Development of a Scalable Synthesis of an Azaindolyl-Pyrimidine Inhibitor of Influenza Virus Replication

Article abstract of DOI:10.1021/acs.oprd.6b00063

A scalable, asymmetric route for the synthesis of the influenza virus replication inhibitor 2 is presented. The key steps include an enzymatic desymmetrization of cis-1,3-cyclohexanediester in 99% yield and 96% ee, S_NAr displacement of a methanesulfinylpyrimidine, and a Curtius rearrangement to form a morpholinyl urea. This high-yielding route allowed us to rapidly synthesize hundreds of grams of 2 in 99% purity to support in vivo studies.

Full text of DOI:10.1021/acs.oprd.6b00063

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Full Paper
Development of a Scalable Synthesis of an Azaindolyl-
Pyrimidine Inhibitor of Influenza Virus Replication
Jianglin Liang, John Cochran, Warren Dorsch, Ioana Davies, and Michael Clark
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00063 • Publication Date (Web): 08 Apr 2016
Downloaded from http://pubs.acs.org on April 9, 2016
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Development of a Scalable Synthesis of an
AzaindolylꢀPyrimidine Inhibitor of Influenza Virus
Replication
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Jianglin (Colin) Liang,* John E. Cochran, Warren A. Dorsch, Ioana Davies and Michael P.
Clark
Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210,
United States
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ABSTRACT: A scalable, asymmetric route for the synthesis of the influenza virus replication
inhibitor 2 is presented. The key steps include an enzymatic desymmetrization of cisꢀ1,3ꢀ
cyclohexanediester in 99% yield and 96% ee, SNAr displacement of a methanesulfinylpyrimidine
and a Curtius rearrangement to form a morpholinyl urea. This highꢀyielding route allowed us to
rapidly synthesize hundreds of grams of 2 in 99% purity to support in vivo studies.
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Keywords: enzymatic desymmetrization; scale up; influenza virus inhibitor; Curtius
rearrangement
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INTRODUCTION
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Each year in the United States, between 5 and 20% of the population becomes infected with
influenza viruses. Influenza (flu) is a potentially fatal infectious disease responsible for more
than 200,000 hospitalizations and from 3,000 to 49,000 deaths annually in the United States
during nonpandemic seasons, as shown by recent reports.1 The current standard of care (SOC)
for influenza in the United States is based on neuraminidase inhibitors (oseltamivir, zanamivir
and peramivir), however, this class of antivirals is facing significant concern over viral
resistance.2
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Recently we reported the discovery of a novel class of orally bioavailable, azaindoleꢀbased
inhibitors of human influenza virus replication, including VXꢀ787 (1).3 Here we report the first
scaleꢀup synthesis of a related analog 2, a potent azaindoleꢀbased inhibitor. The structure of 2 is
based on an azaindoleꢀpyrimidine scaffold that contains a syntheticallyꢀchallenging (1R,3S)ꢀcisꢀ
diaminocyclohexane.
Initial Synthetic Route to Compound 2
The initial synthesis of 2 (Scheme 1 and Scheme 2) began with the cyclization of a commercially
available cis/trans mixture of cyclohexaneꢀ1,3ꢀdicarboxylic acid 3. Subjecting the mixture to
DCC caused the cisꢀdiacid to cyclize to the anhydride 4 which could be readily separated from
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unreacted transꢀdiacid. The anhydride 4 was reꢀopened with pTSA and triethylorthoformate in
EtOH to give the pure cisꢀ1,3ꢀcyclohexane dicarboxylate ester 5 in 90% yield. Enzymatic
desymmetrization4 using lipase AYS Amano5 selectively hydrolyzed the diester 5 in 90% yield
and 96% ee to afford the cisꢀcyclohexane monoacid 6. Although Boaz reported that no emulsion
was observed in this step,5a we encountered a significant emulsion using the same work up
procedure. This may have been due to the scale on which we were performing the reaction (400
g), and the large loading (42wt%) of the lipase. Curtius rearrangement of enantiopure 6 with
DPPA/TEA formed the corresponding intermediate isocyanate, that was trapped by BnOH to
give Cbzꢀprotected aminoester 7 in a oneꢀpot sequence. Nꢀprotected amino ester 7 was
hydrolyzed to acid 8 under basic conditions. However, a second Curtius rearrangement to
convert 8 to 9 was unsuccessful and led to an unidentified byꢀproduct. Alternatively, 8 was
converted to the corresponding primary amide and subsequent Hofmann rearrangement using
CuBr2/LiOtBu worked efficiently to afford 88% yield of the desired Bocꢀprotected amine 9,
although the presence of copper salts made the work up challenging.6 Compound 9 was
hydrogenated to give desired key intermediate 10 in almost quantitative yield (Scheme 1).
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With chiral monoꢀprotected diaminocyclohexane 10 in hand, the remaining steps of synthesis are
straightꢀforward. Compound 10 displaced the sulfoxide 113a to afford compound 12, and
subsequent Boc deprotection, morpholine urea formation and deꢀtosylation formed the final
compound 2 (Scheme 2).7
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Scheme 1 Initial Route to Key Intermediate Chiral cisꢀDiaminocyclohexane 10
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This convergent route was developed by the medicinal chemistry team to explore SAR,
particularly as compound 12 serves as an excellent intermediate for synthesizing a wide variety
of analogs. However, the need to supply hundreds of grams of compound 2 for advanced studies
required that we address the weaknesses of the synthetic route. Most notably the following
specific challenges were identified as requiring change, improvement or elimination: (1) the high
enzyme loading and difficult work up of lipase resolution; (2) the workꢀup and removal of
copper salts following the Hofmann rearrangement; (3) the long overall sequence (12 total steps)
and 8.7% overall yield; (4) the requirement for chromatographic purification after 6 of the 12
reactions.
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Scheme 2 Initial Synthesis of 2
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Retrosynthetic Analysis
To deliver hundreds of grams of compound 2, we set 4 goals for a new and improved synthesis:
(1) simplified reaction work up; (2) minimal use of chromatography; (3) a shorter synthetic
sequence; and (4) higher overall yield. With these goals in mind, we envisioned the
retrosynthetic analysis shown in Scheme 3. We analyzed the initial route and identified 7 as a
critical intermediate. Compound 2 could potentially be synthesized from acid 14 via Curtius
rearrangement followed by reaction with morpholine. Acid 14 could be obtained by
displacement of sulfoxide 11 with the amine 15 (from hydrogenation of 7), followed by an
efficient global deprotection of both the ester and tosyl groups. The advantage of this route is
that the morpholineꢀbased urea is installed in a more direct manner and both the Hofmann
rearrangement and Boc deprotection steps have been eliminated (Scheme 3).
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Scheme 3 Retrosynthetic Analysis of 2
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F
F
H
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H
N
N
H
N
N
N
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N
CO2H
N
Curtius
O
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F
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F
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14
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H
O
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F
11
N
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Ts
Enzymatic
Desymmetrization
CbzHN
H2N
HO2C
CO2Et
CO2Et
CO2H
7
15
3
Scalable Synthesis of 2
The new synthesis was started with commercially available dicarboxylic acid 3 (mixture cis and
transꢀisomers). Reflux of 3 in AcCl overnight accomplished both the equilibration of the transꢀ
isomer to cisꢀisomer, as well as the cyclization of the latter to the desired anhydride intermediate
4.8 The anhydride was refluxed in EtOH in the presence of H2SO4 to give the ringꢀopened mesoꢀ
diester 5 in 94% yield over 2 steps after distillation in a twoꢀstep oneꢀpot process. Since the
enzymatic reaction conditions used in initial synthesis caused isolation problems, we lowered the
lipase loading to 10wt% and found that reaction went to completion overnight and much less
emulsion was observed during work up. Same 10wt% enzyme loading was used by Yoshida
with a similar lipase in an enzymatic hydrolysis reaction on halfꢀton sacle.9 Acid 6 was isolated
by aqueous extraction in 98% yield and 96% ee. All of the steps from the dicarboxylate acid 3
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through the monoester 6 were run on ca. 1 kg scale without any issue proving the robustness of
the route (Scheme 4).
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Scheme 4 Scalable Synthesis of 2
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Lipase AYS
buffer (pH 7.2)
DPPA, TEA,
BnOH, PhCH3
1. AcCl, reflux
2. H2SO4, EtOH
HO2C
CO2H
EtO2C
CO2Et
HO2C
CO2Et
94%
98% yield, 96% ee
85%
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F
H
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11, DIPEA
H2, Pd/C
99%
CO2Et
CbzHN
CO2Et
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CO2Et
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2. Morpholine
H
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LiOH, THF/H2O
85%
CO2H
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F
F
N
67%
N
14
2
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H
N
N
H
O
Efforts were made to directly convert monoꢀacid 6 to amine 15 under Curtius conditions using
HCl, however, the reaction was messy and lowꢀyielding. So the intermediate isocyanate was
trapped with benzyl alcohol, followed by hydrogenation to cleanly give amine 15 as an HCl salt.
The SNAr displacement of sulfoxide 11 with amine 15 in the presence of Hunig’s base gave 16 in
73% yield by simple silica gel plug purification. Both ester hydrolysis and tosyl group removal
were successfully carried out using LiOH, and compound 14 was precipitated out after
acidification and collected by filtration. Compound 14 was treated with DPPA/TEA, followed
by the addition of morpholine to form the desired urea. The final compound 2 was purified by
chromatography, and fractions were collected, followed by trituration from MTBE to form
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MTBE solvate (1:1 ratio). This solvate was recrystallized from acetone/water to give pure
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compound 2 with >99% purity for in vivo studies.
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CONCLUSION
We have developed an enantioselective, scalable and efficient process for the synthesis of 2, a
potent inhibitor of influenza virus replication. Compared with the initial synthesis, the sequence
was shortened from 12 steps to 7 steps and overall yield was improved from 8.7% to 32%. The
process from commercially available diacid 3 to enantiopure monoꢀacid 6 was significantly
optimized with high yields and easy workups. All steps were run on 100+ gram scale and no
chromatography was needed except at the final step. This scalable synthesis allowed us to
synthesis and deliver hundreds of grams of highꢀpurity material on time to support in vivo
studies.
EXPERIMENTAL SECTION
General Information. All commercially available reagents and anhydrous solvents were used
without further purification. Purity assessment for final compounds was based on analytical
HPLC: 4.6 mm × 50 mm Waters YMC ProꢀC18 column, 5 ꢁm, 120A. Mobile phases are as
follows: A, H2O with 0.2% formic acid; B, acetonitrile with 0.2% formic acid; gradient, 10−90%
B in 3 min with 5 min run time. The flow rate is 1.5 mL/min. Unless specified otherwise, all
compounds were ≥95% pure. Mass samples were analyzed on a Quattro LC, Quatro II or
Thermo QExactive (for HRMS) mass spectrometer operated in a single MS mode with
electrospray ionization. Samples were introduced into the mass spectrometer using
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chromatography. The mobile phase for all mass analysis consisted of acetonitrile−water
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mixtures with either 0.2% formic acid or ammonium formate. H NMR spectra were recorded
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using a Bruker Avance IIꢀ300 (300 MHz) or Bruker Avance IIꢀ400 (400 MHz) instrument.
Column chromatography was performed using Teledyne ISCO RediSep normal phase (35−70
ꢁm) or RediSep Gold normal phase (25−40 ꢁm) silica flash columns using a Teledyne ISCO
Companion XL purification system.
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The procedures outlined in this section are those employed for the reactions run at the largest
scale. Analytical characterizations were obtained on materials that were representative or
purified for that propose.
Diethyl-cyclohexane-1,3-dicarboxylate (5). Commercially available diacid 3 (858 g, 4.98 mol,
3:1 trans/cis ratio) was mixed with acetyl chloride (1.5 L), and the mixture was heated to reflux
overnight with mechanical stirring. A distillation setup was added to flask and the volatiles were
removed by distillation in vacuo. The residual oil was dissolved in EtOH (3 L) and concentrated
sulfuric acid (266 mL, 5 mol) was added slowly (exothermic). The mixture was heated to reflux
overnight, and the volatiles were removed by rotary evaporation. The remaining oil was
dissolved in DCM (5 L) and washed with 1 N NaOH (2 L). The organic layer was dried over
MgSO4 and evaporated in vacuo to afford a dark brown oil. The oil was distilled under high
vacuum to afford product 5 (1068.5 g, 94% yield) as a colorless oil (bp ~175oC).
1H NMR (300 MHz, CDCl3) δ 4.13 (q, J = 7.1 Hz, 4H), 2.42 – 2.16 (m, 3H), 2.05 – 1.82 (m,
3H), 1.66 – 1.45 (m, 1H), 1.48 – 1.31 (m, 3H), 1.25 (t, J = 7.1 Hz, 6H).
(1S,3R)-3-ethoxycarbonylcyclohexanecarboxylic acid (6). The diester 5 was mixed with pH
7.2 phosphate buffer (8 L, Aldrich). Amino lipase AYS (100 g) was added and the mixture was
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stirred overnight at RT. A drop in pH to 4.5 was observed. HPLC analysis was very clean
showing only product. The reaction was acidified with concentrated HCl to pH 2 and filtered
over celite. The celite cake was washed with EtOAc (2x800 mL), and filtrate was extracted with
EtOAc (2x5 L). The combined organic layers were dried over MgSO4 and evaporated in vacuo
to afford product 6 (922.5 g, 98% yield) as a yellow oil. Chiral HPLC showed 96% ee (Chiral
Pak IA column, 4.6x250 mm, 5 µm, 90:10 heptane/isopropanol as mobile phase).
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Specific rotation: [α]20D= 3.92⁰ (c = 1.12 in DCM); 1H NMR (300 MHz, d6ꢀDMSO) δ 12.10 (s,
1H), 4.05 (q, J = 7.1 Hz, 2H), 2.41 ꢀ 2.17 (m, 2H), 2.05 (d, J = 13.0 Hz, 1H), 1.93 ꢀ 1.70 (m, 3H),
1.41 ꢀ 1.10 (m, 7H). HRMS (ESI) [M+H]+ calculated for C10H17O4 201.1121, found 201.1119.
Ethyl (1R,3S)-3-benzyloxycarbonylaminocyclohexanecarboxylate (7). To (1S,3R)ꢀ3ꢀ
ethoxycarbonylcyclohexanecarboxylic acid (6) (140 g, 700 mmol) in toluene (1.4 L) was added
diphenylphosphoryazide (DPPA) (166 mL, 769 mmol) and triethylamine (107 mL, 769 mmol).
The mixture was refluxed for 2 h under N2. Gas release was observed. The reaction mixture was
cooled to 60oC and benzyl alcohol (87 mL, 839 mmol) was added in one portion. The mixture
was heated to 80oC overnight. After cooling to RT, EtOAc (1 L) and water (1.5 L) were added,
the mixture was stirred vigorously and the layers were separated. The organic layer was washed
with brine, dried over Na2SO4, and evaporated in vacuo. The residual oil was dissolved in DCM
(200 mL) and purified by filtration over a silica gel plug (1 kg). The plug was eluted with
hexane/EtOAc (3:1), and the fractions were collected and evaporated in vacuo to afford 206 g of
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a sticky solid. H NMR showed it contained around 12wt% benzyl alcohol (calculated yield
85%). This solid was used directly in the next step. A sample of 7 for analytical characterization
was prepared by ISCO silica gel chromatography.
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Specific rotation: [α]25D= ꢀ33.3o (c = 1 in DCM). 1 H NMR (300 MHz, CDCl3 ) δ 7.48 – 7.30 (m,
5H), 5.11 (s, 2H), 4.67 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.55 (s, 1H), 2.42 (t, J = 11.8 Hz, 1H),
2.28 (d, J = 12.6 Hz, 1H), 2.10 – 1.79 (m, 3H), 1.50 – 1.19 (m, 6H), 1.19 – 1.00 (m, 1H). HRMS
(ESI) [M+H]+ calculated for C17H24NO4 306.1700, found 306.1700.
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Ethyl (1R,3S)-3-aminocyclohexanecarboxylate (HCl salt) (15): Ethyl (1R,3S)ꢀ3ꢀ
benzyloxycarbonylaminocyclohexanecarboxylate (7) (270 g, 88% pure, 778 mmol) in MeOH
(800 mL) was added to a Parr pressure reactor vessel. Palladium on carbon (18.8 g, 5% Pd by
wt) was added. The reactor was pressurized under 50 psi of H2 and the reaction was maintained
at this pressure for two days, until no further H2 consumption was observed. The mixture was
filtered through celite to remove catalyst and to the filtrate was added 5N HCl in iPrOH (195
mL, 972 mmol). The resulting solution was stirred for 30 min and all solvents were removed in
vacuo to afford a light yellow oil. MTBE (1 L) was added and the resulting suspension of white
solid was stirred for 0.5 h. The suspension was filtered and the filter cake was washed with
MTBE once, and then dried under vacuum in an oven to yield 15.(hydrochloride salt) as a white
solid (160 g, 99% yield).
Specific rotation: [α]20D= ꢀ6.4⁰ (c = 1 in MeOH); 1H NMR (300 MHz, d6ꢀDMSO) δ 8.14 (s, 3H),
4.07 (q, J = 7.1 Hz, 2H), 3.13 – 2.92 (m, 1H), 2.48 – 2.32 (m, 1H), 2.15 (d, J = 12.2 Hz, 1H),
2.00 – 1.68 (m, 3H), 1.47 – 1.06 (m, 7H). HRMS (ESI) [M+H]+ calculated for C9H18NO2
172.1332, found 172.1333.
Ethyl (1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-
yl]pyrimidin-4-yl]amino]cyclohexanecarboxylate (16): To the mixture of 5ꢀfluoroꢀ3ꢀ(5ꢀ
fluoroꢀ4ꢀmethylsulfinylꢀpyrimidinꢀ2ꢀyl)ꢀ1ꢀ(pꢀtolylsulfonyl)pyrrolo[2,3ꢀb]pyridine (11)3a (181.4
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g, 404.4 mmol) , ethyl (1R,3S)ꢀ3ꢀaminocyclohexanecarboxylate hydrochloride (15) (84 g, 404.4
mmol) in dry THF (4 L) was added DIPEA (155 mL, 890 mmol). The reaction mixture was
heated to reflux under N2 for two days, and cooled down. EtOAc (4 L) was added and the
solution was washed with brine (2x4 L). The organic layer was dried over Na2SO4 and
concentrated down. The residual oil was purified by filtration over a silica gel plug (2 kg),
followed by elution with 30% ethyl acetate in hexane. The fractions were collected and
evaporated to dryness, yielding product 16 as a white solid (165 g, 73% yield).
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Specific rotation: [α]21D= ꢀ85.7⁰ (c = 1 in CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H),
8.48 (dd, J = 9.0, 2.8 Hz, 1H), 8.35 ꢀ 8.29 (m, 1H), 8.14 ꢀ 8.06 (m, 3H), 7.33 ꢀ 7.28 (m, 2H), 5.11
(d, J = 6.5 Hz, 1H), 4.26 ꢀ 4.08 (m, 3H), 2.62 (tt, J = 11.7, 3.6 Hz, 1H), 2.49 (d, J = 12.6 Hz, 1H),
2.39 (s, 3H), 2.21 (d, J = 12.7 Hz, 1H), 2.09 (d, J = 11.7 Hz, 1H), 2.05 ꢀ 1.93 (m, 1H), 1.63 ꢀ 1.39
(m, 3H), 1.39 ꢀ 1.28 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H). 19F NMR (282.4 MHz, CDCl3) ꢀ133.66, ꢀ
158.31 ppm. HRMS (ESI) [M+H]+ calculated for C27H28F2N5O4S 556.1825, found 556.1829.
(1R,3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-
yl]amino]cyclohexanecarboxylic acid (14): To the mixture of ethyl (1R,3S)ꢀ3ꢀ[[5ꢀfluoroꢀ2ꢀ[5ꢀ
fluoroꢀ1ꢀ(pꢀtolylsulfonyl)pyrrolo[2,3ꢀb]pyridinꢀ3ꢀyl]pyrimidinꢀ4ꢀ
yl]amino]cyclohexanecarboxylate (16) (164 g, 295 mmol) in THF (1 L) and water (1 L) was
added LiOH (35.4 g, 1.48 mol). The reaction mixture was heated to reflux overnight. The
reaction was cooled to 20oC, and 6 N HCl was added until the pH was adjusted to 6. THF was
removed by evaporation in vacuo which precipitated a yellow solid. To the resulting suspension
was added acetonitrile (500 mL) and the resulting suspension was stirred for 0.5 h. The
suspension was filtered, and the cake was washed twice with water, acetonitrile and finally
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DCM. The resulting white solid was dried under vacuum at 50oC to afford 14 (93.6 g, 85%
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Specific rotation: [α]21D= ꢀ109.4⁰ (c = 1 in DMSO). 1H NMR (300 MHz, d6ꢀDMSO) δ 12.28 (s,
1H), 8.42 (dd, J = 9.8, 2.9 Hz, 1H), 8.35 – 8.18 (m, 2H), 8.14 (d, J = 4.0 Hz, 1H), 7.57 (s, 1H),
4.12 (d, J = 11.0 Hz, 1H), 2.51 – 2.34 (m, 1H), 2.36 – 2.13 (m, 1H), 2.13 – 1.74 (m, 3H), 1.66 –
1.15 (m, 4H). HRMS (ESI) [M+H]+ calculated for C18H18F2N5O2 374.1423, found 374.1427.
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N-[(1R,3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-
yl]amino]cyclohexyl]morpholine-4-carboxamide (2): To the suspension of (1R,3S)ꢀ3ꢀ[[5ꢀ
fluoroꢀ2ꢀ(5ꢀfluoroꢀ1Hꢀpyrrolo[2,3ꢀb]pyridinꢀ3ꢀyl)pyrimidinꢀ4ꢀyl]amino]cyclohexanecarboxylic
acid (14) (65 g, 174 mmol) in dry THF (1.3 L) was added Et3N (34 mL, 244 mmol). The
reaction was purged with nitrogen for 20 min. DPPA (45 mL, 209 mmol) was added and the
mixture was heated to 50oC for 2 h. HPLC showed that all starting material was consumed.
Morpholine (45.5 mL, 522 mmol) was added and the reaction was kept at reflux overnight. The
reaction mixture was cooled to 20oC, and EtOAc (1 L) was added. The mixture was washed
with saturated NaHCO3 (2x1 L), and evaporated under vacuum. The residual oil was purified on
an ISCO Companion XL using 1.5 kg silica gel column and a gradient 0ꢀ20% of MeOH in DCM.
The fractions were collected and evaporated, affording 68 g of crude white solid. MTBE (800
mL) was added and heated to reflux for 0.5 h, then cooled down. The suspension was filtered,
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and cake was dried under vacuum in oven at 50oC. H NMR showed it was 1:1 MTBE solvate.
To the solid was added acetone/water (4:1, 120 mL) and the mixture was stirred for 0.5 h. The
mixture was filtered, and cake was washed with DCM (2x50 mL), dried in oven under vacuum at
50oC to yield compound 2 as white solid with 99% chemical purity (54 g, 67%).
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Specific rotation: [α]21D= ꢀ165.7⁰ (c = 1 in MeOH). 1H NMR (300 MHz, d6ꢀDMSO) δ 12.23 (s,
1H), 8.42 (dd, J = 9.8, 2.9 Hz, 1H), 8.34 ꢀ 8.18 (m, 2H), 8.14 (d, J = 4.0 Hz, 1H), 7.49 (d, J = 7.5
Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 4.24 ꢀ 4.00 (m, 1H), 3.75 ꢀ 3.57 (m, 1H), 3.57 ꢀ 3.42 (m, 4H),
3.28 ꢀ 3.09 (m, 4H), 2.15 (d, J = 11.4 Hz, 1H), 2.01 (d, J = 11.2 Hz, 1H), 1.83 (d, J = 9.7 Hz,
2H), 1.60 ꢀ 1.07 (m, 4H). 19F NMR (282.4 MHz, d6ꢀDMSO) ꢀ138.10, ꢀ158.25 ppm. HRMS (ESI)
[M+H]+ calculated for C22H26F2N7O2 458.2111, found 458.2110.
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ASSOCIATED CONTENT
Supporting Information.
1H NMR spectra for compounds 2, 5ꢀ7, 14-16.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: jianglin_liang@vrtx.com.
Notes
The authors declare no completing financial interest.
ACKNOWLEDGMENT
We thank Barry Davis for collecting highꢀresolution mass spectra, Marc Towle for chiral HPLC
analysis, Jeremy Green for reviewing the manuscript and also thank the Flu chemistry team for
support and preliminary work.
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ABBREVIATIONS
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SAR, structureꢀactivity relationship; SOC, standard of care; DPPA, diphenylphosphoryl azid;
DCC, N,N'ꢀDicyclohexylcarbodiimide; DCM, dichloromethane; THF, tetrahydrofuran; TEA,
triethylamine; AcCl, acetyl chloride; BnOH, benzyl alcohol; MTBE, methyl tertꢀbutyl ether.
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