Asymmetric Synthesis of a Potent HIV-1 Integrase Inhibitor

Article abstract of DOI:10.1021/acs.joc.6b01229

The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.

Full text of DOI:10.1021/acs.joc.6b01229

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Article
Asymmetric Synthesis of a Potent HIV-1 Integrase Inhibitor
Jeffrey T Kuethe, Guy R. Humphrey, Michel Journet, Zhihui Peng, and Karla Glaser Childers
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01229 • Publication Date (Web): 29 Jul 2016
Downloaded from http://pubs.acs.org on July 31, 2016
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The Journal of Organic Chemistry
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Asymmetric Synthesis of a Potent HIVꢀ1 Integrase
Inhibitor
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Jeffrey T. Kuethe,*1 Guy R. Humphrey, Michel Journet, Zhihui Peng, Karla G. Childers
Department of Process Chemistry, Merck & Co., Inc. P.O. Box 2000, Rahway, New Jersey 07065
Jeffrey_Kuethe@Merck.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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ABSTRACT: The development of a practical asymmetric total synthesis of the potent HIVꢀ1 integrase
inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly
efficient manner followed by cyclization of the 8ꢀmembered ring. Control of the atropisomers of
intermediates and final compound 5 is also described.
Introduction
Replication of human immunodeficiency virus (HIV) involves three enzymes: reverse
transcriptase, protease, and integrase. Current mainstay therapies for the treatment of HIV and acquired
immunodeficiency syndrome (AIDS) involve inhibition of HIV reverse transcriptase2 and HIV
protease,3 and a combination of these three antiretroviral therapies has been used as an effective strategy
to reduce viral loads.4 While these important therapeutic targets have proven highly successful at
reducing viral loads, drug resistance and side effects continue to fuel intensive efforts for new drug
targets in HIV therapy. The third viral enzyme, HIV integrase, has become an especially attractive target
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given its critical role in HIV replication and viral infectivity.5 Spanning nearly two decades, global
research efforts to identify drugs that inhibit HIV integrase resulted in identification of Merck's
Isentriss® (raltegravir) 1 as the first HIV integrase inhibitor approved for the treatment of HIV/AIDS
(Scheme 1).6 Several alternative structural classes7 have emerged with the discoveries of elvitefravir 2,8
dolutegravir 3,9 and MKꢀ0536 4.10,11 As part of Merck's continuing effort to discover and develop novel
HIV integrase inhibitors, compound 5 was identified as a potent and selective inhibitor of HIV integrase
with substantially improved viral resistance and a robust pharmacokinetic profile.12 Key obstacles for
the synthesis of compound 5 included construction of the challenging 8ꢀmembered ring bearing a chiral
hydroxy group and preparation of the core naphthyridine core. Herein, we report the development of a
practical and efficient asymmetric synthesis of the HIVꢀ1 integrase inhibitor 5.
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Scheme 1
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The Journal of Organic Chemistry
Me
Me
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O
N
Me
HO
Me
O-K+
F
O
N
MeO
N
O
H
H
N
N
N
N
Cl
CO2H
Me Me
O
O
F
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Raltegravir
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Elvitegravir
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O
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O
N
H
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Me
Me
Me
O
N
N
F
Cl
H
F
O
N
O
OH
O
Me
O
OH
3
Dolutegravir
4
MK-0536
Me
OH
Me
N
O
F
Me
N
N
Cl
O
O
OH
5
Results and Discussion
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Our retrosynthetic approach to inhibitor 5 is outlined in Scheme 2 and centered on construction
of the formidable 8ꢀmembered ring via the combination of naphthyridine acid 6 and chiral amino
alcohol 7. Preparation of naphthyridine acid 6 was envisioned to arise from readily available
unsaturated sulfoxide 8. Construction of the naphthyridine ring being accomplished through a process
similar to that utilized for the preparation of integrase inhibitor 4.11 Amino alcohol 7 could be derived
from ring opening of Dꢀ(ꢀ)ꢀpantolactone 9 by Nꢀmethylamine.
Scheme 2.
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Our investigations began with the known unsaturated sulfoxide 8.11 Initial experiments were focused
on application of the chemistry utilized in the synthesis of integrase inhibitor 4 (Scheme 3). For
example, reaction of Nꢀ(diphenylmethlene)glycine ethyl ester 10 with sulfoxide 8 in the presence of 10
mol% LiOtꢀBu afforded intermediate 11 as an inseparable mixture of diastereomers in near quantitative
yield. Acylation using monoethyl oxalylchloride 12 in the presence of NEt3 furnished intermediate 13
which was isolated in > 95% yield following an aqueous workup. Heating intermediate 13 in toluene at
90 ºC for 30 minutes afforded compound 14 as a mixture of olefin isomers together with PhSOH and
Ph2S2. Crude compound 14 was not isolated, but directly treated with 4 equivalents of LiBr and 2
equivalents of DABCO in order to affect cyclization to the naphthyridine ring 15.11 While the desired
cyclization event occurred to provide compound 15 under these reaction conditions, the isolated yield
was < 25%. A large number of unidentified reaction impurities were formed under these conditions.
The most significant impurity identified was sulfide 16 presumably formed by reaction of 14 with Ph2S2.
To prevent the formation of impurity 16, it became necessary to resort to silica gel chromatography to
remove the sulfur byꢀproducts formed in the thermal elimination of sulfoxide 13 prior to cyclization.
Treating the purified intermediate 14 with LiBr and DABCO resulted in an increased yield of 15 to ~
80% with no formation of byꢀproduct 16. Unfortunately, all efforts to remove the sulfur impurities
chemically from intermediate 14 were ineffective rendering this approach not amenable for future
development.
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The Journal of Organic Chemistry
Scheme 3
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9
Ph
CO2Et
NH2
EtO2C
N
1.
F
Ph
F
10
N
N
Cl
SOPh
Cl
SOPh
10 mol% LiOt-Bu
2. HCl
O
O
8
11
3. neutralize, extract
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mixture of diastereomers
quantitative
O
CO2Et
NH
EtO2C
O
F
Cl
CO2Et
12
F
O
N
toluene
90 °C
H
N
OEt
N
OEt
Cl
O
Cl
SOPh
NEt3, toluene
O
O
O
13
14
mixture of olefin isomers
EtO2C
O
CO2Et
NH
F
OEt
F
LiBr (4 equiv)
N
+
H
SPh
N
O
DABCO (2 equiv)
N
Cl
Cl
O
Toluene or THF, rt 18 h
O
16
15
O
OH
Having established that the general route to intermediate 15 employing the chemistry utilized for the
manufacture of compound 4 (Scheme 3) was unsuitable for scale up due to low yields and the need for
chromatography, our attention turned to identifying an alternative route. It was envisioned that
reordering of the sequence of steps and removal of the sulfur byꢀproducts formed in the thermal
elimination step by crystallization would offer significant advantages in terms of controlling the product
purity and yields.13 To this end, compound 11 was prepared as described in Scheme 3. After an
extractive workup, compound 11 was heated to 90 ºC for 30 min (Scheme 4). Upon completion, the
toluene was concentrated under reduced pressure to a small volume and isopropyl acetate (IPAc) was
added to aid in solubilizing sticky yellow impurities and sulfur residues. This resulted in a slurry of
enamine 17 which was filtered and could be routinely be isolated in 55ꢀ60% yield. In an effort to further
optimize this step it was discovered that the isolated yield of enamine 17 increased to 65ꢀ70% when one
equivalent of Hünigs base was added to the thermal elimination reaction mixture resulting in a cleaner
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reaction profile. Under these conditions, compound 17 was isolated as a colorless solid in 68% yield.
The transꢀstereochemistry about the double bond of 17 was confirmed by NMR spectroscopy (COSY,
NOESY, HMBC, ADEQUATE) where a 2% NOE was observed between the amine protons and the
protons adjacent to the amide carbonyl. Compound 17 was also demonstrated to be chemically stable
and not prone to isomerization.
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Scheme 4
Acylation of 17 with acid chloride 12 in THF was first performed at 5 ºC in the presence of NEt3 and
afforded intermediate 16 in 91% HPLC assay yield (Scheme 5).14 Also formed under these reaction
conditions was a significant byꢀproduct (5ꢀ10%) identified as pyrrole 18.15 In order to minimize the
formation of pyrrole 18, the preparation of naphthyridine ester 15 from enamine 17 was fully optimized
in terms of base, temperature, and solvent resulting in a oneꢀpot conversion of enamine 17 to
naphthyridine 15. The optimal conditions selected involved acylation of imine 17 with acid chloride 12
in the presence of the more bulky Hünigs base at ꢀ5 ºC which effectively reduced the formation of 18 to
< 1% as determined by HPLC analysis of the crude reaction mixture. Careful control of the addition of
acid chloride 12 was required to maintain the internal reaction temperature < 0 ºC during the course of
the addition. When the internal temperature was allowed to rise above 5 ºC during the addition
increased amounts of pyrrole byꢀproduct 18 (5ꢀ8%) were observed. Once the acylation was complete,
direct addition of 4 equivalents of LiBr and 2 equivalents of DABCO to the reaction of mixture
containing compound 16 was followed by allowing the mixture to warm to room temperature. Addition
of aqueous HCl to the reaction mixture resulted in crystallization of naphthyridine 15. Dilution with
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The Journal of Organic Chemistry
water and filtration gave 15 in analytically pure form in 88% overall yield for the oneꢀpot process.
Finally, saponification of 15 was conducted in EtOH/THF in the presence of 5N NaOH. Upon
completion, the reaction mixture was cooled to 15 ºC and made acidic with conc. HCl which furnished a
slurry that was filtered and dried to afford naphthyridine acid 6 as a highly crystalline solid in 99% yield.
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Scheme 5
The preparation of amino alcohol 7 started with commercially available Dꢀ(ꢀ)pantolactone 9 (Scheme 6).
Protection of the hydroxyl group of pantolactone was required prior to ring opening with methyl amine.
While a number of protecting groups were evaluated, the THP protecting group proved to be the most
robust in terms of downstream processing despite the fact that it added a layer of complexity by the
introduction of diastereomeric mixtures. Treatment of lactone 9 with 3,4ꢀdihydroꢀ2Hꢀpyran in CH2Cl2
in the presence of a catalytic amount of TsOH at room temperature gave the THP derivative 19 in
quantitative yield. Compound 19 was not isolated, and was followed by direct addition of 2.5
equivalents of MeNH2 (8 M in EtOH) at room temperature resulting in ring opening of the lactone and
the formation of amide 20 in > 95% yield. After a solvent switch to toluene, the crude reaction mixture
was treated with 2.5 equivalents of RedꢀAl® and heated to 90 ºC for 4 h. After quenching into 20 wt%
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aqueous KOH to remove the aluminum salts, the solvent was removed to give amino alcohol 7 as a 3:1
mixture of diastereomers which were sufficiently pure for use in the next reaction without the need for
further purification.
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Scheme 6
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The first generation synthesis of compound 24 involved a series of transformations where compound 24
was the first isolated intermediate (Scheme 7). This was necessary in order to avoid removal of minor
diastereomers arising from the anomeric center of the THP group.16 The coupling of naphthyridine acid
6 and amino alcohol 7 was carried out with 5 mol% of 1ꢀhydroxyꢀ7ꢀazabenzotriazole (HOAt) and 1.2
equivalents of EDC in the presence of 3 equivalents of Nꢀmethylmorpholine (NMM) in DMF at room
temperature for 2 days to afford intermediate 21 in 80% HPLC assay yield. Alternatavely, the coupling
could be achieved in a comparable yield by switching HOAt to HOBt; however, this required 1.1
equivalents of HOBt in order to drive the reaction to completion and did not affect the reaction rate.
Construction of the 8ꢀmembered ring at this point required activation of the primary alcohol and
subsequent cyclization of the nitrogen onto the neopentyl center. Activation of intermediate 21 was
accomplished by treatment with 5 equiv. of NEt3 and 5 equiv. of MsCl to give trisꢀmesylate 22 in near
quantitative yield. After the mesylation was complete, quenching the reaction mixture with sat.
NaHCO3 was necessary in order to effectively quench all the excess MsCl. This operation was found to
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The Journal of Organic Chemistry
be crucial for good stability of trisꢀmesylate 22 since any trace of acid would cleave the THP protecting
group. Trisꢀmesylate 22 was used in the next step without further purification. Attempted cyclization of
trisꢀmesylate 22 in the presence of Cs2CO3 typically led to selective deꢀmesylation at the 3ꢀposition of
the pyridine ring and no cyclization to 24.17 In order to address this issue, protection of this hydroxyl
group was investigated. The selective monoꢀdemesylation was conducted with 2 equivalents of Cs2CO3
at 80 ºC for 2 hours. At this temperature, < 5% of bisꢀdemesylation was observed (i.e. removal of
second mesylate adjacent to the pyridine nitrogen). After cooling to room temperature, 3 equivalents of
MeI were added to afford methoxyꢀbisꢀmesylate 23. Protection of the hydroxyl group at this point was
found to be critical for the subsequent cyclization to proceed to the 8ꢀmembered ring in the presence of
Cs2CO3. When the hydroxyl group was unprotected, low conversions were observed, presumably due to
the precipitation of the cesium salt of the hydroxyl group. The original route for cyclization of the 8ꢀ
memebered ring involved intramolecular cyclization of a primary mesylate, in the presence of Cs2CO3 in
DMF at 150 ºC in a microwave.18 The cyclization of our bisꢀmesylate 23 to compound 24 was fully
optimized with respect to solvent and temperature. Methoxyꢀbisꢀmesylate 23 was treated with 3
equivalents of Cs2CO3 at 105 ºC in dimethylacetamide (DMAc) for 5 hours to affect cyclization to the 8ꢀ
membered ring. After the cyclization was complete, the reaction mixture was cooled to room
temperature and water was added to precipitate compound 24 which was isolated in 80% yield.
Compound 24 exists as a complex mixture of both THP diastereomers (~3:1) and an approximate 85:15
mixture of atropisomers about the amide bond due to restricted amide bond rotation (vide infra).
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Scheme 7
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Me OTHP
N
Me OTHP
CO2H
NH
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2
3
4
5
6
7
8
O
O
N
F
HOAt, EDC, NMM
DMF
OMs
OH
MsCl, Et3N
EtOAc
N
N
NH
Cl
O
OTHP
H
N
N
O
OH
OMs
N
O
95%
OH
O
OMs
O
OH
21
Not Isolated
6
Me Me
7
2
2
Not Isolated
80%
3:1 mixture of
diasteromers
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~85:15 mixture of
atropisomers
Me
OTHP
Me
N
Me OTHP
O
O
N
OMs
1. Cs2CO3, DMAc
F
Me
1) Cs2CO3, DMAc
N
N
2) MeI
91%
105 °C, 3 h
2. H2O
N
Cl
O
N
OMs
O
OMe
80%
O
OMe
24
23
Not Isolated
The end game synthesis of the final compound is depicted in Scheme 8. The mixture of both
diastereomers and atropiosmers of 24 were treated with a catalytic amount of pꢀTsOH in MeOH at 50 ºC
for 2 h to cleave the THP protecting group and initially afford 25 as an 85:15 mixture of atropisomers.
Compound 25 crystallized from EtOAc and was isolated as a single atropisomer in 56% isolated yield.
The final synthetic step required removal of the methoxy group with BBr3. Treatment of 25 with 2.1
equivalents of BBr3 at 5 ºC resulted in smooth deprotection leading to crude 5. After an aqueous
workup, the solvent was switched from CH2Cl2 to EtOH which resulted in crystallization of compound
5a as an ethanol solvate in 92% isolated yield and as a single atropisomer. The choice to isolate the
crystalline ethanol solvate offered the advantage of a final purity upgrade before the final isolation of the
more stable anhydrous/solventꢀfree phase of compound 5. Conversion of compound 5a to the final API
was accomplished by slurrying compound 5a in MTBE for 20 h followed by filtration to give final
compound 5 in 98% yield and as a single atropisomer.
Scheme 8
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The Journal of Organic Chemistry
Me
Me
OH
Me
Me
OTHP
Me
1
2
N
N
O
O
3
F
4
5
6
7
1. p-TsOH, MeOH, 50 °C
F
Me
N
N
2. Crystallization, EtOAc
N
N
Cl
O
Cl
O
60%
O
OMe
25
O
OMe
24
8
9
Single atropisomer
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Me
N
O
Me
OH
N
O
OH
Me
Me
Me
MTBE slurry
1. BBr3, CH2Cl2
2. EtOH
F
F
Me
N
N
N
N
99%
O
Cl
O
Cl
92%
O
OH
EtOH
O
OH
5a
5
Anhydrous, solvent free
single atropisomer
Isolated EtOH solvate
for purity upgrade
Although the synthesis of 5 was effectively demonstrated on multiꢀkilogram scale, key aspects of the
conversion of naphthyridine acid 6 to final product 5 still needed to be addressed including streamꢀ
lining the route, eliminating the need for protection/deprotection of the pyridine hydroxyl group, and
further optimization of the 8ꢀmembered ring closure reaction. Thus a second generation synthesis was
required and is highlighted in Scheme 9. Reaction of naphthyridine acid 6 with 3.5 equivalents of
pivaloyl chloride in the presence of 5 equiv. of NEt3 in THF followed by filtration of the triethylamine
hydrochloride and switching the solvent to heptane afforded crystalline trispivalate 26 in 94% isolated
yield. While compound 26 was discovered to be somewhat unstable to open air, it maintained good
stability when stored under inert conditions. Reaction of 26 with amino alcohol 7 initially forms the
amide bond displacing the ester pivalate quantitatively in < 30 minutes. Hydrolysis of the corresponding
bispivalate intermediate was then accomplished by direct addition of 50% NaOH to furnish intermediate
21 in near quantitative yield. As in the first generation synthesis, compounds 21 and 27 were not
isolated and were carried crude into the next step without purification. Treatment of 21 with an excess
of potassium tertꢀbutoxide in the presence of 1ꢀ(pꢀtoluenesulfonyl)imidazole in toluene gave the monoꢀ
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tosylated intermediate 27 in 94% yield. There was no evidence of tosylation of the hydroxyl groups on
the pyridine ring under these conditions as the excess potassium tertꢀbutoxide effectivly cleaves these
potential intermediates.19 After an aqueous workup, monoꢀtosylate 27 was used directly in the next step
as a solution in DMSO. The cyclization step was extensively examined in terms of both base and
solvent combinations. The optimal conditions involved slow addition of DBU in DMSO to a solution of
27 in DMSO at 95 ºC to afford crude 24 as a 87:13 mixture of atropisomers. Treatment of 24 with HCl
at 40 ºC and cooling to room temperature resulted in the crystallization of 5a as an ethanol solvate
which was isolated in 80% yield over the two steps and as a single atropisomer.
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Scheme 9
O
OPiv
N
1. NEt3, Piv-Cl
THF
1. THF
6
OTHP
2. Filtration, solvent switch
to heptane
N
H
OPiv
N
OH
O
OPiv
26
Me Me
99%
95%
7
2. 50% NaOH
Me OTHP
Me OTHP
O
N
O
N
OH
OTs
KO-tBu
NH
NH
Ts-imidazole
Toluene/THF
N
N
O
O
O
OH
21
Not Isolated
O
OH
27
Not Isolated
94%
1. DBU (3 equiv)
5a EtOH solvate
DMSO, 95 °C, 12 h
2. HCl, EtOH
80% over two steps
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The Journal of Organic Chemistry
Atropisomerism is often observed when the free rotation about a bond is sufficiently restricted to result
in stereoisomers called atropisomers whose interconversion is slow enough to allow for their separation
and characterization.20 Typically atropisomerism is thought of in terms of restricted rotation about
biaryl systems with BINAP serving as a representative example of molecules exhibiting this property.
Tertiary aromatic amides also may be susceptible to restricted bond rotation and exhibit
atropisomerization.21,22 In a structurally related system to 5, a similar naphthyridine displayed
atropisomerism where the atropisomers were easily separated due to highly restrictive amide bond
rotation.23 Compounds 24, 25, 5a, and final product 5 all have sufficient hindrance to rotation about the
amide bond to permit separation of the atropisomers. The two atropisomers for compound 5 are
depicted in Scheme 10. The desired atropisomer (aR,4R)ꢀ5 has the carbonyl of the amide bond pointing
up, whereas, the undesired (aS,4R)ꢀ5 has the carbonyl pointing back.24,25 The undesired atropisomer of
compound 5 demonstrated significantly less antiviral activity and had a markedly different
pharmacokinetic profile from compound 5. Compounds 24, 25, 5a, and final product 5 all exist as an
interconverting mixture of atropisomers when in solution. This is due to the fact that the methyl group
is not sufficently large enough to prevent this interconversion. Reꢀequilibration of the atropisomers
occurs in solution at a rate of ~ 2% per day at room temperature depending on the solvent and
temperature. For example, in EtOH conversion of pure atropisomer 5 proceeds to a ~85:15 mixture of
atropisomers after stirring for 8 days at room temperature. However, at 37 ºC, after just three days, the
ratio of atropisomers was observed to be 85:15. Fortunately, the desired atropisomer of 5 was the
thermodynamically more stable. In the solid state as a pure atropisomer, compounds 24, 25, 5a, and
final product 5 all proved to be chemically and conformationally stable and no interconversion was
observed when stored at room temperature.
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Scheme 10.
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Conclusion:
In conclusion we have developed a practical, efficient asymmetric first generation synthesis of the potent
HIVꢀ1 integrase inhibitor 5 which proceeded in 10 synthetic steps and 14% overall yield from readily
available unsaturated sulfoxide 8. The route was robust, required no chromatography, and was scalable
to multiꢀkilogram scale. The second generation synthesis also proceeded in 10 synthetic steps but the
yield was improved to 28% overall yield. These synthetic routes were highlighted by a 5ꢀstep synthesis
of the challenging 8ꢀmembered ring that does not require isolation of any intermediates. The additional
hurdle of controlling atropisomerization presented an added layer of complexity that was solved via
crystallization of the desired atropisomer.
Experimental Section
All reagents were purchased from commercial sources and used as received. H and 13C NMR spectra
1
were recorded at 400 and 100 MHz, respectively, with chemical shifts given in ppm relative to TMS at δ
= 0. Reaction mixtures and products were analyzed by reverse phase HPLC using a 4.6 X 250 mm
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The Journal of Organic Chemistry
RP18 column. Solvent compositions consisted of 0.1% H3PO4 and acetonitrile with a flow rate of 1.5
mL/min.
1
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3
4
5
6
7
8
Preparation of Ethyl 2-amino-2-(1-(3-chloro-4-fluorobenzyl)-2-oxo-3-(phenylsulfinyl)piperidin-
4-yl)acetate (11). In a 100 L round bottom flask equipped with a mechanical stirrer, nitrogen inlet,
thermocouple, and a 2 L addition funnel was added 5.00 kg (13.7 mol) of unsaturated sulfoxide 8, 4.00
kg (15.1 mol) of glycine imine 10, and 40 L of THF. The resulting slurry was stirred at room
temperature until all the solids dissolved and was then cooled in an ice bath to an internal temperature of
0 °C. To the homogeneous solution was then added drop wise 1.4 L (1.4 mol) of a 1M solution of
lithium tertꢀbutoxide while maintaining the internal temperature < 15 ºC. The solution was cooled to 0
ºC and was stirred at this temperature for 45 min at which point HPLC indicated complete consumption
of the starting material. To the cooled reaction mixture was added 35 L of 2N HCl at such a rate that the
internal temperature warmed gradually to room temperature. The hazy yellow solution was stirred at
room temperature for 45 min and transferred to a 200 L extractor. The mixture was diluted with 25 L of
MTBE and the layers separated. The organic layer was back extracted with 5 L of 2N HCl. The
combined aqueous layers were washed with MTBE (2 X 25 L) to completely remove residual
benzophenone. The acidic aqueous layer was charged into a 100 L round bottom flask, diluted with 25
L of isopropyl acetate (IPAc), and cooled to 0 ºC. To the solution was added drop wise 25 L of 5N
NaOH keeping the internal temperature < 5 ºC and the final pH was 8.5. The layers were separated and
the aqueous layer was back extracted with 8 L of IPAc. The IPAc solution was utilized directly in the
next step without further purification.
9
10
11
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Preparation of Amino-[1-(3-Chloro-4-fluorobenzyl)-2-oxo-piperidin-(4Z)-ylidene]-acetic acid
ethyl ester (17). To a 100 L round bottom flask equipped with a mechanical stirrer, nitrogen inlet,
thermocouple, and water cooled condenser was charged with 6.4 kg (13.7 mol) of crude 11 as a solution
in IPAc. The solvent was concentrated under reduced pressure with a constant feed of toluene and the
volume was adjusted to a total volume of 65 L (KF = 200 ppm). To the solution was added 2.4 L (13.8
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mol) of Hünigs base and the slurry was heated to 90 ºC. After 30 minutes at 90 °C, the reaction was
assayed for conversion and then cooled to ~70 ºC. The reaction mixture was concentrated under reduced
pressure and volume was reduced to ~18 L, upon which a slurry formed. To the slurry was added 2 L of
IPAc and the slurry allowed to cool to room temperature and stirred for 3 h. The slurry was filtered,
rinsed with a mixture of 12L of 5:1 heptane:IPAC, and dried overnight under vacuum/N2 sweep to give
1
2
3
4
5
6
7
8
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11
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1
3.0 kg (99 wt%, 65%) of 17 as a fluffy white solid Mp 109ꢀ110 °C; H NMR (CDCl3, 400 MHz) δ 1.31
(t, 3H, J = 7.1 Hz), 2.97 (t, 2H, J = 5.6 Hz), 3.18 (s, 2H), 3.26 (t, 2H, J = 5.6 Hz), 3.44 (s, 2H), 4.25 (q,
13
2H, J = 7.1 Hz), 4.57 (s, 2H), 7.10 (m, 2H), 7.33 (m, 1H); C NMR (CDCl3, 100 MHz) δ 14.3, 27.6,
36.2, 46.1, 49.3, 61.2, 116.3, 116.8 (d, J = 21 Hz), 121.5 (d, J = 17 Hz), 127.5, 127.8 (d, J = 7 Hz),
130.3, 134.2, 157.4 (d, J = 241 Hz), 164.4, 168.1. Anal. Calcd. For C16H18ClFN2O3: C, 56.39; H, 5.32;
N, 8.22. Found: C, 56.42; H, 5.29; N, 8.17.
Preparation of Ethyl 6-(3chlooro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,7,8-hexahydro-2,6-
naphthyridine-1-carboxylate (15). In a 100 L round bottom flask equipped with a mechanical stirrer,
nitrogen inlet, thermocouple, and 2L addition funnel was charged 3.50 kg (8.80 mol) of imine 17 and 45
L of THF. The solution was cooled to 0 °C and 1.70 L (9.68 mol) of Hünigs base was added in one
portion. To the resulting solution was added drop wise, via the addition funnel, 1.20 L (9.24 mol) of
monoethyl oxalyl chloride 12 at such a rate that the temperature was maintained below 3.5 °C. The
reaction mixture was stirred for 30 min below 3.5 °C at which point 3.06 kg (35.2 mol) of LiBr and1.97
kg (17.60 mol) of DABCO were introduced as solids. The resulting mixture was allowed to warm to
room temperature and stirred for 16 h at room temperature. The reaction mixture was quenched with 35
L of a (2N) aq. HCl (35 L) and stirred at room temperature for 30 min. The mixture was then
concentrated under reduced pressure in order to remove approximately ½ to ¾ of the total THF charge.
The resulting slurry was diluted to the original quench volume with water. Approximate amount of THF
removed was 36ꢀ38 L. The slurry was stirred at room temperature for 30 min and filtered. The wet cake
was slurry washed with water (2x12 L) and then with MTBE (3x12 L) and dried under vacuum/N2
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1
sweep to afford 2.95 kg (85%) of ester 15 as a colorless solid: mp 198ꢀ199 °C; H NMR (CDCl3, 400
1
2
3
4
5
MHz) δ 1.26 (t, 3H, J = 7.1 Hz), 3.13 (t, 2H, J = 5.7 Hz), 3.48 (t, 2H, J = 5.7 Hz), 4.21 (q, 2H, J = 7.1
13
Hz), 4.65 (s, 2H), 7.33 (m, 2H), 7.54 (m, 1H), 11.35 (br s, 1H), 13.8 (br s, 1H); C NMR (CDCl3, 100
6
7
8
MHz) δ 14.4, 23.5, 45.6, 49.1, 61.9, 113.1, 117.5 (d, J = 21 Hz), 119.9 (d, J = 17 Hz), 120.1, 120.6,
9
19
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129.0 (d, J = 7 Hz), 130.5, 134.7, 155.8, 156.1, 157.3 (d, J = 241 Hz), 161.8, 167.6; F NMR (CDCl3,
75 MHz) δ ꢀ115.7. Anal. Calcd. For C18H16ClFN2O5: C, 54.76; H, 4.09; N, 7.10. Found: C, 54.83; H,
4.06; N, 6.99.
Preparation of Ethyl 6-(3chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,7,8-hexahydro-2,6-
naphthyridine-1-carboxylic acid (6). In a 100 L flask equipped with a mechanical stirrer, nitrogen
inlet, and thermocouple was added 3.08 kg (7.80 mol) of ester 15 and 37 L of a 1:1 mixture of
EtOH/THF. To the resulting slurry was added the 9.4 L of (5N) aq. NaOH and the mixture was warmed
to 50ꢀ53 °C for 45 min. The slurry was then diluted with 10 L of water (~3.33 L/kg) and was stirred for
an additional hour at 50ꢀ53 °C. Upon completion of the hydrolysis, the slurry was cooled to 15 °C and
acidified with 6 L of conc. HCl and stirred at room temperature for 12 h. The slurry was filtered, washed
with water (3x12 L) and dried under vacuum/N2 sweep at +35 °C to afford 2.82 kg (99% yield) of
1
naphthyridine acid 6 as a colorless solid. Mp 275 °C (decomp); H NMR (DMSOꢀd6, 400 MHz) δ 3.17
(t, 2H, J = 6.4 Hz), 3.47 (t, 2H, J = 6.4 Hz), 4.65 (s, 2H), 7.32 (m, 2H), 7.54 (m, 2H), 13.84 (br s, 1H);
13C NMR (DMSOꢀd6, 100 MHz) δ 23.6, 45.7, 49.1, 112.9, 117.5 (d, J = 21 Hz), 119.7, 119.9 (d, J = 21
Hz), 120.1, 129.0 (d, J = 7 Hz), 134.7, (d, J = 3 Hz), 155.9, 156.8, 157.1 (d, J = 241 Hz), 163.3, 167.7;
19F NMR (DMSOꢀd6, 75 MHz) δ ꢀ118.7. Anal. Calcd. For C16H12ClFN2O5: C, 52.40; H, 3.30; N, 7.64.
Found: C, 52.38; H, 3.25; N, 7.59.
Preparation of (3R)-2,2-Dimethyl-4-(methylamino)-3-((tetrahydro-2H-pyran-2-yl)oxy)butan-1-
ol (7). In a 100 L flask equipped with a mechanical stirrer, nitrogen inlet, and thermocouple was added
5.20 kg (40 mol) of D(ꢀ)ꢀPantolactone 9, 15.6 L of dichloromethane, and 19.8 g (0.1 mol) of
TsOH·H2O. The solution was cooled to ꢀ5 ºC utilizing a dry ice/acetone bath and 3.69 kg (44.0 mol) of
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3,4ꢀdihydroꢀ2Hꢀpyran was added over 30 min while keeping the internal temperature below 20 ºC. The
resulting solution was stirred at room temperature for 1 h and 12.4 L (100 mol) of a 33 wt% solution of
methyamine in EtOH was added in one portion. The resulting yellow solution was stirred at room
temperature of 18 h. The reaction mixture was diluted with 15 L of toluene and concentrated under
reduced pressure to near dryness and then reconcentrated under reduced pressure to remove residual
methylamine and EtOH. The solvent was adjusted to a final volume of ~ 90 L of toluene and used in
the next step without purification.
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To the above solution of 20 in toluene was transfered to a 200 L jacketted reactor and the solution
was cooled to an internal temperature of ꢀ5 ºC. To the solution was added drop wise 30.2 L (100 mol) of
a ~ 65 wt% solution of RedꢀAl® in toluene over a period of 45 min while keeping the internal
temperature below 20 ºC. Hydrogen offꢀgassing was observed during the first 10 L addition of RedꢀAl.
The resulting mixture was then heated to 90 ºC for 4 h and allowed to cool to room temperature. The
mixture was further cooled to ꢀ5 ºC and quenched with 8.7 L of isopropyl alcohol keeping the internal
temperature below 20 ºC. The solution was inversely quenched into a 52 L of a 20 wt% aqueous KOH
solution and the layers separated. The organic phase was washed with water (2 X 35 L) and was
concentrated under reduced pressure to provide 8.96 kg crude oil (8.25 kg) 92 wt% by NMR assay (90%
overall yield from 7) as a light yellow oil and as a 3:1 mixture of THP diastereomers that were used in
1
the next step without further purification. Major diastereomer: H NMR (CDCl3, 400 MHz) δ 0.94 (s,
3H), 0.97 (s, 3H), 1.55 (m, 4H), 1.78 (m, 1H), 1.84 (m, 1H), 2.44 (s, 3H), 2.66 (m, 1H), 2.81 (dd, 1H, J
= 12.8 and 4.5 Hz), 3.21 (d, 1H, J = 11.5 Hz), 3.46 (d, 1H, J = 11.5 Hz), 3.52 (m, 1H), 3.59 (t, 1H, J =
4.5 Hz), 3.96 (m, 1H), 4.70 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 20.3, 21.4, 23.94, 25.2, 31.3, 36.1,
1
39.3, 49.5, 63.7, 67.1, 79.6, 97.4. Minor diastereomer: H NMR (CDCl3, 400 MHz) δ 0.87 (s, 3H), 0.98
(s, 3H), 1.55 (m, 4H), 1.78 (m, 1H), 1.84 (m, 1H), 2.43 (s, 3H), 2.66 (m, 1H), 2.89 (m, 1H), 2.99 (d, 1H,
13
J = 11.5 Hz), 3.36 (m, 1H), 3.52 (m, 1H), 3.60 (d, 1H, J = 11.5 Hz), 3.88 (m, 1H), 4.51 (m, 1H); C
NMR (CDCl3, 100 MHz) δ 20.7, 22.1, 23.9, 25.2, 30.9, 35.7, 40.1, 51.3, 64.1, 66.0, 85.5, 102.8.
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First Generation Synthesis of 5a:
Preparation of
1
2
3
4
(4R)-11-(3-Chloro-4-fluorobenzyl)-9-methoxy-2,5,5-trimethyl-4-
5
6
((tetrahydro-2H-pyran-2-yl)oxy)-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-
7
a][2,6]naphthyridine-1,8,10(11H)-trione (25). To a 75 L round bottom flask equipped with a
mechanical stirrer, nitrogen inlet, and thermocouple was added 4.00 kg (10.91 mol) of naphthyridine
acid 6, 3.29 kg (13.09 mol) of 92 wt% aminoalcohol 7, 3.61 L (32.73 mol) of Nꢀmethylmorpholine, 74 g
(0.55 mol) of HOAt, and 2.51 kg (13.09 mol) of EDC. The mixture was dissolved in 28 L of DMF and
stirred at room temperature for 60 h. The reaction mixture was diluted with 40 L of EtOAc and 28 L of
water. The mixture was transferred to an extractor and the layers were separated. The aqueous layer
was back extracted with an additional 40 L of EtOAc. The combined extracts were washed with water
(2 X 40 L) and concentrated in a 100 L round bottom flask under reduced pressure while azeotropically
drying with a feed of EtOAc during the concentration. The volume was adjusted to ~ 50 L (KF < 300
ꢀg/g) to provide 5.06 kg by HPLC assay (80% yield) of amide 21 which was used in the next step
without further purification.
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To the above solution of 5.06 kg (8.72 mol by assay) of amide 21 was added 6.08 L (43.62 mol)
of NEt3 and the solution was cooled in an ice bath to an internal temperature of 5 °C. To the mixture
was slowly added drop wise 3.38 L (43.62 mol) of MsCl while maintaining the internal temperature
below 20 °C. After the addition, the slurry was stirred at room temperature for one hour and was
quenched into a 50 L solution of saturated aqueous NaHCO3. The biphasic solution was stirred at room
temperature for one hour and the layers are separated. The organic layer was washed with 50 L of water,
and the solvent was switched to DMAc under reduced pressure in a 100 L round bottom flask to give a
final volume of ~50 L (KF < 300 ꢀg/g) and provided 6.75 kg by assay (95%) of 22 which was used in
the next step without further purification.
To above solution of 6.75 kg by assay (8.29 mol) of trisꢀmesylate 22 in DMAc was added added
5.40 kg (16.58 mol) of Cs2CO3 and the mixture was heated to 80 °C. After two hours at 80 °C, the
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mixture was cooled to room temperature and 1.55 L (24.88 mol) of MeI was added. The mixture was
stirred at room temperature for 15 hours and diluted with 40 L of water. The mixture was transferred to
a 200 L extractor and further diluted with 50 L of EtOAc. The layers were separated and the organic
layer was washed with 40 L of water. The solvent was concentrated under reduced pressure in a 50 L
round bottom flask while first azeotropically drying by EtOAc distillation and finally solvent switching
to DMAc to provide a final volume of ~9 L (KF < 300 ꢀg/g) and 5.66 kg by assay (91% assay yield) of
23 that was used in the next step without further purification.
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In a 100 L round bottom flask equipped with a mechanical stirrer, nitrogen inlet, addition funnel,
and thermocouple was added 7.37 kg (22.63 mol) of Cs2CO3 and 31 L of DMAc and the slurry was
heated to an internal temperature of 105 °C. To this slurry was slowly added via the addition funnel over
4 h the above solution of 5.66 kg by assay (7.54 mol) of 23 in 9 mL of DMAc. After the addition was
complete, the mixture was stirred at the same temperature for an additional 3 h and cooled to room
temperature. To the mixture was added 50 L of water over the course of 1 h and the resulting slurry was
stirred at room temperature for 15 h. The slurry was filtered and the wet cake was washed with water (2
X 20 L) and dried under vacuum/N2 sweep for 24 h at room temperature to give a brown solid (6.94 kg,
~ 50 wt%, 3.47 kg by assay, 80% assay yield) of 24 as an 85:15 mixture of amide atroisomers and 3:1
mixture of diastereomers which was used directly in the next step without further purification.
Preparation
of
(R)-11-(3-Chloro-4-fluorobenzyl)-4-hydroxy-9-methoxy-2,5,5-trimethyl-
3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]naphthridine-1,8,10(11H)-trione (25). In a 100 L
round bottom flask equipped with a mechanical stirrer, nitrogen inlet, and thermocouple was added 3.47
kg by assay (6.02 mol) as a 85:15 mixture of amide atropisomers of 24, 30 L of MeOH, and 343 g (1.81
mol) of TsOH·H2O. The mixture was heated to 50 °C for 2 hours and cooled to room temperature. The
solvent was switched to EtOAc under reduced pressure with a constant feed of EtOAc while maintaining
the volume at ~ 30 L. During concentration the product crystallized. The final volume was adjusted to ~
25 L and the resulting slurry was stirred at room temperature for 2 h, filtered, and the wet cake was
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washed with EtOAc (2 X 5 L). The cake was dried under vacuum/N2 sweep at room temperature for 24
1
2
3
h to provide 1.66 kg (56%) of 25 as a colorless solid and a single amide atropisomer: mp 190ꢀ192 °C
4
5
6
1
(DSC); [α]D +1.60 (c 1.0, MeOH); H NMR (DMSOꢀd6, 400 MHz) δ 0.72 (s, 3H), 1.08 (s, 3H), 2.40
7
8
9
(m, 1H), 2.60 (m, 1H), 2.91 (d, 1H, J = 15.1 Hz), 3.07 (s, 3H), 3.18 (d, 1H, J = 15.1 Hz), 3.34 (m, 1H),
3.44 (m, 2H), 3.59 (dd, 1H, J = 15.2 and 9.8 Hz), 3.82 (s, 3H), 4.55 (d, 1H, J = 15.2 Hz), 4.57 (d, 1H, J
= 15.2 Hz), 4.74 (d, 1H, J = 15.2 Hz), 5.10 (d, 1H, J = 4.6 Hz), 7.35 (m, 1H), 7.40 (t, 1H, J = 9.0 Hz),
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7.54 (dd, 1H, J = 7.3 and 2.0 Hz); C NMR (DMSOꢀd6, 100 MHz) δ 14.9, 25.2, 27.2, 33.7, 38.7, 45.9,
49.2, 51.0, 53.4, 60.1, 72.7, 111.7, 117.4 (d, J = 20.8 Hz), 119.9 (d, J = 18.4 Hz), 127.7, 128.7 (d, J = 7.5
19
Hz), 130.1, 134.0, 136.0 (d, J = 3.7 Hz), 149.5, 157.0 (d, J = 245.1 Hz), 159.3, 160.6, 162.4; F NMR
(DMSOꢀd6, 75 MHz) δ ꢀ118.6. Anal. Calcd. For C24H27ClFN3O5: C, 58.60; H, 5.53; N, 8.54. Found:
C, 58.30; H, 5.54; N, 8.45.
Preparation of (R)-11-(3-Chloro-4-fluorobenzyl)-4,9-hydroxy-2,5,5-trimethyl-3,4,5,6,12,13-
hexahydro-2H-diazocino[2,1-a][2,6]naphthyridine-1,8,10(11H)-trione EtOH Solvate (5a). In a 50 L
round bottom flask equipped with a mechanical stirrer, nitrogen inlet, and thermocouple was added 1.66
kg (3.37 mol) of 25 and 15 L of CH2Cl2 and the mixture was cooled to an internal temperature of 5 °C.
To this solution was added 7.1 L (7.1 mol) of a 1 M solution of BBr3 over 1 hour while maintaining the
internal temperature < 20 °C. The resulting slurry was stirred at room temperature for one hour and
cooled to 5 °C. To the slurry was added drop wise 2.5 L of MeOH followed by the addition of 20 L of
water in one portion. The mixture was stirred at room temperature for 1 h and the layers separated. The
organic layer was washed with 20 L of a 1% aqueous solution of NaHCO3 followed by 20 L of water.
The solvent was concentrated under reduced pressure with the constant addition of ethanol and a final
volume of ~ 16 L. The resulting slurry was stirred at room temperature of 2 h, filtered, and the wet cake
was washed with 5 L of EtOH. The solid was dried under vacuum/N2 sweep for 24 h to give 1.62 kg
(92%) of 5a as an EtOH solvate and as a pure atropisomer and a colorless solid. Mp 145ꢀ147 °C (DSC);
1H NMR (DMSOꢀd6, 400 MHz) δ 0.72 (s, 3H), 1.06 (t, 3H, J = 7.3Hz); 1.08 (s, 3H), 2.44 (dt, 1H, J =
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15.4 and 5.4 Hz), 2.71 (m, 1H), 2.91 (d, 1H, J = 15.2 Hz), 3.07 (s, 3H), 3.16 (d, 1H, J = 15.2 Hz), 3.33
(m, 1H), 3.42ꢀ3.56 (m, 4H), 3.61 (dd, 1H, J = 15.1 and 9.5 Hz), 4.34 (t, 1H, J = 4.8 Hz), 4.54 (d, 1H, J =
14.2 Hz), 4.62 (d, 1H, J = 15.2 Hz), 4.75 (d, 1H, J = 15.2 Hz), 5.08 (d, 1H, J = 4.8 Hz), 7.41 (m, 2H),
7.60 (dd, 1H, J = 7.2 and 2.0 Hz), 13.1 (s, 1H); 13C NMR (DMSOꢀd6, 100 MHz) δ 14.9, 19.0, 23.9, 27.2,
33.7, 38.8, 46.0, 49.1, 51.1, 53.5, 56.5, 109.9, 111.8, 117.4 (d, J = 20.8 Hz), 120.1 (d, J = 18.0 Hz),
128.7, 129.0 (d, J = 8.3 Hz), 130.4, 134.7 (d, J = 3.5 Hz), 152.2, 157.0, 157.1 (d, J = 246.0 Hz), 162.4,
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167.4; F NMR (DMSOꢀd6, 75 MHz) δ ꢀ118.1. Anal. Calcd. For C25H31ClFN3O6: C, 57.31; H, 5.96;
N, 8.02. Found: C, 57.09; H, 5.93; N, 7.96.
Preparation
of
(R)-11-(3-Chloro-4-fluorobenzyl)-4,9-hydroxy-2,5,5-
trimethyl3,4,5,6,12,130hexahydro-2H-diazocino[2,1-a][2,6]naphthyridine-1,8,10(11H)-trione (5).
In a 50 L round bottom flask equipped with a mechanical stirrer and thermocouple was added 2.80 kg
(5.34 mol) of the above EtOH solvate X and 28 L of MTBE. The resulting slurry was stirred at room
temperature of 20 h. The slurry was filtered and the wet cake washed with 5 L of MTBE and dried
under vacuum/N2 sweep for 24 h at room temperature to provide 2.50 kg (98%, > 99 wt%) of 5 as a
colorless solid containing 0.5 wt% of MTBE that could not be further removed: mp: 242ꢀ243 °C (DSC);
[α]D +1.19 (c 1.0, MeOH); 1H NMR (DMSOꢀd6, 400 MHz) δ 0.72 (s, 3H), 1.10 (s, 3H), 2.44 (dt, 1H, J =
15.4 and 5.4 Hz), 2.71 (m, 1H), 2.91 (d, 1H, J = 15.1 Hz), 3.06 (s, 3H), 3.16 (d, 1H, J = 15.1 Hz), 3.33
(m, 1H), 3.51 (m, 2H), 3.61 (dd, 1H, J = 15.1 and 9.5 Hz), 4.54 (d, 1H, J = 14.2 Hz), 4.62 (d, 1H, J =
15.1 Hz), 4.76 (m, 1H, J = 15.1 Hz), 5.10 (d, 1H, J = 4.6 Hz), 7.40 (m, 2H), 7.60 (d, 1H, J = 7.2 and 2.0
Hz), 13.1 (s, 1H); ); 13C NMR (DMSOꢀd6, 100 MHz) δ 14.9, 23.9, 27.2, 33.7, 38.9, 46.0, 49.1, 51.0,
53.5, 75.8, 109.9, 111.9, 117.5 (d, J = 21.4 Hz), 120.0 (d, J = 18.2 Hz), 128.7, 129.0 (d, J = 7.3 Hz),
130.5, 134.8 (d, J = 3.76 Hz), 152.2, 157.0, 157.1 (d, J = 243.o Hz), 162.4, 167.4; 19F NMR (DMSOꢀd6,
75 MHz) δ ꢀ118.1. Anal. Calcd. For C23H25ClFN3O5: C, 57.80; H, 5.27; N, 8.79. Found: C, 57.72; H,
5.13; N, 8.76.
Second generation Synthesis of 5a:
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Preparation of 6-(3-Chloro-4-fluorobenzyl)-5-oxo-3,4-bis(pivalyloxy)-5,6,7,8-tetrahydro-2,6-
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2
naphthyridine-1-carboxylic pivalic anhydride (26). To a 100 ml flask was charged with 15 mL of
THF, 1.0 g (2.73 mmol) of naphthyridine acid 6 (1.0 g, 2.73 mmol) and 1.90 ml (13.65 mmol) of NEt3 is
added and the resulting slurry was cooled to 10 ºC. To the slurry was added drop wise 1.18 ml (9.56
mmol) of trimethylacetyl chloride and the mixture was stirred at room temperature for 5 h. The resulting
slurry was filtered and the solids were washed with 5 mL of dry THF. The filtrate was concentrated
under reduced pressure with a constant feed of heptane to a final volume of ~ 15 mL. The resulting
slurry was stirred at room temperature of 1 h, filtered, and washed with 10 mL of heptane and dried at
40 ºC in a vacuum oven for 12 h to afford 1.59 g (95%) of trispivalate 26 as a colorless solid: 1H NMR
(CDCl3, 500 MHz) δ 0 1.36 (s, 9H), 1.40 (s, 9H), 1.41 (s, 9H), 3.42 (br m, 2H), 3.52 (br m, 2H), 4.71 (br
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m, 2H), 7.13 (t, 1H, J = 8.5 Hz), 7.20 (m, 1H), 7.40 (dd, 1H, J = 7.1 and 2.3 Hz); ); C NMR (CDCl3,
100 MHz) δ 8.6, 26.4, 26.7, 27.0, 27.1, 39.3, 39.6, 44.9, 45.8, 49.3, 116.8 (J = 21.7 Hz), 121.3, (J = 17.0
Hz), 127.7 (J = 7.3 Hz), 130.2, 133.5 J = 4.4 Hz), 133.5, 137.3, 137.9, 141.2, 149.9, 157.7 (J = 255 Hz),
159.7, 162.0, 174.8, 175.0, 175.2. Anal. Calcd. For C31H36ClFN2O8: C, 60.14; H, 5.86; N, 4.53.
Found: C, 59.81; H, 5.87; N, 4.49.
Preparation of (R)-11-(3-Chloro-4-flurorbenzyl)-4,9-hydroxy-2,5,5-trimethyl-3,4,5,6,12,13-
hexahydro-2H-diazocino[2,1-a][2,6]naphthyridine-1,8,10(11H)-trione EtOH Solvate (5a). To a
solution of 1.0 g (1.62 mol) of trispivalate 26 in 7 ml of THF was added 0.41 g (1.62 mmol) of a 92 wt%
solutoin of aminoalcohol 7 in 1 ml of THF. After stirring for 15 min at room temperature, the mixture
was cooled to 5 °C and 2 mL of MeOH was added followed by the addition of 0.52 mL (9.72 mmol) of
a 50 wt% solution of aqueous NaOH while keeping the internal temperature < 15 °C. The clear solution
is stirred for 1 h and 5 mL of a 2N solution of HCl was added slowly while keeping the internal
temperature < 15 °C to give a pH of 6ꢀ6.5. The mixture was extracted with 5 mL of toluene and the
organic layer was washed with 10 mL of a 15% wt solution of brine. The organic layer is azeotropically
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dried with a constant feed of toluene and the final volume adjusted to ~ 6 mL to give amide 21 that was
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used in the next step without further purification.
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To the solution of 1.0 g (1.72 mmol) of amide 21 in 6 mL of toluene was added 12 ml of THF and
the solution was cooled to 5 °C. To the solution was added 1.16 g (10.32 mmol) of solid potassium tertꢀ
butoxide in one portion. The resulting mixture was stirred at 10ꢀ15 °C for 1 h and 0,73 g (3.27 mmol)
of 1ꢀ(pꢀtoluenesulfonyl)imidazole was added in one portion. The resulting mixture was stirred at the
same temperature for 1 h, and cooled to < 10 °C and quenched with 6 mL of a 2N solution of HCl to
give a pH of 6ꢀ6.5. The layers were separated and the organic layer washed with 10 ml of water. The
solution was azeotropically dried with a constant feed of toluene till the KF was < 500 ꢀg/g of water and
then solvent switched to DMSO and a final volume of 4 mL of 27 which was used in the next reaction
without further purification.
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To a solution of 0.61 mL (4.08 mmol) of DBU (0.61 ml, 4.08 mmol) in 6 mL of at 95 °C was slowly
added a solution 1.00 g (by assay, 1.36 mmol) of the monotosylate 27 in 4 ml of DMSO and the mixture
was stirred at 95 °C for additional 6 hours. The mixture was cooled to 15 °C and diluted with 10 ml of
EtOAc and 6 mL of 0.4 N aqueous HCl (0.4 N, ~6 ml) was added to give a final pH = 6.5ꢀ7.0. The
layers were separated and the aqueous layer back extracted with 8 mL of EtOAc. The combined organic
extracts were washed with 10 mL of water (2X), treated with 0.27 g of DarcoꢀG60 at room temperature
for 1 h, and filtered through a pad of cellulose. The filtrated was concentrated under reduced pressure
and solvent switched to EtOH by the constant addition of EtOH during the concentration. The final
volume was 5 mL of 24 which contained 0.54 g (70%) which was used in the next step without further
purification.
To a solution of the 1.0 g (1.78 mmol) of intermediate 24 in 10 mL of EtOH was added 0.18 mL
(0.89 mmol) of a 5N solution of HCl in isopropanol. The mixture was stirred at 40 °C for two hours.
During the course of the reaction, the EtOH solvate of 5a crystallized. The resulting slurry was cooled to
room temperature and stirred for 3 h. The slurry was filtered and washed with 5 mL of EtOH, dried in a
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vacuum oven at 40 ºC for 12 hours to afford 0.75 g (80%) of 5a as a colorless solid and a single
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atropisomer that was identical to that prepared in the first generation synthesis.
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Acknowledgements: The Authors wish to thank Lisa DiMicheal, Robert Reamer, Alexei Buevich, and
Peter G. Dormer of Merck & Co., Inc. for valuable NMR assistance and Dr. Edward Sherer for
computational asistance. The Authors also which to thank former Merck & Co., Inc. employees Danny
Mancheno, Dr. Remy Angelaud, Dr. Philip Pye for experimental assistance.
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Supporting Information Available: Spectrocopic data for compounds 5, 5a, 6, 7, 15, 17, and 25. This
material is available free of charge via the Internet at http://pubs.acs.org.
1
ISHC Member.
2
For a leading reference, see: Seeney, Z. K.; Klumpp, K. Curr. Opin. Drug Discovery Dev. 2008, 11,
458ꢀ470.
3
For a leading rreferene, see: von Hentig, N. Drugs Today 2008, 44, 103ꢀ132.
4
For a review, see: HIV Chemother. 2005, 1.
5
For a leading reference, see: Pace, P.; Rowley, M. Curr. Opin. Drug Discovery Dev. 2008, 11, 471ꢀ
479.
6
(a) Cabrera, C. Curr. Opin. Invest. Drugs 2008, 31, 310. (b) Rowley, M. Prog. Med. Chem. 2008, 46,
1ꢀ28. (c) Evering, T. H.; Markowitz, M. Drugs Today 2007, 43, 865ꢀ877. (d) Dayam, R. G. R.; Alꢀ
Mawsawi, L. Q.; Neamati, N, Med. Res. Rev. 2008, 28, 118ꢀ154.
7
Karmon, S. L.; Markowitz, M. Drugs, 2013, 73, 213ꢀ228.
8
Klibanov, O. M.Curr. Opin. Investig. Drugs. 2009, 10, 190ꢀ200. (b) Reviriego, C. Drugs Today
2014, 50, 209ꢀ217.
9
Katlama, C.; Murphy, R. Expert Opin. Invest. Drugs 2012, 21,523ꢀ530.
10
Métiflot, M.; Johnson, B.; Smith, S.; Zhao, X. Z.; Marchand, C.; Burke, T.; Hughes, S.; Pommier,
Y. Antimicrob. Agents Chemother. 2011, 55, 5127ꢀ5133.
11
Egbertoson, M. S.; Wai, J. S.; Cameron, M.; Hoerrner, R. S. In Antiviral Drugs: From Basic
Discovery through Clinical Trials; Kazmierski, W. M., Ed.; John Wiley & Sons, Inc.: New York, 2011;
pp 163ꢀ180.
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1
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12
Vacca, J. P.; Wai, J. S.; Payne, L. S.; Isaacs, R. C. A.; Han, W.; Egbertson, M.; Pracitto, R. PCT Int.
Appl. 2006, WO2006121831 A2 20061116.
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4
5
6
7
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13
For an initial disclosure for the synthesis of compound 6 which doesn’t discribe synthetic details, see:
Raheem, I. T.; Walji, A. M.; Klein, D.; Sanders, J. M.; Powell, D. A.; Abeywickrema, P.; Barbe, G.;
Bennet, A.; Childers, K.; Christensen, M.; Clas, S.ꢀD.; Dubost, D.; Embrey, M.; Grobler, J.; Hafey, M.
J.; Hartingh, T. J.; Hazuda, D. J.; Kuethe, J. T.; Dunn, J. M.; Miller, M. D.; Moore, K. P.; Nolting, A.;
Pajkovic, N.; Patel, S.; Peng, Z.; Rada, V.; Rearded, P.; Schreier, J. D.; Sisko, J.; Steele, T. G.; Truchon,
J.ꢀF.; Wai, J.; Xu, M.; Colemen, P. J. J. Med. Chem. 2015, 58, 8154ꢀ8165.
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HPLC assay yield referes toquantitative HPLC analysis employing an anlytical standard.
15
Byꢀproduct 20 was not isolated, but was identified by NMR analysis of the crude reaction mixture.
16 Intermediates leading to compound 24 were not crystalline making their isolation problematic.
17 Selective deꢀmesylation was confirmed by NMR analysis of the crude reaction mixture.
18
For the synthesis of this precursor see reference 12.
19
Aryl sulfonate esters are readily cleaved under basic conditions, for some leading references, see:
Wuts, P. G. M. Greene’s Protective Groups in Organic Chemistry, 5th ed.; John Wiley & Sons, Inc.:
Hoboken, New Jersey, 2014; pp 541ꢀ545.
20
For a leading reference, see: Ahmed, A.; Bragg, R. A.; Clayden, J.; Lai, L. W.; McCarthy, C.; Pink,
J. H.; Westlund, N.; Yasin, S. A. Tetrahedron, 1998, 54, 13277ꢀ13294.
21
For leading examples, see: (a) Barrett, K. T.; Miller, S. J. J. Am. Chem. Soc. 2013, 135, 2963ꢀ2966.
(b) Tabata, H.; Wada, N.; Takada, Y.; Oshitari, T.; Takahashi, H.; Natsugari, H. J. Org. Chem. 2011,
76, 5123ꢀ5131. (c) Tabata, H.; Suzuki, H.; Akiba, K.; Takahashi, H.; Natsugari, J. Org. Chem. 2010,
75, 5984ꢀ5993. (d) Clayden, J.; Johnson, P.; Pink, J. H.; Helliwell, M. J. Org. Chem. 2000, 65, 7033ꢀ
7040.
22
For refereneces on amide atropisomers in manufactured pharmaceuticals, see: (a) Parker, J. S.;
Smith, N. A.; Welham, M. J.; Moss, W. O. Org. Process Res. And Dev. 2004, 8, 45ꢀ50. (b) Friary, R.
J.; Spangler, M.; Osterman, R.; Schulman, L.; Schwerdt, J. H. Chirality 1996, 8, 364ꢀ (c) Chenard, B.
L.; Devries, K. M.; Welch, W. M. WO09838187, 1998.
23 For an account of atroisomers within a strucurally related naphthyridine, see: Natsugari, H.; Ikeura,
Y.; Kamo, I.; Ishimaura, T.; Ishichi, Y.; Fujishima, A.; Tanaka, T.; Kasahara, F.; Kawada, M.; Doi, T. J.
Med. Chem. 1999, 42, 3982ꢀ3993.
24
The stereochemical assignment was based on similar assigmments in reference 19 where the letter a
before R and S denotes axial chirality, see: Chan, R. S.; Ingold, C.; Prelog, V. Angew. Chem., Int. Ed.
Engl. 1966, 5, 385ꢀ415.
25 The 3ꢀD representations in Scheme 10 were calculated using the program PyMOL.
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