 133.38, 128.47,
ACCEPTED MANUSCRIPT
128.42, 126.28, 123.19, 122.40, 110.15, 77.32, 77.21, 77.01,
76.69, 67.29, 58.07, 48.74, 34.18, 30.59, 28.41, 26.79, 19.86,
15.26.
4.6. Route D: Optimized route to deliver 100 g of 24
4.6.1. 4-Ethyl-N-isobutylaniline hydrochloride (5.HCl)
4.5.2.
(S)-N-(4-Ethylphenyl)-N-isobutyl-3-(S-methylsulfon-
In a 15 L double jacketed reactor 4-ethylaniline (442 mL, 3.56
mol, 1.00 eq.) and isobutyraldehyde (324 mL, 3.56 mol, 1.00 eq.)
were charged at 23 °C followed by tert-butylmethylether (4.50
L). Reaction mixture turned to a deep red solution. This solution
was stirred at 23 °C for 1 h and then cooled to 15 °C. At this
temperature solid sodium triacetoxyborohydride (1.13 Kg, 5.34
mol, 1.50 eq.) was added portionwise (~200 g per portions) over
1 hour. An exotherm was observed after each addition and the
internal temperature was kept below 25 °C between each
addition. After the last addition the reaction mixture was allowed
to warm to 23 °C and stirred at this temperature for 18 h. LC/MS
analysis after this time revealed complete conversion. To the
reaction medium was added water (2.50 L) (no exotherm or gaz
evolution was observed) and the mixture was stirred at 23 °C for
15 minutes. Phases were separated and the aqueous layer was
discarded. The organic layer was washed with water (2.50 L).
The reactor was cleaned and the organic layer re-charged. To this
solution was added at 23 °C 3M HCl in cyclopentylmethylether
(1.40 L, 3.00 M, 4.27 mol, 1.20 eq.). Crystallization occurred
rapidly and the suspension was stirred for 2 h at 23 °C. The solid
was collected by filtration and the cake washed with TBME (2 x
1.00 L) collected and dried under vacuum at 45 °C for 18 h to
afford the title compound (575 g, 75% yield) as a white
crystalline solid: mp = 147 °C; UPLC-MS (tR=1.11 min,
purity=100%), ESI m/z 179.1 (M+H)+; 1H NMR (400 MHz,
CDCl3) δ 11.21 (s, 2H), 7.48 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.4
Hz, 2H), 3.01 (t, 2H), 2.59 (q, J=7.6 Hz, 2H), 2.09 (m, 1H), 1.17
(t, J=7.6 Hz, 3H), 0.98 (d, J=6.7 Hz, 6H); 13C NMR (101 MHz,
DMSO) δ 143.9, 135.0, 129.1, 122.6, 57.8, 27.7, 25.3, 20.2, 15.6.
imidoyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzene-
sulfonamide (24) and (R)-N-(4-ethylphenyl)-N-isobutyl-3-(S-
methylsulfon-imidoyl)-4-((tetrahydro-2H-pyran-4-
yl)methoxy)benzene-sulfonamide (25)
A solution of 1 (2.60 g, 5.11 mmol) in a mixture of MeOH-
MeCN-DCM (52 mL:52 mL:13 mL) was purified by stack
injections using SFC at 20 mg / mL (PIC Solution Preparative
SFC; column: Chiralpak IA, 5 µM x 4.6 x 250 mm; eluent: 65%
CO2 / 35% iso-propanol; flow rate, 4 mL / min.; 100 Bar) to
afford 24 as the first eluting fraction (0.92 g, 35.4%): (tR=2.49
min, purity=100%), [α]D20 = +0.6° (c = 2 g/L, EtOH); and 25 as
the second eluting fraction (0.97 g, 37.3%): (tR=5.31 min,
purity=100%), [α]D20 = -0.6° (c = 2 g/L, EtOH).
4.5.3. (5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)-2-((tetrahydro-
2H-pyran-4-yl)methoxy)phenyl)(methyl)(oxo)-l6-sulfaniminium
((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-
yl)methanesulfonate (25.camphorsulfonate)
To a solution of 25 (from elution fraction 2) (0.50 g, 0.9 mmol)
in DCM (3.0 mL) at 23 °C was added a solution of (1R)-(−)-10-
camphorsulfonic acid (228 mg, 0.9 mmol) in DCM (3.0 mL). The
solution was stirred at 23 °C for 24 h and evaporated to dryness
to yield a white solid. In a 20 mL vial, the solid was suspended in
10 mL of acetonitrile and 5 mL of DCM were added until
complete dissolution occurred. The vial was then sealed and the
screw cap perforated with a needle. The vial was then allowed to
settle for several days at 23°C while large needle shape crystals
slowly formed. Crystals of 25.camphorsulfonate were collected
by filtration, dried under vacuum and used as such for single
4.6.2. 4-Bromo-N-(4-ethylphenyl)-N-isobutyl-3-(methylthio)-
benzenesulfonamide (16)
1
crystal X-Ray analysis. H NMR (400 MHz, DMSO-d6) δ 7.92
(d, J = 2.5 Hz, 1H), 7.88 (dd, J = 8.8, 2.4 Hz, 1H), 7.56 (d, J =
8.9 Hz, 1H), 7.23 (d, J = 8.3 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H),
4.27 – 4.12 (m, 2H), 3.96 – 3.87 (m, 2H), 3.70 (s, 3H), 3.37 (td, J
= 11.7, 2.2 Hz, 2H), 3.30 (dd, J = 7.3, 3.8 Hz, 2H), 2.89 (d, J =
14.7 Hz, 1H), 2.73 – 2.56 (m, 3H), 2.39 (d, J = 14.7 Hz, 1H),
2.29 – 2.20 (m, 1H), 2.20 – 2.09 (m, 1H), 1.94 (t, J = 4.6 Hz,
1H), 1.90 – 1.61 (m, 5H), 1.51 – 1.24 (m, 6H), 1.19 (t, J = 7.6
Hz, 3H), 1.05 (s, 3H), 0.86 (dd, J = 6.6, 3.6 Hz, 6H), 0.75 (s, 3H)
In a 15 L double jacketed reactor was introduced 4-ethyl-N-
isobutylaniline hydrochloride (183 g, 0.86 mol, 1.05 eq.)
followed by a suspension of 4-bromo-3-(methylthio)benzene-1-
sulfonyl chloride 9 (260 g, 0.82 mol, 1.00 eq.) in acetonitrile
(1.73 L). The reaction mixture was warmed up to 50 °C and N,N-
diisopropylethylamine (352 ml, 2.05 mmol, 2.50 eq.) was added
slowly. An exotherm was observed upon addition with internal
temperature rising to 60 °C. The reaction mixture turned to a
solution and was stirred at 50 °C for 3 h. LC/MS analysis after
this time revealed complete conversion with less than 3% of
starting material remaining. The reaction mixture was warmed up
to 70 °C and slowly was added 1N aqueous HCl (1.70 L). A
precipitate formed rapidly. The suspension was stirred at 50 °C
for 30 minutes and allowed to cool down to 23°C over 1 h. The
solid was collected by filtration, washed with water and dried on
the filter for 2 h with a flux of N2. The crude wet solid was
charged in the clean reactor and isopropanol (3.70 L) was added.
The suspension was warmed to 80 °C and turned to a solution.
The solution was stirred under reflux for 15 minutes and allowed
to cool down to 23 °C slowly over 4 h. The solid was collected
by filtration, washed with 1.00 L of iPrOH and dried under
vacuum at 45 °C to afford the title compound (320 g, 88% yield)
as a beige solid: mp = 114 °C; HPLC-MS (tR=11.9 min,
purity=98.9%), ESI m/z 443.5 (M+H)+; 1H NMR (400 MHz,
DMSO-d6) δ 7.83 (d, J=8.3 Hz, 1H), 7.26 (dd, J=8.3, 2.2 Hz,
1H), 7.22 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.2 Hz, 2H), 6.98 (d,
4.5.4. N-(4-Ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-
((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (23)
A
solution of 4-bromo-N-(4-ethylphenyl)-N-isobutyl-3-(S-
methylsulfonimidoyl)benzene-sulfonamide (8, 15.0 mg, 30 µmol)
in (tetrahydro-2H-pyran-4-yl)methanamine (11.3 µl, 0.10 mmol)
was stirred overnight and purified directly by mass-triggered
preparative LC/MS to afford the title compound (23, 15.0 mg,
93%) as a white solid: UPLC-MS (tR=1.30 min, purity=100%),
1
ESI m/z 509.33 (M+H)+; H NMR (400 MHz, DMSO-d6) δ 7.84
(t, J=5.5 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.50 (d, J=9.0 Hz,
1H), 7.20 (d, J=8.1 Hz, 2H), 7.00 (d, J=7.9 Hz, 2H), 6.95 (d,
J=8.9 Hz, 1H), 4.74 (s, 1H), 3.89 (dd, J=11.6, 4.0 Hz, 2H), 3.24
(dd, J=7.4, 3.3 Hz, 2H), 3.17 (q, J=6.8 Hz, 2H), 3.01 (s, 3H),
2.61 (q, J=7.4 Hz, 2H), 1.87 (s, 1H), 1.66 (d, J=13.3 Hz, 2H),
1.46 – 1.37 (m, 1H), 1.28 (dd, J=14.5, 10.3 Hz, 2H), 1.18 (t,
J=7.7 Hz, 3H), 0.84 (d, J=6.7 Hz, 6H); 13C NMR (CDCl3, 101

12
J=2.0 Hz, 1H), 3.35 – 3.28 (m, 2H), 2.61 (q, J=7.6 Hz, 2H), 2.32
(s, 3H), 1.43 (m, 1H), 1.18 (t, J=7.6 Hz, 3H), 0.85 (d, J=6.6 Hz,
6H); 13C NMR (101 MHz, DMSO) δ 143.6, 141.3, 137.5, 136.2,
133.2, 128.3, 128.1, 125.0, 124.0, 122.9, 56.8, 27.6, 26.3, 19.5,
15.3, 14.5.
and the cake washed with 2 x 500 mL of diisopropylether.
ACCEPTED MANUSCRIPT
The solid was dried under vacuum at 45 °C for 18 h to afford the
title compound (408 g, 82 %, 96.1 HPLC A% purity) as a beige
solid: mp = 167°C; HPLC-MS (tR =9.7 min, purity=96.1%), ESI
m/z 498.1 (M+H)+, H NMR (400 MHz, DMSO-d6) δ 8.30 (d,
1
J=8.0 Hz, 1H), 7.98 – 7.90 (m, 2H), 7.23 (d, J=8.4 Hz, 2H), 6.99
(d, J=8.4 Hz, 2H), 3.89 (s, 3H), 3.44 – 3.21 (m, 2H), 2.61 (q,
J=7.5 Hz, 2H), 1.45 (m, 1H), 1.18 (t, J=7.6 Hz, 3H), 0.88 (d,
J=6.6 Hz, 3H), 0.84 (d, J=6.6 Hz, 3H), 13C NMR (101 MHz,
DMSO) δ 144.2, 137.9, 137.9, 136.3, 135.7, 134.4, 130.2, 128.8,
128.3, 125.5, 111.0, 57.5, 40.9, 27.8, 26.4, 19.6, 19.6, 15.4.
HRMS: (M+H)+ calculated for C20H24BrN3O3S2 498.04424;
found 498.05118.
4.6.3.
4-Bromo-3-(N-cyano-S-methylsulfinimidoyl)-N-(4-
ethylphenyl)-N-isobutylbenzenesulfonamide (27)
In a 15 L double jacketed reactor were charged 16 (540 g, 1.22
mol, 1.00 eq.) and potassium tert-butoxide (164 g, 1.46 mol, 1.20
eq.) followed by THF (2.70 L) and methanol (4.80 L). At 23 °C
was added a solution of cyanamide (66.7 g, 1.59 mol, 1.30 eq.) in
methanol (540 mL). No exotherm was observed. Solid N-
bromosuccinimide (326 g, 1.83 mol, 1.50 eq.) was added
portionwise over 30 min. (a slight exotherm from 23 to 26 °C
was observed). A yellow precipitate formed rapidly and the
suspension was stirred for 18 h at 23 °C. LC/MS analysis after
this time revealed complete conversion. The reaction mixture was
diluted with 3.5 L of 5% aqueous Na2S2O5 solution. The
suspension turned white (slight exotherm observed) and was
cooled down to 5 °C. The solid was collected by filtration,
washed with 1.0 L of water and dried under high vacuum at 45
°C for 36 h to afford the title compound (525 g, 89% yield) as a
4.6.5.
4-Bromo-3-(N-carbamoyl-S-methylsulfonimidoyl)-N-(4-
ethylphenyl)-N-isobutylbenzenesulfonamide (29)
In a 10 L double jacketed reactor was introduced 28 (445 g, 0.89
mol, 1.00 eq.) followed by dichloromethane (1.30 L) and water
(32.1 ml, 1.79 mol, 2.00 eq.). To this solution was added slowly
at 23 °C trifluoroacetic acid (2.2 L) (no exotherm was observed).
The solution turned dark brown and was stirred at 23 °C for 20 h.
LC/MS analysis after this time revealed complete conversion.
The solution was cooled down to 0 °C and water (4.0 L) was
added slowly, keeping the internal temperature below 25 °C.
Then dichloromethane (1.0 L) was added and phases were
separated. The aqueous layer was extracted with dichloromethane
(1.0 L) and discarded. The combined organic layers were washed
with water (2 x 1.0 L). Phases were separated and the organic
white solid: mp
=
191 °C; HPLC-MS (tR=9.3 min,
purity=97.1%), ESI m/z 504.0 (M+Na)+; H NMR (400 MHz,
DMSO-d6) δ 8.10 (d, J=8.3 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.75
(dd, J=8.3, 2.2 Hz, 1H), 7.24 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.3
Hz, 2H), 3.37 – 3.28 (m, 2H), 3.09 (s, 3H), 2.61 (q, J=7.6 Hz,
2H), 1.43 (m, 1H), 1.18 (t, J=7.6 Hz, 3H), 0.86 (d, J=6.6 Hz,
6H); 13C NMR (101 MHz, DMSO) δ 144.0, 138.7, 138.7, 136.0,
135.2, 132.2, 128.7, 128.3, 126.2, 125.3, 119.7, 57.4, 35.8, 27.7,
26.4, 19.6, 15.3; HRMS: (M+H)+ calculated for
C20H24BrN3O2S2 482.04933; found 482.05649.
1
layer (slurry) was recharged in the reactor. 1.5
L of
dichloromethane were distilled off and then 3.0 L of iPrOH
followed by 1.0 L of water were added. The suspension was
stirred at 23 °C for 1 h and the solid collected by filtration and
dried under vacuum at 45 °C for 18 h to afford the title
compound (327 g, 71% yield): mp = 211 °C; HPLC-MS (tR=7.7
min, purity=97.6%), ESI m/z 515.1 (M+H)+; 1H NMR (400 MHz,
DMSO-d6) δ 8.08 (d, J=8.1 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 7.70
(dd, J=8.3, 2.3 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.3
Hz, 2H), 6.51 (s, 1H), 6.16 (s, 1H), 3.45 (s, 3H), 3.29 (d, J=7.3
Hz, 2H), 2.61 (q, J=7.5 Hz, 2H), 1.43 (m, 1H), 1.18 (t, J=7.6 Hz,
3H), 0.87 (d, J=2.5 Hz, 3H), 0.85 (d, J=2.6 Hz, 3H); 13C NMR
(101 MHz, DMSO) δ 159.8, 143.9, 140.8, 137.7, 136.5, 136.0,
132.2, 130.1, 128.7, 128.4, 124.2, 57.6, 40.8, 27.7, 26.4, 19.6,
15.3; HRMS: (M+H)+ calculated for C20H26BrN3O4S2
516.05481; found 516.06201.
4.6.4. 4-Bromo-3-(N-cyano-S-methylsulfonimidoyl)-N-(4-ethyl-
phenyl)-N-isobutylbenzenesulfonamide (28)
In a 15 L double jacketed reactor was charged 27 (483 g, 1.00
mol, 1.00 eq.) followed by dichloromethane (1.93 L) and
acetonitrile (1.93 L). To this solution was added ruthenium(III)
chloride hydrate (3.39 g, 0.02 mol, 0.02 eq.) followed by a
solution of periodic acid (274 g, 1.20 mol, 1.20 eq.) in water (966
mL). The black suspension was stirred at 23 °C for 1 h. HPLC
analysis after this time revealed 6% remaining starting material.
Extra periodic acid (12.0 g, 0.05 mol, 0.05 eq) was added (solid)
and stirring was pursued for 1 h. LCMS analysis after this time
revealed complete conversion. Water (2.00 L) was added to the
solution and layers were separated. The aqueous layer was
extracted with DCM (1.00 L) and the combined organic layers
were charged in the reactor. A solution of sodium metabisulfite
(300 g, 1.58 mol, 1.58 eq.) in 3.00 L of water was added.
Biphasic mixture was stirred vigorously for 15 minutes (color
changed from dark-brown to yellow) and phases were separated.
The aqueous layer was extracted with 500 mL of
dichloromethane. Combined organic layers were charged in the
reactor, washed with 1.00 L of water and filtered to remove
mechanical impurities. The reactor was cleaned and the filtrate
was charged and distilled to a residual volume of 2.00 L. 3.00 L
of iPrOH were added and distillation was pursued to a residual
volume of 2.00 L. 3.00 L of iPrOH were added and distillation
was pursued to a residual volume of 2.00 L. 3.80 L of
diisopropylether were slowly added to the reaction mixture at 80
°C followed by acetone (300 mL) to solubilize crusts. The
solution was then allowed to cool down to 23 °C over 48 h while
a white solid crystallized. The solid was collected by filtration
4.6.6.
(S)-N-(4-ethylphenyl)-N-isobutyl-3-(S-methyl-sulfonim-
idoyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzene-
sulfonamide (24)
In a 4 L double jacketed reactor were charged 29 (405 g, 0.73
mol, 1.00 eq.) and cesium carbonate (831 g, 2.55 mol, 3.50 eq.)
followed by a solution of 4-(hydroxymethyl)tetrahydropyran
(339 g, 2.92 mol, 4.00 eq.) in 1,4-dioxane (2.63 L). This
suspension was warmed to reflux (105 °C) and 1.4 L of 1,4-
dioxane were distilled off in 7 h. Distillation was stopped after
this time and the suspension stirred at 100 °C for 24 h. LC/MS
analysis after this time revealed complete conversion. The
reaction mixture was cooled down to 80 °C and cesium carbonate
was removed by filtration. The solid was rinse with 2 x 500 mL
of acetone. The filtrate was charged in the clean reactor and
heated to 60 °C to yield a clear dark mixture. To this solution was
added a solution of p-toluenesulfonic acid monohydrate (166 g,
0.88 mol, 1.20 eq.) in acetone (750 mL). A solid formed rapidly
and the suspension was allowed to cool down to 23 °C over 48 h.
The solid was collected by filtration, washed with 500 mL of
acetone and dried overnight under vacuum to yield a beige solid

13
(386 g). This solid was charged in the clean reactor and
suspended in 2-methyltetrahydrofuran (3.0 L). The suspension
was warmed to 50 °C and half of a solution of sodium hydroxide
(117 g, 2.92 mol, 4.00 eq.) in water (1.5 L) was added. When
complete solubility was reached, phases were separated at 50 °C.
The organic layer was washed with the second half of the NaOH
solution and finally with 500 mL of water. The mixture was then
warmed to reflux and 2-methyltetrahydrofuran was distilled off
to a final volume of 200 mL. tert-butylmethylether (1.0 L) was
added slowly to the hot reaction mixture followed by acetone
(830 mL) keeping the internal temperature above 50 °C to ensure
full solubility. Then 2.30 L of tert-butylmethylether were slowly
added and the solution stirred for 45 min under reflux. The
solution was allowed to cool to 23 °C over 18 h. The suspension
was then cooled to 5 °C and stirred at this temperature for 2 h.
The solid was collected by filtration at 5 °C and dried under
vacuum at 45 °C for 24 h to afford 1 (racemate, 279 g, 70%
yield, 98.5 HPLC A% purity) as a white solid. Chiral
separation: Enantiomer separation was performed by our partner
Kyrapharm on 250 g of the racemate under the following
conditions: Stationnary phase = CHIRALPACK AD, semi-
automated Prochrom LC200 apparatus, 200 mm DAC column
packed at 100 bars. 17 injections were performed using EtOH as
the eluent with a 40 L/h flow rate. Fractions containing the
desired enantiomer was evaporated to dryness under reduced
pressure to afford the title compound (121 g) as a white solid: mp
= 155°C; LC/MS (tR=1.61 min), HPLC-MS (tR=7.9 min,
purity=99.6%), ESI m/z 509.2 (M+H)+; Chiral SFC (tR=2.4 min,
compound (78.0 g, 92% yield) as a white solid: UPLC-MS
1
ACCEPTED MANUSCRIPT
(tR=1.66 min), ESI m/z 239.3.2 (M+H)+, H NMR (400 MHz,
DMSO-d6) δ 7.19 – 7.05 (m, 2H), 7.03 – 6.86 (m, 2H), 3.93 –
3.81 (m, 4H), 3.34 (td, J=11.7, 2.2 Hz, 2H), 2.36 (s, 3H), 2.07 –
1.88 (m, 1H), 1.70 (ddd, J=12.9, 4.1, 2.0 Hz, 2H), 1.38 (dtd,
J=13.3, 11.8, 4.5 Hz, 2H); 13C NMR (101 MHz, DMSO) δ 154.7,
127.2, 125.4, 124.8, 121.2, 111.3, 72.5, 66.8, 34.7, 29.3, 13.3;
HRMS: (M+H)+ calculated for C13H18O2S 239.10275; found
239.10994 (M+H)+.
4.7.2.
N-(Methyl(2-((tetrahydro-2H-pyran-4-yl)methoxy)-
phenyl)-λ4-sulfaneylidene)cyanamide (32)
To a stirred solution of 31 (30.0 g, 0.13 mol, 1.00 eq.) and
potassium tert-butoxide (16.9 g, 0.15 mol, 1.20 eq.) in THF (210
mL) at 23 °C was added a solution of cyanamide (6.88 g, 0.16
mol, 1.30 eq.) in methanol (90.0 mL). No significant exotherm
was observed. Solid N-bromosuccinimide (33.6 g, 0.19 mol, 1.50
eq.) was added portionwise. An exotherm was observed after
each addition, total addition time of 30 minutes with internal
temperature rising to 45 °C. LC/MS analysis after 10 minutes
revealed complete conversion. The reaction mixture was diluted
with 10% Na2S2O5 (200 mL) and evaporated under reduced
pressure to remove the organic solvents. The aqueous layer was
extracted with 2-methyltetrahydrofuran (2 x 200 mL) and the
combined organic layers were dried and evaporated to dryness to
yield an orange liquid which was further purified by
chromatography eluting with DCM-EtOAc (0-30%) to afford the
title compound (19.1 g, 54% yield) as a white crystalline solid:
UPLC-MS (tR=1.15 min,), ESI m/z 279.0 (M+H)+; 1H NMR (400
MHz, DMSO-d6) δ 7.82 (dd, J=7.9, 1.6 Hz, 1H), 7.65 (ddd,
J=8.6, 7.4, 1.6 Hz, 1H), 7.34 – 7.26 (m, 2H), 4.10 – 3.99 (m, 2H),
3.95 – 3.85 (m, 2H), 3.37 (dd, J=11.8, 2.2 Hz, 2H), 3.05 (s, 3H),
2.14 – 1.99 (m, 1H), 1.76 – 1.62 (m, 2H), 1.47 – 1.28 (m, 2H).
1
purity=99.9% ee); H NMR (400 MHz, DMSO-d6) δ 8.00 (d,
J=2.5 Hz, 1H), 7.67 (dd, J=8.8, 2.5 Hz, 1H), 7.39 (d, J=8.8 Hz,
1H), 7.20 (d, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz, 2H), 4.58 (br s,
1H), 4.10 (dt, J=11.8, 5.8 Hz, 2H), 3.90 (dd, J=11.0, 4.1 Hz, 2H),
3.44 – 3.21 (m, 4H), 3.20 (s, 3H), 2.61 (q, J=7.6 Hz, 2H), 2.17 –
2.03 (m, 1H), 1.73 (d, J=9.9 Hz, 2H), 1.41 (q, J=11.0, 9.7 Hz,
3H), 1.18 (t, J=7.6 Hz, 3H), 0.85 (dd, J=6.6, 4.4 Hz, 6H); 13C
NMR (101 MHz, DMSO-d6) δ 159.0, 143.5, 136.4, 133.6, 132.1,
129.2, 128.5, 128.5, 128.3, 114.1, 73.8, 66.7, 57.2, 43.7, 34.4,
29.1, 29.1, 27.7, 26.4, 19.6, 15.3.
4.7.3. N-(Methyl(oxo)(2-((tetrahydro-2H-pyran-4-yl)methoxy)-
phenyl)-λ6-sulfaneylidene)cyanamide (33)
To a stirred solution of 32 (11.0 g, 0.04 mol, 1.00 eq.) and
ruthenium(III) chloride hydrate (267 mg, 1.18 mmol, 0.03 eq.) in
acetonitrile (110 mL) and dichloromethane (44 mL) at 23 °C was
added a solution of periodic acid (9.91 g, 0.04 mol, 1.10 eq.) in
water (44.0 mL). LC/MS analysis after 1 h revealed complete
conversion. The reaction was quenched by addition of 10%
Na2S2O5 and diluted with DCM. Phases were separated and the
aqueous layer washed with DCM. Combined organic layers were
washed with 10% Na2S2O5, dried and evaporated to dryness to
yield a brown oil. The oil was purified by flash chromatography
on SiO2 eluting with DCM-EtOAc (0-30%) to afford the title
compound (4.75 g, 40 %) as a white crystalline solid: UPLC-MS
(tR=1.18 min), ESI m/z 295.0 (M+H)+; 1H NMR (400 MHz,
DMSO-d6) δ 7.90 (dd, J=8.0, 1.7 Hz, 1H), 7.85 (ddd, J=9.0, 7.3,
1.8 Hz, 1H), 7.47 – 7.42 (m, 1H), 7.29 (td, J=7.8, 0.9 Hz, 1H),
4.12 (ddd, J=39.6, 9.4, 6.3 Hz, 2H), 3.90 (ddd, J=11.2, 4.5, 1.9
Hz, 2H), 3.67 (s, 3H), 3.43 – 3.31 (m, 2H), 2.20 – 2.05 (m, 1H),
1.83 – 1.62 (m, 2H), 1.51 – 1.27 (m, 2H).
4.7. Route E: Last generation route to 1
4.7.1.
4-((2-(Methylthio)phenoxy)methyl)tetrahydro-2H-pyran
(31)
In a 1 L flask was charged triphenylphosphine (112 g, 0.43 mol,
1.20 eq.), 4-(hydroxymethyl)tetrahydropyran (45.6 g, 0.39 mol,
1.10 eq.) and 2-methylsulfanyl-phenol (50 g, 0.36 mol, 1.00 eq.)
in toluene (500 mL). The reaction mixture was warmed to 50 °C.
At this temperature was added slowly diethyl azodicarboxylate
(170 g, 0.39 mol, 1.10 eq.) (40% w/w solution in toluene). An
exotherm was observed upon addition and the temperature of the
reaction mixture was kept below 65 °C. The reaction mixture was
stirred overnight at 23 °C. LC/MS analysis after this time
revealed complete conversion. The slurry was warmed to 50-60
°C and magnesium chloride (74.7 g, 0.78 mol, 2.20 eq.) (70
microns from Aldrich) was added. Stirring was pursued for 1 h.
The reaction mixture was cooled to 23 °C and filtered. The cake
was washed with 50 mL of toluene. To the filtrate was added 500
mL of heptane and stirring was pursued for 2 h at 23 °C. The
reaction mixture was filtered and evaporated to dryness under
reduced pressure. The residue was triturated in 500 mL of a 8:2
heptane/toluene mixture. A solid formed and was removed by
filtration. The filtrate was evaporated to dryness to yield and
orange oil. This oil was triturated in 250 mL of heptane and
crystallized rapidly as a white solid. Trituration was pursued for
1 h at 23 °C and the solid collected by filtration to afford the title
4.7.4. 3-(N-Cyano-S-methylsulfonimidoyl)-N-(4-ethylphenyl)-N-
isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzene-
sulfonamide (34)
To 33 (300 mg, 1.02 mmol, 1.00 eq.) at 10 °C was added pure
chlorosulfonic acid (1.36 mL, 20.0 mmol, 20.0 eq.) and the
solution was stirred at 23 °C. LCMS analysis after 1.5 h
(pyrrolidine quench) revealed complete conversion. The reaction
mixture was slowly poured over ice and extracted with DCM.

14
Phases were separated and the organic layer was washed with
water, dried and evaporated to dryness. The white solid obtained
References and notes
ACCEPTED MANUSCRIPT
1. a) Greb, J. E.; Goldminz, A. M.; Elder, J. T.; Lebwohl, M. G.;
was dissolved in DCM (6.0 mL) and N,N-diisopropylethylamine
(0.53 mL, 3.05 mol, 3.00 eq.) was added followed by 4-ethyl-N-
isobutylaniline hydrochloride (240 mg, 1.12 mol, 1.10 eq.). The
reaction mixture was stirred at 23 °C for 18 h. HPLC analysis
after 18 h (pyrrolidine quench) revealed complete conversion.
The reaction mixture was diluted with 1N HCl and phases were
separated. The organic layer was washed with sat. aqueous
NaHCO3, brine, dried and evaporated to dryness. The orange
solid was purified was purified by flash chromatography on SiO2
eluting with DCM-EtOAc (0-50%) to afford the title compound
(220 mg, 40% yield) as a white solid: UPLC-MS (tR=1.69 min),
Gladman, D. D.; Wu, J. J.; Mehta, N. N.; Finlay, A. Y.; Gottlieb,
A. B. Nat. Rev. Disease Primers 2016, 2, 1-17.
2. a) Kojetin, D. J.; Burris T. Nat. Rev. Drug Discov. 2014,13,197–
216; b) Banerjee, D.; Zhao, L.; Wu, L.; Palanichamy, A.; Ergun,
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Allaire; N.; Guertin, K.; Wang, T.; Chao, J.; Loh, C.; Fontenot,
J. D. Immunology 2016, 147, 399–413; c) Cyr, P.; Bronner, S. M.;
Crawford, J.J. Bioorg. Med. Chem. Lett. 2016, 26, 4387–4393 and
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3. http://ir.vitaepharma.com/phoenix.zhtml?c=219654&p=irol-
newsArticle&ID=2149044
4. Ouvry, G.; Atrux-Tallau, N.; Bihl, F.; Bondu, A.; Bouix-Peter, C.;
Carlavan, I.; Christin, O.; Cuadrado, M.-J.; Defoin-Platel, C.;
Deret, S.; Duvert, D.; Feret, C.; Forissier, M.; Fournier, J.-F.;
Froude, D.; Hacini-Rachinel, F.; Harris, C. S.; Hervouet, C.;
Huguet, H.; Lafitte, G.; Luzy, A.-P.; Musicki, B.; Orfila, D.;
Ozello, B.; Pascau, C.; Pascau, J.; Parnet, V.; Peluchon, G.; Pierre,
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Thoreau, E.; Vatinel, R.; Vial, E.; Hennequin, L. F.
ChemMedChem 2018, 13, 321-337.
5. Ouvry, G.; Bihl, F. ; Bouix-Peter, C. ; Christin, O. ; Defoin-Platel,
C. ; Deret, S. ; Feret, C. ; Froude, D. ; Hacini-Rachinel, F. ; Harris,
C. S. ; Hervouet, C. ; Lafitte, G. ; Luzy, A-P. ; Musicki, B. ;
Orfila, D. ; Parnet, V. ; Pascau, C.; Pascau, J.; Pierre, R. ; Raffin,
C. ; Rossio, P. ; Spiesse, D. ; Taquet, N. ; Thoreau, E.; Vatinel, R.;
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6. a) Lücking, U. Angew. Chem. Int. Ed Engl. 2013, 52, 9399-9340;
b) Frings, M.; Bolm, C.; Blum, A.; Gnamm, C. Eur. J. Med.
Chem. 2017 126, 225-245; c) Sirvent, J.A; Lücking, U.
ChemMedChem 2017, 12, 487-501; Zenzola, M.; Doran, R.;
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8. a) Birault, V.; Campbell, A. J.; Harrison, S. A.; Le, J.; Shukla, L.
WO2013/160418, 31 Oct, 2013; b) Birault, V.; Campbell, A. J.;
Harrison, S.; Le, J. WO2015/061515, 30 Apr, 2015. GSK’s lead
compound is suspected to be GSK2981278.
1
ESI m/z 534.3 (M+H)+; H NMR (400 MHz, DMSO-d6) δ 8.03
(dd, J=8.8, 2.4 Hz, 1H), 7.74 (d, J=2.3 Hz, 1H), 7.64 (d, J=9.0
Hz, 1H), 7.22 (d, J=8.3 Hz, 2H), 6.96 (d, J=8.3 Hz, 2H), 4.32 –
4.12 (m, 2H), 3.91 (ddd, J=11.3, 4.5, 1.9 Hz, 2H), 3.72 (s, 3H),
3.41 – 3.36 (m, 2H), 3.42 – 3.17 (m, 2H), 2.61 (q, J=7.6 Hz, 2H),
2.22 – 2.08 (m, 1H), 1.84 – 1.63 (m, 2H), 1.51 – 1.33 (m, 3H),
1.18 (t, J=7.6 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.6 Hz,
3H); 13C NMR (101 MHz, DMSO) δ 159.2, 143.9, 136.3, 136.2,
129.7, 129.6, 128.7, 128.3, 123.0, 115.4, 111.7, 74.8, 66.6, 57.4,
41.5, 34.2, 29.1, 28.8, 27.8, 26.4, 19.7, 19.6, 15.4.
4.7.5. N-(4-Ethylphenyl)-N-isobutyl-3-(S-methylsulfonimidoyl)-4-
((tetrahydro-2H-pyran-4-yl)methoxy)benzene-sulfonamide (1)
To 34 (200 mg, 0.37 mmol, 1.00 eq.) in DCM (3 ml) was added
trifluoroacetic anhydride (83.0 mg, 0.39 mmol, 1.05 eq.) and the
solution was stirred at 23 °C for 2 h. HPLC analysis after 2 h
revealed
complete
conversion
to
the
intermediate
trifluoroacetamide. The reaction mixture was quenched with
water (0.50 mL) and evaporated to dryness. The residue was
dissolved in MeOH (3 mL) and K2CO3 (100 mg, 0.74 mmol, 2.00
eq.) was added. The suspension was stirred at 23 °C for 1 h.
LC/MS analysis after 1 h revealed complete conversion. The
reaction mixture was diluted with water (5.0 mL) and a white
solid precipitated. The solid was collected by filtration to afford
the title compound (173 mg, 92% yield) as a white solid: UPLC-
9. Chakraborti, A. K.; Nayak, M. K.; Sharma, L. J. Org. Chem.
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1
MS (tR=1.61 min, purity=97.2%), ESI m/z 509.2 (M+H)+; H
11. Okamura, H.; Bolm, C. Org. Lett., 2004, 6, 1305–1307.
12. Porte, A. M.; Caggiano, T. J.; Diamantidis, G.; Hauze, D. B.;
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16. Choong, I. C.; Lew, W.; Lee, D.; Pham, P.; Burdett, M. T.; Lam,
J. W.; Wiesmann, C.; Luong, T. N.; Fahr, B.; DeLano, W. L.;
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18. Bellale, E. V.; Chaudhari, M. K.; Akamanchi, K. G. Synthesis
2009, 19, 3211-3213.
19. a) Dixon, D. D.; Grina, J.; Josey, J. A.; Rizzi, J. P.; Schlachter, S.
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PCT Int. Appl., 2007079982.
NMR (400 MHz, DMSO-d6) δ 8.00 (d, J=2.5 Hz, 1H), 7.67 (dd,
J=8.8, 2.5 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.20 (d, J=8.0 Hz,
2H), 7.00 (d, J=8.0 Hz, 2H), 4.58 (br, 1H), 4.10 (dt, J=11.8, 5.8
Hz, 2H), 3.90 (dd, J=11.0, 4.1 Hz, 2H), 3.44 – 3.21 (m, 4H), 3.20
(s, 3H), 2.61 (q, J=7.6 Hz, 2H), 2.17 – 2.03 (m, 1H), 1.73 (d,
J=9.9 Hz, 2H), 1.41 (q, J=11.0, 9.7 Hz, 3H), 1.18 (t, J=7.6 Hz,
3H), 0.85 (dd, J=6.6, 4.4 Hz, 6H); 13C NMR (101 MHz, DMSO-
d6) δ 159.0, 143.5, 136.4, 133.6, 132.1, 129.2, 128.5, 128.5,
128.3, 114.1, 73.8, 66.7, 57.2, 43.7, 34.4, 29.1, 29.1, 27.7, 26.4,
19.6, 15.3.
Acknowledgments
The authors would like to acknowledge the support of our
CRO partners, in particular, Santai Labs for supplying building
block 9 on large-scale. Grégoire Mouis and Ghizlane El-Bazbouz
are gratefully acknowledged for their help with the purification of
a selection of these compounds. Prof. Gérard Coquerel is
acknowledged for the absolute configuration elucidation of
compound 25.
20. a) Heinrich, T.; Zenke, F.; Rohdich, F.; Friese-Hamim, M.; Hahn,
D. PCT Int. Appl., 2016020031; b) Schulze, V.; Kosemund, D.;
Wengner, A. M.; Siemeister, G.; Stoeckigt, D.; Lienau, P.;
Schirok, H.; Briem, H. PCT Int. Appl., 2012143329.
21. See the supporting information for the synthesis of
25.camphorsulfonate
Supporting information
22. a) Mancheño, O. G.; Bolm, C. Org. Lett. 2007, 9, 2951-2954; b)
Mancheño, O. G.; Bistri, O.; Bolm, C. Org. Lett. 2007, 9, 3809-
3811.
23. Addition of a small amount of water to DCM ensure a
reproducible hydrolysis time on scale
The structural elucidation of compound 25 (1R)-(−)-10-
camphorsulfonic acid salt as well as LCMS chromatograms and
NMR spectra for a majority of compounds described in this paper
are included at no extra charge.
24. Double chlorosulfonylation was achieved at 150°C with a highly
exothermic quench limiting its throughput on larger scale

15
25. ~500€ per mol from Aldrich
ACCEPTED MANUSCRIPT
26. Isola, A. M.; Klintz R.; Koser S.; Watts J.P.; Muenster P.; Holman
N. J. Tometzki G. B. Patent CA2222854, 1998