Development of a Practical Synthesis of a Peripherally Selective Noradrenaline Reuptake Inhibitor Possessing a Chiral 6,7-trans-Disubstituted-1,4-oxazepane as a Scaffold

Article abstract of DOI:10.1021/acs.oprd.7b00313

A practical synthesis of a peripherally selective noradrenaline reuptake inhibitor that has a chiral 6,7-trans-disubstituted-1,4-oxazepane as a new class of scaffold is described. The amino alcohol possessing the desired stereochemistry was obtained with excellent dr and ee, starting from a commercially available aldehyde via a Morita-Baylis-Hillman reaction, Michael addition, isolation as maleic acid salt, reduction, and diastereomeric salt formation with (+)-10-camphorsulfonic acid. The desired single stereoisomer obtained at an early stage of the synthesis was used for seven-membered ring formation in fully telescoped processes, providing the chiral 6,7-trans-disubstituted-1,4-oxazepane efficiently. In addition to controls of dr and ee of the chiral 1,4-oxazepane, and control of N,O-selectivity in S_N2 reaction of the intermediate mesylate with a pyridone derivative, finding appropriate intermediates that were amenable to isolation and upgrade of purity enabled a practical chiral HPLC separation-free, column chromatograph-free synthesis of the drug candidate with excellent chemical and optical purities in a higher overall yield.

Full text of DOI:10.1021/acs.oprd.7b00313

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Full Paper
Development of a Practical Synthesis of a Peripherally
Selective Noradrenaline Reuptake Inhibitor Possessing a
Chiral 6,7-Trans-disubstituted-1,4-oxazepane as a Scaffold
kazuhisa Ishimoto, Kotaro Yamaguchi, Atsushi Nishimoto, Mika Murabayashi, and Tomomi Ikemoto
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00313 • Publication Date (Web): 01 Nov 2017
Downloaded from http://pubs.acs.org on November 1, 2017
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Development of a Practical Synthesis of a
Peripherally Selective Noradrenaline Reuptake
Inhibitor Possessing a Chiral 6,7ꢀTransꢀ
disubstitutedꢀ1,4ꢀoxazepane as a Scaffold
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Kazuhisa Ishimoto,* Kotaro Yamaguchi, Atsushi Nishimoto, Mika Murabayashi,
and Tomomi Ikemoto†
Process Chemistry, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 17ꢀ85,
Jusohonmachi 2ꢀChome, Yodogawaꢀku, Osaka 532ꢀ8686, Japan
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ABSTRACT:
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A practical synthesis of a peripherally selective noradrenaline reuptake inhibitor that has a chiral
6,7ꢀtransꢀdisubstitutedꢀ1,4ꢀoxazepane as a new class of scaffold is described. The amino alcohol
possessing the desired stereochemistry was obtained with excellent dr and ee, starting from a
commercially available aldehyde via MoritaꢀBaylisꢀHillman reaction, Michael addition, isolation
as maleic acid salt, reduction, and diastereomeric salt formation with (+)ꢀ10ꢀcamphorsulfonic
acid. The desired single stereoisomer obtained at an early stage of the synthesis was used for
sevenꢀmembered ring formation in fully telescoped processes, providing the chiral 6,7ꢀtransꢀ
disubstitutedꢀ1,4ꢀoxazepane efficiently. In addition to controls of dr and ee of the chiral 1,4ꢀ
oxazepane, and control of N,Oꢀselectivity in SN2 reaction of the intermediate mesylate with a
pyridone derivative, finding appropriate intermediates that were amenable to isolation and
upgrade of purity enabled a practical chiral HPLC separationꢀfree, column chromatographꢀfree
synthesis of the drug candidate with excellent chemical and optical purity in higher overall yield.
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KEYWORDS: peripherally selective noradrenaline reuptake inhibitor, chiral 6,7ꢀtransꢀ
disubstitutedꢀ1,4ꢀoxazepane, optical resolution by diastereomeric salt formation, chiral HPLC
separation/column chromatographyꢀfree synthesis, SN2 reaction of 2ꢀpyridoneꢀ3ꢀcarboxilic acid
esters
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INTRODUCTION
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Noradrenaline reuptake inhibitors (NRIs) are known to have potential as medicines for patients
with stress urinary incontinence.1 In order to suppress adverse effects of centrally acting
conventional NRIs,2 development of "peripherally selective" NRIs as a new class of therapeutic
agents for stress urinary incontinence has been pursued. Compound 1·HCl was identified as a
candidate for a peripherally selective NRI and has been developed by Takeda Pharmaceutical
Company Limited.3 The key structural feature of 1·HCl is the chiral 6,7ꢀtransꢀdisubstitutedꢀ1,4ꢀ
oxazepane core (Figure 1). Since this class of compounds has not attracted much attention as a
scaffold for medicines so far, the number of reports of their syntheses has been limited.3, 4
Therefore, the synthesis of 1·HCl is intriguing not only for medicinal chemists, but also for
organic chemists.
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Figure 1. Structure of peripherally selective NRI 1·HCl
The medicinal chemistry synthesis of 1·HCl is shown in Scheme 1. A mixture of rac-4 and
rac-4' was prepared by MoritaꢀBaylisꢀHillman reaction of aldehyde 2 with methyl acrylate
followed by Michael addition of benzyl amine, and the desired trans isomer rac-4 was separated
by column chromatography. The methyl ester of rac-4 was reduced by CaCl2/NaBH4, and the
resulting primary alcohol of rac-5 was protected with TBS. The protected rac-6 was reacted with
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chloroacetyl chloride, and ring closure by addition of 1 M NaOH gave sevenꢀmembered lactam
rac-8. Reduction of rac-8 with LiAlH4/AlCl3 gave oxazepane rac-9, which was debenzylated
with 1ꢀchloroethyl chloroformate (ACEꢀCl), and the resulting secondary amino group was
protected with a Boc group. The obtained rac-10 was optically resolved by HPLC using a chiral
column to give the desired single enantiomer. The optically pure alcohol 10 was mesylated and
reacted with methyl 2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboxylate (12a) to give ester 13. Hydrolysis
of the methyl ester and subsequent deprotection of the Boc group by treatment with 4 M HCl in
EtOAc gave 1·HCl.
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Scheme 1. Medicinal Chemistry Synthesis of 1·HCl a
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aReagents and conditions: (a) methyl acrylate, DABCO, MeCN, rt; (b) BnNH2, Et3N, MeOH,
rt; (c) CaCl2, NaBH4, THF, EtOH, 0 °C to rt; (d) TBSCl, Et3N, imidazole, DMAP, THF, 0 °C to
rt; (e) chloroacetyl chloride, Et3N, THF, 0 °C to rt; (f) 1 M NaOH, THF, 0 °C to rt; (g) LiAlH4,
AlCl3, THF, 0 °C to rt; (h) (1) 1ꢀchloroethyl chloroformate, MeCN, rt, (2) 1 M HCl, MeOH,
80 °C, (3) Boc2O, Et3N, 0 °C to rt; (i) optical resolution by HPLC; (j) MsCl, Et3N, THF, 0 °C to
rt; (k) methyl 2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboxylate 12a, K2CO3, 1,2ꢀdimethoxyethane,
80 °C; (1) 2 M NaOH, EtOH, 30 °C; (m) 4 M HCl in EtOAc, rt.
In an effort to support earlyꢀstage development of this new class of drug candidate, we
initiated development of a practical synthesis of 1·HCl. Our synthetic strategy is described in
Scheme 2. The most obvious synthetic challenge was to determine a means to construct the two
neighboring stereocenters on the sevenꢀmembered ring. In order to establish a practical synthesis
of 1·HCl, a facile synthesis of the chiral 6,7ꢀtransꢀdisubstitutedꢀ1,4ꢀoxazepane that does not rely
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on optical resolution by HPLC and column chromatographic separation was required. We
planned to obtain the desired enantiomer by optical resolution utilizing diastereomeric salt
formation. It is known that optical resolution at an early step is generally preferable from a
standpoint of cost and efficiency.5 Considering possible epimerization at the stereocenter
adjacent to the methyl ester of 4 during the reduction to 5, we strived to obtain a diastereomeric
salt of 5 with a chiral acid that gives the desired (1R, 2S) stereoisomer of 5. It was envisioned
that the stereocenters of 5 would be retained without epimerization until the final product,
judging from structures of intermediates and chemical transformations in downstream processes.
Having the single stereoisomer in hand, preparation of the sevenꢀmembered ring was elaborated.
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Scheme 2. Retrosynthetic analysis of 1·HCl
In addition to the synthesis of the chiral 6,7ꢀtransꢀdisubstitutedꢀ1,4ꢀoxazepane, another
challenge existed for establishing a scalable synthesis of 1·HCl; isolation and purification of
intermediates were problematic, because most of the intermediates are oily compounds as
described in scheme 1. In the course of investigation into the sevenꢀmembered ring formation,
alcohol 15 was identified as a new intermediate that could be isolated as HCl salt (15·HCl) with
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good purity. We expected that the reaction of 15·HCl with a 2ꢀpyridoneꢀ3ꢀcarboxylic acid ester
would give 16, and debenzylation followed by hydrolysis would give 1. Whereas the medicinal
chemistry synthesis changed the protecting group for the amino group from a Bn group to a Boc
group and conducted deprotection at the last step, our synthetic route was thought to be more
straightforward and would also provide potential opportunities to isolate 16 and/or 17 as a salt
utilizing the amino group in 16/17. Herein we describe process development of a practical
synthesis of the chiral 6,7ꢀtransꢀdisubstitutedꢀ1,4ꢀoxazepane and a strategy toward establishing a
scalable synthesis of 1·HCl.
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RESULTS AND DISCUSSION
Preparation of 5·(+)-CSA. The synthesis of chiral amino alcohol 5 is summarized in
Scheme 3. Although it is known that MoritaꢀBaylisꢀHillman reaction is generally a rather slow
reaction,6 the reaction of aldehyde 2 with methyl acrylate in MeOH using 0.5 equiv of DABCO
as a catalyst proceeded relatively quickly, reaching >90% conversion in 17 h, and gave rac-3 in
92% yield. After extraction with EtOAc, washing with brine, and solvent switch, rac-3 was used
for the next reaction without isolation.7
For Michael addition of benzylamine to rac-3, several solvents were screened to improve
trans/cis ratio.8 The solvent screening showed that MeOH was the best solvent, and gave rac-4
in 72:28 dr at room temperature. When the reaction temperature was decreased to 0 °C, dr
increased up to 82:18.9 Interestingly, other screened solvents (EtOH, 2ꢀpropanol, MeCN, toluene,
EtOAc, DMSO, N,Nꢀdimethylacetamide, pyridine, triethylamine) all gave the cis isomer as the
major product (41:59 to 20:80 dr). Isolation of rac-4 without chromatographic separation
required investigation, because rac-4 is an oily compound and the undesired cis isomer rac-4' is
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a crystalline solid. Screening of acids showed that maleic acid (MA) formed a good salt with
rac-4 in EtOAc to give a white solid, and isolation of the salt was effective for purging the cis
isomer rac-4'. Compound rac-4 was isolated as maleic acid salt (rac-4·MA) in 80% yield with
95:5 dr from rac-3. Fortunately, the remaining cis isomer was confirmed to be removed in the
later optical resolution step.
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After salt break with EtOAc/aqueous NaHCO3 and solvent switch to THF, free rac-4 was
subjected to reduction utilizing Ca(BH4)2 generated in situ from CaCl2 and NaBH4 in
EtOH/THF.10,11 In this reaction, the order of addition of reagents was found to be crucial. When
5.0 equiv of NaBH4 was added portionwise to 2.5 equiv of CaCl2 in EtOH/THF, Ca(BH4)2 was
properly generated and addition of a THF solution of rac-4 to the mixture gave rac-5 in 85%
yield. In contrast, when CaCl2 was added to NaBH4 in EtOH/THF, vigorous gas evolution and
rapid exotherm were observed. Probably due to failure of generation of Ca(BH4)2, addition of a
THF solution of rac-4 to this mixture gave ethyl ester of rac-4 as the main product, which would
be formed by transesterification, and rac-5 as the minor product, respectively. On completion of
the reaction led by addition of reagents in the proper order, the reaction mixture was quenched
by sequential addition of MeOH, H2O and 2 M HCl. The pH of the reaction mixture was
adjusted to 7–8 by addition of 8 M NaOH, and insoluble salts were filtered off. After solvent
switch to EtOAc, washing with 5% aqueous NaHCO3 and brine, and concentration, the obtained
rac-5 was used for the optical resolution without isolation.
More than 150 chiral acids were screened for the optical resolution of rac-5, revealing that
inexpensive (+)ꢀ10ꢀcamphorsulfonic acid ((+)ꢀCSA) was a good resolving agent for the desired
stereoisomer (1R, 2S)-5. The obtained rac-5 in MeOH/EtOAc (1:3) was treated with 0.5 equiv of
(+)ꢀCSA, and the generated diastereomeric salt 5·(+)-CSA was isolated by filtration. The crude
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product (typically 75–80% ee) was recrystallized from MeOH/EtOAc (1:4) to give 5·(+)-CSA in
42% yield with >99.9% ee. The cis isomer was removed during the isolation of 5·(+)-CSA and
was not detected in the obtained 5·(+)-CSA.
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Scheme 3. Synthesis of 5·(+)-CSAa
aFor the synthesis of rac-4·MA, the amounts of reagents were calculated based on the amount of
2. For the synthesis of 5·(+)-CSA, the amounts of reagents were calculated based on the amount
of rac-4·MA.
Preparation of 15·HCl. With the single stereoisomer in hand, seven memberedꢀring formation
was investigated (Scheme 4). After salt brake of 5·(+)-CSA, free 5 was treated with TBSCl in the
presence of imidazole for protection of the primary alcohol. Following extraction with EtOAc,
washing with brine, and solvent switch to THF, the crude 6 was reacted with chloroacethyl
chloride in the presence of triethylamine. Addition of 3.0 equiv of 2 M NaOH to this mixture in
one pot provided lactam 8 in 83% yield for 3 steps from 5·(+)-CSA. Lactam 8 was used for the
next reaction after workup (pH adjustment to 8–9 by addition of 1M HCl, extraction with EtOAc,
washing with brine, and solvent switch to THF) without isolation.
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In the medicinal chemistry synthesis, reduction of the amide group of lactam 8 was
conducted using AlCl3/LiAlH4, which is known to generate AlH3.12 It was reported that this
reduction system generally has a weaker reducing potency compared to LiAlH4, and the use of
AlCl3/LiAlH4 instead of LiAlH4 for the reduction of 8 effectively prevented generation of a
dechlorinated byproduct, which was difficult to remove in downstream processes. Considering
safety issues related to the use of LiAlH4 on a large scale, application of an alternative reagent
for AlCl3/LiAlH4 was sought. When RedꢀAl was used for the reaction, the reduction did not
proceed. Surprisingly, the use of RedꢀAl (4.0 equiv) with AlCl3 (1.0 equiv) made the reaction
proceed and gave oxazepane 9 in 91% yield in a small scale reaction. However, this combination
of reagents showed poor reproducibility, forcing us to give up this reagent system. Finally,
NaBH4/I2 reagent system13 was adopted for the reduction of 8 instead of an expensive BH3ꢁTHF
solution. A solution of 2.0 equiv of I2 in THF was added dropwise at 0 °C over 2 h to the
solution of 8 and 4.2 equiv of NaBH4 in THF. The reaction reached full conversion in 1 h, after
being warmed to room temperature without generation of the dechlorinated byproduct.14 The
reaction was completely quenched by dropwise addition of MeOH and stirring the mixture for 12
h at room temperature. Oxazepane 9 was extracted with EtOAc, and washed with water, brine,
and 5% aqueous NaHCO3.
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Since 9 is also an oily compound and was found to be difficult to isolate, we decided to
convert 9 to another isolable intermediate in order to purge impurities generated during the
sevenꢀmembered ring formation. We found that treatment of the obtained EtOAc solution of 9
with 3.0 equiv of 4 M HCl in EtOAc at 40–50 °C for 2 h gave 15·HCl as a white solid, which
was easily isolated by filtration. Although the synthesis of 15·HCl from 5·(+)-CSA was achieved
through fully telescoped processes, 15·HCl was isolated in good yield (total 76%) with good
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purity (>98 area%, >99% ee, dechlorinated byproduct<0.1 area%) as a result of the extensive
study.
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Scheme 4. Synthesis of 15·HCla
aFor the synthesis of 8, the amounts of reagents were calculated based on the amount of 5·(+)-
CSA. For the synthesis of 15·HCl, the amounts of reagents were calculated based on the amount
of 8 (HPLC assay yield).
Preparation of 2-pyridone-3-carboxilic acid esters 12a–12c. Preparation of 2ꢀpyridoneꢀ3ꢀ
carboxilic acid methyl ester 12a was then examined. We first tried to synthesize compound 12a
by treating 2ꢀhydroxyꢀ3ꢀpyridinecarboxylic acid 18 in refluxing MeOH in the presence of a
catalytic amount or 1.0 equiv of H2SO4; however, the reaction stalled around 50–80%
conversion.15 Next, 12a was synthesized by the reaction of MeOH with acid chloride 19
converted from 18 using SOCl2 and a catalytic amount of DMF (Scheme 5).16 Although the
reaction proceeded well and reached 94% conversion, workup was found to be difficult due to
high solubility of 12a in water. Thus, we decided to synthesize isopropyl ester 12b17 and nꢀbutyl
ester 12c, which were expected to have relatively low solubility in water. As expected,
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compounds 12b and 12c were amenable to extraction with EtOAc and washing with water/brine.
After workup, compounds 12b and 12c were crystallized from EtOAc/nꢀheptane or nꢀheptane to
provide 12b and 12c in 86% yield and 86% yield, respectively.
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Scheme 5. Synthesis of 12a–12c
Preparation of 1·HCl. As a preliminary experiment, 2ꢀpyridoneꢀ3ꢀcarboxilic acid isopropyl
ester 12b was reacted with mesylate 20, which was converted from alcohol 15, using 1,2ꢀ
dimethoxyethane (DME) as the solvent (Scheme 6). In this reaction, both the nitrogen atom and
the oxygen atom of 12b reacted with mesylate 20 to give 16b and Oꢀisomer 16b' in 35% yield
and 35% yield, respectively.18
Scheme 6. Preliminary experiment for the synthesis of 16
In order to increase the N, Oꢀselectivity for the SN2 reaction with mesylate 20, 2ꢀpyridonesꢀ3ꢀ
carboxilic acid esters 12a–12c, solvents and temperatures were screened (Table 1).19 The ester
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group of the 2ꢀpyridones did not largely affect the N, Oꢀselectivity. Among the screened solvents,
MeCN was found to be the best solvent for the reaction (entry 1–6). Also, when the reaction
temperature was decreased to 25–40 °C, the N, Oꢀselectivity increased (entries 8, 9). Finally, the
reaction was conducted in MeCN at 25–40 °C to give the desired product 16 in 75–77% yields
after column chromatographic separation (entries 9–11).
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16
17
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60
Table 1. SN2 reaction of mesylate 20 with 2ꢀpyridoneꢀ3ꢀcarboxilic acid esters 12a–12c
temp
(°C)
60
time
(h)
2
16:16'
(HPLC area% ratio)
2.6:1
yield
Entry
R =
solvent
(%)
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
DMEa
DMAcb
DMSO
THF
ꢀ
ꢀ
60
2
4.8:1
3
60
2
6.7:1
ꢀ
4
60
2
2.7:1
ꢀ
5
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
60
2
2.9:1
ꢀ
6
60
2
7.9:1
ꢀ
7
80
1
6.2:1
ꢀ
8
40
3
10.4:1
ꢀ
9
25
16
2
11.6:1
77
75
77
10
11
40
10.0:1
n-Bu MeCN
40
2
9.2:1
a1,2ꢀdimethoxyethane. bN,Nꢀdimethylacetamide.
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The obtained product 16 was found to be amorphous or an oily compound, which made it
difficult to separate 16 from Oꢀisomer 16' without column chromatographic separation.20 Thus, a
mixture of 16 and 16' was subjected to the next reaction without isolation, and an appropriate
intermediate that was amenable to isolation and upgrade of purity was searched for in
downstream processes (Scheme 7). In the modified procedure, 15·HCl was directly converted to
mesylate 20 without salt brake using 3.0 equiv of triethylamine and 1.2 equiv of MsCl, and used
for the SN2 reaction with 12b after workup and solvent switch to MeCN. Debenzylation of 16b
was conducted using ACEꢀCl21, because debenzylation of 16b using H2 and a Pd catalyst gave
the dechlorinated byproduct that was hard to remove. Following the reaction with 1.1 equiv of
ACEꢀCl in MeCN at 0 °C for 2 h, the resulting intermediate carbamate was decomposed by
addition of 2ꢀpropanol with heating at 50 °C for 2 h to give 17b. The solvent was switched to
EtOAc, and the EtOAc solution of 17b was washed with 5% aqueous NaHCO3 and brine.
In spite of our effort to isolate 17b as a crystalline solid, it was difficult to crystallize 17b
without column chromatographic purification, probably due to hindrance by several kinds of
impurities, including the Oꢀisomer and benzyl chloride liberated as a byproduct during the
debenzylation.22 At this point, we screened several acids for isolation of 17b as a salt.
Fortunately, we found that (+)ꢀCSA formed a good salt with 17b (17b·(+)-CSA) in EtOAc,
enabling isolation of 17b.23 The obtained EtOAc solution of 17b was treated with 0.8 equiv of
(+)ꢀCSA and the generated salt was collected by filtration, affording 17b·(+)-CSA in 71% yield
for 3 steps from 15·HCl without residual Oꢀisomer or benzyl chloride. To our delight, after salt
brake of 17b·(+)-CSA, it was possible to obtain free 17b as a crystalline solid. Crystallization of
17b from EtOAc/nꢀheptane was effective for upgrading 17b (17b·(+)·CSA: 93–96 area%, 17b:
>99 area%), thereby allowing us to strictly control the purity of the final product.
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We also prepared methyl ester 17a and nꢀbutyl ester 17c. Whereas 17a was a crystalline solid,
17c was found to be an oily compound. Taking into account the easy workup for preparation of
12b, isopropyl esters 12b, 16b, and 17b were finally selected as the intermediates for the
synthesis of 1·HCl.
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Successfully obtaining the penultimate intermediate 17b with excellent purity, the end game
was investigated. Although hydrolysis of the isopropyl ester of 17b with aqueous NaOH in EtOH
proceeded smoothly, extraction of 1 was found to be difficult due to low solubility of 1 in
common organic solvents, which would be ascribed to zwitterionic nature of 1. When we tried to
crystallize 1 directly from the reaction mixture by adding hydrochloric acid and setting pH of the
reaction mixture to the isocratic point, compound 1 unfortunately became oily product. Thus, we
changed our strategy and tried to conduct the hydrolysis using hydrochloric acid in organic
solvents, and to isolate the generated hydrochloric acid salt 1·HCl by filtration. As a result of
solvent screening, it was found that the hydrolysis of 17b with 3.0 equiv of concentrated
hydrochloric acid in 2ꢀbutanone proceeded well at 70 °C, and precipitation of the desired 1·HCl
was observed during the reaction. The reaction mixture was diluted with diisopropyl ether, and
1·HCl was isolated by filtration in 84% yield with excellent chemical and optical purity (99.7
area%, >99.9% ee24). The optical purity of 5·(+)-CSA was confirmed to be fully retained
throughout the downstream processes as expected.
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Scheme 7. Synthesis of 1·HCl a
3
4
5
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7
8
9
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aFor the synthesis of 17b·(+)-CSA, the amounts of reagents were calculated based on the amount
of 15·HCl.
CONCLUSION
We have developed a practical synthesis of the potential peripherally selective NRI 1·HCl. The
chiral amino alcohol 5 that has the desired stereochemistry was successfully prepared from
aldehyde 2 via MoritaꢀBaylisꢀHillman reaction, Michael addition, isolation as maleic acid salt,
reduction, and diastereomeric salt formation with (+)ꢀCSA with excellent dr and ee. Since the
optical purity of 5·(+)-CSA was fully retained until the final product, our strategy to set optical
resolution at an early stage of the synthesis enabled effective preparation of 1·HCl. The sevenꢀ
membered ring was formed in the fully telescoped processes using the obtained 5·(+)-CSA,
which provided the chiral 6,7ꢀtransꢀdisubstitutedꢀ1,4ꢀoxazepane efficiently. N,Oꢀselectivity for
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the SN2 reaction of 2ꢀpyridoneꢀ3ꢀcarboxylic acid ester 12b with mesylate 20 was increased by
optimizing the reaction conditions. In addition to the controls of dr, ee, and N,Oꢀselectivity,
finding appropriate intermediates (rac-4·MA, 5·(+)-CSA, 15·HCl, 17b·(+)·CSA, 17b) that could
be isolated and upgraded enabled a chromatographic/chiral HPLC separationꢀfree synthesis of
1·HCl with excellent chemical and optical purity. Also, as a result of our investigation, the
overall yield was higher (11%) compared to the medicinal chemistry synthesis (6%). We believe
that our practical synthesis is useful for preparation of chiral 6,7ꢀtransꢀdisubstitutedꢀ1,4ꢀ
oxazepane derivatives and will contribute to studies on bioactivities of these compounds.
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EXPERIMENTAL SECTION
All materials were purchased from commercial suppliers and used without any additional
purification. Melting points were determined on a Stanford Research Systems OptiMelt MPA
1
13
100, and are uncorrected unless otherwise noted. H and C NMR spectra were recorded on a
BRUKER AVANCE 600 spectrometer with tetramethylsilane as an internal standard. Chemical
shifts are shown in ppm. HPLC analysis of the compounds and reaction monitoring was carried
out on a Shimadzu LCꢀ2010CHT. Highꢀresolution mass spectrometry (HRMS) data was obtained
on a Shimadzu Prominence UFLC system with a Thermofisher LTQ Orbitrap Discovery. IR
spectra were recorded on a Thermo Electron FTꢀIR Nicolet 4700 (ATR).
HPLC conditions. (A) Inertsil ODSꢀ3 column, 5 µm, 250 mm × 4.6 mm i.d.; UV detector at
220 nm; isocratic elution with 50 mM aqueous KH2PO4 (pH 7.0) /MeCN (50:50) at 1.0 mL/min
flow rate; column temperature: 25 °C. Retention times: 2 (13.7 min), rac-3 (12.1 min), rac-
4·MA (22.2 min), rac-4' (16.7 min).
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(B) Inertsil ODSꢀ3 column, 5 µm, 250 mm × 4.6 mm i.d.; UV detector at 220 nm; eluent:
(A) 50 mM aqueous KH2PO4 (pH 7.0) /MeCN (80:20) (B) 50 mM aqueous KH2PO4 (pH 7.0)
/MeCN (50:50); gradient: A:B 100:0 (0 min) – 80:20 (50 min) – 0:100 (60 min) – 0:100 (70
min); flow late at 1.0 mL/min; column temperature: 25 °C. Retention times: 5·(+)-CSA (42.0
min), cis-5 (40.3 min).
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(C) Inertsil ODSꢀ3 column, 5 µm, 150 mm × 4.6 mm i.d.; UV detector at 220 nm; Eluent:
(A) 0.1% H3PO4 in H2O (B) 0.1% H3PO4 in MeCN; gradient: A:B 90:10 (0 min) – 10:90 (10
min) – 10:90 (15 min); flow late at 1.3 mL/min; column temperature: 25 °C. Retention times:
12b (4.9 min), 12c (5.9 min), 15·HCl (6.5 min), 16b (7.6 min), 17b/17b·(+)-CSA (6.6 min), 20
(7.2 min).
(D) Inertsil ODSꢀ3 column, 5 µm, 150 mm × 4.6 mm i.d.; UV detector at 220 nm; eluent (A)
0.1% H3PO4 in H2O (B) 0.1% H3PO4 in MeCN; gradient: A:B 90:10 (0 min) – 5:95 (7 min) –
5:95 (15 min); flow late at 1.3 mL/min; column temperature: 25 °C. Retention times: 6 (5.6 min),
7 (9.9 min), 8 (10.4 min), 9 (6.8 min).
(E) Inertsil ODSꢀ3 column, 5 µm, 150 mm × 4.6 mm i.d.; UV detector at 220 nm; eluent (A)
20 mM aqueous KH2PO4/MeCN (90:10) (B) 20 mM aqueous KH2PO4/MeCN (30:70); gradient;
A:B 100:0 (0 min) – 0:100 (15 min) – 0:100 (20 min); flow late at 1.3 mL/min; column
temperature: 25 °C. Retention times: 1 (7.1 min).
Chiral HPLC conditions. (A) Ultron ESꢀPhCD, 5 µm, 150 mm × 6.0 mm i.d.; UV detector at
210 nm; isocratic elution with 50 mM aqueous KH2PO4/MeCN (50:50) at 1.0 mL/min flow rate;
column temperature: 25 °C. Retention times: 5·(+)-CSA (8.4 min), ent-5 (10.2 min).
(B) CHIRALPAK ASꢀRH, 5 µm, 150 mm × 4.6 mm i.d.; UV detector at 220 nm; isocratic
elution with 20 mM aqueous NH4HCO3 (pH 9.0, adjusted by diethylamine) /MeCN (60:40) at
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1.0 mL/min flow rate; column temperature: 25 °C. Retention times: 15·HCl (22.8 min), ent-
15·HCl (40.8 min).
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8
9
(C) CHIRALPAK ZWIX (+), 3 µm, 250 mm × 3.0 mm i.d.; UV detector at 220 nm; isocratic
elution with MeOH/MeCN/H2O (49:49:2) /50 mM formic acid/25 mM diethylamine at 1.0
mL/min flow rate; column temperature: 25 °C. Retention times: 17b/17b·(+)-CSA (47.0 min),
ent-17b/ent-17b·(+)-CSA (50.7 min).
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(D) CHIRALCEL OZꢀRH, 5 µm, 150 mm × 4.6 mm i.d.; UV detector at 220 nm; isocratic
elution with 50 mM aqueous KH2PO4 (pH 2.0) /MeCN (40:60) at 0.2 mL/min flow rate; column
temperature: 25 °C. Retention times: N-Boc 1 (28.1 min), ent-N-Boc 1 (24.8 min).
Methyl
(2RS,3RS)-2-[(Benzylamino)methyl]-3-(4-chloro-3-fluorophenyl)-3-
hydroxypropanoate (2Z)-but-2-enedioate (1:1) (rac-4·MA). To a mixture of 4ꢀchloroꢀ3ꢀ
fluorobenzaldehyde 2 (200 g, 1.26 mol) and methyl acrylate (119 g, 1.39 mol) in MeOH (400
mL) was added DABCO (70.7 g, 631 mmol), and the mixture was stirred at 20–30 °C for 17 h.
To the mixture were added EtOAc (2 L) and 10% aqueous NaCl (2 L), and the layers were
separated. The organic layer was washed with 10% aqueous NaCl (1 L) and concentrated in
vacuo to give methyl 2ꢀ[(4ꢀchloroꢀ3ꢀfluorophenyl)(hydroxy)methyl]propꢀ2ꢀenoate (rac-3). To a
solution of rac-3 in MeOH (600 mL) was added dropwise benzylamine (149 g, 1.39 mol) in
MeOH (200 mL) at 0 °C. After stirring at 0 °C for 16 h, EtOAc (2 L) and 10% aqueous NaCl (2
L) were added and the layers were separated. The organic layer was concentrated in vacuo to
give
methyl
(2RS,3RS)ꢀ2ꢀ[(Benzylamino)methyl]ꢀ3ꢀ(4ꢀchloroꢀ3ꢀfluorophenyl)ꢀ3ꢀ
hydroxypropanoate (rac-4). To the residue of rac-4 was added dropwise maleic acid (131 g, 1.13
mol) in EtOAc (3 L), and the mixture was stirred at 20–30 °C for 1 h. The resulting solids were
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collected by filtration, washed with EtOAc (1 L) and dried in vacuo at 50 °C to give rac-4·MA
(436 g, 74%) as a white solid. HPLC purity: 94.7 area% (rac-4': 5.3 area%. HPLC condition A).
A small portion of the product was recrystallized from MeOH/EtOAc (1:10) to obtain a sample
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1
for analysis. Mp 144–145 °C; H NMR (600 MHz, DMSOꢀd6) δ 2.86 (br dd, J = 12.8, 2.6 Hz,
1H), 3.04–3.14 (m, 1H), 3.24 (br dd, J = 12.8, 9.8 Hz, 1H), 3.62 (s, 3H), 4.03–4.21 (m, 2H), 5.03
(br d, J = 4.5 Hz, 1H), 6.03 (s, 2H), 7.12–7.20 (m, 1H), 7.33 (br dd, J = 10.4, 1.3 Hz, 1H), 7.40 (s,
13
5H), 7.57 (br t, J = 7.9 Hz, 1H), 8.59 (br s, 1H); C NMR (151 MHz, DMSOꢀd6) δ 43.2, 49.5,
50.4, 52.2, 70.9, 114.4 (2JCF = 21.1 Hz), 118.3 (2JCF = 18.1 Hz), 123.2 (3JCF = 3.0 Hz), 128.6
(2C), 128.9, 129.9 (2C), 130.4, 131.7, 135.9 (2C), 143.8 (3JCF = 6.0 Hz), 157.0 (1JCF = 246.1 Hz),
167.2 (2C), 170.8; IR (ATR) 3151, 2179, 1722, 1572, 1481, 1353, 1265, 1177, 1087, 1003, 983,
965, 921, 904, 863, 835, 755, 701, 569, 548, 527, 488 cm−1; HRMS (ESI): [M+H]+ calcd for
C18H20ClFNO3 (rac-4), 352.1116; found, 352.1110.
[(1S, 4R)-(7,7-Dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)]methanesulfonic Acid - (1R,2S)-2-
[(Benzylamino)methyl]-1-(4-chloro-3-fluorophenyl)propane-1,3-diol (1:1) (5·(+)-CSA). To a
suspension of rac-4·MA (100 g, 214 mmol) in EtOAc (1 L) was added 5% aqueous NaHCO3 (1
L), and the mixture was stirred at 20–30 °C for 30 min. The layers were separated and the
organic layer was concentrated in vacuo to give rac-4. To the resulting rac-4 was added THF
(400 mL). CaCl2 (59.3 g, 534 mmol) was added to a mixture of THF (400 mL) and EtOH (400
mL), and the mixture was stirred at 20–30 °C for 1 h under N2 flow. To this mixture was added
portionwise NaBH4 (40.5 g, 1.07 mol) at 0 °C, and the mixture was stirred for 30 min at this
temperature under N2 atmosphere. To this mixture was added dropwise the above prepared THF
solution of rac-4 at 0 °C, and the mixture was stirred at this temperature for 16 h under N2
atmosphere. MeOH (500 mL) was added dropwise to the mixture at 0 °C, followed by addition
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of H2O (500 mL) and 2 M HCl (700 mL). To the mixture was added 8 M NaOH (100 mL), and
pH of the mixture was adjusted to 7. After stirring for 30 min, the suspension was filtrated and
washed with EtOAc (500 mL). The filtrate was concentrated in vacuo to remove organic solvents.
To the resulting aqueous solution was added EtOAc (1 L), and the layers were separated. The
aqueous layer was extracted with EtOAc (1 L), and the combined organic layer was concentrated
in vacuo. To the residue were added EtOAc (500 mL) and 5% aqueous NaHCO3 (500 mL), and
the layers were separated. The organic layer was washed with 10% aqueous NaCl (500 mL) and
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concentrated
in
vacuo
to
give
(1RS,2SR)ꢀ2ꢀ[(benzylamino)methyl]ꢀ1ꢀ(4ꢀchloroꢀ3ꢀ
fluorophenyl)propaneꢀ1,3ꢀdiol (rac-5). To a solution of rac-5 in MeOH (100 mL) and EtOAc
(300 mL) was added (+)ꢀCSA (24.8 g, 107 mmol). The mixture was stirred at 50 °C for 1 h, at
20–30 °C for 1 h and at 0–10 ºC for 1 h. The resulting solids were collected by filtration, washed
with EtOAc (300 mL) and dried in vacuo at 50 °C to give crude 5·(+)-CSA. To a solution of
crude 5·(+)-CSA in MeOH (400 mL) was added dropwise EtOAc (1.5 L) at 50 °C. The mixture
was stirred at 50 °C for 1 h, at 20–30 °C for 1 h and at 0–10 ºC for 1 h. The resulting solids were
collected by filtration, washed with EtOAc (300 mL) and dried in vacuo at 50 °C to give 5·(+)-
CSA (42.8 g, 36%) as a white solid. HPLC purity: 99.8 area% (HPLC condition B). Optical
Purity: >99.9% ee (chiral HPLC condition A). Mp 180–181 °C; 1H NMR (600 MHz, DMSOꢀd6)
δ 0.74 (s, 3H), 0.93–1.13 (m, 3H), 1.19–1.35 (m, 2H), 1.80 (d, J = 18.1 Hz, 1H), 1.84 (dt, J =
11.1, 3.3 Hz, 1H), 1.89–1.97 (m, 1H), 2.04–2.14 (m, 1H), 2.23 (br dd, J = 18.1, 3.0 Hz, 1H), 2.38
(d, J = 14.7 Hz, 1H), 2.62–2.74 (m, 1H), 2.89 (d, J = 14.7 Hz, 1H), 2.94–3.06 (m, 2H), 3.30–3.33
(m, 1H), 3.44 (br dd, J = 10.8, 4.3 Hz, 1H), 4.08–4.25 (m, 2H), 4.66 (br d, J = 6.8 Hz, 1H), 5.03
(br s, 1H), 6.06 (br s, 1H), 7.16 (br d, J = 8.3 Hz, 1H), 7.30 (br d, J = 10.6 Hz, 1H), 7.38–7.45 (m,
13
3H), 7.47 (br d, J = 4.9 Hz, 2H), 7.56 (t, J = 8.1 Hz, 1H), 8.54 (br s, 2H); C NMR (151 MHz,
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DMSOꢀd6) δ 19.5, 20.1, 24.1, 26.4, 42.1, 42.2, 44.4, 46.3, 46.7, 47.0, 50.4, 58.2, 60.2, 70.8,
114.6 (2JCF = 21.1 Hz), 117.9 (2JCF = 16.6 Hz), 123.5 (3JCF = 3.0 Hz), 128.7 (2C), 128.9, 129.9
(2C), 130.3, 131.8, 145.7 (3JCF = 6.0 Hz), 157.0 (2JCF = 246.1 Hz), 216.3; IR (ATR) 3240, 2964,
1739, 1622, 1449, 1279, 1178, 1152, 1061, 1006, 964, 859, 823, 764, 747, 699, 615, 597, 583,
535, 523, 509, 408 cm−1; HRMS (ESI): [M+H]+ calcd for C17H20ClFNO2 (5), 324.1167; found,
324.1163.
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[(6S,7R)-4-Benzyl-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methanol Hydrochloride
(1:1) (15·HCl). To a suspension of 5·(+)-CSA (100 g, 180 mmol) in EtOAc (1 L) was added 5%
aqueous NaHCO3 (400 mL) and 1 M NaOH (200 mL), and pH was adjusted to 8.5–8.8. The
mixture was stirred at 20–30 °C for 10 min, and the layers were separated. The organic layer was
washed with 5% aqueous NaHCO3 (300 mL) and 10% aqueous NaCl (300 ml) and concentrated
in vacuo to give (1R,2S)ꢀ2ꢀ[(benzylamino)methyl]ꢀ1ꢀ(4ꢀchloroꢀ3ꢀfluorophenyl)propaneꢀ1,3ꢀdiol
(5). To a solution of 5 in THF (175 mL) were added imidazole (18.4 g, 270 mmol) and TBSCl
(29.8 g, 198 mmol) under 15 °C, and the mixture was stirred at 20–30 °C for 1.5 h. To this
solution were added EtOAc (500 mL) and 10% aqueous NaCl (500 mL), and the layers were
separated. The organic layer was washed with 10 % aqueous NaCl (500 mL) and concentrated in
vacuo to give (1R,2S)ꢀ3ꢀ(benzylamino)ꢀ2ꢀ({[tertꢀbutyl(dimethyl)silyl]oxy}methyl)ꢀ1ꢀ(4ꢀchloroꢀ
3ꢀfluorophenyl)propanꢀ1ꢀol (6). To a solution of 6 in THF (500 mL) was added triethylamine
(21.9 g, 216 mmol). To this mixture was added dropwise chloroacethyl chloride (22.4 g, 198
mmol) at 0 °C, and the mixture was stirred at 20–30 °C for 1 h. To the mixture was added slowly
2 M NaOH (270 mL, 540 mmol), maintaining the temperature below 15 °C. After stirring at 20–
30 °C for 13 h, 1 M HCl (320 mL) was added and pH was adjusted to 8–9. To the mixture was
added EtOAc (500 mL), and the layers were separated. The organic layer was washed with 10%
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aqueous NaCl (300 mL × 2) and concentrated in vacuo to give (6S,7R)ꢀ4ꢀbenzylꢀ6ꢀ({[tertꢀ
butyl(dimethyl)silyl]oxy}methyl)ꢀ7ꢀ(4ꢀchloroꢀ3ꢀfluorophenyl)ꢀ1,4ꢀoxazepanꢀ3ꢀone (8) (HPLC
assay yield 83%, 71.4 g, 149 mmol). To a solution of 8 in THF (714 mL) was added NaBH4
(23.7 g, 626 mmol) at 0 °C under N2 atmosphere. To this mixture was added dropwise I2 (75.6 g,
298 mmol) in THF (357 mL) at 0 °C over 2 h, and the mixture was stirred at 20–30 °C for 1 h
under weak N2 flow (Caution. H2 was generated). The reaction was quenched by dropwise
addition of MeOH (357 mL) at 20–30 °C, and the mixture was stirred at 20–30 °C for 12 h under
weak N2 flow. The mixture was concentrated in vacuo. EtOAc (710 mL) and H2O (355 mL)
were added, and the layers were separated. The organic layer was washed with H2O (355 mL),
10% aqueous NaCl (355 mL), 5% aqueous NaHCO3 (355 mL), 10% aqueous NaCl (355 mL)
and concentrated in vacuo to give (6S,7R)ꢀ4ꢀbenzylꢀ6ꢀ({[tertꢀbutyl(dimethyl)silyl]oxy}methyl)ꢀ
7ꢀ(4ꢀchloroꢀ3ꢀfluorophenyl)ꢀ1,4ꢀoxazepane (9). To a solution of 9 in EtOAc (714 mL) was added
4 M HCl in EtOAc (112 mL, 447 mmol), and the mixture was stirred at 50 °C for 2 h. The
mixture was cooled to 20–30 °C, and the resulting solids were collected by filtration and washed
with EtOAc (142 mL × 3). The wet solids were suspended in MeCN (714 mL), and the mixture
was stirred at 40–50 °C for 1 h, at 20–30 °C for 1 h and then filtrated. Wet solids were washed
with MeCN (213 mL × 3) and dried in vacuo at 40 °C to give 15·HCl (52.9 g, 76%) as a white
solid. HPLC purity: 98.2 area% (HPLC condition C). Optical Purity: >99% ee (chiral HPLC
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condition B). Mp 239–242 °C; H NMR (600 MHz, DMSOꢀd6)25 δ 2.55–2.65 (m, 0.25H), 3.04
(br dd, J = 10.4, 4.7 Hz, 1H), 3.08–3.22 (m, 2.5H), 3.25 (br d, J = 7.6 Hz, 2H), 3.38–3.47 (m,
1.5H), 3.49 (br s, 0.25H), 3.62 (br d, J = 13.2 Hz, 1H), 3.65–3.72 (m, 1H), 3.93 (br s, 0.25H),
4.11 (br dd, J = 13.0, 8.5 Hz, 1.25H), 4.36–4.53 (m, 2.5H), 4.58 (br d, J = 10.6 Hz, 1.25H), 4.97
(br s, 1.25H), 7.27 (br d, J = 7.9 Hz, 0.25H), 7.33 (br d, J = 7.9 Hz, 1H), 7.47 (br d, J = 3.4 Hz,
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3.75H), 7.51–7.57 (m, 1.25H), 7.58–7.66 (m, 1.25H), 7.67–7.79 (m, 2.5H), 11.2 (br s, 0.25H),
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11.4 (br s, 1 H); 13C NMR (151 MHz, DMSOꢀd6)25 δ 41.8, 52.6, 54.8, 55.0, 55.9, 57.8, 60.0, 60.2,
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60.3, 60.4, 63.1, 78.9, 81.2, 115.4 (d, JCF = 21.1 Hz), 116.2 (d, JCF = 21.1 Hz), 119.2 (2JCF
=
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16.6 Hz), 124.7, 125.1 (d, JCF = 3.0 Hz), 128.8 (2C), 129.4, 130.2, 130.4, 130.7, 131.2, 131.4
(2C), 141.8 (d, JCF = 6.0 Hz), 142.7, 157.1 (d, 1JCF = 246.1 Hz ). IR (ATR) 3268, 2929, 2614,
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1581, 1490, 1428, 1107, 1060, 1017, 970, 954, 906, 851, 823, 764, 748, 698, 638, 570, 537, 516,
490, 418 cm−1; HRMS (ESI): [M+H]+ calcd for C19H22ClFNO2 (15), 350.1323; found, 350.1312.
Propan-2-yl 2-Oxo-1,2-dihydropyridine-3-carboxylate (12b). To a solution of 2ꢀhydroxyꢀ3ꢀ
pyridinecarboxylic acid 18 (5.00 g, 35.9 mmol) and DMF (525 mg, 7.19 mmol) in THF (50 mL)
was added dropwise thionyl chloride (5.55 g, 46.7 mmol) at 0 °C, and the mixture was stirred at
20–30 °C for 2.5 h. The mixture was cooled to 0 °C, and 2ꢀpropanol (25 mL) was slowly added
at this temperature. The mixture was warmed to 20–30 °C and stirred at this temperature for 2h.
The mixture was cooled to 0–10 °C, and 4 M NaOH (40 mL) was slowly added and pH was
adjusted to 8–9. To this mixture was added EtOAc (50 mL) and the layers were separated. The
aqueous layer was extracted with EtOAc (50 mL), and the combined organic layer was washed
with 10% aqueous NaCl (10 mL × 2) and concentrated in vacuo. To the residue was added
EtOAc (15 mL), and nꢀheptane (45 mL) was slowly added at 40–50 °C. The mixture was cooled
to 0–10 °C and stirred for 1 h, and then filtrated. Wet solids were washed with EtOAc/nꢀheptane
(1:5, 10 mL) and dried in vacuo at 50 °C to give 12b (5.57 g, 86%) as a white solid. HPLC
purity: 99.5 area% (HPLC condition C). Mp 95–97 °C; 1H NMR (600 MHz, DMSOꢀd6) δ 1.25 (d,
J = 6.4 Hz, 6H), 5.02 (dt, J = 12.7, 6.1 Hz, 1H), 6.19–6.33 (m, 1H), 7.65 (dd, J = 6.4, 2.3 Hz,
1H), 7.98 (dd, J = 7.2, 2.3 Hz, 1H), 12.1 (br s, 1H); 13C NMR (151 MHz, DMSOꢀd6) δ 21.6 (2C),
67.3, 104.2, 120.4, 140.9, 144.5, 159.4, 164.1; IR (ATR) 3580, 2973, 1715, 1635, 1601, 1556,
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1376, 1269, 1232, 1166, 1104, 1063, 927, 887, 777, 731, 656, 580, 562, 538, 485 cm−1; HRMS
(ESI): [M+H]+ calcd for C9H12NO3, 182.0817; found, 182.0810.
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Butyl 2-Oxo-1,2-dihydropyridine-3-carboxylate (12c). To a solution of 18 (10.0 g, 71.9 mmol)
and DMF (1.05 g, 14.4 mmol) in THF (100 mL) was added dropwise thionyl chloride (11.1 g,
93.5 mmol) at 0 °C, and the mixture was stirred at 20–30 °C for 2.5 h. The mixture was cooled to
0 °C, and nꢀbutanol (30 mL) was slowly added at this temperature. The mixture was warmed to
20–30 °C and stirred at this temperature for 2.5 h. To the mixture were added EtOAc (100 mL)
and 5% aqueous NaHCO3 (10 mL), and the mixture was cooled to 0–10 °C. To the mixture was
slowly added 4 M NaOH (45 mL), and pH was adjusted to 8–9. To this mixture were added
EtOAc (100 mL) and H2O (50 mL), and the layers were separated. The aqueous layer was
extracted with EtOAc (100 mL), and the combined organic layer was washed with 5% aqueous
NaHCO3 (50 mL) and concentrated in vacuo. To the residue was added nꢀheptane (60 mL), and
the mixture was stirred at 20–30 °C for 10 min, and then filtrated. Wet solids were washed with
nꢀheptane (40 mL × 2) and dried in vacuo at 50 °C to give 12c (12.0 g, 86%) as a white solid.
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HPLC purity: 99.8 area% (HPLC condition C). Mp 84–85 °C; H NMR (600 MHz, CDCl3) δ
0.97 (t, J = 7.4 Hz, 3H), 1.46 (sxt, J = 7.5 Hz, 2H), 1.65–1.83 (m, 2H), 4.31 (t, J = 6.6 Hz, 2H),
6.43 (br t, J = 6.6 Hz, 1H), 7.80 (br d, J = 4.5 Hz, 1H), 8.25 (dd, J = 7.2, 1.9 Hz, 1H); 13C NMR
(151 MHz, CDCl3) δ 13.8, 19.2, 30.7, 65.0, 107.2 (br s), 119.1 (br s), 141.7 (br s), 145.4, 163.0,
164.9; IR (ATR) 3585, 2950, 1727, 1634, 1601, 1556, 1487, 1467, 1337, 1268, 1232, 1167, 1119,
1069, 948, 902, 812, 772, 729, 660, 585, 565, 535, 487, 444 cm−1; HRMS (ESI): [M+H]+ calcd
for C10H14NO3, 196.0974; found, 196.0965.
[(1S, 4R)-(7,7-Dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)]methanesulfonic Acid - Propan-2-yl
1-{[(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-
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dihydropyridine-3-carboxylate (1:1) (17b·(+)-CSA). To a suspension of 15·HCl (29.0 g, 75.2
mmol) in THF (300 mL) was added triethylamine (22.8 g, 226 mmol), and the mixture was
stirred at 20–30 °C for 1 h. To the mixture was added methanesulfonyl chloride (10.3 g, 90.2
mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h and concentrated in vacuo. To the
residue were added EtOAc (300 mL) and 10 % aqueous NaCl (150 mL), and the layers were
separated. The organic layer was washed with 10 % aqueous NaCl (150 mL) and concentrated in
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[(6S,7R)ꢀ4ꢀbenzylꢀ7ꢀ(4ꢀchloroꢀ3ꢀfluorophenyl)ꢀ1,4ꢀoxazepanꢀ6ꢀyl]methyl
methanesulfonate (20). To a solution of 20 in MeCN (600 mL) were added 12b (16.4 g, 90.2
mmol) and K2CO3 (20.8 g, 150 mmol), and the mixture was stirred at 20–30 °C for 16 h and
concentrated in vacuo. To the residue were added EtOAc (600 mL) and 10 % aqueous NaCl (300
mL), and the layers were separated. The organic layer was washed with 10 % aqueous NaCl (300
mL) and concentrated in vacuo to give propanꢀ2ꢀyl 1ꢀ{[(6S,7R)ꢀ4ꢀbenzylꢀ7ꢀ(4ꢀchloroꢀ3ꢀ
fluorophenyl)ꢀ1,4ꢀoxazepanꢀ6ꢀyl]methyl}ꢀ2ꢀoxoꢀ1,2ꢀdihydropyridineꢀ3ꢀcarboxylate (16b). To a
solution of 16b in MeCN (300 mL) was added 1ꢀchloroethyl chloroformate (11.8 g, 82.5 mmol)
at 0 °C, and the mixture was stirred at 0 °C for 2 h and concentrated in vacuo to approximately
60 mL. To the solution was added 2ꢀpropanol (300 mL), and the mixture was stirred at 50 °C for
2 h and concentrated in vacuo. To the residue were added EtOAc (600 mL) and 5 % aqueous
NaHCO3 (150 mL), and the layers were separated. The aqueous layer was extracted with EtOAc
(300 mL), and the combined organic layer was washed with 10% aqueous NaCl (150 mL). To
the organic layer was added (+)ꢀCSA (14.0 g, 60.1 mmol) at 20–30 °C, and the solution was
concentrated in vacuo. To the residue was added AcOEt (600 mL), and the mixture was stirred at
20–30 °C for 30 min. To the mixture was added dropwise nꢀheptane (300 mL), and the mixture
was stirred at 20–30 °C for 30 min. The resulting solids were collected by filtration, washed with
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EtOAc/nꢀheptane (2:1, 450 mL) and dried in vacuo at 50 °C to give 17b·(+)-CSA (35.0 g, 71 %
from 15·HCl) as a white solid. HPLC purity: 95.9 area% (HPLC condition C). Optical Purity:
>99% ee (chiral HPLC condition C). A small portion of the product was triturated with
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MeCN/EtOAc (1:1) to obtain a sample for analysis. Mp 207–209 °C; H NMR (600 MHz,
DMSOꢀd6) δ 0.75 (s, 3H), 1.05 (s, 3H), 1.25 (br d, J = 6.4 Hz, 6H), 1.27–1.35 (m, 2H), 1.80 (br d,
J = 18.1 Hz, 1H), 1.85 (ddd, J = 11.6, 7.8, 4.0 Hz, 1H), 1.94 (br t, J = 4.2 Hz, 1H), 2.24 (dt, J =
18.1, 3.4 Hz, 1H), 2.40 (br d, J = 14.4 Hz, 1H), 2.62–2.73 (m, 1H), 2.89 (d, J = 14.7 Hz, 1H),
3.12 (br s, 1H), 3.15–3.22 (m, 2H), 3.23–3.32 (m, 2H), 3.69 (br dd, J = 13.2, 5.7 Hz, 1H), 3.76–
3.87 (m, 1H), 3.91–4.10 (m, 2H), 4.54 (br d, J = 9.8 Hz, 1H), 5.00 (dt, J = 12.5, 6.2 Hz, 1H),
6.23 (br t, J = 6.8 Hz, 1H), 7.27 (br d, J = 6.8 Hz, 1H), 7.45–7.51 (m, 1H), 7.55 (br t, J = 8.1 Hz,
13
1H), 7.74 (br dd, J = 6.4, 1.9 Hz, 1H), 7.86 (dd, J = 7.2, 1.9 Hz, 1H), 8.90 (br s, 2H); C NMR
(151 MHz, DMSOꢀd6) δ 19.5, 20.1, 21.6 (2C), 24.1, 26.4, 40.7, 42.1, 42.2, 45.1, 46.7, 46.7, 47.1,
49.5, 58.2, 63.7, 67.6, 82.2, 104.3, 115.9 (2JCF = 21.1 Hz), 119.1 (2JCF = 18.1 Hz), 120.4, 125.1
(3JCF = 3.0 Hz), 130.4, 141.1 (3JCF = 6.0 Hz), 143.5, 144.0, 156.9 (1JCF = 246.1 Hz), 158.4, 163.6,
216.3; IR (ATR) 3565, 3500, 2965, 1731, 1642, 1548, 1258, 1203, 1109, 1040, 968, 872, 758,
600, 534, 509, 419 cm−1; HRMS (ESI): [M+H]+ calcd for C21H25ClFN2O4 (17), 423.1487; found,
423.1481.
Propan-2-yl 1-{[(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-
dihydropyridine-3-carboxylate (17b). To a suspension of 17b·(+)-CSA (32.0 g, 48.9 mmol) in
EtOAc (480 mL) was added 2 M NaOH (97.8 mL, 196 mmol), and the mixture was stirred at
20–30 °C for 10 min. The layers were separated, and the organic layer was washed with 5%
NaHCO3 (64 mL) and 10% aqueous NaCl (64 mL), and concentrated in vacuo. To the residue
was added EtOAc (64 mL), and nꢀheptane (192 mL) was slowly added at 40–50 °C. The mixture
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was gradually cooled to 0–10 °C, stirred for 1 h, and then filtrated. Wet solids were washed with
EtOAc/nꢀheptane (1:5, 64 mL) and dried in vacuo at 50 °C to give 17b (18.4 g, 89%) as a white
solid. HPLC purity: 99.1 area% (HPLC condition C). Optical Purity: >99% ee (chiral HPLC
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condition C). Mp 123–124 °C; H NMR (600 MHz, CDCl3) δ 1.33 (dd, J = 6.0, 3.0 Hz, 6H),
1.75 (br s, 1H), 2.66–2.75 (m, 1H), 2.80 (dd, J = 14.2, 3.2 Hz, 1H), 2.95–3.06 (m, 3H), 3.63 (ddd,
J = 12.7, 9.3, 4.5 Hz, 1H), 4.05 (dd, J = 12.8, 5.3 Hz, 1H), 4.09–4.20 (m, 2H), 4.29 (d, J = 7.6 Hz,
1H), 5.04–5.35 (m, 1H), 6.13 (t, J = 6.8 Hz, 1H), 7.18 (dd, J = 8.3, 1.5 Hz, 1H), 7.23 (dd, J =
10.0, 1.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.42 (dd, J = 6.4, 2.3 Hz, 1H), 7.99 (dd, J = 7.2, 2.3
Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 21.9 (2C), 46.7, 48.0, 51.7, 52.2, 68.5, 74.8, 84.7 (4JCF
= 1.5 Hz), 104.3, 114.8 (2JCF = 21.1 Hz), 120.0 (2JCF = 18.1 Hz), 121.7, 122.9 (3JCF = 3.0 Hz),
130.7, 142.6, 143.4 (3JCF = 6.0 Hz), 143.7, 158.0 (1JCF = 249.2 Hz), 159.5, 164.0; IR (ATR) 3348,
2937, 1716, 1647, 1584, 1547, 1492, 1452, 1390, 1371, 1337, 1263, 1098, 1057, 967, 879, 810,
764, 750, 688, 628, 533, 456 cm−1; HRMS (ESI): [M+H]+ calcd for C21H25ClFN2O4, 423.1487;
found, 423.1481.
1-{[(6S,7R)-7-(4-Chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-
dihydropyridine-3-carboxylic Acid Hydrochloride (1:1) (1·HCl). To a solution of 17b (5.00 g,
11.8 mmol) in 2ꢀbutanon (25 mL) was added hydrochloric acid (36% solution, 3.59 g, 35.5
mmol), and the mixture was stirred at 70 °C for 2 h. The mixture was cooled to 20–30 °C and
diisopropyl ether (12.5 mL) was slowly added. The mixture was cooled to 0–10 °C and stirred
for 3 h, and then filtrated. Wet solids were washed with 2ꢀbutanon (10 mL × 2) and dried in
vacuo at 50 °C to give 1·HCl (4.14 g, 84%) as a white solid. HPLC purity: 99.7 area% (HPLC
condition E). Optical purity of 1·HCl was determined after being converted to the NꢀBoc
derivative. A small portion of 1·HCl (10 mg) in H2O (0.5 mL) was treated with 1.5 equiv of
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