A Facile Synthesis of Raltegravir Potassium—An HIV Integrase Inhibitor

Article abstract of DOI:10.1002/jhet.3663

A facile, cost-effective, and commercially viable synthesis of Raltegravir Potassium (1) has been developed from 2-(1-amino-1-methyl-ethyl)-N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-6-oxo-4-pyrimidinecarboxamide (9) with high purity and in good yields. In addition, a new approach for the synthesis of key amine intermediate (9) of Raltegravir Potassium (1) from commercially available 2-amino-2-methylpropanenitrile hydrochloride (2) is also described. The key features of the synthesis are fewer synthetic steps, employing the inexpensive reagents and eco-friendly.

Full text of DOI:10.1002/jhet.3663

Month 2019 A Facile Synthesis of Raltegravir Potassium—An HIV Integrase Inhibitor
Kishore Karumanchi,a,b*
a
a
a
Gangadhara Bhima Shankar Nangi, Subba Reddy Danda, Ramadas Chavakula,
b
b
Raghu Babu Korupolu, and Kishore Babu Bonige
a
Chemical Research and Development, APL Research Centre-II, Aurobindo Pharma Ltd., Survey No. 71 & 72, Indrakaran
Village, Kandi Mandal, Sangareddy, Telangana 502329, India
Department of Engineering Chemistry, Andhra University College of Engineering, Visakhapatnam, Andhra Pradesh
b
530003, India
*
E-mail: kkishore009@gmail.com
Received March 20, 2019
DOI 10.1002/jhet.3663
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A facile, cost-effective, and commercially viable synthesis of Raltegravir Potassium (1) has been
developed from 2-(1-amino-1-methyl-ethyl)-N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-
6
-oxo-4-pyrimidinecarboxamide (9) with high purity and in good yields. In addition, a new approach for
the synthesis of key amine intermediate (9) of Raltegravir Potassium (1) from commercially available
-amino-2-methylpropanenitrile hydrochloride (2) is also described. The key features of the synthesis are
fewer synthetic steps, employing the inexpensive reagents and eco-friendly.
2
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
methyl-1,3,4-oxadiazol-2-yl)-carbonyl]amino}ethyl)-6-
oxo-4-pyrimidinecarboxylate with 4-fluorobenzylamine
to produce 1. The major disadvantages of the above
chemical synthesis include several number low
yielding steps, unselective N-methylation, Pd/C-catalyzed
hydrogenation for benzylchloroformate deprotection
(non-eco-friendly), final amidation step, multiple
chromatographic purifications, multiple use of halogenated
solvents, and using highly toxic and expensive
1,4-dioxane. Furthermore, this chemical process also
contains additional protection and deprotection steps for
the preparation of 1. Thus, this chemical synthesis is not
preferable for commercial production because of
environmental concerns.
Another literature report [3] describes the second-
generation manufacturing route for the preparation of 1 by
the condensation of pivaloyl-protected amine intermediate
(9) with oxadiazole carbonyl chloride (10). The synthesis
of key amine intermediate (9) is also started from the
benzylchloroformate protection of acetone cyanohydrin
[1]. And in the end, the debenzylation is performed by
Human immunodeficiency virus type-1 (HIV-1) is the
contributory agent of acquired immunodeficiency
syndrome. HIV-1 integrase is one of the three virally
encoded enzymes essential for replication and therefore a
rational target for chemotherapeutic intervention in the
treatment of HIV-1 infection. Raltegravir Potassium (1) is
a commercially available antiretroviral agent, discovered
by Merck Research Laboratories. It is the first HIV
integrase inhibitor, approved by USFDA for the treatment
of HIV-1 infection [1]. Raltegravir Potassium is marketed
under the brand name ISENTRESS.
A literature review revealed several synthetic routes of
Raltegravir Potassium (1). The first generation
manufacturing route [2] describes the preparation of
1
starting from Strecker’s reaction of commercially
accessible acetone cyanohydrin in 10 synthetic steps.
Additionally, another variant of process is also described
in this literature report [2] by the condensation of methyl-
1
,6-dihydro-5-(benzoyloxy)-1-methyl-2-(1-methyl-1-{[5-
©
2019 Wiley Periodicals, Inc.

K. Karumanchi, G. B. S. Nangi, S. R. Danda, R. Chavakula, R. B. Korupolu, and K. B. Bonige
Vol 000
Pd/C-catalyzed hydrogenation. Additionally, difficulties
observed during the Pd/C-catalyzed hydrogenation for
debenzylation are also described in this report. Glycolic
acid is used as an additive to resolve the solubility issue
during the hydrogenation. Furthermore, there is a
possibility of desfluoro impurity during the hydrogenation
using Pd/C. However, this synthetic route also consists of
hydrogenation and pivaloyl protection that are not
necessary.
addition between 4 to dimethyl acetylenedicarboxylate
(DMAD) and subsequent thermal rearrangement afforded
2-(1-methyloxycarbonylamino-1-methyl-ethyl)-5-hydroxy
-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methy
lester (6). Coupling reaction of 6 with 4-fluoroben
zylamine in the presence of triethylamine produced N-[(4-
fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-2-[(1-methyl
-1-[[(methoxy)carbonyl]amino]ethyl-6-oxo-4-pyrimidine
carboxamide (7). N-methylation of compound 7 with
Further, another report [4] discloses the preparation of 1
by the condensation of oxadiazole carbonyl chloride (10)
with commercially available acetone cyanohydrin [1], in
order to avoid protection/deprotection of amino group in
acetone cyanohydrin. However, this synthesis consists of
operations including acid/base treatments as well as
thermal rearrangement at high temperature. Later, another
literature report [5] describes the identification and
synthesis of potential impurities observed during the
manufacturing of 1. In addition, the formation of some of
the impurities due to the degradation of oxadiazole
moiety of 1 is also described in this report. Moreover,
one of the impurities is synthesized by treating 1 with
base. Thus, it clearly indicates the sensitivity and
degradation tendency of oxadiazole moiety. Therefore, it
is extremely difficult to control the degradation in this
route of synthesis. Thus, these synthetic routes are not
advantageous for large-scale production.
trimethylsulphoxoniumiodide[Me S(O)I] in the presence
3
of magnesium hydroxide or magnesium oxide resulted
N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-me
thyl-2-[(1-methyl-1-[[(methoxy)carbonyl]amino]ethyl]-6-
oxo-4-pyrimidine carboxamide (8). The deprotection of
MOC group in 8 in the presence of NaOH afforded 2-(1-
amino-1-methyl-ethyl)-N-[(4-fluorophenyl)methyl]-1,6-di
hydro-5-hydroxy-1-methyl-6-oxo-4-pyrimidine
carbo
xamide (9). The amidation of 9 with oxadiazole carbonyl
chloride (10) in the presence of N-methylmorpholine
produced Raltegravir (11). Treatment of Raltegravir (11)
with aqueous KOH in ethanol accomplished Raltegravir
Potassium (1) as a crystalline colorless solid.
Optimization of compound 4.
The first step in our
synthesis was initiated from the protection of amino
group in 2. Our aim was to eliminate Pd/C-catalyzed
hydrogenation in order to resolve the previous difficulties
described in literature for debenzylation. In support of
that, several protecting reagents were tested including
MOC, ethylchloroformate, di-tert-butyl dicarbonate, and
fluorenylmethyloxycarbonylchloride that could eliminate
the hydrogenation. Among these, we chose commercially
inexpensive MOC [7] as a protecting reagent for amino
group in 2. After selecting the suitable protecting reagent,
we studied different suitable base reagents including
diisopropyl amine, triethylamine, sodium carbonate, and
sodium hydroxide. Theoretically, 2 mole equivalents of
base reagent and 1 mole equivalent of MOC were
required for the amino group protection. However, we
achieved best results while 1.1 mole equivalents of MOC
and 2.25 mole equivalents of diisopropylethylamine in
dichloromethane (DCM) at 0–10°C to obtain the
optimum yield and purity.
With compound 3 in hand, the preparation of oxime
compound (4) from 3 using hydroxyl amine was
investigated. As per literature [2,3], the free hydroxyl
amine solution was isolated by treating hydroxylamine
hydrochloride in methanol in the presence of NaOH.
The precipitated salts were removed by filtration, and
the filtrate containing free hydroxylamine was used for
the oxime preparation. During the initial development,
we carried out oxime reaction in situ by treating 3 with
free hydroxylamine solution in methanol. We tried to
execute this process in kilo lab but unfortunately
observed the degradation of hydroxylamine solution
In consequence, there is a need for substitute synthetic
pathways, which, for example, utilize inexpensive
reagents and are eco-friendly. In this perspective, we
have developed an improved and scalable synthesis for
the preparation of Raltegravir Potassium (1) with 99.9%
chromatographic purity.
RESULTS AND DISCUSSION
Though, all aforementioned issues for the permanent
manufacturing of Raltegravir Potassium (1), we
recognized and focused on two major challenges, namely,
the elimination of inherently hazardous Pd/C-catalyzed
hydrogenation as well as the elimination of pivaloyl
protection/deprotection that are incompatible.
The present article covered by our patent [6] provides the
preparation of Raltegravir Potassium (1) (Scheme 1)
commenced from commercially available 2-amino-2-
methylpropanenitrile hydrochloride (2) in seven synthetic
steps. Protection of amino group in compound 2 with
methylchloroformate (MOC) in the presence of
diisopropylethylamine produced (cyano-dimethyl-methyl)
carbamic acid methylester (3). Addition of hydroxyl
amine to 3 generated its corresponding oxime, that is,
[1-(N-hydroxycarbamimidoyl)-1-methyl-ethyl]carbamic
acid methylester (4) as a crystalline solid. Michael
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
A Facile Synthesis of Raltegravir Potassium—An HIV Integrase Inhibitor
Scheme 1. A facile and improved synthesis of Raltegravir Potassium (1).
in methanol. To understand the degradation
of hydroxylamine solution, we examined the
sensitivity/stability of hydroxylamine solution towards
temperature, air, and base. Based on the results, we
anticipated that the degradation of hydroxylamine
solution was due to either oxygen or temperature.
Later, we modified the reaction conditions and
succeeded substantially by carrying out the reaction in
situ under nitrogen atmosphere without using free
hydroxylamine solution in methanol. And in the
workup, the inorganic salts present in the reaction mass
were saturated with demineralized water, and the
product was collected by filtration to obtain optimum
yield and purity.
Optimization of compound 6.
After optimizing the
robust synthesis of oxime reaction, we then focused on
the preparation of DMAD adduct (5), which upon
thermal rearrangement in situ to produce 6. DMAD
adduct (5) was prepared by Michael addition of oxime
compound (4) with 1.1 mole equivalents of DMAD in
mild conditions in methanol. After completion of the
reaction, DMAD adduct (5) was isolated by evaporating
methanol under vacuum as an isomeric mixture. Thermal
rearrangement [8,9] of the above obtained isomeric
Journal of Heterocyclic Chemistry
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K. Karumanchi, G. B. S. Nangi, S. R. Danda, R. Chavakula, R. B. Korupolu, and K. B. Bonige
Vol 000
residue at high temperature (120–125°C for 2 h followed
by 130–135°C for 5 h) afforded 6. After studying the key
process parameters for the thermal rearrangement, we
shifted our attention on isolation of pure product. During
the initial lab experiments, we isolated compound 6 from
a mixture of MTBE and methanol. But we achieved low
yield, poor crystal nature and description of 6. To resolve
the aforementioned issues, we screened several solvents
including methanol, acetone, and isopropanol for the
isolation of 6. Agreeably, the best results were achieved
while methanol was used for the isolation of 6.
and quality were observed while the reaction was
performed with magnesium oxide (MgO) instead of Mg
(OH) . The experimental details are stated in Table 1.
2
Optimization of compound 9.
Subsequently, our
attention was shifted towards the optimization of MOC
group deprotection. Considering the cost, we selected
commercially inexpensive NaOH for MOC deprotection
reaction. In order to develop the robust synthesis for
MOC deprotection reaction, we screened different
parameters including solvents, mole ratios of base, and
temperature. Gratifyingly, we achieved best results while
3 mole equivalents of NaOH was used at 105–110°C in
n-butanol. Under these optimum conditions, we
achieved 98% of product conversion with 99.8%
of chromatographic purity. This deprotection was
successfully performed without adding any additive.
After the isolation, the amine intermediate 9 was obtained
Optimization of compound 7. The coupling reaction of
6
with 4-fluorobenzylamine resulted desired 7. During our
initial experiments in lab, we carried out the
coupling reaction of 6 with 1 mole equivalent of
4
-fluorobenzylamine to afford 7. However, the reaction
was not completed. Later, different mole equivalents of
-fluorobenzylamine were screened for this coupling
4
as a monohydrate. To achieve anhydrous amine
reaction. Thereafter, the reaction was completed while
compound 6 was treated with 2.1 mole equivalents of
intermediate 9 for the subsequent amidation reaction, the
moisture in amine intermediate 9 was removed by
Dean–Stark apparatus. The experimental details are stated
in Table 2.
4-fluorobenzylamine in methanol under reflux condition.
In the view of cost, the reaction was modified by using a
mixture of 1.1 mole equivalents of inexpensive
triethylamine (as a base) and 1.1 mole equivalents of
Optimization of Raltegravir (11).
Consequently, our
aim was to eliminate protection and deprotection of
hydroxy group in 9 during the amidation reaction with 10.
In support of that, we carried out the amidation reaction
with 2 mole equivalents of expensive oxadiazole carbonyl
chloride (10) (1 mole equivalent for desired amidation
reaction and 1 mole equivalent for the protection of
hydroxy group in 9). As expected, the reaction was
completed, but the cost was enhanced. Thus, we intended
to reduce the consumption of expensive 10 in this reaction
in order to reduce the cost. Later, we introduced
commercially inexpensive trimethylsilylchloride [11] as a
partial protecting reagent for hydroxy group of amine
intermediate 9. In addition, trimethylsilylchloride was also
useful to maintain moisture-free condition in this
amidation reaction. Most agreeably, the coupling of
trimethylsilyl-protected compound 9 (formed by the
treatment of 9 with trimethylsilylchloride) with oxadiazole
carbonyl chloride 10, subsequent treatment with aqueous
KOH produced Raltegravir (11). This amidation between
4
-fluorobenzylamine in order to achieve good conversion
for this coupling reaction. Under these optimum
conditions, we achieved 98% of conversion and 99% of
chromatographic purity.
Optimization of compound 8.
Despite several
reagents
were
available
for
N-methylation,
trimethylsulfoxoniumiodide [10] was selected to be the
suitable reagent because of relative cost, safety profile, and
ease of handling. In addition, magnesium hydroxide was
selected as a base reagent for N-methylation of 7. With the
intention to develop a robust N-methylation reaction,
different mole ratios of trimethylsulfoxoniumiodide as
well as magnesium hydroxide were screened. We
attained best results, while 2 mole equivalents of
trimethylsulfoxoniumiodide as well as Mg (OH)2 in
N-methyl-2-pyrrolidinone used for N-methylation
reaction. Under these specified conditions, highest yield
and purity was achieved. Surprisingly, almost same yield
Table 1
Reagent, solvent, and time screening studies of 8.
Entry
Me
3
S(O)I (moles)
Mg (OH)
2
(moles)
MgO
Solvent
Temp. (°C)
Time (h)
Conversion (%)
1
2
3
4
5
1.6
2.0
2.0
2.0
2.0
1.6
2.0
2.0
2.0
—
—
—
—
—
2.0
NMP
NMP
NMP
NMP
NMP
100–110
80–85
120–125
95–105
95–105
4
14
3
4
4
75
92
74
94
93
†
NMP, N-methyl-2-pyrrolidinone.
†
Ideal condition.
Journal of Heterocyclic Chemistry
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Month 2019
A Facile Synthesis of Raltegravir Potassium—An HIV Integrase Inhibitor
Table 2
Reagent, solvent, and time screening studies of 9.
Entry
NaOH (moles)
Solvent
Temp. (°C)
Time (h)
Conversion (%)
1
2
3
4
2.5
2.0
2.5
2.5
3.0
Water
Ethanol
15% Aq n-butanol
2% Aq n-butanol
n-Butanol
95–100
75–78
100–110
105–110
105–110
9
10
3
1
3
NA
64
68
90
98
‡
5
‡
Ideal condition.
9
and 10 using trimethylsilylchloride in the presence of N-
Phenyl 4.6 × 150, 3.5 μm at 25°C with flow rate of
1.0 mL/min. The run time was 40 min, and the detection
was at UV, 240 nm.
methylmorpholine resulted excellent product conversion.
The experimental details of amidation reaction were
presented in Table 3. Treatment of Raltegravir (11) with
aqueous KOH in ethanol generated desired Raltegravir
Potassium (1).
EXPERIMENTAL
Preparation of [1-(N-hydroxycarbamimidoyl)-1-methyl-
ethyl]carbamic acid methylester (4). To a suspension of
MATERIALS AND METHODS
2
-amino-2-methylpropanenitrile hydrochloride (2) (250 g,
All the solvents and raw materials were purchased from
the commercial sources and used without purification. The
IR spectra were recorded in solid-state KBr dispersion
2.073 mol) in DCM (1750 mL), diisopropylethylamine
(602 g, 4.66 mol) was added at 20–30°C under nitrogen
atmosphere. The reaction mass was cooled to 0–5°C, and
methyl chloroformate (216 g, 2.28 mol) was added for
about 60 min. The reaction mass was stirred for 60 min
at 0–10°C, and demineralized water (750 mL) was added
to the reaction mass. The pH of the reaction mass was
adjusted to 2.0 to 2.5 with concentrated HCl at 0–10°C.
The reaction mass was warmed to 20–30°C. The organic
layer was separated and was washed with demineralized
water (500 mL), prior to the distillation under reduced
pressure to afford compound 3 as colorless oil.
Separately, in another reactor, hydroxylamine
hydrochloride (194.5 g, 2.79 mol) was suspended in
methanol (375 mL) at 20–30°C under nitrogen
atmosphere. The slurry was cooled to 0–5°C, and NaOH
(110 g, 2.73 mol) solution in methanol (625 mL) was
added. Compound 3 was diluted in methanol (250 mL)
and was added to this reaction mass at 0–10°C. The
reaction mass was warmed and stirred at 20–30°C for
16 h. After completion of the reaction, acetic acid (40 g,
1
using Perkin Elmer FTIR spectrometer. The H NMR and
1
3
C NMR spectra were recorded on Bruker-Advance
00 MHz and Varian 500 MHz spectrometers. The
3
chemical shifts were reported in δ ppm relative to
tetramethylsilane (TMS) (internal standard). The mass
spectra were recorded on API 2000 Perkin Elmer PE-
SCIEX mass spectrometer. Melting points were
determined and were uncorrected by Polmon melting
point apparatus (model no. MP-96). The purity/impurity
ratios and the reaction monitoring of compound 3 were
determined by GC system with Flame Ionization Detector
(Agilent 7890 A GC) with DB-17 column containing 6%
cyanopropyl phenyl and 94% dimethyl polysiloxane
copolymer capillary column of 60 mL length and
0.53 mm ID, and film thickness was 1 μm. Column flow
was 5.0 mL/min, and the run time was 60 min. The
purity/impurity ratios and the reaction monitoring of
remaining compounds were determined by Eclipse XDB
Table 3
Reagent optimization studies of amidation reaction.
Entry
9 moles
10 moles
TMSCl (moles)
NMM (moles)
Solvent
Conversion (11) (%)
1
2
3
4
1.0
1.0
1.0
1.0
1.0
2.10
2.20
1.50
1.25
1.20
—
—
—
2.50
2.25
5.0
3.0
3.0
3.5
3.5
ACN
DCM
DCM
DCM
DCM
74
86
81
92
93
§
5
ACN, acetonitrile; DCM, dichloromethane; NMM, N-methylmorpholine; TMSCl, trimethylsilylchloride.
§
Ideal condition.
Journal of Heterocyclic Chemistry
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K. Karumanchi, G. B. S. Nangi, S. R. Danda, R. Chavakula, R. B. Korupolu, and K. B. Bonige
Vol 000
0.66 mol) was added uniformly. Thereafter, the reaction
DMSO-d ) δ: 168.67, 162.90, 158.33, 155.18, 153.85,
6
mass was concentrated under reduced pressure.
Demineralized water (500 mL) was added to the
concentrated mass, and the slurry was stirred for 1 h at
147.45, 134.84 (2C), 129.54 (2C), 125.82, 115.26 (2C),
54.87, 51.51, 26.03; HRMS (ESI) calculated for
+
C H FN O (M + H) 379.1418, found: 379.1361.
17
19
4 5
2
0–30°C. The product was collected by filtration and
Preparation of N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-
hydroxy-1-methyl-2-[(1-methyl-1-[[(methoxy)carbonyl]
dried to afford compound 4 (280 g, 78%) as a colorless
solid. Purity by HPLC: 99.8%, mp: 142–146°C. H NMR
1
amino]ethyl]-6-oxo-4-pyrimidine carboxamide (8).
To
a suspension of compound 7 (200 g, 0.528 mol) in
N-methyl-2-pyrrolidinone (320 mL), trimethylsul
(
(
300 MHz, DMSO-d ) δ: 1.36 (s, 6H), 3.48 (s, 3H), 5.16
s, 2H), 6.90 (s, 1H), 9.04 (s, 1H); C NMR (300 MHz,
6
1
3
DMSO-d ) δ: 155.99, 155.02, 53.24, 50.90, 25.93;
phoxoniumiodide (233 g, 1.05 mol) and magnesium
hydroxide (62 g, 1.05 mol) were added. The reaction mass
was warmed and stirred at 95–105°C for 4 h. The reaction
mass was cooled to 20–30°C, and methanol (344 mL)
followed by aqueous HCl (5N, 172 mL) were added
uniformly. The reaction mass was stirred for 15 min, and
aqueous sodium metabisulphite solution (2.6M, 10 mL)
and aqueous HCl (5N, 172 mL) were added. The reaction
mass was then warmed and stirred at 30–35° for 1 h. The
resulting slurry was cooled and stirred at 10–15°C for 1 h.
The product was collected by filtration and dried to yield
compound 8 (187 g, 90%) as an off-white solid. Purity by
6
+
HRMS (ESI) calculated for C H N O (M + H)
6
13 3 3
176.1035, found: 176.1040.
Preparation of 2-(1-methyloxycarbonylamino-1-methyl-
ethyl)-5-hydroxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic
acid methylester (6). To a 15–20°C solution of compound
4
(250 g, 1.427 mol) under nitrogen atmosphere in
methanol (1250 mL), DMAD (223 g, 1.56 mol) was
added. The reaction mass was stirred for 2 h at 20–30°C.
The reaction mass was concentrated under reduced
pressure to afford compound 5 as dark brown oil.
O-xylene (625 mL) was added to the above concentrated
mass and was warmed to 120–125°C. The reaction mass
was stirred for 2 h at 120–125°C and then stirred for 5 h
at 130–135°C. The reaction mass was cooled to 40–
1
HPLC: 99.7%, mp: 206–211°C. H NMR (300 MHz,
DMSO-d ) δ: 1.61 (s, 6H), 3.34–3.54 (m, 6H), 4.50–4.52
6
(d, 2H, J = 6.3 Hz), 7.14–7.20 (m, 2H), 7.36–7.41
(m, 2H), 7.94 (s, 1H), 8.99–9.03 (t, 1H, J = 6.45 Hz),
50°C, and methanol (750 mL) was added. The slurry was
13
warmed and stirred under a gentle reflux for 1 h. The
reaction mass was cooled and stirred at 20–25°C for 1 h.
The product was collected by filtration and dried to
afford compound 6 (262 g, 64%) as a pale brown solid.
12.17 (s, 1H); C NMR (300 MHz, DMSO-d ) δ: 168.43,
6
162.87, 159.65, 158.67, 155.03, 152.49, 145.54, 134.86
(2C), 129.50 (2C), 124.27, 115.23 (2C), 56.50, 51.32,
32.55, 27.48; HRMS (ESI) calculated for C H FN O
4 5
18
21
1
+
Purity by HPLC: 99%, mp: 218–219°C. H NMR
(M + H) 393.1574, found: 393.1574.
(
3
(
300 MHz, DMSO-d ) δ: 1.45–1.48 (s, 6H), 3.49 (s, 3H),
6
Preparation of 2-(1-amino-1-methyl-ethyl)-N-[(4-fluoro
phenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-6-oxo-4-
.81–3.84 (d, 2H), 7.29 (s, 1H), 10.24 (s, 1H), 12.53
13
s, 1H); C NMR (300 MHz, DMSO-d ) δ: 166.09,
pyrimidine carboxamide (9).
To a suspension of
6
1
5
59.35, 155.11, 153.36, 144.71, 127.79, 54.77, 52.15,
1.14, 26.05; HRMS (ESI) calculated for C H N O
1 15 3 6
compound 8 (200 g, 0.509 mol) in n-butanol (600 mL),
sodium hydroxide (61 g, 1.52 mol) was added. The
reaction mass was warmed and stirred at 105–110°C for
1
+
(M + H) 286.1039, found: 286.1046.
3
h. The reaction mass was cooled to 80–90°C, and
Preparation of N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-
hydroxy-2-[(1-methyl-1-[[(methoxy)carbonyl]amino]ethyl-6-
oxo-4-pyrimidine carboxamide (7). To a suspension of 6
n-butanol (400 mL) was distilled out from the reaction
mass under reduced pressure. Thereafter, the reaction
mass was cooled to 0–5°C, and demineralized water
(600 mL) was added. The pH of the reaction mass was
adjusted to 6.5 to 7.0 with aqueous HCl at 0–5°C. The
precipitated product was stirred for 1 h at 0–5°C and was
collected by filtration. The wet product was suspended in
toluene (2 L), and the moisture was collected by
Dean–Stark apparatus. The slurry was cooled and stirred
for 2 h at 20–30°C under nitrogen atmosphere. The
product was collected by filtration under nitrogen
atmosphere and dried to afford compound 9 (150 g, 85%)
(
(
(
200 g, 0.701 mol) in methanol (320 L), triethylamine
78 g, 0.771 mol) followed by 4-fluorobenzylamine
97 g, 0.771 mol) were added slowly portionwise for 30–
4
0 min. The reaction mass was warmed and stirred under
a gentle reflux for 6 h. After cooling the reaction mass to
0–55°C, acetic acid (84.13 g, 42.35 mol) and
5
demineralized water (330 mL) were added uniformly.
The reaction mass was then cooled and stirred for 2 h at
20–30°C. The product was collected by filtration and
dried to afford compound 7 (260 g, 98%) as a pale brown
solid. Purity by HPLC: 99.4%, mp: decomposed at
as an off-white solid. Purity by HPLC: 99.9%, mp:
1
1
2
10°C. H NMR (300 MHz, DMSO-d ) δ: 1.52 (s, 6H),
196–198°C. H NMR (300 MHz, DMSO-d ) δ: 1.55
6
6
3
.50 (s, 3H), 4.49–4.52 (d, 2H, J = 6.3 Hz), 7.13–7.21
(s, 6H), 3.72 (s, 3H), 4.44–4.46 (d, J = 6.3 Hz), 7.09–
13
(m, 2H), 7.36–7.42 (m, 3H), 9.22–9.26 (t, 1H,
7.16 (m, 2H), 7.30–7.34 (m, 2H), 10.00 (s, 1H);
C
1
3
J = 3.75 Hz), 12.42 (s, 2H); C NMR (300 MHz,
NMR (300 MHz, DMSO-d ) δ: 167.94, 162.73, 161.23,
6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
A Facile Synthesis of Raltegravir Potassium—An HIV Integrase Inhibitor
1
1
59.52, 149.81, 135.50 (2C), 129.25 (2C), 123.33, 115.10,
14.82, 55.79, 41.32, 33.20, 28.51 (2C); HRMS (ESI)
for 2 h. The product was collected by filtration and dried
to afford 1 as a colorless solid (185 g, 85%). Purity by
HPLC: 99.91%, mp: 283.62°C, lit [12]. 286°C. H NMR
+
1
calculated for C H FN O (M + H) : 335.1519, found:
16
19
4 3
335.1523.
(500 MHz, DMSO-d ) δ: 1.69 (s, 6H), 2.56–2.49
6
(
m, 3H), 3.33–3.39 (d, J = 14 Hz, 3H), 4.43–4.44 (d, 2H,
J = 3.2 Hz), 7.09–7.13 (m, 2H), 7.31–7.33 (m, 2H), 9.73
s, 1H), 11.70 (s, 1H).
Preparation of N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-
hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-
oxadiazole-2-yl)carbonyl]-amino]ethyl]-6-oxo-4-pyrimidine
carboxamide (Raltegravir) (11). To a 25–40°C suspension
(
of compound 9 (200 g, 0.598 mol) in DCM (1600 mL),
N-methylmorpholine (212 g, 2.09 mol) and trimethyl
silylchloride (147 g, 1.346) were added portionwise
under nitrogen atmosphere. The reaction mass was stirred
CONCLUSION
In summary, we described a facile, efficient, and
commercially viable synthesis of Raltegravir Potassium. In
addition, a new approach for the synthesis of 2-(1-amino-
for
2 h under reflux. The resultant slurry was
cooled to 0–5°C.
Meanwhile, in another reactor, to a 0–5°C suspension
of 1,3,5-oxadiazole potassium (10A) (129 g, 0.778) in
DCM (800 mL), N,N-dimethylformamide (2.2 g,
1
-methylethyl)-N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-
hydroxy-1-methyl-6-oxo-4-pyrimidinecarboxamide (9), a
key amine intermediate of Raltegravir Potassium, was also
described. This present synthetic approach has the
following advantages over the previous reported
preparations: (i) avoids non-eco-friendly hydrogenation,
0.029 mol) followed by oxalyl chloride (91.1 g,
0.714 mol) were added at À5 to 5°C for about 30–
40 min under nitrogen atmosphere. The reaction mass
was stirred for 4 h at 0–5°C, and the resultant
oxadiazole carbonyl chloride (10) was added
portionwise to the above prepared silylated slurry of
compound 9 at 0–5°C. The reaction mass was stirred
for 2 h at 0–5°C, and demineralized water (400 mL)
was added. The reaction mass was warmed and stirred
for 10 min at 20–25°C. The pH of the reaction mass
was adjusted to 10.5 with aqueous KOH solution.
Further, the reaction mass was stirred for 2 h at
(
ii) uses inexpensive reagents, for example, MOC and
trimethylsilylchloride, (iii) includes a simple workup
procedure, (iv) avoids unnecessary synthetic steps, for
example, pivaloyl protection, and (v) avoids the usage
unnecessary reagents, for example, glycolic acid as an
additive for solubility. These modifications make the
whole synthesis cost-effective, production-friendly,
greener, and practical. These advances have been executed
effectively at 12 kg scale in pilot plant.
20–25°C, and the pH of the reaction mass was
readjusted to 4.4–4.6 with acetic acid. The organic
layer was separated and washed with demineralized
water (2 × 600 mL). The organic layer was then
distilled out completely under reduced pressure. To the
obtained residue, ethanol (1200 mL) was added,
warmed, and stirred under reflux for 2 h. The resultant
slurry was cooled and stirred for 1 h at ambient
temperature. The product was collected by filtration and
was dried to afford 11 as an off-white solid (266 g,
Acknowledgments. The authors acknowledge the management
of Aurobindo Pharma Limited for allowing publishing this
work. The authors also thank the Chemical Research
Department and Analytical Research Development for the
support and fruitful cooperation.
ABBREVIATIONS
9
1%). Purity by HPLC: 99.89%, mp: 216–218°C,
1
lit [1]. 216°C. H NMR (500 MHz, DMSO-d ) δ: 1.74
6
DCM: dichloromethane
MOC: methylchloroformate
DMAD: dimethyl acetylenedicarboxylate
(
3
(
1
s, 6H), 2.50–2.56 (m, 3H), 3.33–3.48 (t, J = 38.5 Hz,
H), 4.52–4.50 (d, 2H, J = 3.2 Hz), 7.15–7.17
m, 2H), 7.38–7.41 (m, 2H), 9.07 (s, 1H), 9.84 (s, 1H),
2.20 (s, 1H); HRMS (ESI) calculated for
+
C H FN O (M + H) : 445.1636, found: 445.1631.
2
0
21
6 5
REFERENCES AND NOTES
Preparation of N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-
hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-
oxadiazole-2-yl)carbonyl]-amino]ethyl]-6-oxo-4-pyrimidine
carboxamide potassium salt (Raltegravir Potassium) (1).
To a 39–41°C suspension of Raltegravir (11) (200 g) in
ethanol (2000 mL), 35% w/w aqueous potassium
hydroxide solution (81.7 g) was added. The slurry was
allowed to cool to ambient temperature and was stirred
[
1] Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi,
M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D. J.;
Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muragila, E.; Nizi, E.;
Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer,
M. V.; Rowley, M. J Med Chem 2008, 51, 5843.
[2] Crescenzi, B.; Gardelli, C.; Muragila, E.; Orvieto, F.; Pace, P.;
Pescatore, G.; Petrocchi, A.; Poma, M.; Rowley, M.; Scarpelli, R.;
Summa, V.; Nizi, E. US Patent 7,169,780 B2, 2001; Chem Abstr
138:354001.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. Karumanchi, G. B. S. Nangi, S. R. Danda, R. Chavakula, R. B. Korupolu, and K. B. Bonige
Vol 000
[
3] Humphery, G. R.; Pye, P. J.; Zhong, Y. L.; Angelaud, R.;
[9] Culbertson, T. P. J Heterocyclic Chem 1979, 16, 1423.
[10] Sarik, M.; Upender, K. N.; Pramod, S. P. Synth Commun
2008, 38, 3074.
Askin, D.; Belyk, K. M.; Maligres, P. E.; Mancheno, D. E.; Miller, R.
A.; Reamer, R. A.; Weissman, S. A. Org Process Res Dev 2011, 15, 73.
[
4] Mukund, K. G.; Swapnil, P. S.; Golakchandra, S. M.;
[11] Giovanni, S.; Roberto, B.; Franca, B.; Giovanna, B.;
Raimondo, M.; Paolo, R. Chem Rev 2004, 104, 199.
[12] Belyk, K. M.; Morrison, H. G.; Mahajan, A. J.; Kumke, D. J.;
Tung, H-H.; Wai, L.; Pruzinsky, V. US Patent 7,754,731 B2, 2010; Chem
Abstr 145:28009.
Gulabrao, D. P.; Shivnath, B. S.; Pankaj, S.; Samit, S. M. US PatentChem
Abstr 2011, 9, 159, 809 B2, 196987.
[5] Gulabrao, D. P.; Siddheshwar, W. K.; Shivnath, B. S.; Pankaj,
S. P.; Mangesh, S. D.; Ashok, T. C.; Swapnil, P. S.; Golak, C. M.;
Mukund, K. G. Org Process Res Dev 2012, 16, 1422.
[6] Shankar Reddy, B.; Jagan Mohan Reddy, S.; Subba Reddy, D.;
Bhima Shankar, G.; Somappa Somannavar, Y.; Kishore, K.;
Sivakumaran, M. US10,259,778 B2, 2019; Chem Abstr 2016:1451002.
SUPPORTING INFORMATION
[7] Sampson, P.; Ragan, J. A. (2009). Methyl Chloroformate. En-
cyclopedia of Reagents for Organic Synthesis. https://onlinelibrary.wiley.
com/doi/abs/https://doi.org/10.1002/047084289X.rm160.pub2 (accessed
on May 2019).
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
[8] Philip, J. P.; Yong-Li, Z.; Gavin, O. J.; Robert, A. R.; Kendall,
N. H.; David, A. Angew Chem Int Ed 2008, 47, 4134.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet