An Improved Synthesis of Elvitegravir

Article abstract of DOI:10.1002/jhet.2477

An improved process for the active pharmaceutical ingredient of a new HIV integrase inhibitor elvitegravir (1) has been developed. It starts from commercially available 2,4-dimethoxyacetophenone, which is selectively halogenated into the position 5. The 5-halo acetophenones are condensed with dialkyl carbonates to give the corresponding benzoylacetates. Their treatment with N,N-dimethylformamide dimethyl acetal followed by (S)-valinol then provided the corresponding intermediate benzoyl acrylates. Cyclization to the required 1,4-dihydroquinolin-4-oxo derivatives by aromatic nucleophilic substitution of the 2-methoxy group was achieved by treatment with N,O-bis(trimethylsilyl)-acetamide, which also protected the OH group as the trimethylsilyl derivative. Finally, the Negishi coupling with 2-fluoro-3-chlorobenzylzinc bromide and the following hydrolysis provided elvitegravir (1). The preferred variant, the seven-step procedure starting from 2,4-dimethoxyacetophenone, provides elvitegravir in 29.3% yield.

Full text of DOI:10.1002/jhet.2477

Month 2015
An Improved Synthesis of Elvitegravir
Stanislav Rádl,a,b Jan Stach, Ondřej Píša, Josef Cinibulk, Jaroslav Havlíček, Markéta Zajícová, and Tomáš Pekárek
a
b
a
a
a
a
*
aZentiva—A Sanofi Company, U kabelovny 130, 102 01 Prague 10, Czech Republic
bUniversity of Chemistry and Technology, Technická 5, 166 28 Prague 6, Czech Republic
*
E-mail: stanislav.radl@zentiva.cz
Received August 22, 2014
DOI 10.1002/jhet.2477
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
Dedicated to the memory of Prof. Alan R. Katritzky.
An improved process for the active pharmaceutical ingredient of a new HIV integrase inhibitor elvitegravir
(1) has been developed. It starts from commercially available 2,4-dimethoxyacetophenone, which is selec-
tively halogenated into the position 5. The 5-halo acetophenones are condensed with dialkyl carbonates to
give the corresponding benzoylacetates. Their treatment with N,N-dimethylformamide dimethyl acetal
followed by (S)-valinol then provided the corresponding intermediate benzoyl acrylates. Cyclization to the
required 1,4-dihydroquinolin-4-oxo derivatives by aromatic nucleophilic substitution of the 2-methoxy group
was achieved by treatment with N,O-bis(trimethylsilyl)-acetamide, which also protected the OH group as the
trimethylsilyl derivative. Finally, the Negishi coupling with 2-fluoro-3-chlorobenzylzinc bromide and the
following hydrolysis provided elvitegravir (1). The preferred variant, the seven-step procedure starting from
2,4-dimethoxyacetophenone, provides elvitegravir in 29.3% yield.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
to introduce the 2-fluoro-3-chlorobenzyl group in a late
step of the synthesis. Our retrosynthetic scheme is shown
in Scheme 3.
Elvitegravir (1) is an oral HIV integrase inhibitor used for
the treatment of HIV infections [1]. Owing to its fast meta-
bolic deactivation, elvitegravir must be used together with a
cytochrome P450 inhibitor. Currently, the drug is approved
as a fixed dose combination with such inhibitor cobicistat
(2) and two anti-HIV drugs emtricitabine and tenofovir
disoproxil fumarate known as Stribild [2] (Fig. 1).
When we started development of a generic equivalent of
elvitegravir, besides general paper on novel HIV-1
integrase inhibitors [3] derived from antibacterial quino-
lones, only patent information of its synthesis was available.
The basic patent procedure [4] starts from 2,4-
difluorobenzoic acid (Scheme 1), a common intermediate
of the synthesis of antibacterial quinolones [5]. However,
the penultimate intermediate 6 is a common problematic
impurity of this process. A process-dependent dimeric
impurity has also been described [6].
A process patent procedure (Scheme 2) starts from 2,4-
dimethoxybenzoic acid, which is in three steps transformed into
intermediate 8 [7]. Disadvantage of this approach is the fact that
the most expensive compound (2-fluoro-3-chlorobenzyl bro-
mide) is used in an early stage of the synthesis.
For the reasons given earlier, we decided to develop a
new synthesis of elvitegravir (1) starting from easily
available 2,4-dimethoxyacetophenone. We also decided
RESULTS AND DISCUSSION
Selective
bromination/iodination
of
2,4-dimethoxy
acetophenone (12).
Direct bromination of acetophenone
under common conditions is known to go selectively to the
side acetyl group. Similar preference is known for most
acetophenones, including 2,4-dimethoxyacetophenone [8].
A
mixture of the corresponding product of
monobromination in the side chain with 2-bromo-1-(5-
bromo-2,4-dimethoxyphenyl)ethanone, the product of
dibromination, was obtained by bromination in diethyl
ether in the presence of AlCl3 [8c]. However, selective
aromatic bromination of 2,4-dimethoxyacetophenone (12)
into the position 5 giving compound 13a is described either
with bromine in acetic acid at ꢀ20°C [9a] or with
N-bromosuccinimide in the presence of p-toluenesulfonic
acid (PTSA) without solvent [9b]. Although the solvent-
free reactions are considered to be a perspective green
approach, the scale-up from using trituration in a porcelain
mortar into an industrially useful setup could be difficult.
Therefore, reproduction of the bromination in acetic acid at
lower temperature was performed. While at temperature
© 2015 HeteroCorporation

S. Rádl, J. Stach, O. Píša, J. Cinibulk, J. Havlíček, M. Zajícová, and T. Pekárek
Vol 000
Figure 1. Structures of elvitegravir (1) and cobicistat (2).
Scheme 1. Synthesis of elvitegravir (1) from 2,4-difluorobenzoic acid.
Scheme 2. Synthesis of elvitegravir (1) from 2,4-dimethoxybenzoic acid.
under ꢀ5°C the reaction mixture totally solidified, at 0°C, the
hardly mechanically stirrable mixture provided complex
mixtures containing mainly polybrominated compounds
[liquid chromatography–mass spectrometry (LC–MS)].
Therefore, we have studied the bromination in solvent
mixtures containing acetic acid. The best results were
obtained using mixtures of acetic acid and acetonitrile.
However, optimization of the ratio of acetonitrile–acetic
acid led to the conclusion that comparable results could be
obtained by also using acetonitrile as the only solvent. We
have also found that the reaction is sufficiently selective up
to ꢀ10°C, a rapid increase of the amounts of impurities at
higher temperatures was observed. Although in gram
quantities the sufficient selectivity at ꢀ10°C was repeatedly
achieved, in 100g scale, bromination at ꢀ20°C was
preferred. Iodination of 2,4-dimethoxyacetophenone with
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DOI 10.1002/jhet

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An Improved Synthesis of Elvitegravir
Scheme 3. Retrosynthetic scheme of the Zentiva synthesis of elvitegravir (1) from 2,4-dimethoxyacetophenone.
iodine monochloride under similar conditions provided the
corresponding 5-iodo compound 13b (Scheme 4).
Synthesis of benzoylacetates 14 from 2,4-dimethoxy
and often used in the synthesis of antibacterial quinolones
[5]. It is usually performed via the corresponding
ethoxymethylene or dimethylaminomethylene intermediates.
For our purpose, we decided to use the latter possibility
because the treatment of the starting benzoylacetate with
N,N-dimethylformamide dimethyl acetal (DMFDMA) is
performed under milder conditions. We screened the
reaction of 14a with DMFDMA in several solvents
(DMF, toluene, MeOH, mixtures of toluene–MeOH)
and also in neat DMFDMA. As the reaction in most
solvents was not quite clean and the reaction times
necessary for full conversion were usually high
(>10 h), reaction in neat DMFDMA at 80°C was
selected for further development. Under these
conditions, all compounds 15 were prepared in good
yields.
acetophenones 13.
In the next step, 1-(5-halo-2,4-
dimethoxyphenyl)ethanones 13 are transformed into
benzoylacetates 14. This type of transformation is usually
performed by condensation with corresponding dialkyl
carbonates in the presence of sodium hydride [10],
usually in benzene, toluene, or tetrahydrofuran (THF).
We have studied the reaction of acetophenones 13 with
NaH as the base using dimethyl and diethyl carbonate in
several solvents (THF, toluene, DMF, and mixtures of the
mentioned solvents). Dialkyl carbonates are considered as
cheap and green compounds, and therefore, finally, we
used them as reagents and solvents with no additional
solvent used. Attempts to substitute NaH by a different
base (MeONa, t-BuOK, (Me3Si)2NNa, (Me3Si)2NLi)
under similar conditions failed to obtain comparable results.
Reaction of N,N-dimethylaminomethylene benzoylacetates
with a wide range of primary amines providing the
corresponding alkylaminomethylene derivatives is well
documented [5]. In case of valinol, the reaction proceeded
well without necessity to protect the hydroxyl group.
Simple stirring of 15 with L-valinol in methanol at room
Transformation of benzoyl acetates 14 into (S)-methyl 3-(1-
hydroxy-3-methylbutan-2-ylamino)-2-(5-bromo-2,4-dimetho
xybenzoyl)-acrylates 16. Transformation of benzoylacetates
into alkylaminomethylene benzoylacetates is well known
Scheme 4. Synthesis of (S)-methyl 3-(1-hydroxy-3-methylbutan-2-ylamino)-2-(5-bromo-2,4-dimethoxybenzoyl)-acrylates 16.
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S. Rádl, J. Stach, O. Píša, J. Cinibulk, J. Havlíček, M. Zajícová, and T. Pekárek
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temperature provided 80–90% yields of compounds 16
(Scheme 4).
leading to 18, an intermediate of synthesis of a
ciprofloxacin analog. On the other hand, there are
several such reactions described in patents [12b,c] and
especially conditions discovered by Mundla and
Randall [12b] using N,O-bis(trimethylsilyl)-acetamide
(BSA) as the cyclization agent seems to be quite
advantageous.
When we treated compound 16a with K2CO3 in DMF
under the conditions described by Grohe and Heitzer
[12a], after 1 h, a complex mixture containing about 36%
of the required product 19a was formed. According to
LC–MS, a product of elimination 20 and dimeric products
21 and 22 were also present in amounts of about 7, 24, and
12%, respectively (Scheme 6).
It is evident that the hydroxy group in intermediates 16
should be protected. We decided to apply conditions de-
scribed by Mundla and Randall [12] using BSA as a cycli-
zation agent. This approach has been described for
cyclization of ethyl ester 16b with BSA providing after
workup corresponding compound 19b, which was then
protected with tert-butyldimethylsilyl (TBDMS) group
[12b]. We have applied this approach, and compounds
19a and 24a were prepared. For full conversion of com-
pounds 16 [high-performance liquid chromatography
(HPLC)], at least 2.5 equivalents of BSA must be used,
and DMF was selected as a solvent of choice. We also tried
to develop a mild workup to be able to isolate directly the
trimethylsilyl intermediate 23a. Finally, we succeeded
Cyclization of intermediates 16 into corresponding
4-oxo-1,4-dihydro-quinoline-3-carboxylates.
Synthesis of
a
wide range of 4-oxo-1,4-dihydro-quinoline-3-
carboxylates from corresponding benzoyl aminoacrylates
under basic conditions (Scheme 5) is well documented
and is even industrially used for production of some
antibacterial quinolones. Usually, leaving groups X= F,
Cl are used [5]. This procedure was applied also in the
synthesis of elvitegravir intermediate 5 described in the basic
patent (Scheme 1) [4]. Several examples of the
denitrocyclization reaction (X = NO2) are also described
[11]. Nevertheless, there is only one example describing
aromatic nucleophilic substitution of the methoxy group
(X = OMe) in scientific literature. Grohe and Heitzer
[12a] described cyclization of 17 (R1 = H, R2 = Et,
R3 = cyclopropyl) by heating of 17 with K2CO3 in DMF
Scheme 5. Synthesis of 4-oxo-1,4-dihydro-quinoline-3-carboxylates
from corresponding benzoyl aminoacrylates.
Scheme 6. K2CO3 mediated cyclization of 16a.
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An Improved Synthesis of Elvitegravir
using aqueous workup at about 0°C. Alkaline hydrolysis of
ester 19a provided the corresponding acids 25a (Scheme 7).
The corresponding ethyl ester 23b, as well as iodo deriva-
tives 23c and 23d, was obtained similarly.
For the introduction of 2-fluoro-3-chlorobenzyl group
into the quinolone skeleton, we applied Negishi coupling
with 3-chloro-2-fluorobenzylzinc bromide (27) used in
the elvitegravir patents [4,7]. The Negishi coupling of both
6-bromo and 6-iodo derivatives provided good yields of
compounds 28, but in the case of iodo derivatives, the
purity achieved was lower. Therefore, we finally used com-
pound 23a as the intermediate of choice. We also tested the
possibility to use acid 25a, protect both the OH and COOH
groups as the trimethylsilyl derivatives 26, and to use the
formed disilylated compound without isolation directly to
the Negishi coupling. This approach was found viable,
but the final elvitegravir (1) was not so pure (Scheme 8).
The developed procedure was used also for the synthesis
of (R)-elvitegravir starting from intermediate bromo deriv-
ative 15a and (R)-(ꢀ)-valinol. (R)-Elvitegravir and the
Scheme 7. Synthesis of 4-oxo-1,4-dihydro-quinoline-3-carboxylates by BSA promoted cyclization.
Scheme 8. Synthesis of elvitegravir (1).
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S. Rádl, J. Stach, O. Píša, J. Cinibulk, J. Havlíček, M. Zajícová, and T. Pekárek
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corresponding (R)-enantiomer of 28a were used as stan-
dards for the chiral purity HPLC determination, which
proved that no evident racemization takes place during
the reaction sequences used.
internal diameter 4.6mm; Phenomenex, Torrance, CA,
USA). Gradient elution with mobile phase A [phosphate
buffer (1. 2 g NaH2PO4) diluted in 1000 mL of water, pH
adjusted to 3.0 with 50% phosphoric acid], and mobile
phase B (methanol) was used. Flash chromatography was
performed on silica gel Merck, particle size 0.04–0.063mm.
Centrifugally accelerated axial chromatography was per-
formed using Cyclograph instrument (Analtech, Newark,
DE, USA) with silica gel pre-scraped rotors.
CONCLUSION
We have developed a robust processes for synthesis of
elvitegravir (1) starting from 2,4-dimethoxyacetophenone. The
starting compound was transformed into (S)-3-(1-hydroxy-3-
methylbutan-2-ylamino)-2-(5-halo-2,4-dimethoxybenzoyl)-ac-
rylates 16, which were cyclized with BSA to suitable 5-halo
4-oxo-1,4-dihydro-quinoline-3-carboxylates. Introduction
of the 2-fluoro-3-chlorobenzyl group by Negishi coupling
provides finally elvitegravir (1). The principal advantage
of the process is the fact that the most expensive interme-
diate (3-chloro-2-fluorobenzyl bromide) is used in the
penultimate step. The preferred variant, the seven-step
procedure starting from 2,4-dimethoxyacetophenone and
using for the Negishi coupling methylester 23a, provides
elvitegravir (1) in 29.3% yield. The same procedure was
used for the synthesis of the opposite (R)-elvitegravir
using bromo derivative 15a as the key intermediate.
1-(5-Bromo-2,4-dimethoxyphenyl)ethanone (13a). Bromine
(50 g) was added during 2 h to a solution of 2,4-
dimethoxyacetophenone (12, 45g, 0.25mol) in acetonitrile
(500 mL) stirred at ꢀ20°C. The resulting suspension was
stirred for additional 3 h at this temperature and then poured
to a mixture of ice (200g) and water (200mL). The insoluble
portion was filtered and washed with water. The product was
dried in vacuo at 50°C to give 62.2 g (96.4%) of pink crystals
containing according to HPLC 93.5% of 13a and 1.7% of
starting compound 12, which was used for the next step
without further purification. Mp 136–138°C (Ref. [8b] mp
1
138–139°C). H NMR (CDCl3) δ (ppm): 8.04 (s, 1H, H-6),
6.45 (s, 1H, H-3), 3.96 (s, 3H, MeO), 3.94 (s, 3H, MeO),
2.56 (s, 3H, MeCO). 13C NMR (CDCl3) δ (ppm): 196.3,
160.4, 160.1, 135.2, 121.6, 102.8, 95.8, 56.4, 55.8, 31.8. IR:
ν(C–H) 2974, 2838, ν(C¼O) 1647, ν(C¼C)AR 1594, 1470,
ν(C–O) 1275cmꢀ1. UV λmax (log ε): 219 (4.32), 229 (4.34),
265 (4.14), 314 (3.92).
EXPERIMENTAL
All chemicals used in the synthesis were purchased from
Sigma-Aldrich (Milwaukee, WI, USA) and were used with-
out purification.
1-(5-Iodo-2,4-dimethoxyphenyl)ethanone (13b). A solution
of iodine monochloride (10g) in acetonitrile (5mL) was
Melting points were measured on a Kofler block or
Stuart (Bibby Scientific, Stone, UK) melting point appara-
tus SMP30 and are uncorrected. NMR experiments were
carried out on a Bruker Avance 500 (Rheinstetten,
Germany) at 500.13 MHz (1H) and 125.76 MHz (13C).
Reference for 1H δ (CDCl3)= 7.26ppm, δ (DMSOd6)
added
during
1 h
to
a
solution
of
2,4-
dimethoxyacetophenone (12, 9 g, 50 mmol) in acetonitrile
(75mL) stirred at ꢀ20°C. The resulting suspension was
stirred for additional 4 h at this temperature and then poured
to a mixture of ice (25 g) and water (25 mL). The insoluble
portion was filtered, washed with water, and dried in vacuo
to give 14.2 g of crude product. Crystallization from
methanol provided 11.3g (73.8%) of yellowish crystals; mp
139–143°C (Ref. [13] mp 145°C) and HPLC purity of
= 2.50ppm and for 13C
δ (CDCl3) =77.00 ppm, δ
(DMSOd6) =39.50 ppm. IR spectra were measured on a
Fourier transform infrared spectrometer Nicolet Nexus
(Thermo, Waltham, MA) using ZnSe attenuated total
reflection crystal technique by accumulation of 64 scans
with two 1/cm resolution. The UV spectra were
recorded in methanol on a Lambda 25 spectrophotometer
(PerkinElmer, Waltham, MA) in the range of 200–700nm.
Optical rotation measurements were recorded on a
PerkinElmer model 341 polarimeter in MeOH (c approx.
1%) using a 10-cm cell. The mass spectra (MS/MS; ioniza-
tion mode atmospheric-pressure chemical ionization
(APCI)(+)) were measured on an active pharmaceutical
ingredient 3000 PE machine (Sciex Instruments, Applied
Biosystems, Framingham, MA, USA). The purity of the pre-
pared substances was evaluated by thin-layer chromatogra-
phy on silica gel (FP KG F 254, Merck, Darmstadt,
Germany) and by HPLC system HP 1050 with UV detection
(column Phenomenex Luna 5μ C18(2) length: 0.25m,
1
99.6%. H NMR (CDCl3) δ (ppm): 8.23 (s, 1H, H-6), 6.39
(s, 1H, H-3), 3.94 (s, 3H, MeO), 3.93 (s, 3H, MeO), 2.55 (s,
3H, MeCO). 13C NMR (CDCl3) δ (ppm): 196.3, 162.3,
161.5, 141.3, 122.5, 95.0, 75.0, 56.5, 55.7, 31.7. IR: ν(C–H)
2973, 2839, ν(C¼O) 1645, ν(C¼C)AR 1588, 1470, ν(C–O)
1270, 1230 cmꢀ1. UV λmax (log ε): 208 (4.62), 234 (4.45),
265 (4.18), 318 (3.93).
Methyl 3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropanoate
(14a). Hexane (100mL) was added to a 60% w/w sodium
hydride dispersion in mineral oil (12g, 300mmol), and the
mixture was stirred under nitrogen for 10min. Then the
stirring was stopped, hexane was removed with syringe, and
another portion of hexane (100 mL) was added and after
10 min again removed. Then toluene was added (100 mL)
followed by dimethyl carbonate (18 g, 200mmol), and the
mixture was heated to reflux. A solution of 5-bromo-2,4-
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Month 2015
An Improved Synthesis of Elvitegravir
dimethoxyacetophenone (13a, 26g, 100mmol) in THF
(24mL) was added dropwise over 1 h, and the mixture was
refluxed for additional 2 h. After cooling, the mixture was
poured onto a mixture of ice (100g) and water (100 mL),
and the mixture was acidified with 10% HCl to pH5–6. The
mixture was extracted with ethyl acetate (2 ×200mL), the
extract was washed with brine (3 × 100 mL) and dried
with MgSO4. The residue after evaporation (34g) was
purified by crystallization from methanol to give 23.2g
(73.4%) of off-white crystals; mp 109–111°C (HPLC
synthesis of 14a, ethyl ester 14d was obtained in 78.6%
yield as off-white crystals; mp 87–89°C (ethanol). HPLC
purity 94.7%. H NMR (CDCl3) δ (ppm): 8.31 (s, 1H, H-
1
6), 6.35 (s, 1H, H-3), 4.16 (q, J= 7.2 Hz, 2H, OCH2CH3),
3.93 (s, 3H, MeO), 3.90 (s, 3H, MeO), 3.87 (s, 2H,
CH2), 1.22 (t, J= 7.2 Hz, 3H, OCH2CH3). 13C NMR
(CDCl3) δ (ppm): 189.9, 168.2, 163.0, 161.5, 141.7,
120.8, 94.7, 75.5, 60.9, 56.6, 55.5, 50.3, 14.1. IR: ν(C–
H) 2975, ν(C¼O) 1735, 1658, ν(C¼C)AR 1581, 1447,
ν(C–O) 1278, 1256, 1140 cmꢀ1. UV λmax (log ε): 237
(4.48), 270 (4.21), 323 (4.02). Anal Calcd. for
C13H15IO5: C, 41.29; H, 4.00. Found: C, 41.07; H, 3.88.
1
purity 98.8). H NMR (CDCl3) δ (ppm): 8.14 (s, 3H, H-
6), 6.43 (s, 3H, H-3), 3.96 (s, 3H, MeO), 3.91 (s, 5H,
MeO+CH2), 3.71 (s, 3H, COOMe). 13C NMR (CDCl3) δ
(ppm): 189.8, 168.6, 160.9, 160.5, 135.6, 119.9, 103.5,
95.6, 56.5, 55.7, 52.1, 50.2. IR: ν(C–H) 2924, 2831,
ν(C¼O) 1734, 1652, ν(C¼C)AR 1593, 1456, ν(C–O) 1270,
1214cmꢀ1. UV λmax (log ε): 217 (4.34), 234 (4.35), 269
(4.19), 318 (4.03). High-resolution mass spectrometry
(HRMS) for C12H14BrO5 (M+H)+ Calcd: 317.0025,
found: 317.0025. Anal Calcd. for C12H13BrO5: C, 45.57;
H, 4.15; Br, 24.97. Found: C, 45.12; H, 4.44; Br, 24.55.
Methyl 2-(5-bromo-2,4-dimethoxybenzoyl)-3-(dimethylamino)-
acrylate (15a).
A mixture of methyl 3-(5-bromo-2,4-
dimethoxyphenyl)-3-oxopropanoate (14a; 12.5g, 39.4mmol)
and DMFDMA (30 mL) was stirred at 80°C under nitrogen
for 3h. The mixture was evaporated under reduced pressure,
and the residue was crystallized from methanol to 12.7 g
(86.6%) of yellow crystals; mp 122–124°C (HPLC purity
1
99.1%). H NMR (CDCl3) δ (ppm): 7.83 (bs, 1H, –CH¼),
7.64 (s, 1H, H-6), 6.40 (s, 1H, H-3), 3.93 (s, 3H, MeO), 3.81
(s, 3H, MeO), 3.04 (s, 3H, COOMe), 3.11 (bs, 6H, Me2N).
13C NMR (CDCl3) δ (ppm): 188.0, 168.8, 158.9, 158.5,
155.9, 134.6, 125.3, 103.2, 102.1, 95.7, 56.3, 55.9, 50.9,
41.8. IR: ν(C–H) 2942, ν(C¼O) 1668, ν(C¼C)AR +ν(C¼C)
1572, ν(C¼C)AR 1435, ν(C–O) 1281, 1208, 1088 cmꢀ1. UV
210 (4.37), 233 (4.29), 270 (4.26), 328 (4.28). Anal Calcd.
for C15H18BrNO5: C, 48.40; H, 4.87; N, 3.76. Found: C,
48.28; H, 5.07; N, 3.93.
Ethyl 3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropanoate
(14b).
Using diethyl carbonate and the procedure
described for the synthesis of 14a, ethyl ester 14b was
obtained in 75.0% yield as off-white crystals; mp 77–84°C
(ethanol). HPLC purity 97.7%. 1H NMR (CDCl3) δ (ppm):
8.14 (s, 1H, H-6), 6.43 (s, 1H, H-3), 4.18 (q, J=7.1Hz,
2H, OCH2CH3), 3.96 (s, 3H, MeO), 3.91 (s, 3H, MeO),
3.89 (s, 2H, CH2), 1.23 (t, J=7.1Hz, 3H, OCH2CH3). 13C
NMR (CDCl3) δ (ppm): 190.0, 168.2, 160.8, 160.4, 135.6,
120.0, 103.4, 95.6, 60.9, 56.5, 55.7, 50.5, 14.1. IR: ν(C–H)
2987, ν(C¼O) 1733, 1666, ν(C¼C)AR 1588, 1472, ν(C–O)
1256, 1216, 1146cmꢀ1. UV λmax (log ε): 208 (4.76), 232
(4.35), 269 (4.18), 317 (4.00). HRMS for C13H16 BrO5
(M+) Calcd: 331.0181, found: 331.0173. Anal Calcd. for
C13H15BrO5: C, 47.27; H, 4.58; Br, 23.91. Found: C,
46.85; H, 4.72; Br, 23.65.
Ethyl 2-(5-bromo-2,4-dimethoxybenzoyl)-3-(dimethylamino)-
acrylate (15b). Using procedure described for the synthesis
of 15a, ethyl ester 15b was obtained in 92.0% yield as
yellow crystals; mp 134–140°C (ethanol). HPLC purity
1
98.8%. H NMR (CDCl3) δ (ppm): 7.79 (bs, 1H, –CH¼),
7.64 (s, 1H, H-6), 6.39 (s, 1H, H-3), 3.95 (q, J=7.1Hz, 2H,
OCH2CH3), 3.92 (s, 3H, MeO), 3.80 (s, 3H, MeO), 3.09 (bs,
6H, Me2N), 0.95 (t, J= 7.1Hz, 3H, OCH2CH3). 13C NMR
(CDCl3) δ (ppm): 188.2, 168.6, 158.8, 158.4, 156.1, 134.3,
125.7, 103.4, 101.9, 95.7, 59.6, 56.3, 55.8, 41.7, 14.0. IR:
ν(C–H) 2978, ν(C¼O) 1692, ν(C¼C) 1620, ν(C¼C)AR
1592, ν(C–O) 1276, 1205, 1117cmꢀ1. UV λmax (log ε): 209
(4.53), 233 (4.26), 269 (4.25), 328 (4.25). Anal Calcd. for
C16H20BrNO5: C, 49.76; H, 5.22; N, 3.63. Found: C, 49.55;
H, 5.37; N, 3.77.
Methyl 3-(5-iodo-2,4-dimethoxyphenyl)-3-oxopropanoate
(14c). Starting from iodo derivative 13b adhering to the
process described for the synthesis of 14a, iodo
derivative 14c was obtained in 83.6% yield as off-white
crystals; mp 120–123°C (methanol). HPLC purity 99.2%.
1H NMR (CDCl3) δ (ppm): 8.34 (s, 1H, H-6), 6.36
(s, 1H, H-3), 3.95 (s, 3H, MeO), 3.91 (s, 3H, MeO), 3.90
(s, 2H, CH2), 3.71 (s, 3H, COOMe). 13C NMR (CDCl3)
δ (ppm): 189.8, 168.7, 163.1, 161.5, 141.8, 120.7, 94.7,
75.7, 56.6, 55,6, 52.1, 50.1. IR: ν(C–H) 2922, 2829,
ν(C¼O) 1730, 1649, ν(C¼C)AR 1583, 1446, ν(C–O)
1265, 1213 cmꢀ1. UV λmax (log ε): 237 (4.51), 270
(4.25), 322 (4.06). Anal Calcd. for C12H13IO5: C, 39.58;
H, 3.60. Found: C, 39.27; H, 4.09.
Methyl 2-(5-iodo-2,4-dimethoxybenzoyl)-3-(dimethylamino)-
acrylate (15c). Using procedure described for the synthesis
of 15a, iodo derivative 15c was obtained in 83.4% yield as
yellow crystals; mp 153–157°C (methanol). HPLC purity
1
98.8%. H NMR (CDCl3) δ (ppm):8.02 (bs, 1H, –CH¼),
7.66 (s, 1H, H-6), 6.37 (s, 1H, H-3), 3.93 (s, 3H, MeO), 3.84
(s, 3H, MeO), 3.53 (s, 3H, COOMe), 3.10 (bs, 6H, Me2N).
13C NMR (CDCl3) δ (ppm): 188.0, 168.9, 160.9, 160.1,
155.9, 140.4, 126.1, 103.2, 94.9, 56.4, 74.4, 55.8, 50.9, 44.6.
IR: ν(C–H) 2941, ν(C¼O) 1665, ν(C¼C)AR +ν(C¼C) 1569,
Ethyl
3-(5-iodo-2,4-dimethoxyphenyl)-3-oxopropanoate
(14d). Using diethyl carbonate and starting from iodo
derivative 13b adhering to the process described for the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Rádl, J. Stach, O. Píša, J. Cinibulk, J. Havlíček, M. Zajícová, and T. Pekárek
Vol 000
ν(C¼C)AR 1434, ν(C–O) 1278, 1206, 1088cmꢀ1. UV λmax
(log ε): 208 (4.52), 238 (4.38), 269 (4.30), 331 (4.29). Anal
Calcd. for C15H18INO5: C, 42.98; H, 4.33; N, 3.33. Found:
C, 42.73; H, 4.53; N, 3.64.
from 11.2 g (30 mmol) of 2-(5-bromo-2,4-dimethoxybenzoyl)-
3-(dimethylamino)acrylate (15a) and 3.2g (31mmol) of (R)-
(ꢀ)-valinol using procedure described for the synthesis
of compound 16a, 11.5 g (89.1%) of the corresponding
R-isomer was obtained as slightly yellowish
crystals; mp 140–143°C (HPLC purity 99.6%). [α]D20
(MeOH) = +39.5°.
Ethyl 2-(5-iodo-2,4-dimethoxybenzoyl)-3-(dimethylamino)-
acrylate (15d).
Using procedure described for the
synthesis of 15a, iodo derivative 15d was obtained in
86.6% yield; yellow crystals, mp 151–156°C (ethanol).
HPLC purity 97.8%. 1H NMR (CDCl3) δ (ppm): 8.00
(bs, 1H, –CH¼), 7.64 (s, 1H, H-6), 6.34 (s, 1H, H-3),
3.95 (q, J= 7.1Hz, 2H, OCH2CH3), 3.91 (s, 3H, MeO),
3.80 (s, 3H, MeO), 3.09 (bs, 6H, Me2N), 0.95 (t,
J =7.1 Hz, 3H, OCH2CH3). 13C NMR (CDCl3) δ (ppm):
188.6, 168.1, 160.8, 160.0, 156.0, 140.3, 126.6, 103.3,
94.9, 74.1, 59.6, 56.4, 55.7, approx. 40 (observed at 50°C,
not at 25°C), 14.1. IR: ν(C–H) 2969, ν(C¼O) 1692,
ν(C¼C) 1619, ν(C¼C)AR 1585, ν(C–O) 1272, 1203,
1112 cmꢀ1. UV λmax (log ε): 208 (4.60), 238 (4.36), 269
(4.28), 331 (4.27). Anal Calcd. for C16H20INO5: C, 44.36;
H, 4.65; N, 3.23. Found: C, 44.55; H, 4.37; N, 3.49.
(S)-Ethyl 3-(1-hydroxy-3-methylbutan-2-ylamino)-2-(5-bromo-
2,4-dimethoxybenzoyl)-acrylate (16b). Starting from ethyl
ester 15b and using procedure described for the
synthesis of 16a, compound 16b was obtained in
88.8% yield as yellowish crystals; mp 113–116°C
(ethanol). HPLC purity 95.7%. 1H NMR (CDCl3) δ
(ppm): 10.82 (dd, J= 13.0, 10.2Hz, 0.8H, NH), 9.18
(dd, J=14.3, 9.7Hz, 0.2H, NH), 7.96 (d, J=13.6Hz,
0.8H, –CH¼), 7.91 (d, J =14.2Hz, 0.2H, –CH¼),7.47
(s, 0.2H, H-6), 7.41 (s, 0.8H, H-6), 6.388 (s, 0.2H, H-3),
6.380 (s, 0.8H, H-3), 3.87–3.98 (m, 5H, OCH2Me
+ MeO), 3.61–3.74 (m, 5H, MeO+ CH2OH), 3.04–3.09
(m, 1H, CHN), 2.85 (m, 0.8H, OH), 2.60 (m, 0.2H, OH),
1.90–1.95 (m, 1H, CHMe2), 0.89–1.00 (m, 9H, CHMe2,
OCH2Me). 13C NMR (CDCl3) δ (ppm): 191.6, 189.6,
169.1, 167.7, 160.0, 159.8, 157.5, 157.4, 157.3, 156.9,
134.9, 133.0, 126.5, 126.4, 102.6, 101.8, 101.59, 101.56,
95.9, 95.8, 68.7, 68.1, 63.1, 59.5, 56.3, 56.2, 55.9, 55.8,
55.7, 50.0, 29.3, 29.2, 20.5, 19.5, 18.0, 14.0, 13.7. IR:
ν(O–H) 3419, ν(C–H) 2967, ν(C¼O) 1665, ν(C¼C)AR
+ ν(C¼C) 1594, ν(C¼C)AR 1428, ν(C–O) 1272,
1205cmꢀ1. UV λmax (log ε): 206 (4.70), 316 (4.26). Anal
Calcd. for C19H26BrNO6: C, 51.36; H, 5.90; N, 3.15.
Found: C, 51.11; H, 6.08; N, 3.33.
(S)-Methyl 3-(1-hydroxy-3-methylbutan-2-ylamino)-2-(5-
bromo-2,4-dimethoxybenzoyl)-acrylate (16a). A solution
of (S)-(+)-valinol (5 g, 48.5 mmol) in methanol (20 mL)
was added to
dimethoxybenzoyl)-3-(dimethylamino)acrylate
a
suspension of 2-(5-bromo-2,4-
(15a;
16.4 g, 44 mmol) in methanol (120 mL), and the mixture
was stirred at room temperature for 4 h. The mixture was
concentrated under reduced pressure to 1/3 of the
original volume, the mixture was stirred in ice bath for
1 h, and insoluble portion was filtered off. The crystals
were washed with hexane (25mL) and water (2 ×25mL)
and dried to provide 18.2 g (96.0%) of off-white crystals;
(S)-Methyl 3-(1-hydroxy-3-methylbutan-2-ylamino)-2-(5-
1
mp 141–145°C. HPLC purity 98.5%. H NMR (CDCl3)
iodo-2,4-dimethoxybenzoyl)-acrylate (16c).
Starting from
δ (ppm): 10.85 (dd, J = 13.0, 10.2 Hz, 0.8H, NH), 9.17
(dd, J = 14.3, 9.7 Hz, 0.2H, NH), 7.98 (d, J = 13.6 Hz,
0.8H, –CH¼), 7.88 (d, J = 14.2 Hz, 0.2H, –CH¼),7.55 (s,
0.2H, H-6), 7.47 (s, 0.8H, H-6), 6.401 (s, 0.8H, H-3),
6.396 (s, 0.2H, H-3), 3.92+3.91 (s, 3H, MeO), 3.67–3.76
(m, 5H, MeO+CH2OH), 3.53+3.54 (s+s, 3H, COOMe),
3.05–3.12 (m, 1H, CHN), 2.57 (t, J=5.7Hz, 0.8H, OH),
2.39 (t, J=5.7Hz, 0.2H, OH), 1.92–2.00 (m, 1H, CHMe2),
0.95–1.01 (m, 6H, CHMe2). 13C NMR (CDCl3) δ (ppm):
191.2, 189.1, 169.8, 168.0, 160.4, 159.8, 157.7, 157.4,
157.6, 157.0, 133.6, 132.6, 126.1, 125.8, 101.9, 101.8,
101.71, 101.69, 95.8, 95.6, 68.8, 68.2, 63.4, 63.3, 56.3,
56.2, 56.0, 55.8, 50.8, 50.6, 29.4, 29.3, 19.57, 19.55,
18.2, 18.1. IR: ν(O–H) 3491, ν(C–H) 2969, ν(C¼O)
1662, ν(C¼C)AR +ν(C¼C) 1595, ν(C¼C)AR 1434, ν(C–O)
1284, 1204cmꢀ1. UV λmax (log ε): 206 (4.79), 236 (4.35),
317 (4.30). [α]2D0 (MeOH)=ꢀ38.8°. Anal Calcd. for
C18H24BrNO6: C, 50.24; H, 5.62; N, 3.26. Found: C,
50.51; H, 5.78; N, 3.44.
iodo derivative 15c and using procedure described for
the synthesis of 16a, compound 16c was obtained in
83.2% yield as yellowish crystals; mp 115–119°C
(methanol). HPLC purity 97.2%. 1H NMR (CDCl3) δ
(ppm): 10.82 (dd, J = 13.0, 10.2Hz, 0.8H, NH), 9.15
(dd, J =14.3, 9.7 Hz, 0.2H, NH), 7.96 (d, J= 13.6Hz,
0.8H, –CH¼), 7.85 (d, J = 14.2Hz, 0.2H, –CH¼), 7.72
(s, 0.2H, H-6), 7.64 (s, 0.8H, H-6), 6.34 (s, 0.2H, H-3),
6.33 (s, 0.8H, H-3), 3.89 + 3.88 (s, 3H, MeO), 3.69
+ 3.72 (m, 5H, MeO + CH2OH), 3.51+ 3.62 (s +s, 3H,
COOMe), 3.07–3.09 (m, 1H, CHN), 3.04–3.06 (m,
0.8H, OH), 2.94 (m, 0.2H, OH), 1.91–1.95 (m, 1H,
CHMe2), 0.93–0.98 (m, 6H, CHMe2). 13C NMR
(CDCl3) δ (ppm): 191.4, 189.0, 169.7, 168.0, 160.4,
160.0, 159.8, 159.7, 158.7, 158.2, 139.4, 138.3, 127.0,
126.6, 101.6, 101.5, 95.1, 94.9, 774.1, 73.9, 68.7, 68.1,
63.22, 63.20, 56.4, 56.3, 55.9, 55.6, 50.8, 50.5, 29.6,
29.31, 29.29, 19.52, 18.1. IR: ν(O–H) 3368, ν(C–H)
2958, ν(C¼O) 1664, ν(C¼C) 1618, ν(C¼C)AR 1589,
1442, ν(C–O) 1251, 1204 cmꢀ1. UV λmax (log ε): 208
(4.70), 238 (4.42), 316 (4.27). Anal Calcd. for
(R)-Methyl 3-(1-hydroxy-3-methylbutan-2-ylamino)-2-(5-
bromo-2,4-dimethoxybenzoyl)-acrylate (R-16a).
Starting
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
An Improved Synthesis of Elvitegravir
C18H24INO6: C, 45.30; H, 5.07; N, 2.93. Found: C,
45.69; H, 5.27; N, 3.15.
hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydro-
quinoline-3-carboxylate (19a, 1g, 2.5mmol), imidazole
(1.5g, 22mmol) and tert-butyldimethylsilyl chloride (1.,5 g,
10 mmol) in DMF (15 mL) was stirred at room temperature
for 1 h. The mixture was diluted with ethyl acetate (50mL),
and the solution was washed with water and then dried
with MgSO4. Crystallization of the residue after
evaporation from toluene provided 0.6 g (46.6%) of
white solid; mp 227–235°C. 1H NMR (CDCl3) δ
(ppm): 8.70 (s, 1H, H-5), 8.66 (s, 1H, H-2), 6.86 (s,
1H, H-8), 4.17–4.19 (m, 1H, CHN), 3.93–4.05 (m, 2H,
CH2O), 4.00 (s, 3H, MeO), 3.88 (s, 3H, COOMe),
2.38–2.45 (m, 1H, CHMe2), 1.17 (d, J = 6.5 Hz, 3H,
CHMe2), 0.86 (d, J = 6.5Hz, 3H, CHMe2), 0.76 (s, 9H,
tert-Bu), ꢀ0.06 (s, 3H, SiMe), ꢀ0.09 (s, 3H, SiMe).
13C NMR (CDCl3) δ (ppm): 172.3, 166.0, 158.9, 146.1,
141.6, 132.7, 124.0, 111.0, 110.2, 96.9, 66.7, 62.6, 56.5,
52.0, 29.2, 25.5, 19.9, 19.6, ꢀ5.7, ꢀ5.9. IR: ν(C–H) 2949,
ν(C¼O) 1721, ν(C¼C)AR 1606, 1581, 1481, ν(C–O)
1263, 1196, ν(Si–O) 1101 cmꢀ1. UV λmax (log ε): 253
(4.63), 270 (4.59), 319 (4.16), 332 (4.18).
(S)-Ethyl
3-(1-hydroxy-3-methylbutan-2-ylamino)-2-(5-
iodo-2,4-dimethoxybenzoyl)-acrylate (16d). Starting from
ethyl ester 15d and using procedure described for the
synthesis of 16a, compound 16d was obtained in 86.8%
yield as yellowish crystals; mp 111–116°C (ethanol).
HPLC purity 99.5%. 1H NMR (CDCl3) δ (ppm): 1H
NMR (CDCl3) δ (ppm): 10.78 (dd, J= 13.0, 10.2Hz,
0.8H, NH), 9.15 (dd, J = 14.3, 9.7 Hz, 0.2H, NH), 7.92
(d, J = 13.6Hz, 0.8H, –CH¼), 7.89 (d, J =14.2 Hz, 0.2H,
–CH¼), 7.61 (s, 0.2H, H-6), 7.56 (s, 0.8H, H-6), 6.286
(s, 0.2H, H-3), 6.280 (s, 0.8H, H-3), 3.83–3.93 (m, 5H,
CH2 + MeO), 3.58–3.70 (m, 5H, MeO +CH2OH), 3.00–
3.04 (m, 1H, CHN), 2.85 (m, 0.8H, OH), 2.78 (m, 0.2H,
OH), 1.86–1.90 (m, 1H, CHMe2), 0.85–0.96 (m, 9H,
CHMe2, OCH2Me). 13C NMR (CDCl3) δ (ppm): 191.5,
189.6, 169.2, 167.7, 161.9, 160.9, 159.8, 159.7, 158.6,
158.1, 140.9, 138.1, 127.4, 122.8, 101.9, 101.6, 95.1,
95.0, 68.7, 68.1, 63.2, 56.4, 56.3, 55.8, 55.7, 55.6, 49.9,
29.6, 29.3, 20.5, 19.5, 18.1, 14.1, 13.8. IR: ν(O–H) 3436,
ν(C–H) 2963, ν(C¼O) 1656, ν(C¼C)AR +ν(C¼C) 1587,
ν(C¼C)AR 1431, ν(C–O) 1265, 1205 cmꢀ1. UV λmax
(log ε): 208 (4.84), 237 (4.38), 313 (4.22). Anal Calcd.
for C19H26INO6: C, 46.45; H, 5.33; N, 2.85. Found:
C, 46.72; H, 5.57; N, 3.01.
(S)-6-Bromo-1,4-dihydro-1-(1-hydroxy-3-methylbutan-2-yl)-
7-methoxy-4-oxo-quinoline-3-carboxylic acid (25a). N,O-bis
(Trimethylsilyl)-acetamide (5g, 25mmol) was added to a
suspension of compound 16a (4.8g, 10mmol) in
acetonitrile (10mL), and the suspension was stirred at r.
t. for 30min and at 70–75°C for 4h. After addition of
water (5mL), the mixture was stirred at 70°C for 2h
and then at r.t. overnight. Then 20% aqueous solution
of KOH (5 mL) was added and stirred at r.t. for
additional 4 h. Precipitate formed after acidification
with acetic acid was filtered off, washed with
acetonitrile (2 × 2 mL) and water (5 mL) and dried to
provide 3.3g (85.9%) of off-white solid; mp 259–262°C.
(S)-Methyl 6-bromo-1-(1-hydroxy-3-methylbutan-2-yl)-7-
methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylate (19a).
To a solution of (S)-methyl 3-(1-hydroxy-3-methylbutan-
2-ylamino)-2-(5-bromo-2,4-dimethoxybenzoyl)-acrylate
(16a; 1.72 g, 4 mmol) in DMF (25 mL) was added N,O-
bis(trimethylsilyl)-acetamide (3 g), and the mixture was
stirred at 100°C for 5 h. The mixture was diluted with
water and stirred at room temperature overnight. The
insoluble portion was filtered off, washed with water,
and dried to give 1.4 g (87.9%) of white crystals; mp
1
HPLC purity 99.6%. H NMR (DMSOd6) δ (ppm): 15.12
(s, 1H), 8.92 (s, 1H, H-2), 8.49 (s, 1H, H-5), 7.55 (s, 1H,
H-8), 5.22 (t, J=4.6Hz, 1H, OH), 4.90 (m, 1H, CHN),
4.10 (s, 3H, MeO), 3.99 (m, 1H, CH2OH), 3.80 (m, 1H,
CH2OH), 2.38 (m, 1H, CH), 1.16 (m, J=6.5Hz, 3H,
Me), 0.74 (m, J=6.5Hz, 3H, Me). 13C NMR (DMSOd6)
δ (ppm): 175.6, 165.9 159.6, 146.2, 141.6, 129.8, 120.1,
111.1, 107.8, 100.0, 66.5, 60.1, 57.7, 29.2, 19.1, 18.9. IR:
ν(O–H) 3436, ν(C–H) 2968, ν(C¼O) 1722, ν(C¼C)AR
1609, 1536, 1451, ν(C–O) 1271cmꢀ1. UV λmax (log ε):
255 (4.62), 269 (4.60), 318 (4.10), 330 (4.09). Anal
Calcd. for C16H18BrNO5: C, 50.02; H, 4.72; N, 3.65.
Found: C, 50.33; H, 5.00; N, 3.73.
1
140–146°C (HPLC purity 99.4%). H NMR (CDCl3) δ
(ppm): 8.55 (s, 1H, H-2), 7.71 (s, 1H, H-5), 6.85 (s,
1H, H-8), 5.84 (t, J = 7.1 Hz, 1H, OH), 4.22–4.32 (m,
2H, CH2OH), 4.08–4.13 (m, 1H, CHN), 4.05 (s, 3H,
MeO), 3.84 (s, 3H, COOMe), 2.43–2.52 (m, 1H,
CHMe2), 1.24 (d, J = 6.4 Hz, 3H, CHMe2), 0.71 (d,
J = 6.4 Hz, 3H, CHMe2). 13C NMR (CDCl3) δ (ppm):
172.0, 165.1, 159.3, 146.8, 141.4, 130.9, 122.6, 110.6,
109.4, 96.7, 68.9, 60.8, 56.7, 51.7, 28.5, 20.4, 19.5. IR:
ν(O–H) 3219, ν(C–H) 2943, ν(C¼O) 1690, ν(C¼C)AR
1607, 1576, 1432, ν(C–O) 1258, 1239 cmꢀ1. UV λmax
(log ε): 209 (4.62), 253 (4.64), 270 (4.58), 319 (4.16),
332 (4.16). [α]2D0 (MeOH) = ꢀ28.6°. Anal Calcd. for
C17H20BrNO5: C, 51.27; H, 5.06; N, 3.52. Found: C,
50.89; H, 5.33; N, 3.67.
(S)-Methyl 6-bromo-1,4-dihydro-7-methoxy-1-(3-methyl-1-
(trimethylsilyloxy)butan-2-yl)-4-oxo-quinoline-3-carboxylate
(23a).
To a solution of (S)-methyl 3-(1-hydroxy-3-
methylbutan-2-ylamino)-2-(5-bromo-2,4-dimethoxybenzoyl)-
acrylate (16a; 17.2 g, 40 mmol) in DMF (150mL) was added
N,O-bis(trimethylsilyl)-acetamide (20 g), and the mixture was
stirred at 100°C under nitrogen for 5h. The mixture was
(S)-Methyl 6-bromo-1,4-dihydro-1-(1-(tert-butyldimethylsi
lyloxy)-3-methylbutan-2-yl)-7-methoxy-4-oxo-quinoline-3-car
boxylate (24a).
A solution of (S)-methyl 6-bromo-1-(1-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Rádl, J. Stach, O. Píša, J. Cinibulk, J. Havlíček, M. Zajícová, and T. Pekárek
Vol 000
cooled down to 5°C and placed in an ice bath, and then
water was added (200 mL). The formed precipitate was
filtered off, washed with cold water, and dried in vacuo at
20–22°C to give 18.5 g (98.3%) of 23a as white solid; mp
193–196°C (HPLC purity 94,5%), which was used for
the next step without further purification. 1H NMR
(CDCl3) δ (ppm): 8.72 (s, 1H, H-5), 8.67 (s, 1H, H-2),
6.89 (s, 1H, H-8), 4.09–4.17 (m, 1H, CHN), 3.93–4.01
(m, 2H, CH2O), 4.00 (s, 3H, MeO), 3.91 (s, 3H,
COOMe), 2.36–2.43 (m, 1H, CHMe2), 1.15
(d, J = 6.5 Hz, 3H, CHMe2), 0.81 (d, J = 6.5Hz, 3H,
CHMe2), ꢀ0.02 (s, 9H, SiMe3). 13C NMR (CDCl3) δ
(ppm): 172.3, 166.0, 158.9, 146.2, 141.6, 132.5, 123.9,
110.8, 110.2, 97.1, 66.6, 61.9, 56.5, 52.0, 29.3, 19.9,
19.5, ꢀ0.9. IR: ν(C–H) 2950, ν(C¼O) 1722, ν(C¼C)AR
1608, 1583, 1482, ν(C–O) 1262, 1195, ν(Si–O)
1099 cmꢀ1. UV λmax (log ε): 253 (4.74), 270 (4.70), 319
(4.25), 331 (4.26). [α]2D0 (MeOH) = ꢀ38.2°.
procedure described for the synthesis of 23a, compound
23d was obtained in 83.7% yield; off-white crystals, mp
167–171°C (HPLC purity 98.2%), which was used for
the next step without further purification. IR: ν(C–H)
2958, ν(C¼O) 1717, ν(C¼C)AR 1622, 1581, 1472, ν(C–
O) 1253, 1195, ν(Si–O) 1094cmꢀ1. UV λmax (log ε): 228
(4.43), 254 (4.64), 272 (4.61), 322 (4.15), 335 (4.16).
Preparation of a 1M solution of 3-chloro-2-fluorobenzylzinc
bromide (27) in THF. A solution of 1,2-dibromoethane
(0.8 g) and trimethylsilyl chloride (0.8 mL) in dry THF
(10 mL) was added to a suspension of granular Zn (12 g;
30–100mesh) in dry THF (150mL) stirred under argon at
60°C. After 1 h, a solution of 3-chloro-2-fluorobenzyl
bromide (36.4g, 163mmol) in THF (150mL) was added
with syringe pump during 1h, and the mixture was stirred
at this temperature for additional 1 h (most of the metal
was dissolved).
(S)-Methyl
6-(3-chloro-2-fluorobenzyl)-1,4-dihydro-1-(1-
hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-quinoline-3-car
boxylate (28a)
(R)-Methyl 6-bromo-1,4-dihydro-7-methoxy-1-(3-methyl-1-
(trimethylsilyloxy)butan-2-yl)-4-oxo-quinoline-3-carboxylate (R-
23a). Starting from 10g (23.2 mmol) of derivate (R)-16a
Method A.
To a solution of compound 23a (3.3 g,
7 mmol) in THF (35 mL) under argon atmosphere was
added PdCl2(PPh3)2 (0.2 g). Then the temperature was
elevated to 60°C, and a 1M solution of 3-chloro-2-
fluorobenzylzinkbromide in THF (10 mL) was added by
syringe pump during 1 h, and the mixture was stirred at
this temperature for an additional 1 h. After cooling, the
mixture was poured into a mixture of saturated aqueous
solution of NH4Cl (50 mL) and ethyl acetate (50 mL).
After thorough shaking, the layers were separated, and
the organic layer was consecutively washed with
saturated aqueous NH4Cl (20 mL), saturated NaHCO3
(20 mL), and brine (20 mL). The formed dark solution
was stirred with charcoal (2 g) for 4 h, charcoal was
removed through celite, and the filtrate was evaporated to
give yellowish residue (4.5 g). The residue was dissolved
in methanol (50 mL), 5% aqueous HCl (0.5 mL) was
added, and the mixture was stirred at room temperature
for 24h (white precipitate). After cooling, the precipitate
was filtered off providing after drying 2.8 g of crude
product containing 94% of 28a. Recrystallization from
toluene then provided 2.1 g (64.9%) of white crystals; mp
and using procedure described for the synthesis of
compound 23a, 10.4g (95.1%) of the corresponding R-
isomer was obtained as white solid; mp 191–194°C (HPLC
purity 92.1%). [α]2D0 (MeOH)=+38.5°.
(S)-Ethyl 6-bromo-1,4-dihydro-7-methoxy-1-(3-methyl-1-
(trimethylsilyloxy)butan-2-yl)-4-oxo-quinoline-3-carboxylate
(23b). Starting from ethyl ester 16b and using procedure
described for the synthesis of 23a, compound 23b was
obtained in 91.8% yield as white crystals, mp 154–174°C
(HPLC purity 96.6%), which was used for the next step
1
without further purification. H NMR (CDCl3) δ (ppm):
8.68 (s, 1H, H-5), 8.46 (s, 1H, H-2), 6.83 (s, 1H, H-8),
4.01–4.12 (m, 1H, CHN), 3.99–4.11 (m, 2H, CH2O),
3.97 (s, 3H, MeO), 3.95 (q, J = 7.0 Hz, 2H, OCH2CH3),
2.33–2.45 (m, 1H, CHMe2), 1.11 (d, J = 6.5 Hz, 3H,
CHMe2), 0.96 (t, J= 7.0 Hz, 3H, OCH2CH3), 0.78
(d, J= 6.5Hz, 3H, CHMe2), ꢀ0.05 (s, 9H, SiMe3). 13C
NMR (CDCl3) δ (ppm): 175.2, 165.6, 159.0, 146.7,
142.7, 133.8, 122.8, 109.5, 107.3, 98.4, 67.8, 61.9, 59.8,
55.2, 28.8, 19.8, 19.6, 14.1, ꢀ0.7. IR: ν(C–H) 2960,
ν(C¼O) 1720, ν(C¼C)AR 1607, 1584, 1480, ν(C–O)
1262, 1195, ν(Si–O) 1097 cmꢀ1. UV λmax (log ε): 253
(4.58), 270 (4.55), 319 (4.13), 332 (4.13).
1
192–194°C. HPLC purity 98.3%. H NMR (DMSOd6) δ
(ppm): 8.63 (s, 1H, H-2), 7.89 (s, 1H, H-5), 7.47 (m, 1H,
Ar-H), 7.27 (s, 1H, H-8), 7.17–7.22 (m, 2H, Ar-H), 5.11
(t, J = 5.0 Hz, 1H, OH), 4.60–4.68 (m, 1H, CHN), 4.05
(s, 2H, CH2), 3.92–3.98 (m, 4H, MeO, CH2OH), 3.78
(m, 1H, CH2OH), 3.72 (s, 3H, COOMe), 2.29–2.35 (m,
1H, CHMe2), 1.14 (d, J =6.6 Hz, 3H, CHMe2), 0.74
(d, J =6.6 Hz, 3H, CHMe2). 13C NMR (DMSOd6) δ
(ppm): 171.7, 160.6, 165.4, 155.6, 145.7, 141.6, 130.2,
128.7, 128.6, 127.2, 125.5, 125.3, 121.7, 119.6, 109.5,
97.5, 65.2, 60.2, 56.5, 51.2, 29.0, 28.4, 19.2, 19.1. IR:
ν(O–H) 3438, ν(C–H) 2948, ν(C¼O) 1716, ν(C¼C)AR
1609, 1580, 1460, ν(C–O) 1256cmꢀ1. UV λmax (log ε):
(S)-Methyl 6-iodo-1,4-dihydro-7-methoxy-1-(3-methyl-1-
(trimethylsilyloxy)-butan-2-yl)-4-oxo-quinoline-3-carboxylate
(23c).
Starting from iodo derivate 16c and using
procedure described for the synthesis of 23a, compound
23c was obtained in 86.8% yield; off-white crystals, mp
192–194°C (HPLC purity 98.4%), which was used for
the next step without further purification.
(S)-Ethyl
(trimethylsilyloxy)-butan-2-yl)-4-oxo-quinoline-3-carboxylate
(23d).
6-iodo-1,4-dihydro-7-methoxy-1-(3-methyl-1-
Starting from iodo derivate 16d and using
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
An Improved Synthesis of Elvitegravir
211 (4.69), 254 (4.79), 269 (4.73), 315 (4.32). [α]D20
(DMSO) = ꢀ29.5°.
(S)-6-(3-Chloro-2-fluorobenzyl)-1,4-dihydro-1-(1-hydroxy-
3-methylbutan-2-yl)-7-methoxy-4-oxo-quinoline-3-carboxylic
acid–elvitegravir (1)
Method B.
Starting from iodo derivate 23c (0.52g,
Method A.
A mixture of 28a (4.6 g, 10mmol),
1 mmol) using procedure described as Method A, the
crude compound 28a was obtained in 75.8% yield
(HPLC purity 86.2%). Centrifugally accelerated axial
chromatography (CH2Cl2–MeOH) provided 0.25g
(54.1%) of compound 28a; white crystals, mp 195–201°C
(methanol). HPLC purity 98.8%.
methanol (45 mL), water (45 mL), and NaOH (2.5 g,
62.5 mmol) was stirred at room temperature for 5 h. The
slightly cloudy solution was diluted with water (25 mL)
and filtered, and the clear solution was acidified with
10% aqueous HCl. The formed precipitate was filtered
off, washed with water, and dried in vacuo to give 3.5g
(78.1%) of white solid; mp 153–156°C (Ref. [3], mp
151–152°C). [α]2D0 (MeOH) = ꢀ29.2° (Ref. [3] gives [α]2D5
(MeOH)= ꢀ29.7°). HPLC purity 98.9%. 1H NMR
(DMSOd6) δ (ppm): 8.88 (s, 1H, H-2), 8.04 (s, 1H, H-5),
7.47 (s, 1H, H-8), 7.18–7.22 (m, 3H, Ar-H), 4.86–4.92
(m, 1H, CHN), 4.11 (s, 2H, CH2), 4.04 (s, 3H, MeO),
3.98–4.00 (m, 1H, CH2OH), 3.78–3.81 (m, 1H, CH2OH),
2.36–2.39 (m, 1H, CHMe2), 1.16 (d, J= 6.5 Hz, 3H,
CHMe2), 0.73 (d, J =6.,5 Hz, 3H, CHMe2). 13C NMR
(DMSOd6) δ (ppm): 176.2, 166.3, 161.9, 155.7, 145.4,
142.4, 130.2, 128.8, 128.6, 127.7, 126.4, 125.3, 119.6,
118.9, 107.3, 98.1, 66.3, 60.1, 56.8, 29.2, 28.5, 19.1,
19.0. IR: ν(O–H) 3391, ν(C–H) 2969, ν(C¼O) 1699,
1612, ν(C¼C)AR 1456, ν(C–O) 1256cmꢀ1. UV λmax
(log ε): 209 (4.54), 258 (4.69), 313 (4.13). HRMS for
C23H24ClFNO5 (M + 1)+ Calcd: 448.1327, found:
448.1322.
Method C.
To a solution of compound 24a (0.5 g,
1 mmol) in THF (5 mL) under argon atmosphere was
added PdCl2(PPh3)2 (0.1 g). Then the temperature was
elevated to 60°C, and a 1M solution of 3-chloro-2-
fluorobenzylzinkbromide in THF (1.5 mL) was added by
syringe pump during 1 h, and the mixture was stirred at
this temperature for additional 4h. After cooling, the
mixture was poured into 1M aqueous HCl (20 mL), and
the mixture was stirred at room temperature for 4 h and
then extracted with dichloromethane (4 × 20 mL). The
extract was evaporated under reduced pressure and
dissolved in methanol (5 mL), and after addition of a
solution of sodium hydroxide (1 g) in water (10 mL), the
mixture was stirred at room temperature for 15h. Then
the mixture was acidified with acetic acid, and the formed
cloudy solution was left to stand in a refrigerator
overnight. The insoluble portion was filtered off to
provide 0.25g (56%) of off-white product; mp 193–200°C
(HPLC purity of 96.3%).
Method B.
Similar hydrolysis of 28b provided
elvitegravir (1) in 73.3% yield. HPLC purity 97.2%.
N,O-Bis(trimethylsilyl)-acetamide (2g,
(R)-Methyl
hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-quinoline-3-car
boxylate (R-28a).
6-(3-chloro-2-fluorobenzyl)-1,4-dihydro-1-(1-
Method C.
10mmol) was added to a suspension of compound 25a
(1.3 g, 3.4 mmol) in anhydrous THF (15 mL), and the
mixture was stirred at r.t. for 15min under argon. PdCl2
(PPh3)2 (40mg) was added, the temperature was elevated
Starting from 7.05 g (15 mmol)
derivate (R)-23a and using procedure described as
Method A in the synthesis of compound 28a, 4.9 g
(70.7%) of the corresponding R-isomer was obtained
as a white crystals; mp 192–198°C (HPLC purity
to 60°C, and
a
1M solution of 3-chloro-2-
fluorobenzylzinkbromide in THF (5 mL) was added by
syringe pump during 1 h, and the mixture was stirred at
this temperature for additional 1.5h. After cooling to 25°C,
water (10 mL) was added, followed by 5% HCl (0.5 mL)
and saturated solution of NH4Cl (10 mL), and the mixture
was extracted with ethyl acetate (50 mL). The extract was
washed with saturated solution of NH4Cl (10 mL) and
brine (2 × 10mL) and dried with MgSO4. The residue
after evaporation was crystallized from methanol
(charcoal) to give 1.3 g (85.6%) of off-white crystals; mp
151–156°C (decomp.). HPLC purity 96.3%.
1
95.7%). H NMR (DMSOd6) δ (ppm): 8.63 (s, 1H, H-
2), 7.89 (s, 1H, H-5), 7.47 (td, J = 7.6, 1.8 Hz, 1H, Ar-
H), 7.27 (s, 1H, H-8), 7.17–7.22 (m, 2H, Ar-H), 5.12
(t, J = 5.0 Hz, 1H, OH), 4.62–4.67 (m, 1H, CHN), 4.05
(s, 2H, CH2), 3.97 (s, 3H, MeO), 3.94–3.95 (m, 1H,
CH2OH), 3.78 (m, 1H, CH2OH), 3.72 (s, 3H,
COOMe), 2.27–2.32 (m, 1H, CHMe2), 1.13
(d, J = 6.6 Hz, 3H, CHMe2), 0.74 (d, J = 6.6 Hz, 3H,
CHMe2). 13C NMR (DMSOd6) δ (ppm): 171.7, 160.6,
165.4, 155.6, 145.7, 141.6, 130.2, 128.7, 128.6, 127.2,
125.5, 125.3, 121.7, 119.6, 109.5, 97.5, 65.2, 60.2,
56.5, 51.2, 29.0, 28.4, 19.2, 19.1.
(R)-6-(3-Chloro-2-fluorobenzyl)-1,4-dihydro-1-(1-hydroxy-
3-methylbutan-2-yl)-7-methoxy-4-oxo-quinoline-3-carboxylic
acid–elvitegravir (R-1). Starting from 1.15 g (2.5 mmol)
(S)-Ethyl
6-(3-chloro-2-fluorobenzyl)-1,4-dihydro-1-(1-
hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-quinoline-3-car
boxylate (28b). Starting from ethyl ester 23b and using
procedure described for the synthesis of 28a (Method A),
compound 28b was obtained in 80.8% yield; mp 178–183°C
(HPLC purity 93.8%), which was used for the next step
without further purification.
of derivate (R)-28a and using procedure described as
Method A in the synthesis of elvitegravir (1), 0.75 g
(66.9%) of R-isomer of elvitegravir was obtained as off-
white solid; mp 149–153°C (HPLC purity 98.1%). 1H
NMR (DMSOd6) δ (ppm): 8.88 (s, 1H, H-2), 8.04 (s, 1H,
H-5), 7.46 (s, 1H, H-8), 7.18–7.38 (m, 3H, Ar-H), 4.86–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Rádl, J. Stach, O. Píša, J. Cinibulk, J. Havlíček, M. Zajícová, and T. Pekárek
Vol 000
[4] Satoh, M.; Kawakami, H.; Itoh, Y.; Shinkai, H.; Motomura, T.;
Aramaki, H.; Matsuzaki, Y.; Watanabe, W.; Wamaki, S. (Japan Tobacco
Inc.) US 7,176,220 (WO 2004/0046115).
[5] (a) Radl, S.; Bouzard, D. Heterocycles 1992, 34, 2143; (b)
Ahmed, A.; Daneshtalab, M. J. Pharm Pharmaceut Sci 2012, 1, 52; (c)
Boteva, A. A.; Krasnykh, O. P. Chemistry of Heterocyclic Compounds
2009, 45, 757.
4.92 (m, 1H, CHN), 4.11 (s, 2H, CH2), 4.04 (s, 3H, MeO),
3.99 (dd, J= 12.4, 5.3 Hz, 1H, CH2OH), 3.78
(d, J= 12.4Hz, 1H, CH2OH), 2.36–2.39 (m, 1H,
CHMe2), 1.16 (d, J =6.5 Hz, 3H, CHMe2), 0.73
(d, J = 6.,5Hz, 3H, CHMe2). 13C NMR (DMSOd6) δ
(ppm): 176.2, 163.3, 161.9, 155.7, 145.4, 142.4, 130.2,
128.9, 128.1, 126.5, 126.4, 125.3, 119.6, 118.9, 107.3,
98.1, 66.3, 60.1, 56.8, 29.1, 28.5, 19.1, 19.0. [α]D20
(MeOH) = +29.5°. HRMS for C23H24ClFNO5 (M + 1)+
Calcd: 448.1327, found: 448.1352.
[6] Crasto, A. M. Org Spectroscopy Intl. (http://
orgspectroscopyint.blogspot.fr/search?q=elvitegravir).
[7] (a) Matsuda, K.; Koji, A.; Ohki, S.; Hoshi, J.; Yamasaki, T.
(Japan Tobacco Inc.) US 8,383,819; (b) Matsuda, K.; Koji, A.; Ohki, S.;
Yamasaki, T.; Hoshi, J. (Japan Tobacco Inc.) US 8,420,821.
[8] (a) Rival, Y.; Grassy, G.; Michel, G. Chem Pharm Bull 1992,
40, 1170; (b) Skoumbourdis, A. P.; Huang, R.; Southall, N.; Leister, W.;
Guo, V.; Cho, M.-H.; Inglese, J.; Nirenberg, M.; Austin, C. P.; Xia, M.;
Thomas, C. J. Bioorg Med Chem Lett 2008, 18, 1297; (c) Kihara, M.;
Nakanishi, A.; Kobayashi, S. Heterocycles 1989, 29, 957.
[9] (a) Mihigo, S. O.; Mammob, W.; Bezabih, M.; Andrae-
Marobela, K.; Abegaz, B. M. Bioorg Med Chem Lett 2010, 18, 2464;
(b) Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron, 2008, 64, 5191.
[10] (a) Nakano, J.; Uchida, K.; Fujimoto, Y. Heterocycles 1989,
29, 427; (b) Chen, Y.-F.; Lin, Y.-C.; Huang, P.-K.; Chan, H.-C.;
Kuo, S.-C.; Lee, K-H.; Huang, L.-J. Bioorg Med Chem 2013, 21, 5064;
[11] Rádl, S. Adv Het Chem 2002, 83, 189.
Acknowledgments. The authors’ thanks are due to Drs Jan Srbek
and Jiří Břicháč for the LC–MS and HRMS and to Dr David
Michalík and Ms Ilona Šuková for optical rotation measurements.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet