Practical Synthetic Method for the Preparation of Pyrone Diesters: An Efficient Synthetic Route for the Synthesis of Dolutegravir Sodium

Article abstract of DOI:10.1021/acs.oprd.8b00410

A highly efficient and practical synthetic method for the preparation of pyrone diesters was established. The pyrone diester 3c can be prepared from readily available starting materials on a multihundred gram scale. The pyrone diester 3c can easily be converted to dolutegravir sodium (1). The synthetic route demonstrated herein provides an efficient and atom-economical synthetic method for preparing this potent anti-HIV agent.

Full text of DOI:10.1021/acs.oprd.8b00410

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Practical Synthetic Method for the Preparation of Pyrone Diesters:
An Efficient Synthetic Route for the Synthesis of Dolutegravir
Sodium
Tatsuro Yasukata,*,† Moriyasu Masui,§ Fumiya Ikarashi,† Kazuya Okamoto,† Takanori Kurita,‡
Masahiko Nagai,§ Yoshihide Sugata,§ Naoki Miyake,‡ Shinichiro Hara,§ You Adachi,§
and Yukihito Sumino†
†API R&D Laboratory, CMC R&D Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813,
Japan
‡Production Technology Department, Manufacturing Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-chome, Amagasaki,
Hyogo 660-0813, Japan
§Shionogi Pharmaceutical Research Center, Shionogi and Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan
S
* Supporting Information
ABSTRACT: A highly efficient and practical synthetic method for the preparation of pyrone diesters was established. The
pyrone diester 3c can be prepared from readily available starting materials on a multihundred gram scale. The pyrone diester 3c
can easily be converted to dolutegravir sodium (1). The synthetic route demonstrated herein provides an efficient and atom-
economical synthetic method for preparing this potent anti-HIV agent.
KEYWORDS: dolutegravir sodium, pyrone diester, hydroquinone cocrystal, intramolecular aminolysis
synthetic method of pyrone intermediates which can offer an
efficient synthetic route to dolutegravir sodium.
INTRODUCTION
■
Dolutegravir sodium, an inhibitor of HIV integrase, is a
promising drug for the treatment of HIV infection and is being
used worldwide (see Figure 1). Dolutegravir has a highly
RESULTS AND DISCUSSION
■
A preparation method for an appropriately functionalized
pyrone intermediate in short synthetic steps is desired. The
previously developed synthetic method starting from maltol
includes oxidative conversion of the methyl moiety of maltol
into carboxylate, resulting in more synthetic steps and is less
atom-economical (Scheme 1).1 One promising intermediate is
pyrone diester 3, which can be readily prepared from enamine
4 and oxalate 5 without any oxidation steps.5 Furthermore, one
of the ester moieties of pyrone 3 can easily be converted into
amide, leading to a more efficient synthetic method for the
preparation of 1 (Scheme 2).
Figure 1. Dolutegravir sodium (1).
functionalized pyridone substructure, and the construction of
its core structure has been a key issue in the development of a
method to synthesize it. As pyridones can be readily prepared
from corresponding pyrones, many synthetic methods for
preparing dolutegravir via a pyrone intermediate have been
explored and reported thus far.1
A medicinal chemistry-based synthetic route to dolutegravir
employing maltol, which has a pyrone moiety, was applied to
preparative scale manufacturing as reported in the preceding
paper.1d−f However, the methods used require relatively long
synthetic steps and also include a cryogenic reaction.
Therefore, there has been a search for more efficient synthetic
methods not using maltol.2,3 We have already reported
synthetic routes for preparing dolutegravir via a highly
functionalized pyrone intermediate without using maltol, but
no practical synthetic method for pyrone intermediates has yet
been reported.4 In this paper, we disclose a preparative scale
Treatment of enamine 4a and diethyl oxalate (5a) furnished
the corresponding pyrone 3a (Table 1). In the case of THF
solvent, a considerable amount of phenolic byproduct 6 was
found to be formed (entries 1−3). This byproduct was
speculated to be formed by dimerization of enamine 4a under
the basic condition (Scheme 3). To suppress the side reaction
between enamine 4a and its enolate, the reaction conditions
were extensively explored.
We first examined the solvent for acceleration of the enolate
formation and found aprotic polar solvents with more
dissolving ability to be effective for suppressing byproduct 6
Special Issue: Japanese Society for Process Chemistry
Received: November 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00410
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Scheme 1. Synthetic Route to Dolutegravir Sodium (1) Starting from Maltol
Scheme 2. Retrosynthetic Pathway for Dolutegravir Sodium (1) through a Pyrone Diester Intermediate 3
condensation of the anion of DMA with diethyl oxalate. This
byproduct formation could be suppressed by adopting 1,3-
dimethyl-2-imidazolidinone (DMI) with no acidic protons as a
solvent. Therefore, DMI was considered to be the better
solvent.
Table 1. Optimization of Pyrone Formation
We next explored the addition method and the bases used.
Addition of the enamine and oxalate into the solution of NaOt-
Bu in DMI improved the yield of 3a (entry 6). This indicates
that an enolate generated from 4a should be allowed to
immediately react with an oxalate. Using THF with the same
addition method decreased the yield of 3a along with an
increase of byproduct 6, indicating that use of an aprotic polar
solvent is beneficial for pyrone formation (entry 7).
Preparation of pyrone 3 was further examined using NaOt-
Bu and dimethyl oxalate (5b) in DMI (Table 2). Increasing
the amount of 5b to 3 equiv drastically improved the yield of
the desired pyrone 3b, whereas the amount of NaOt-Bu did
not affect the yield of 3b (entries 2 and 3). The drastic
improvement of the yield of 3b by increasing the amount of
oxalate 5b from 2 equiv to 3 equiv would be attributed to the
suppression of the competitive side reaction of the enamine
a
entry
base
NaH
NaOt-Bu
KOt-Bu
NaH
NaH
NaOt-Bu
NaOt-Bu
solvent
yield of 3a (%)
yield of 6 (%)
b
1
THF
THF
THF
DMA
DMI
DMI
THF
19
12
trace
30
26
(34)
(7)
b
2
b
3
(55)
(10)
4 (2)
8 (6)
14
b
4
b
5
c
6
35
26
c
7
a
b
Values in parentheses are LC−MS peak area %. 5a was added to the
mixture of 4a and base. Mixture of 4a and 5a was added to the base.
c
(Table 1, entries 4 and 5). When N,N-dimethylacetamide
(DMA) was used as a solvent, another byproduct (ethyl 4-
(dimethylamino)-2,4-dioxobutanoate) was formed due to
Scheme 3. Speculated Mechanism for the Formation of Byproduct 6
B
DOI: 10.1021/acs.oprd.8b00410
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Organic Process Research & Development
Article
98.5:1.5) by treating the workup solution with hydroquinone.
The diastereoselectivity of the tricyclic scaffold formation
would be due to the difference of reaction rates of the
intramolecular aminolysis between the intermediary diastereo-
meric aminals 12 and 13 in the same manner as reported
previously,7 that is, 12 with a methyl moiety at the axial
position is sterically more favored than 13 due to its lesser
steric hindrance (Figure 2).
Table 2. Pyrone Formation Using Dimethyl Oxalate (5b)
and NaOt-Bu
Amidation of the ester moiety of 10·1/2hydroquinone was
accomplished by direct aminolysis by 2,4-difluorobenzylamine
to afford amide intermediate 11.2b,c Acetic acid was essential
for successful completion of the aminolysis. Hydroquinone was
removed by the workup procedure, and no hydroquinone was
entry
R
NaOt-Bu (equiv) 5b (equiv) product yield of 3 (%)
1
2
3
Et
Et
Et
Et
Et
Me
2.0
3.0
1.5
1.5
3.0
1.5
2.0
3.0
3.0
3.0
3.0
3.0
3b
3b
3b
3b
3b
3c
39
86
85
86
57
85
a
4
1
b
detected in 11 by H NMR analysis. Dolutegravir sodium (1)
5
6
was obtained by removal of the benzyl protecting group of 11
followed by sodium salt formation according to the reported
procedure.1d,e Taking into consideration the quality of API, the
free form of 1 was isolated as an intermediate to remove
solvents and catalyst used in debenzylation step before sodium
salt formation.
The synthetic route for the preparation of 1 developed
herein has advantages that it has short synthetic steps (9 steps)
and only requires an inexpensive and readily available starting
material and base (β-ketoester 7 and NaOMe).
a
b
Carried out in 100 mmol scale. Sodium tert-pentoxide was used as a
base.
including its dimerization as shown in Scheme 3. Additionally,
1.5 equiv of base was found to be sufficient for enolate
formation of enamine 4. The high yield of 3b was also be
reproduced in the preparative scale synthesis (entry 4).
Employing more sterically bulky base, sodium tert-pentoxide,
resulted in a decrease of the yield of 3b (entry 5). By using
methyl ester substrate 4b, pyrone 3c with dimethyl ester
moiety was also obtained in high yield (entry 6).
CONCLUSION
■
For preparation of pyrone dimethyl ester 3c, NaOMe, a less
expensive base than NaOt-Bu, can be used because there is no
possibility of transesterification occurring. Using NaOMe as a
base allows preparative scale synthesis of 3c, with multi-
hundred grams of 3c being obtained starting from the
inexpensive and readily available β-ketoester 7 (Scheme 4).
Sodium tert-pentoxide was used as a base for the preparation
of 8 from 7, since using sodium tert-butoxide gave considerable
amount (∼10%) of tert-butyl ether as a byproduct. Addition-
ally, enamine 4b can also be prepared from 8 using N,N-
dimethylformamide dimethyl acetal as reported previously.2b,c,6
The resulting pyrone dimethyl ester 3c can be easily
transformed into dolutegravir sodium (1) in short synthetic
steps (Scheme 5). Pyrone 3c was converted to pyridone 9 by
using aminoacetaldehyde dimethyl acetal. The reaction
proceeded smoothly and 9 can be isolated from the reaction
mixture by crystallization. The resulting pyridone 9 was then
transformed into a tricyclic intermediate 10 by acid-catalyzed
hydrolysis of acetal and the subsequent reaction with 3-(R)-
aminobutan-1-ol. The resulting tricyclic intermediate 10 did
not crystallize but could be isolated as hydroquinone cocrystal
10·1/2hydroquinone with high diastereoselectivity (dr
We successfully developed an efficient synthetic route for
preparing dolutegravir sodium through a pyrone diester
intermediate 3c. A large-scale synthetic method of dimethyl
3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (3c) was
demonstrated starting from the inexpensive and readily
available starting material methyl 4-chloro-3-oxobutanoate
(7) using NaOMe as a base. The synthetic route from 3c to
1 was also established via the intermediate of the cocrystal of
10 and hydroquinone.
The synthetic route demonstrated herein has the advantage
of efficiency as it has short synthetic steps (9 synthetic steps)
along with its each crystalline intermediate. Furthermore, this
synthetic route does not include any oxidation or cryogenic
reaction, which are often troublesome for scale-up. Also, this
route offers a highly atom-efficient property as the waste from
the process consists of only low molecular weight compounds
(water, methanol, dimethylamine, and toluene). Compare to
the synthetic route starting from maltol (Scheme 1) that
contains oxidative cleavage of styrene and glycol, bromination
for amidation, and use of heavy metal reagents, this synthetic
route is atom-efficient and would be a manufacturing method
with more atom-economical property.
Scheme 4. Synthesis of Pyrone Dimethyl Ester 3c Using NaOMe
a
NaOt-Pent: sodium tert-pentoxide
C
DOI: 10.1021/acs.oprd.8b00410
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Organic Process Research & Development
Article
Scheme 5. Synthetic Route to Dolutegravir Sodium (1) from Pyrone Diester Intermediate 3c
a
d
g
b
c
Aminoacetaldehyde dimethyl acetal, MeOH, reflux (83%). HCO2H−H2SO4 aq, r.t. 3-(R)-aminobutan-1-ol, AcOH, toluene/MeOH, 100 °C.
e
f
Hydroquinone, AcOEt (66%, dr 98.5:1.5, 3 steps). 2,4-Difluorobenzylamine, AcOH, toluene, 100 °C (62%). Pd−C, H2, THF/MeOH (92%).
NaOH aq, EtOH (99%).
solution of citric acid monohydrate (307 g) in water (1900
mL) was added to the reaction mixture and extracted with
ethyl acetate (1600 mL). The organic layer was washed
successively with aqueous solution of 5% sodium hydrogen
carbonate (1400 mL) and saturated aqueous sodium chloride
solution (1400 mL). The organic layer was concentrated under
reduced pressure to give 8 (386.06 g) as a yellow oil. This
crude material was used for next step without further
purification.
Figure 2. Intermediary aminals for intramolecular aminolysis.
Dimethylformamide (182 mL, 2.34 mol) was added to
dimethyl sulfate (210 mL, 2.19 mol) and stirred at 80 °C for 4
h. The resultant solution was cooled to give the methox-
ydimethylmethanaminium methyl sulfate8 (443.4 g) as a
yellow oil. To this was added 1,3-dimethyl-2-imidazolidinone
(10 mL) and cooled to the ice bath temperature. The crude oil
of 8 (386.06 g) was added and the resultant yellow solution
was stirred at ice bath temperature for 4 h. Triethylamine (345
mL, 2.49 mol) was added and stirred at room temperature for
an additional 1.5 h. Cold water (975 g) and 20% aqueous
sodium chloride solution was added and extracted with ethyl
acetate (1950 mL). The organic layer was washed successively
with 2% sodium chloride aq (1300 mL) and 0.4% sodium
chloride aq (1500 mL). The aqueous layer was extracted with
ethyl acetate, and the combined organic layer was dried over
anhydrous magnesium sulfate, concentrated to give 4b (438.1
g) as a brown oil. This crude material was used for next step
without further purification.
To 1,3-dimethyl-2-imidazolidinone (1000 mL) was added
28% methanolic solution of sodium methoxide (438 mL, 2.16
mol) and cooled to the ice bath temperature. To the solution
was added dimethyl oxalate (509 g, 4.31 mol) portionwise and
stirred at room temperature for 30 min. To this was added
crude oil of 4b (430.7 g) and stirred at room temperature for
2.5 h. Methanolic solution of sodium methoxide (29 mL, 0.14
mol) was added and stirred for an additional 1.5 h. The
reaction mixture was added to the mixture of ethyl acetate
(1600 mL), 2 M aqueous hydrochloric acid (2000 mL), and
cold water (798 g) and extracted. The organic layer was
washed with 5% aqueous sodium hydrogen carbonate (2000
mL) and 2% aqueous sodium chloride (2000 mL). The
aqueous layer was extracted with ethyl acetate (2000 mL), and
the combined organic layer was dried over magnesium sulfate
and concentrated. To the resultant brown oil was added
diisopropyl ether (600 mL) and n-hexane (400 mL) with
stirring, and the precipitated solid was collected by filtration,
EXPERIMENTAL SECTION
General. All materials were purchased from commercial
suppliers. Unless otherwise specified, all reagents and solvents
■
1
were used without further purification. H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded in the
solvent indicated on a Bruker AVANCE III HD 400
spectrometer, and mass spectra were determined on a
Shimadzu LCMS-2010EV spectrometer.
5-Ethyl 2-methyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicar-
boxylate (3b). To a suspension of dimethyl oxalate (354.3 mg,
3.0 mmol) and sodium tert-butoxide (144.2 mg, 1.5 mmol) in
1,3-dimethyl-2-imidazolidinone (1.4 mL) was added to a
solution of 4a (291.3 mg, 1.0 mmol) in 1,3-dimethyl-2-
imidazolidinone at 0 °C, and the whole was stirred at room
temperature for 2 h. After completion of the reaction, 2 M
hydrochloric acid aq (10 mL) was added, and the mixture was
stirred for 0.5 h. The resulting precipitate was collected,
washed with water, and dried under reduced pressure to give
1
3b (283.9 mg, 85%) as a white solid. H NMR (400 MHz,
CDCl3) δ 8.48 (s, 1H), 7.50−7.45 (m, 2H), 7.41−7.30 (m,
3H), 5.34 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.39
(t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.5,
162.2, 159.8, 159.8, 150.2, 145.2, 136.0, 129.0, 128.6, 128.5,
120.8, 75.1, 61.8, 53.2, 14.2.
Dimethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxy-
late (3c). To a suspension of sodium tert-pentoxide (424 g,
3.66 mol) in tetrahydrofuran (790 mL) was added a solution
of benzyl alcohol (152 mL, 1.46 mol) in tetrahydrofuran (474
mL) at 15 °C, and the whole was stirred at 40 °C for 2 h, then
cooled with an ice bath. A solution of methyl 4-chloro-3-
oxobutanoate (7) (189 mL, 1.61 mol) in tetrahydrofuran (474
mL) was added at the ice bath temperature, and the reaction
mixture was stirred at 40 °C for 2 h. A solution of 7 (17.2 mL,
0.146 mol) in tetrahydrofuran (10 mL) was added and stirred
for an additional 40 min. After cooling to room temperature, a
D
DOI: 10.1021/acs.oprd.8b00410
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washed with diisopropyl ether (200 mL × 3), and dried to give
3c (314.82 g) as a pale yellow solid. Additional 3c (7.55 g) was
obtained from the concentrated mother liquor by column
chromatography (silica gel, chloroform/ethyl acetate = 99:1).
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.49−7.45 (m,
2H), 7.40−7.30 (m, 3H), 5.34 (s, 2H), 3.93 (s, 3H), 3.89 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 172.4, 162.9, 160.2,
159.7, 150.2, 145.2, 135.9, 129.0, 128.6, 128.5, 120.6, 75.1,
53.2, 52.7.
(20 mL) was added 2,4-difluorobenzylamine (505 mg, 3.53
mmol) and acetic acid (212 mg, 3.53 mmol), and the whole
solution was stirred at 100 °C for 5 h. Water (8 mL) was
added, and the organic layer was separated and washed with
4% aqueous sodium hydroxide (4 mL × 3) and water (4 mL ×
1). The organic layer was concentrated, ethanol was added,
and the solution was cooled to the ice bath temperature. The
precipitate was collected, washed with cold ethanol, and dried
under reduced pressure to give 11 (561 mg, 62%) as a yellow
1
solid. H NMR (400 MHz, CDCl3) δ 10.39 (t, J = 6.0 Hz,
Dimethyl 3-(benzyloxy)-1-(2,2-dimethoxyethyl)-4-oxo-
1,4-dihydropyridine-2,5 -dicarboxylate (9). To a solution of
3c (19.56 g, 61.5 mmol) in methanol (117 mL) was added a
solution of aminoacetaldehyde dimethyl acetal (7.11 g, 67.6
mmol) in methanol (20 mL) at room temperature and stirred
under reflux for 6 h. After completion of the reaction, the
reaction mixture was concentrated and water was added to the
concentrate with stirring. The precipitated solid was collected
and dried under reduced pressure to give 9 (18.10 g, 73%).
Mother liquor was concentrated and extracted with ethyl
acetate. The extract was concentrated and cooled to the ice
bath temperature. The precipitate was collected and dried
under reduced pressure to give 9 (2.51 g, 10%). 1H NMR (400
MHz, CDCl3) δ 8.14 (s, 1H), 7.44−7.41 (m, 2H), 7.36−7.30
(m, 3H), 5.29 (s, 2H), 4.47 (t, J = 4.9 Hz, 1H), 3.93 (s, 3H),
3.91 (d, J = 4.9 Hz, 2H), 3.80 (s, 3H), 3.38 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 171.2, 165.6, 162.3, 149.4, 146.2, 137.0,
134.0, 128.8, 128.3, 128.2, 118.3, 102.9, 74.2, 56.9, 55.8, 53.1,
52.4. MS m/z 406 [M + H]+.
Methyl (4R,12aS)-7-(benzyloxy)-4-methyl-6,8-dioxo-
3,4,6,8,12,12a-hexahydro- 2H-pyrido[1′,2’:4,5]pyrazino[2,1-
b][1,3]oxazine-9-carboxylate (10) hemi hydroquinone coc-
rystal. To a solution of 9 (2.0 g, 4.93 mmol) in 98% formic
acid (18 mL) was added 62% aqueous sulfuric acid (1.80 mL)
and stirred at 5 °C for 2.5 h. Saturated aqueous solution of
sodium hydrogen carbonate was added at 5 °C and extracted
with dichloromethane. The extract was concentrated and the
concentrate was dissolved in toluene (16 mL). To this was
added methanol (0.6 mL, 14.8 mmol), 3-(R)-aminobutan-1-ol
(484 mg, 5.43 mmol), and acetic acid (326 mg, 5.43 mmol)
successively and stirred at 100 °C for 2.5 h. The reaction
mixture was cooled to room temperature and extracted with
ethyl acetate. The extract was washed with water and
concentrated to give yellow oil (2.37 g). The resultant oil
was dissolved in ethyl acetate (14 mL), hydroquinone (272
mg, 2.47 mmol) added, then cooled to 5 °C, and allowed to
stand for 1.5 h. The precipitate was collected, washed with
ethyl acetate (10 mL), and dried under reduced pressure to
give 10·1/2hydroquinone (1.46 g, 66%) as a yellow crystalline
solid. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.66−7.63
(m, 2H), 7.35−7.25 (m, 3H), 6.71 (s, 2H), 5.35 (brs, 1H),
5.34 (d, J = 10.2 Hz, 1H), 5.27 (d, J = 10.2 Hz, 1H), 5.12 (dd,
J = 6.0, 3.7 Hz, 1H), 5.00−4.93 (m, 1H), 4.14 (dd, J = 13.5,
3.7 Hz, 1H), 3.99 (dd, J = 13.5, 6.0 Hz, 1H), 3.92 (dd, J = 8.8,
2.4 Hz, 2H), 3.90 (s, 3H), 2.18−2.08 (m, 1H), 1.47 (ddd, J =
14.0, 4.7, 2.4 Hz, 1H), 1.30 (d, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 172.35, 165.48, 155.71, 154.44, 149.68,
143.68, 136.98, 129.30, 128.77, 128.21, 128.06, 117.46, 116.19,
76.04, 74.13, 62.52, 53.47, 52.42, 44.48, 29.42, 16.02. MS m/z
399 [M + H]+. mp 159 °C.
1H), 8.35 (s, 1H), 7.62−7.59 (m, 2H), 7.39−7.27 (m, 4H),
6.85−6.77 (m, 2H), 5.30 (d, J = 10.2 Hz, 1H), 5.26 (d, J =
10.2 Hz, 1H), 5.14 (dd, J = 5.9, 3.8 Hz, 1H), 5.03−4.95 (m,
1H), 4.63 (d, J = 6.0 Hz, 2H), 4.22 (dd, J = 13.5, 3.8 Hz, 1H),
4.08 (dd, J = 13.5, 5.9 Hz, 1H), 3.95−3.92 (m, 2H), 2.19−2.10
(m, 1H), 1.50 (ddd, J = 13.9, 4.6, 2.3 Hz, 1H), 1.32 (d, J = 7.1
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.6, 164.1, 162.8
(dd, JC−F = 147.8, 12.1 Hz), 160.3 (dd, JC−F = 148.9, 11.7 Hz),
155.6, 153.3, 142.2, 136.8, 130.6 (dd, JC−F = 9.9, 5.5 Hz),
129.5, 129.0, 128.3, 128.1, 121.6 (dd, JC−F = 14.7, 3.7 Hz),
118.8, 111.2 (dd, JC−F = 21.3, 3.7 Hz), 103.8 (dd, JC−F = 25.3
Hz), 76.1, 74.4, 62.5, 53.5, 44.6, 36.5 (d, JC−F = 3.7 Hz), 29.4,
16.0. MS m/z 510 [M + H]+.
Dolutegravir Sodium (1). Under hydrogen atmosphere, a
mixture of 11 (28.0 g, 55.0 mmol) and 10% Pd−C (5.6 g) in
THF (252 mL) and MeOH (28 mL) was stirred for 1 h. After
the precipitate (Pd−C) was filtered and washed with THF (45
mL), 10% Pd−C (5.6 g) was added and the mixture was stirred
for 1.5 h under a hydrogen atmosphere. After the Pd−C was
filtered and washed with CHCl3/MeOH (9/1, 150 mL), the
filtrate was concentrated. After dissolution of the residue in
EtOH (1.38 L) by heating, the solution was gradually cooled
to room temperature. After filtration, the filtrate was
concentrated and cooled. Filtration, washing with EtOH, and
drying provided debenzylated product (21.2 g, 92%) as a
crystal.
After dissolving of the debenzylated product (18.0 g) in
EtOH (54 mL) by heating, followed by filtration, 2 N NaOH
aq (21.5 mL) was added to the solution at 80 °C. The solution
was gradually cooled to room temperature. Filtration, washing
with EtOH (80 mL), and drying provided 1 (18.8 g, 99%) as a
crystal. 1H NMR (400 MHz, DMSO-d6) δ 10.70 (t, J = 6.0 Hz,
1H), 7.89 (s, 1H), 7.40−7.30 (m, 1H), 7.25−7.16 (m, 1H),
7.06−6.98 (m, 1H), 5.22−5.12 (m, 1H), 4.87−4.74 (m, 1H),
4.51 (d, J = 5.4 Hz, 2H), 4.35−4.25 (m, 1H), 4.16 (dd, J = 1.8,
14.1 Hz, 1H), 4.05−3.90 (m, 1H), 3.86−3.74 (m, 1H), 2.00−
1.72 (m, 1H), 1.44−1.32 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00410.
■
S
1H NMR spectrum for compound 3c; 1H, 13C NMR and
MS spectra for compound 9, 10·1/2hydroquinone, and
11; LC−MS chromatogram and a powder X-ray
diffraction spectrum for 10·1/2hydroquinone (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: tatsuro.yasukata@shionogi.co.jp.
■
(4R,12aS)-7-(Benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-
6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2’:4,5]-
pyrazino[2,1-b][1,3]oxazine-9-carboxamide (11). To a sol-
ution of 10·1/2hydroquinone (800 mg, 1.76 mmol) in toluene
ORCID
Tatsuro Yasukata: 0000-0002-9625-0957
E
DOI: 10.1021/acs.oprd.8b00410
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Nyerges, M. Synthesis and Reactions of Reduced Flavones. J. Chem.
Soc., Perkin Trans. 1 1997, 163−169.
Notes
The authors declare no competing financial interest.
(6) We prepared methoxydimethylmethanaminium methyl sulfate
from N,N-dimethylformamide and dimethyl sulfate in consideration
of manufacturing cost.
ACKNOWLEDGMENTS
■
The authors are grateful to Dr. Daiki Nagamatsu (Shionogi
Pharmaceutical Research Center) for analytical support of
taking the powder X-ray diffraction spectra. The authors also
thank Drs. Shozo Takechi and Norihiko Tanimoto (API R&D
Laboratory) for their encouraging and helpful discussions.
(7) Johns, B. A.; Kawasuji, T.; Weatherhead, J. G.; Taishi, T.;
Temelkoff, D. P.; Yoshida, H.; Akiyama, T.; Taoda, Y.; Murai, H.;
Kiyama, R.; Fuji, M.; Tanimoto, N.; Jeffrey, J.; Foster, S. A.;
Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Johnson, M. N.;
Garvey, E. P.; Fujiwara, T. Carbamoyl Pyridone HIV-1 Integrase
Inhibitors. 3. A Diastereomeric Approach to Chiral Nonracemic
Tricyclic Ring Systems and the Discovery of Dolutegravir (S/
GSK1349572) and (S/GSK1265744). J. Med. Chem. 2013, 56, 5901−
5916.
(8) Jarrahpour, A.; Zarei, M. Efficient one-pot synthesis of 2-
azetidinones from acetic acid derivatives and imines using methoxy-
methylene-N,N-dimethyliminium salt. Tetrahedron 2010, 66, 5017−
5023.
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DOI: 10.1021/acs.oprd.8b00410
Org. Process Res. Dev. XXXX, XXX, XXX−XXX