Efficient Method for the Synthesis of Amino-1,3-Oxazines from Thioureas

Article abstract of DOI:10.1021/acs.oprd.0c00369

The synthesis of a subtype-selective inhibitor BACE-1 inhibitor is presented. One of the key transformations in this sequence is the conversion of a thiourea to the bicyclic 1,3-aminooxazine. This article outlines the development and application of this method to the target molecule as well as further exploration of its scope and mechanism.

Full text of DOI:10.1021/acs.oprd.0c00369

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Efficient Method for the Synthesis of Amino-1,3-Oxazines from
Thioureas
Jeffery Richardson,* Peter J. Lindsay-Scott, Vladimir Larichev, and Emily Pocock
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ABSTRACT: The synthesis of a subtype-selective inhibitor BACE-1 inhibitor is presented. One of the key transformations in this
sequence is the conversion of a thiourea to the bicyclic 1,3-aminooxazine. This article outlines the development and application of
this method to the target molecule as well as further exploration of its scope and mechanism.
KEYWORDS: amino-1,3-oxazine, thiourea, process development, cyclization, Alzheimer’s disease, BACE-1 inhibitor
lzheimer’s disease is a progressive neurodegenerative
disorder which is known to be the most common
groups, such as carboxylic acids, which could preferentially react
with EDC, and it was felt that there was a need for
complimentary cyclization methods to expand the scope of
the available cyclization precursors.
The synthesis of an amino alcohol precursor 20 was achieved
in 14 steps beginning with a ring-opening hoologation of 5,21
followed by phase transfer alkylation of the resultant-protected
diol to afford 7. Reduction to aldehyde 8 was achieved cleanly
using DIBAL-H, and the crude aldehyde could be telescoped
directly to oxime 9, which sets up the key [3 + 2] cycloaddition
(Scheme 2).
The cycloaddition was achieved by in situ oxidative formation
of the nitrile oxide, which spontaneously cyclized to form 9 as a
single diastereomer. Subsequent addition of aryl magnesium
reagent generated from the aryl iodide (11) afforded the cis-ring
junction,22 and a series of functional group manipulations
converted protected alcohol 12 to the corresponding difluor-
oethyl compound (19) using XtalFluor-M to introduce the gem-
difluoro moiety.23 Finally, a reductive ring opening formed
amino alcohol (20).
Faced with the challenge of converting high-value amino
alcohol 20 into the corresponding amino-1,3-oxazine, we turned
to an unexpected observation that had been made during the
process development to prepare LY2886721.16 During attempts
to find optimal conditions for the conversion of thiourea 2 into
aminothiazine 23, it was found that a number of conditions
could be used to effect the desired cyclization but that the
attempt to form 22 in situ, using conditions using trimethylsilyl
chloride (TMSCl), dimethyl sulfoxide (DMSO)24 which was
expected to spontaneously cyclize to form the corresponding
aminothiazine (23), instead gave rise solely to the amino-1,3-
oxazine (24) (Scheme 3).
A
pathological process to cause dementia. An abnormal extrac-
ellular plaque in the brain, principally composed of amyloid-beta
(Aβ), is a pathological hallmark of the disease. The enzyme
BACE1 is critical to the production of Aβ and considerable effort
has been devoted to the discovery and development of inhibitors
as potential therapies.1−12 Many of the therapeutic agents that
have reached various stages of development contain 1,3-
aminothiazine1,2,9,13,14 or 1,3-aminooxazine substructures.10−12
During the course of our program to discover subtype-selective
BACE-1 inhibitors, we were interested in the preparation of
multihundred gram quantities of 1.15 In the first-generation
medicinal chemistry synthesis, trifluoromethane sulfonic anhy-
dride was used to cyclize thiourea 2, affording a 1:9 mixture of
amino-1,3-oxazine 3 and amino-1,3-thiazine 4, respectively,
which required chromatographic separation to isolate 3
(Scheme 1).13 To overcome this issue, the unprotected
amino-1,3-oxazine was formed from the aminoalcohol (20)
using cyanogen bromide,15 which, while effective at small scale,
was of concern for larger-scale work because of its highly toxic
nature and potential to liberate hydrogen cyanide. This
necessitated a more practical solution as the program progressed
toward more material intensive studies.
While there are many methods for the preparation of
aminothiazines from thioureas, at the time of this work, there
were fewer reports on the corresponding selective synthesis of
amino-1,3-oxazines from thioureas.12,16−20 While Mitsunobu
reactions generally afford the corresponding aminothiazines, in
some instances where the cyclizing alcohol is less reactive and
thus less able to be activated as a leaving group, amino-1,3-
oxazine formation can dominate, as was observed in Scheme 1
using trifluoromethane sulfonic anhydride in our case.13
Similarly, the thiourea can be activated by alkylation and then
treated with a base to cyclize to afford amino-1,3-oxazines.19,20
After we had completed this work, reports appeared
demonstrating the cyclization to afford 1,3-aminooxazines
using EDC·HCl.12,17,18 This method works well for a number
of examples of complex substrates to effect the desired
transformation (Scheme 1), but there are certain functional
Received: August 14, 2020
https://dx.doi.org/10.1021/acs.oprd.0c00369
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

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Scheme 1. Key Cyclization Step for the Synthesis of Lilly Amino-1,3-oxazine Selective BACE-1 Inhibitor15
Scheme 2. Synthesis of Amino Alcohol Intermediate 20
B
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Scheme 3. Discovery of Selective Amino-1,3-oxazine Formation Reaction
Scheme 4. Synthesis of a Lilly Selective BACE Inhibitor15
Table 1. Exploration of Reaction Conditions
a
b
entry
thiourea
R1
R2
TMSCl (equiv)
DMSO (equiv)
HCl (equiv)
amino-1,3-oxazine
28:27
purity (%)
1
2
3
4
5
6
7
27a
27a
27a
27a
27a
27c
27c
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
1.2
1.2
1.2
1.2
1.2
1.2
1.2
28a
28a
28a
28a
28a
28c
28c
71:29
88:12
98:2
78
100
68
100
100
82
2.0
10.0
2.0
2.0
2.0
2.0
92:8
0:100
100:0
92:8
CH(OEt)2
CH(OEt)2
1.2
1.2
1.2
H
93
a
b
1
Results obtained by H NMR (400 MHz, CDCl3) spectroscopic analysis of the crude reaction mixture after aqueous work-up. Determined by
LCMS analysis calculated as the sum of the area % in the LCMS chromatogram of 25 and 26 relative to additional peaks present in the spectra.
Armed with this finding, it was possible to quickly apply these
conditions to the cyclization of 2, and it was found that the
desired amino-1,3-oxazine (3) was formed cleanly and rapidly
with no trace of the corresponding amino-1,3-thiazine (4).
Indeed, it was possible to form the thiourea in situ under
conditions that are commonly used in the literature,13,25 prior to
addition of cyclization reagents allowing the cyclization to be
performed in a 2-step, 1-pot manner at >500 g scale and
affording 3 in a 96% yield (Scheme 4).15 This reaction was fast,
with small-scale trials showing that the reaction was complete at
the end of the reagent addition, performed consistently at all
scales examined, and produced no observed exothermic events.
The synthesis of 1 was completed through copper-catalyzed
amide formation, where the bromide is converted in situ to the
iodide through an aromatic Finkelstein-type reaction26 before
C−N bond formation and deprotection of the benzoyl group
afforded 1. Thus, the synthesis of 1 was achieved in 18 steps and
7.5% overall yield starting from protected glycidol 5. No obvious
safety concerns were raised for this reaction, for example, the
reaction is not strongly exothermic and does not involve high-
energy functional groups. No further safety evaluation of this
reaction was performed as part of this program.
Having successfully used this approach to deliver 860 g of 3
and intrigued by its potential as a general method for the
C
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Scheme 5. Amino-1,3-oxazine Formation
a
b
Isolated yield. 40 °C.
Figure 1. Functional group additives.
preparation of amino-1,3-oxazines, a deeper understanding of
the scope and mechanism of this TMSCl/DMSO-mediated
formation of amino-1,3-oxazines was sought.
Thioureas are readily prepared using benzoyl isothiocyanate
in CH2Cl2 and a small number of nonproprietary amino alcohols
were obtained from the Lilly compound collection and
converted to the corresponding thioureas 27a−h to enable the
exploration of this cyclization reaction (see Supporting
Information). The conditions used for the large-scale prepara-
tion of 3 were applied to thiourea 27a (Table 1, entry 1). As
expected, 28a was formed cleanly, although the reaction did not
reach full conversion. It was possible that the formation of the
D
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Table 2. Robustness Screen Comparing the TMSCl, HCl, and DMSO Method with EDC·HCl
a
Determined by HPLC analysis versus internal standard.
amino-1,3-oxazine was mediated by adventitious HCl in the
reaction, and so we sought to add additional anhydrous HCl to
the reaction mixture (entry 2). Indeed, an increase in conversion
was observed and increasing the number of equivalents of HCl
rendered these reactions essentially complete, although several
unidentified byproducts were formed. Interestingly, (entry 4 vs
entry 2) for this substrate, exclusion of TMSCl from the reaction
mixture had only a small impact on the outcome. Finally, to
probe the role of DMSO, the reaction was repeated using 2 equiv
of HCl (Table 1, entry 5), but no DMSO. DMSO was found to
be vital for the successful cyclization of the thiourea as without it
the reaction failed to proceed showing only the presence of
thiourea 27a.
Interestingly, both HCl and TMSCl can mediate this reaction,
but the combination proved more effective when applied to 27c,
producing complete conversion in the presence of TMSCl, and
so it was decided to continue its use as part of the general
conditions, even though they are unlikely to be optimal for any
given substrate. These conditions were slightly modified
(reduced temperature) and then applied to the synthesis of
several amino-1,3-oxazines from the corresponding thioureas
(Scheme 5). It was also possible to change the substituent
introduced from the isothiocyanate reagent from benzoyl to
phenyl, although this thiourea required heating to form
aminooxazine 28h.
assess their potential complementarity (Figure 1). A key
selection criterion for each additive was that it did not overlap
in the liquid chromatography−mass spectrometry (LCMS) with
the starting material or product, thus allowing more facile
analysis and comparison.
Performing this study for these conditions and those using
EDC·HCl12 clearly demonstrated that the majority of the
additives do not significantly affect the yield of the desired
amino-1,3-oxazine 28a (Table 2). However, as expected, the
yield using EDC·HCl conditions was dramatically reduced in
the presence of 3-phenyl propionic acid (35) (entry 7). LCMS
analysis showed that the activation of carboxylic acid by EDC
was consuming the reagent, thus making it unavailable to
mediate the cyclization. A similar issue was seen when the
reaction was conducted in the presence of 4-isopropylaniline
(42) or dibenzylamine (43) with both product yields being
found to be 57 and 60%, respectively (Table 2, entries 15 and
16). Despite this, the overall reaction robustness (% oS)30 using
EDC·HCl was found to be 77%.
When comparing the two methods overall the average yield of
the desired reaction in the presence of additives is nearly
identical for both conditions. This result indicates that both
methods show a high level of functional group robustness (%
oS) with the TMSCl, HCl, and DMSO conditions being
significantly faster, often affording the desired product
immediately upon the completion of reagent addition.
In order to further understand the scope and functional group
tolerance of this transformation, we applied a robustness
screening method,27−29 which allowed a systematic evaluation
of the functional group tolerance of the reaction and direct
comparison with the recently described EDC·HCl-mediated
A few key experimental observations provided insights into
how these conditions are able to deliver amino-1,3-oxazines
from thioureas; first, as demonstrated in Table 1, DMSO is
essential for the reaction to proceed. Indeed, during the pilot
experiments to form 3, it was demonstrated that substoichio-
metric quantities of DMSO resulted in incomplete conversion
but that addition of further aliquots of DMSO increased the
cyclization12 in a systematic and easily interpreted manner.30
A
set of 15 additives were selected to display a range of functional
groups that might be affected by either set of conditions and thus
E
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Scheme 6. Mechanistic Investigation
Scheme 7. Plausible Mechanism for Formation of Amino-1,3-oxazines under These Conditions
conversion. Second, during the course of these reactions, a
yellow precipitate is formed, which we presumed to be elemental
sulfur.31,32 Based on these observations, it seems likely that the
reaction proceeds through a carbodiimide intermediate.
In order to try to observe this species, thiourea 44, which
cannot cyclize to afford amino-1,3-oxazine, was subjected to the
reaction conditions and, upon quenching, urea (46) was
obtained. This was consistent with the formation of a
carbodiimide intermediate, but it was not definitively proven
that the newly introduced oxygen atom had come from the
aqueous quench or some other source. In order to confirm that
the urea was formed upon quenching, the reaction was
performed again. This time quenching with dibenzylamine
and indeed the expected guanidine (47) was formed, thus
demonstrating that the urea is not formed during the reaction
itself, but in the aqueous quench. Indeed, 47 and the
corresponding guanidine derived from isopropyl aniline could
be observed in the LCMS analysis of robustness screening
experiments (Table 2, entries 16 and 17).
mediate, which spontaneously cyclizes for form amino-1,3-
oxazine.
CONCLUSIONS
■
In the pursuit of a highly complex potential pharmaceutical
agent (1), we sought a robust and scalable method for the
conversion of 1,3-aminoalcohols to 1,3-aminooxazines. By
exploiting an observation made during the attempts to find
process-friendly conditions to achieve the formation of 1,3-
aminothiazines, we were able to deliver 1 at an 860 g scale. This
method provides a viable and efficient alternative method to
these pharmaceutically important heterocycles and is fast, uses
inexpensive reagents with easily removable byproducts and
reagents. Preliminary mechanistic investigation was highly
suggestive of the formation of a carbodiimide prior to
cyclization.
EXPERIMENTAL PROCEDURES
■
General Information. All reactions were carried out under
an atmosphere of N2, and commercially available reagents were
used as received. Anhydrous solvents DCM, DMSO, and MeCN
were used. Flash column chromatography was carried out using
silica gel columns with a Teledyne ISCO CombiFlash
Companion system. Thin layer chromatography (TLC) was
performed on commercially available precoated TLC plates
(0.25 mm silica gel with fluorescent indicator UV254), and
visualization was achieved by either the quenching of UV
fluorescence or with a KMnO4 stain. 1H and 13C NMR spectra
were recorded on a Bruker AV-HD 400 spectrometer and a
Bruker Advance III 500 spectrometer. Signal positions were
recorded in δ ppm with the abbreviations s, br s, d, dd, dt, ddt,
Monitoring this reaction by 13C NMR demonstrates
consumption of the 44 formation of a species bearing a
quaternary carbon atom that has a chemical shift, in agreement
with the expected value for a carbodiimide intermediate
(Scheme 6).33,34
Combining all the evidence together with the previous work
reported in the literature, a potential mechanism was proposed
(Scheme 7). Given that the reaction can be performed in the
presence of either TMSCl or HCl, it is proposed that both can
serve to activate DMSO to form sulfonium salts, which are
capable of activation of the thiourea, enabling the elimination of
dimethylsulfide and sulfur to form the carbodiimide inter-
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dtd, dtt, dq, t, tt, q, and m denoting singlet, broad singlet,
doublet, doublet of doublets, double triplets, doublet of doublet
of triplet triplets, doublet of triplet of doublets, doublet of triplet
of triplets, doublet of quartets, triplet, triplet of triplets, quartet,
mg) in dichloromethane (40 mL/g) in a water/ice bath was
added benzoyl isothiocyanate (1 equiv) in dichloromethane (10
mL/g) dropwise over an hour via a syringe pump. The reaction
mixture was then stirred at room temperature for an hour. The
reaction mixture was then concentrated to give an oil residue
which was purified as specified below.
(rac)-N-((3-Hydroxy-1-phenylpropyl)carbamothioyl)-
benzamide (27a). 3-Amino-3-phenyl-propan-1-ol (500 mg,
3.31 mmol) was subjected to general procedure 1. The resultant
residue was purified by flash column chromatography (SiO2,
eluting with 0−50% ethyl acetate/heptane) to give 27a (1.030 g,
3.27 mmol, 99% yield) as a white solid. mp 115−117 °C; νmax
(thin film)/cm−1: 3229, 2951, 1669, 1512, 1154; δH (400 MHz,
CDCl3): 11.33 (1H, d, J 8.2), 9.07 (1H, s), 7.83 (2H, d, J 7.6),
7.63 (1H, t, J 7.3), 7.51 (2H, t, J 7.8), 7.39 (4H, d, J 4.3), 7.34−
7.29 (1H, m), 5.81 (1H, td, J 9.2, 4.8), 3.80−3.70 (2H, m), 2.68
(1H, br s), 2.24 (1H, ddt, J 14.1, 8.7, 5.2), 2.12 (1 H, ddt, J 13.8,
9.3, 4.0); δC (100 MHz, CDCl3): 179.6, 167.0, 140.0, 133.7,
131.6, 129.2, 129.0, 127.9, 127.4, 126.6, 58.6, 56.9, 39.1; HRMS
(ESI) m/z: [MH]+ calcd for C17H19N2O2S, 315.1167; found,
315.1170.
1
and multiplet, respectively. All H NMR chemical shifts were
referenced to SiMe4 as an internal standard (0.00 ppm). All 13C
NMR chemical shifts in CDCl3 were referenced to the residual
solvent peak at 77.00 ppm. All 13C chemical shifts in CD2Cl2
were referenced to the residual solvent peak at 53.5 ppm. All
coupling constants, J, are quoted in Hz to the nearest 0.5 Hz.
Infrared spectra were recorded on a Shimadzu IR Affinity 1 FT-
IR spectrometer. Melting points were obtained using a DSC 1
STARe system. High-resolution electrospray ionization (ESI-
TOF) mass spectra were obtained with an Agilent Technologies
6230 series time-of-flight mass spectrometer. Reverse phase
liquid-chromatography mass spectra were obtained with an
Agilent Technologies 1290 series reverse phase liquid-
chromatography mass spectrometer.
The experimental procedures for all steps in Scheme 2 are
described in Lilly patent.15
N-((4aR,5S,7aS)-7a-(5-Bromo-2-fluorophenyl)-5-(1,1-di-
fluoroethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]oxazin-
2-yl)benzamide (3). A solution of 22 (580 g, 1621 mmol) in
CH2Cl2 (5 L) was stirred at 18 °C under nitrogen in a 20 L glass-
jacketed reactor fitted with an overhead stirrer and a
temperature probe. Benzoyl isothiocyanate (345 g, 2114
mmol) was added at once, resulting in a temperature increase
to 20 °C. After 1 h, LCMS showed complete conversion to the
desired product and the reaction mixture was held at this
temperature overnight. The jacket temperature was set to 10 °C
and nitrogen flow was increased, with exit gas passing through a
scrubber containing a mixture of sodium hydroxide (50%w/w,
250 mL, 3.0 equiv) and aqueous bleach (4 L, ∼2 equiv). The
reaction mixture was charged with DMSO (150 mL, 2110 mmol,
1.30 equiv), and then TMSCl (250 mL, 1930 mmol, 1.19 equiv)
was added dropwise at rate ∼1 mL/min, maintaining the
internal temperature below 12 °C. A precipitate (sulfur) became
visible halfway through the addition. After 1 h at 10 °C, the
reaction mixture was quenched with a solution of Na2CO3 (500
g, 4717 mmol, 2.9 equiv) in water (3 L), and the mixture was
stirred for 30 min. The layers were separated, and the organic
layer was washed with water (2 L). The aqueous layer was
extracted with CH2Cl2 (2.5 L). The organic layers were
combined and evaporated to dryness. The residue obtained
was stirred with methanol (4 L) at 40 °C for 1 h and allowed to
stand overnight before filtering through Celite (500 g), washing
the filter with methanol (4 × 500 mL). This solution was
evaporated to afford a crude material that was subsequently
stirred with acetonitrile (3 L) at 40 °C for 1 h and allowed to
stand at room temperature overnight. The solution was filtered
through Celite washing with acetonitrile (4 × 500 mL), and the
filtrate was evaporated to dryness to afford a brown solid (970
g). This was purified by silica gel chromatography (Teledyne
ISCO Torrent, 3 kg column) eluting with 0−30% EtOAc in
isohexane to afford 3 as a beige solid (860 g, 95% purity by
HPLC, 8% residual solvent, 1548 mmol, 96% yield) δH (400
MHz, CDCl3): 12.05 (1H, br s), 8.23 (2H, d, J = 7.6 Hz), 7.62
(1H, dd, J = 7.0, 2.3 Hz), 7.56−7.48 (2H, m), 7.47−7.40 (2H,
m), 7.01 (1H, dd, J = 9.0, 11.5 Hz), 4.47−4.31 (4H, m), 4.16−
4.10 (1H, m), 3.58−3.52 (1H, m), 1.79 (3H, t, J = 19.3 Hz).;
LRMS (ESI) m/z: [MH]+ 483.0/485.0.
(rac)-N-[(3-Hydroxy-3-phenyl-propyl)carbamothioyl]-
benzamide (27b). 3-Amino-1-phenylpropan-1-ol (505 mg, 3.34
mmol) was subjected to general procedure 1. The resultant
residue was purified by flash column chromatography (SiO2,
eluting with 0−40% ethyl acetate/heptane) to give 27b (819
mg, 2.60 mmol, 78% yield) as a yellow oil. νmax (thin film)/cm−1:
3238, 1670, 1518, 1157; δH (400 MHz, CDCl3): 10.98 (1 H, br
s), 9.06 (1H, s), 7.82 (2H, d, J 7.4), 7.61 (1H, t, J 7.4), 7.49 (2H,
t, J 7.8), 7.39−7.32 (4H, m), 7.29−7.25 (1H, m), 4.86 (1H, dd, J
7.6, 5.1), 4.03 (1H, dq, J 13.7, 6.5), 3.76 (1H, dq, J 13.7, 6.0),
2.86 (1H, br s), 2.17−2.05 (2H, m); δC (100 MHz, CDCl3):
168.1, 144.1, 134.2, 131.5, 128.5, 128.5, 127.5, 126.9, 125.6,
72.7, 38.6, 37.5; HRMS (ESI) m/z: [MNa]+ calcd for
C17H18N2NaO2S, 337.0987; found 337.0987.
(rac)-N-((4,4-Diethoxy-3-hydroxybutyl)carbamothioyl)-
benzamide (27c). 4-Amino-1,1-diethoxy-butan-2-ol (500 mg,
2.82 mmol) was subjected to general procedure 1. The resultant
residue was purified by flash column chromatography (SiO2,
eluting with 0−50% ethyl acetate/heptane) to give 27c (737 mg,
2.14 mmol, 76% yield) as a white solid. mp 78−84 °C; νmax (thin
film)/cm−1: 3227, 2975, 1673, 1517, 1060; δH (400 MHz,
CDCl3): 10.97 (1H, br s), 8.96 (1H, s), 7.84 (2H, d, J 8.3), 7.62
(1H, t, J 7.4), 7.51 (2H, t, J 8.0), 4.33 (1H, d, J 6.2), 4.10−4.01
(1H, m), 3.84−3.70 (4H, m), 3.61 (1H, dd, J 9.1, 7.0), 3.58 (1H,
dd, J 7.0, 4.6), 2.57 (1H, d, J 2.7), 2.13−2.05 (1H, m), 1.85−1.76
(1H, m), 1.25 (3H, t, J 7.0), 1.23 (3H, t, J 7.0); δC (100 MHz,
CDCl3): 179.5, 166.5, 133.4, 131.9, 129.0, 127.4, 104.7, 70.8,
63.7, 43.5, 29.9, 15.4; HRMS (ESI) m/z: [MNa]+ calcd for
C16H24N2NaO4S, 363.1354; found 363.1359.
(rac)-N-[[(1R,2S)-2-(Hydroxymethyl)cyclopentyl]-
carbamothioyl]benzamide (27d). Racemic-[(1S,2R)-2-
aminocyclopentyl]methanol (512 mg, 4.45 mmol) was
subjected to general procedure 1. The resultant residue was
purified by flash column chromatography (SiO2, eluting with 0−
50% ethyl acetate/heptane) to give 27d (1.07 g, 3.84 mmol, 86%
yield) as a yellow oil. νmax (thin film)/cm−1: 3183, 2952, 1669,
1490, 1261, 1154; δH (500 MHz, CDCl3): 10.93 (1H, d, J 6.6),
9.08 (1H, s), 7.84 (2H, dd, J 8.6, 1.3), 7.64 (1H, tt, J 7.4, 1.3),
7.53 (2H, t, J 8.1), 4.95−4.91 (1H, m), 3.65 (1H, d, J 10.5), 3.53
(1H, dd, J 11.9, 8.9), 3.09 (1H, br s), 2.42−2.34 (1H, s), 2.14−
2.08 (1H, m), 1.89−1.78 (4H, m), 1.39−1.33 (1H, m); δC (100
MHz, CDCl3): 179.4, 167.1, 133.7, 131.5, 129.2, 127.4, 61.9,
General Procedure 1 for the Synthesis of Thiourea
Derivatives. To a stirred solution of the amino alcohol (∼500
G
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58.5, 46.9, 32.3, 25.4, 21.7; HRMS (ESI) m/z: [MH]+ calcd for
C14H19N2O2S, 279.1167; found, 279.1164.
subjected to general procedure 1. The resultant residue was
purified by flash column chromatography (SiO2, eluting with 0−
50% ethyl acetate/heptane) to give 44 (1.17 g, 4.12 mmol, 96%
yield) as a yellow oil. νmax (thin film)/cm−1: 3234, 3063, 1668,
1507, 1154; δH (400 MHz, CDCl3): 11.12 (1H, d, J 7.4), 8.97
(1H, s), 7.84−7.81 (2H, m), 7.62 (1H, t, J 7.4), 7.50 (2H, t, J
7.4), 7.42−7.35 (4H, m), 7.29 (1H, tt, J 6.2, 2.1), 5.63 (1H,
quintet, J 7.2), 1.67 (3H, d, J 7.0); δC (100 MHz, CDCl3): 178.8,
166.8, 141.6, 133.5, 131.7, 129.1, 128.8, 127.6, 127.3, 126.3,
55.2, 21.6; HRMS (ESI) m/z: [MH]+ calcd for C16H17N2OS,
285.1062; found, 285.1064.
General Procedure 2 for the Synthesis of Amino-1,3-
oxazine Derivatives. To a stirred solution of thiourea (∼500
mg) in dichloromethane (50 mL/g) in a water/ice bath was
added DMSO (1.2 equiv) with hydrochloric acid (4 mol/L) in
1,4-dioxane (2 equiv) in one portion. To the reaction mixture
was added chlorotrimethylsilane (1.2 equiv) dropwise over a
minute. The reaction mixture was then stirred in a water/ice
bath for half an hour. The reaction mixture was filtered through
Celite and to the mixture was added saturated sodium
bicarbonate (20 mL/g). The layers were separated, and the
aqueous layer was extracted with ethyl acetate (20 mL/g). The
combined organics were dried over sodium sulfate, filtered, and
concentrated in vacuo to give a residue which was purified as
specified.
N-(3-Hydroxypropylcarbamothioyl)benzamide (27e). 3-
Aminopropan-1-ol (500 mg, 6.59 mmol) was subjected to
general procedure 1. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 0−20% ethyl
acetate/dichloromethane) to give 27e (1.25 g, 5.19 mmol, 79%
yield) as a white solid. mp 111−113 °C; νmax (thin film)/cm−1:
3215, 2935, 1664, 1525, 1155; δH (400 MHz, CDCl3): 10.90
(1H, br s), 9.02 (1H, s), 7.84 (2H, d, J 7.4), 7.63 (1H, t, J 7.4),
7.52 (2H, t, J 7.8), 3.92 (2H, q, J 6.2), 3.78 (2H, t, J 5.7), 2.37
(1H, br s), 1.93 (2H, dt, J 11.9, 6.1); δC (100 MHz, CDCl3):
180.3, 166.8, 133.6, 131.7, 129.1, 127.4, 59.5, 42.7, 31.4; HRMS
(ESI) m/z: [MH]+ calcd for C11H15N2O2S, 239.0854; found,
239.0857.
(rac)-N-(3-Hydroxybutylcarbamothioyl)benzamide (27f).
4-Aminobutan-2-ol (519 mg, 5.71 mmol) was subjected to
general procedure 1. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 0−40% ethyl
acetate/heptane) to give 27f (1.13 g, 4.48 mmol, 78% yield) as a
white solid. mp 92−95 °C; νmax (thin film)/cm−1: 3229, 2969,
1670, 1511, 1160; δH (400 MHz, CDCl3): 10.94 (1H, br s), 9.07
(1H, s), 7.84 (2H, d, J 7.4), 7.62 (1H, t, J 7.4), 7.51 (2H, t, J 7.8),
4.08 (1H, dddd, J 13.9, 8.6, 6.5, 5.5), 4.02−3.94 (1H, m), 3.72
(1H, dq, J 13.8, 5.6), 2.49 (1H, br s), 1.88 (1H, dddd, J 14.2, 8.9,
5.6, 3.3), 1.76 (1H, ddt, J 14.6, 9.2, 5.6), 1.27 (3H, d, J 6.1); δC
(100 MHz, CDCl3): 179.9, 166.7, 133.5, 131.7, 129.1, 127.4,
65.6, 43.0, 37.5, 23.5; HRMS (ESI) m/z: [MH]+ calcd for
C12H17N2O2S, 253.1011; found, 253.1012.
(rac)-N-[[3-Hydroxy-2,2-dimethyl-1-(p-tolyl)propyl]-
carbamothioyl]benzamide (27g). 3-Amino-2,2-dimethyl-3-(p-
tolyl)propan-1-ol (500 mg, 2.59 mmol) was subjected to general
procedure 1. The resultant residue was purified by flash column
chromatography (SiO2, eluting with 0−40% ethyl acetate/
heptane) to give 27g (600 mg, 1.68 mmol, 65% yield) as a white
solid. mp 228 °C (decomp.); νmax (thin film)/cm−1: 3194, 2948,
1669, 1539, 1156; δH (400 MHz, CDCl3): 11.95 (1H, d, J 8.4),
9.29 (1H, s), 7.81 (2H, d, J 7.4), 7.55 (1H, t, J 6.4), 7.43 (2H, t, J
7.2), 7.24 (2H, d, J 7.2), 7.14 (2H, d, J 7.2), 5.48 (1H, d, J 9.0),
3.57 (1H, d, J 10.9), 3.40 (1H, br s), 3.24 (1H, d, J 10.9), 2.32
(3H, s), 1.06 (3H, s), 0.87 (3H, s); δC (100 MHz, CDCl3):
178.9, 166.9, 136.9, 134.4, 133.3, 131.6, 128.8, 128.6, 128.4,
127.4, 68.5, 65.4, 39.4, 22.8, 21.0, 20.9; HRMS (ESI) m/z:
[MH]+ calcd for C20H25N2O2S, 357.1637; found, 357.1639.
(rac)-1-(3-Hydroxy-1-phenyl-propyl)-3-phenyl-thiourea
(27h). To a stirred solution of 3-amino-3-phenyl-propan-1-ol
(516 mg, 3.41 mmol) in dichloromethane (20.6 mL) in a water/
ice bath was added phenyl isothiocyanate (0.408 mL, 3.41
mmol) in dichloromethane (5.2 mL) dropwise over an hour via
a syringe pump. The reaction mixture was stirred at room
temperature for 1 h and then concentrated. The resultant
residue was purified by flash column chromatography (SiO2,
eluting with 0−20% ethyl acetate/heptane) to give 27h (936
mg, 3.24 mmol, 94% yield) as a white solid. mp 127−129 °C;
νmax (thin film)/cm−1: 3229, 2944, 1527, 1237; δH (400 MHz,
CDCl3): 8.08 (1H, s), 7.41−7.17 (10H, m), 6.82 (1H, s), 5.85
(1H, s), 3.69−3.64 (2H, m), 2.98 (1H, s), 2.20−2.12 (1H, m),
1.88−1.82 (1H, m); δC (100 MHz, CDCl3): 180.1, 140.6, 135.8,
130.1, 128.8, 127.6, 127.3, 126.3, 125.2, 58.5, 56.5, 37.9; HRMS
(ESI) m/z: [MH]+ calcd for C16H19N2OS, 287.1218; found,
287.1224.
(rac)-N-(4-Phenyl-1,3-oxazinan-2-ylidene)benzamide
(28a).
27a (465 mg, 1.45 mmol) was subjected to general
procedure 2. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 0−20% ethyl
acetate/heptane) to give 28a (348 mg, 1.23 mmol, 84%
yield) as a white solid. mp 180−182 °C; νmax (thin film)/
cm−1: 3067, 2967, 1594, 1356, 1147; δH (400 MHz,
CDCl3): 11.48 (1H, br s), 8.22 (2H, dd, J 8.6, 1.8), 7.48
(1H, tt, J 6.4, 1.4), 7.44−7.33 (7H, m), 4.81 (1H, dd, J 7.8,
5.3), 4.46 (2H, dd, J 7.0, 4.9), 2.47−2.40 (1H, m), 2.20−
2.12 (1H, m); δC (100 MHz, CDCl3): 179.0, 163.0, 139.9,
137.2, 131.7, 129.2, 129.1, 128.5, 127.9, 125.9, 64.5, 53.1,
29.9; HRMS (ESI) m/z: [MH]+ calcd for C17H17N2O2,
281.1290; found, 281.1294.
(rac)-N-(6-Phenyl-1,3-oxazinan-2-ylidene)benzamide
(28b). 27b (343 mg, 1.00 mmol) was subjected to general
procedure 2. The resultant residue was purified by flash column
chromatography (SiO2, eluting with 0−20% ethyl acetate/
heptane) to give 28b (176 mg, 0.628 mmol, 62% yield) as a
white solid. mp 151−154 °C; νmax (thin film)/cm−1: 3062, 2971,
1610, 1443, 1340, 1131; δH (400 MHz, CDCl3): 11.31 (1H, br
s), 8.23 (2H, d, J 8.0), 7.45 (1H, tt, J 7.0, 1.6), 7.41−7.31 (7H,
m), 5.37 (1H, dd, J 9.2, 3.1), 3.58−3.44 (2H, m), 2.32−2.15
(2H, m); δC (100 MHz, CDCl3): 179.2, 163.3, 137.9, 137.4,
131.6, 129.1, 128.8, 128.7, 127.9, 125.9, 78.1, 37.7, 27.9; HRMS
(ESI) m/z: [MH]+ calcd for C17H17N2O2, 281.1290; found,
281.1294.
(rac)-N-[6-(Diethoxymethyl)-1,3-oxazinan-2-ylidene]-
benzamide (28c). 27c (500 mg, 1.44 mmol) was subjected to
general procedure 2. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 0−20% ethyl
acetate/heptane) to give 28c (239 mg, 0.757 mmol, 52% yield)
as a colorless oil. νmax (thin film)/cm−1: 3081 (weak), 2976
(weak), 1612 (strong), 1333 (medium), 1065 (medium); δH
(400 MHz, CDCl3): 11.22 (1H, br s), 8.21−8.18 (2H, m), 7.46
(1H, tt, J 7.2, 1.6), 7.39 (2H, t, J 7.8), 4.71 (1H, d, J 3.9), 4.37
(rac)-N-((1-Phenylethyl)carbamothioyl)benzamide (44).
(rac)-1-Phenylethan-1-amine (518 mg, 4.27 mmol) was
H
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Article
(1H, dt, J 8.3, 4.0), 3.86−3.77 (2H, m), 3.71−3.58 (3H, m),
3.46 (1H, ddd, J 12.7, 9.6, 5.9), 2.23−2.10 (2H, m), 1.27 (3H, t,
J 7.0), 1.24 (3H, t, J 7.0); δC (100 MHz, CDCl3): 179.1, 162.9,
137.5, 131.5, 129.1, 127.9, 102.1, 76.9, 65.4, 64.3, 37.5, 19.8,
15.3, 15.3; HRMS (ESI) m/z: [MH]+ calcd for C16H23N2O4,
307.1658; found, 307.1661.
(rac)-N-((4aS,7aR)-Hexahydrocyclopenta[d][1,3]oxazin-
2(1H)-ylidene)benzamide (28d). 27d (391 mg, 1.40 mmol)
was subjected to general procedure 2. The resultant residue was
purified by flash column chromatography (SiO2, eluting with 0−
20% ethyl acetate/heptane) to give 28d (241 mg, 0.987 mmol,
70% yield) as a white solid. mp 112−115 °C; νmax (thin film)/
cm−1: 3065, 2961, 1591, 1359, 1134; δH (400 MHz, CDCl3):
11.08 (1H, br s), 8.20 (2H, d, J 7.2), 7.47 (1H, tt, J 7.0, 1.4), 7.40
(2H, t, J 7.8), 4.40 (1H, dd, J 11.3, 3.9), 4.16 (1H, dd, J 11.3,
5.7), 3.97−3.93 (1H, m), 2.59−2.51 (1H, m), 2.07−1.93 (2H,
m), 1.89−1.63 (4H, m); δC (100 MHz, CDCl3): 178.8, 163.5,
137.3, 131.6, 129.1, 127.9, 66.9, 53.6, 35.2, 34.5, 25.9, 22.6;
HRMS (ESI) m/z: [MH]+ calcd for C14H17N2O2, 245.1290;
found, 245.1293.
(rac)-N-(1,3-Oxazinan-2-ylidene)benzamide (28e). 7e
(500 mg, 2.10 mmol) was subjected to general procedure 2.
The resultant residue was purified by flash column chromatog-
raphy (SiO2, eluting with 0−40% ethyl acetate/heptane) to give
oxazine 28e (374 mg, 1.83 mmol, 87% yield) as a white solid. mp
94−97 °C; νmax (thin film)/cm−1: 3218, 2949, 1590, 1349,
1133; δH (400 MHz, CDCl3): 11.19 (1H, br s), 8.21−8.18 (2H,
m), 7.47 (1H, tt, J 7.2, 1.6), 7.39 (2H, t, J 7.6), 4.45 (2H, t, J 5.5),
3.54 (2H, t, J 6.2), 2.16 (2H, dt, J 10.9, 6.2); δC (100 MHz,
CDCl3): 178.8, 163.0, 137.3, 131.5, 129.0, 127.8, 66.0, 38.1,
20.6; HRMS (ESI) m/z: [MH]+ calcd for C11H13N2O2,
205.0977; found, 205.0979.
18.9; HRMS (ESI) m/z: [MH]+ calcd for C20H23N2O2,
323.1760; found, 323.1765.
(rac)-N,4-Diphenyl-1,3-oxazinan-2-imine (28h). To a
stirred solution of 27h (343 mg, 1.20 mmol) in dichloromethane
(17.2 mL) in a water/ice bath were added DMSO (0.15 mL,
2.16 mmol) and hydrochloric acid solution (4 M in 1,4-dioxane,
0.90 mL, 3.59 mmol). To the reaction mixture was added
chlorotrimethylsilane (0.27 mL, 2.16 mmol) dropwise over 1
min. The reaction mixture was then stirred in a 40 °C heating
block for 30 min, and then it was cooled to room temperature
and filtered through Celite. To the filtrate was added saturated
aqueous sodium bicarbonate solution (10 mL), and the mixture
was extracted with dichloromethane (3 × 10 mL). The
combined organics were dried over sodium sulfate and
concentrated to give a residue, which was purified by flash
column chromatography (SiO2, eluting with 0−50% ethyl
acetate/heptane) to give oxazine 28h (192 mg, 0.761 mmol,
63% yield) as a white solid. mp 127−130 °C; νmax (thin film)/
cm−1: 3027, 2891, 1664, 1598, 1135; δH (400 MHz, CDCl3):
7.32−7.17 (9H, m), 6.91 (1H, t, J 7.2), 6.70 (1H, br s), 4.54
(1H, dd, J 7.6, 5.5), 4.23−4.14 (2H, m), 2.21−2.14 (1H, m),
1.85−1.77 (1H, m); δC (100 MHz, CDCl3): 149.5, 144.4, 141.5,
128.6, 128.3, 126.8, 126.2, 121.6, 119.9, 64.2, 54.0, 30.9; HRMS
(ESI) m/z: [M]+ calcd for C16H17N2O, 253.1341; found,
253.1343.
(rac)-N-((1-Phenylethyl)carbamoyl)benzamide (46). 44
(338 mg, 1.19 mmol) was subjected to general procedure 2.
The resultant residue was purified by flash column chromatog-
raphy (SiO2, eluting with 0−50% ethyl acetate/heptane) to give
46 (250 mg, 0.931 mmol, 78% yield) as a white solid. mp 118−
123 °C; νmax (thin film)/cm−1: 3233, 1686, 1532, 1453, 1270; δH
(400 MHz, CDCl3): 9.26 (1H, s), 9.14 (1H, d, J 7.6), 7.91 (2H,
d, J 7.6), 7.58 (1H, t, J 7.6), 7.45 (2H, t, J 7.8), 7.38−7.32 (4H,
m), 7.28−7.25 (1H, m), 5.11 (1H, quintet, J 7.1), 1.58 (3H, d, J
7.0); δC (100 MHz, CDCl3): 168.3, 153.5, 143.3, 133.1, 132.2,
128.7, 128.7, 127.7, 127.3, 125.9, 49.7, 22.8; HRMS (ESI) m/z:
[MNa]+ calcd for C16H16N2NaO2, 291.1109; found, 291.1110.
(rac)-(Z)-N-((Dibenzylamino)((1-phenylethyl)-
amino)methylene)benzamide (47). To a solution of
thiourea 44 (197 mg, 0.658 mmol) in dichloromethane
(9.9 mL) in a water/ice bath were added DMSO (0.056
mL, 0.790 mmol) and hydrochloric acid solution (4 M in
1,4-dioxane, 0.33 mL, 1.32 mmol). To the reaction mixture
was added chlorotrimethylsilane (0.10 mL, 0.790 mL)
dropwise over 1 min, followed by dibenzylamine (0.25 mL,
1.32 mmol) in one portion. The reaction mixture was then
stirred in a water/ice bath for 30 min, and then it was
filtered through Celite. To the filtrate was added saturated
aqueous sodium bicarbonate solution (10 mL), and the
mixture was extracted with dichloromethane (2 × 10 mL).
The combined organics were dried over sodium sulfate and
concentrated to give a residue, which was purified by flash
column chromatography (SiO2, eluting with 0−20% ethyl
acetate/heptane) to give 47 (135 mg, 0.302 mmol, 46%
yield) as a white solid. mp 145−147 °C; νmax (thin film)/
cm−1: 3251, 1560, 1474, 1348; δH (400 MHz, CDCl3):
8.99 (1H, br s), 8.16 (2H, d, J 7.0), 7.43 (1H, t, J 7.6),
7.37−7.22 (11H, m), 7.16 (4H, d, J 7.0), 7.08 (2H, dd, J
8.0, 2.7), 4.79−4.75 (3H, m), 4.42 (2H, d, J 16.0), 1.46
(3H, d, J 6.6); δC (100 MHz, CDCl3): 174.2, 163.5,
143.5, 138.5, 136.4, 130.8, 129.2, 128.8, 128.7, 127.7,
127.6, 127.3, 125.6, 54.5, 51.8, 24.9; HRMS (ESI) m/z:
[MH]+ calcd for C30H30N3O, 448.2389; found, 448.2388.
(rac)-N-(6-Methyl-1,3-oxazinan-2-ylidene)benzamide
(28f).
27f (1.11 g, 4.42 mmol) was subjected to general
procedure 2. The resultant residue was combined with
cyclopentyl methyl ether (4.0 mL) and heptane (4.0 mL),
and the mixture was stirred vigorously in a 50 °C heating
block for 30 min and then at room temperature for 10
min. The mixture was filtered to give 28f (634 mg, 2.88
mmol, 65% yield) as a white solid. mp 124−127 °C; νmax
(thin film)/cm−1: 3059, 2935, 1608, 1339, 1133; δH (400
MHz, CDCl3): 11.26 (1H, br s), 8.22−8.19 (2H, m), 7.46
(1H, tt, J 6.2,1.4), 7.39 (2H, t, J 8.0), 4.56−4.48 (1H, m),
3.57−3.47 (2H, m), 2.11 (1H, ddt, J 14.1, 5.1, 3.0), 1.89
(1H, dtd, J 14.1, 10.3, 6.6), 1.51 (3H, d, J 6.0); δC (100
MHz, CDCl3): 179.1, 163.3, 137.4, 131.5, 129.1, 127.8,
73.4, 37.8, 27.5, 20.7; HRMS (ESI) m/z: [MH]+ calcd for
C12H15N2O2, 219.1134; found, 219.1135.
(rac)-N-[5,5-Dimethyl-4-(p-tolyl)-1,3-oxazinan-2-ylidene]-
benzamide (27g). 25g (500 mg, 1.40 mmol) was subjected to
general procedure 2. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 0−40% ethyl
acetate/heptane) to give 28g (420 mg, 1.28 mmol, 91% yield) as
a white solid. mp 169−170 °C; νmax (thin film)/cm−1: 3065,
2972, 1588, 1348, 1020; δH (400 MHz, CDCl3): 11.40 (1H, br
s), 8.24 (2H, d, J 8.0), 7.47 (1H, t, J 7.2), 7.40 (2H, t, J 7.8), 7.19
(2H, d, J 8.2), 7.15 (2H, d, J 8.2), 4.43 (1H, s), 4.14 (1H, d, J
11.3), 4.11 (1H, d, J 11.3), 2.36 (3H, s), 1.05 (3H, s), 0.84 (3H,
s); δC (100 MHz, CDCl3): 178.9, 162.5, 138.4, 137.2, 133.4,
131.6, 129.2, 129.1, 127.8, 127.5, 75.0, 62.9, 31.7, 22.9, 21.0,
I
https://dx.doi.org/10.1021/acs.oprd.0c00369
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
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Article
(4) Kennedy, M. E.; Stamford, A. W.; Chen, X.; Cox, K.; Cumming, J.
N.; Dockendorf, M. F.; Egan, M.; Ereshefsky, L.; Hodgson, R. A.; Hyde,
L. A.; Jhee, S.; Kleijn, H. J.; Kuvelkar, R.; Li, W.; Mattson, B. A.; Mei, H.;
Palcza, J.; Scott, J. D.; Tanen, M.; Troyer, M. D.; Tseng, J. L.; Stone, J.
A.; Parker, E. M.; Forman, M. S. The BACE1 Inhibitor Verubecestat
(MK-8931) Reduces CNS b-Amyloid in Animal Models and in
Alzheimer’s Disease Patients. Sci. Transl. Med. 2016, 8, 363ra150.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00369.
Characterization of thioureas, details of mechanistic
study, and scans of spectral data for key compounds
(PDF)
̈
(5) Swahn, B. M.; Kolmodin, K.; Karlstrom, S.; von Berg, S.;
̈
̈
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Soderman, P.; Holenz, J.; Berg, S.; Lindstrom, J.; Sundstrom, M.;
̈
Turek, D.; Kihlstrom, J.; Slivo, C.; Andersson, L.; Pyring, D.; Rotticci,
D.; Ohberg, L.; Kers, A.; Bogar, K.; Von Kieseritzky, F.; Bergh, M.;
̈
AUTHOR INFORMATION
■
̈
Olsson, L. L.; Janson, J.; Eketjall, S.; Georgievska, B.; Jeppsson, F.;
Corresponding Author
̈
Falting, J. Design and Synthesis of β-Site Amyloid Precursor Protein
Jeffery Richardson − Discovery Chemistry Research and
Technologies, Eli Lilly and Company, Windlesham, Surrey
GU20 6PH, U.K.; orcid.org/0000-0002-4450-3828;
Email: jeff.r@sailife.com
Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of
β-Amyloid Peptides. J. Med. Chem. 2012, 55, 9346−61.
̈
̈
(6) Jeppsson, F.; Eketjall, S.; Janson, J.; Karlstrom, S.; Gustavsson, S.;
̈
Olsson, L.-L.; Radesater, A.-C.; Ploeger, B.; Cebers, G.; Kolmodin, K.;
̈
Swahn, B.-M.; Von Berg, S.; Bueters, T.; Falting, J. Discovery of
AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate
for the Treatment of Alzheimer Disease. J. Biol. Chem. 2012, 287,
41245−41257.
Authors
Peter J. Lindsay-Scott − Discovery Chemistry Research and
Technologies, Eli Lilly and Company, Windlesham, Surrey
GU20 6PH, U.K.; orcid.org/0000-0002-4721-3594
Vladimir Larichev − AMRI UK Ltd., Windlesham, Surrey
GU20 6PH, U.K.
Emily Pocock − Discovery Chemistry Research and
Technologies, Eli Lilly and Company, Windlesham, Surrey
GU20 6PH, U.K.
̈
(7) Eketjall, S.; Janson, J.; Kaspersson, K.; Bogstedt, A.; Jeppsson, F.;
̈
Falting, J.; Haeberlein, S. B.; Kugler, A. R.; Alexander, R. C.; Cebers, G.
AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency
and Permeability and Markedly Slow Off-Rate Kinetics. J. Alzheimer’s
Dis. 2016, 50, 1109−1123.
(8) Timmers, M.; Van Broeck, B.; Ramael, S.; Slemmon, J.; De
Waepenaert, K.; Russu, A.; Bogert, J.; Stieltjes, H.; Shaw, L. M.;
Engelborghs, S.; Moechars, D.; Mercken, M.; Liu, E.; Sinha, V.; Kemp,
J.; Van Nueten, L.; Tritsmans, L.; Streffer, J. R. Profiling the Dynamics
of CSF and Plasma Aβ Reduction after Treatment with JNJ-54861911,
a Potent Oral BACE Inhibitor. Alzheimer’s Dement. Transl. Res. Clin.
Interv. 2016, 2, 202−212.
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
(9) Winneroski, L. L.; Erickson, J. A.; Green, S. J.; Lopez, J. E.; Stout, S.
L.; Porter, W. J.; Timm, D. E.; Audia, J. E.; Barberis, M.; Beck, J. P.;
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ACKNOWLEDGMENTS
■
The authors thank Dr. Liam Ball (University of Nottingham) for
helpful discussions on the mechanism and Dr. Erik Hembre for
help during the preparation of this manuscript.
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