(Chloromethyl)dimethylchlorosilane-KF: A Two-Step Solution to the Selectivity Problem in the Methylation of a Pyrimidone Intermediate en Route to Raltegravir

Article abstract of DOI:10.1021/acs.oprd.7b00171

The present work describes a two-step process, namely, silylation with (chloromethyl)dimethylchlorosilane and desilylation, to address the selectivity problem in the N-methylation of a pyrimidone intermediate toward the synthesis of the raltegravir active pharmaceutical ingredient. The said methodology delivers the desired drug substance in which the O-methylated impurity content is below the detection limit by high-performance liquid chromatography analysis. Moreover, this two-step, one-pot procedure provides an apparent advantage in terms of environmental impact with respect to the optimum approach described in the literature, while it compares equally well in terms of cost and operational simplicity.

Full text of DOI:10.1021/acs.oprd.7b00171

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Communication
(Chloromethyl)dimethylchlorosilane-KF a Two-Step
Solution to the Selectivity Problem in the Methylation
of a Pyrimidone Intermediate en route to Raltegravir.
Christos Ioannis Stathakis, Petros Leonidas Gkizis, Elli Alexandraki, Sakellarios Trakossas, Michael
Terzidis, Efstratios Neokosmidis, Constantinos Klearchos Zacharis, Christina Vasiliadou, Elli
Vastardi, Thanos Andreou, Asteria Zitrou, Anastasia-Aikaterini Varvogli, and Theocharis Koftis
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00171 • Publication Date (Web): 31 Jul 2017
Downloaded from http://pubs.acs.org on July 31, 2017
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(Chloromethyl)dimethylchlorosilane-KF a Two-Step
Solution to the Selectivity Problem in the Methylation of
a Pyrimidone Intermediate en route to Raltegravir.
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Christos I. Stathakis,* Petros L. Gkizis, Elli S. Alexandraki, Sakellarios Trakossas, Michael
Terzidis, Efstratios Neokosmidis, Constantinos K. Zacharis, Christina Vasiliadou, Elli Vastardi,
Thanos Andreou, Asteria Zitrou, AnastasiaꢀAikaterini Varvogli and Theocharis V. Koftis*
th
Pharmathen S.A., API R&D Operations, 9 km Thessaloniki-Thermi, Thessaloniki 57001,
Greece
ABSTRACT: The present work describes a two-step process, namely silylation with
(chloromethyl)dimethylchlorosilane and desilylation, to address the selectivity problem in the N-
methylation of a pyrimidone intermediate towards the synthesis of raltegravir API. The said
methodology delivers the desired drug substance in which the O-methylated impurity content is
below detection limit by HPLC analysis. Moreover, this two-step one-pot procedure provides an
apparent advantage in terms of environmental impact with respect to the optimum approach
described in the literature, while it compares equally well in terms of cost and operational
simplicity.
KEYWORDS: Raltegravir, amide methylation, (chloromethyl)dimethylchlorosilane, industrial
preparations.
INTRODUCTION
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Raltegravir, in the form of its potassium salt (1; Figure 1), is an antiretroviral drug developed by
®
Merck & Co, for the treatment of HIV infection and is marketed under the trade name Isentress .
It is the first member of a new class of antiretroviral drugs interfering with the integration
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process of the viral encoded DNA into the host cell genome by inhibiting the enzyme integrase.
This new mode of action has certain advantages over other strategies currently followed (such as
reverse transcriptase inhibition) as it suffers to much lesser extent from resistance due to virus
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mutations. In addition, the new biological target, HIV integrase, has no equivalent in the human
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cell, which substantially lowers the risk of side effects.
Chemically, raltegravir (1) can be regarded as an N-methyl hydroxy-pyrimidone core, bearing a
hydrophobic benzylic moiety at C4 amide substituent, a crucial structural feature for binding to
the active site of the enzyme (Figure 1). Furthermore, the chelation of the triad consisting of the
amidic carbonyl of the C4 substituent and the two consecutive oxygen atoms on the pyrimidone
+
+
ring with two Mg metal ions is important as it resides within the catalytic pocket. Finally, a
second amide substituent, encompassing an oxadiazolyl moiety, is located at the bottom-left side
of the molecule, i.e. at the C2 position of the pyrimidone.
Figure 1. Structure of raltegravir (1) potassium salt
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The first chemical synthesis of the free phenol 1 was accomplished in 10 linear steps and low
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overall yield (3%; Scheme 1). This early synthetic attempt suffered from many drawbacks
which were partially overcome in the improved first generation process for the synthesis of
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raltegravir by Merck. In the latter, ta robust and atom-economical method was established for
the construction of the key hydroxy-pyrimidone core 4, via a thermal rearrangement of 3 (the
adduct of amidoxime 2 to dimethyl acetylenedicarboxylate; Scheme 1).
O
OH
COOMe
COOMe
O
N
OH
OMe
DMAD
N
HN
NH2
NH2
N
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NHCbz
NHCbz
O
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; 54% overall yield
acetone
cyanohydrin
raltegravir (1)
Scheme 1. Preparation of the hydroxy-pyrimidone intermediate 4. DMAD; Dimethyl
acetylenedicarboxylate.
The attempted direct N-methylation of 4, however, proved troublesome, as the isomeric O-
methylated compound 6 was also obtained. In many cases this undesired species was the major
product (Scheme 2; first generation route). After extensive experimentation the best result
achieved with this approach was a 78:22 ratio in favor of the desired 5 (MeI, Mg(OMe) , DMSO,
2
o
6
0 C). From this crude material, pure 5 was isolated in 70% yield after tedious purification still
contaminated by the isomeric 6 (approx. 1% by HPLC). With the poor selectivity in the
methylation reaction identified as the major issue in the synthesis of raltegravir, alternative
approaches were investigated. In the second generation process reported by Merck’s
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laboratories, the optimum methylation conditions described above were applied to the more
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chemically stable amide 7 and delivered a mixture of products in similar ratio of N-methyl 8 to
O-methyl 9 (80:20; Scheme 2). However, prolonged reaction time and addition of traces of water
to the reaction mixture, in combination with molecular iodine produced in situ, led to recycling
of the O-methyl isomer 9 in favor of the N-methyl compound 8. After further optimization
(2 equivs. Mg(OH) , 2 equivs. Me S(O)I, NMP, 100 °C, 6 h), the desired N-methyl intermediate
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was isolated in 89% yield and >99% purity.
Scheme 2. First and second generation methylation processes by Merck
Despite the indisputable improvement of the methylation process, undesirable features for a
multikilogram production still existed. Among them, one can include the in situ production of the
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extremely toxic MeI which, under the harsh reaction conditions (100 C for 6h), raises major
concerns due to safety and environmental risk. In addition, the reaction media, namely NMP (N-
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methylpyrrolidone), is not among the most desirable solvents for industrial applications. To add
to this, in an effort to evaluate the process in our laboratory, we found out that very careful
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removal of the solvent (< 1000 ppm) is essential for the following catalytic hydrogenation step to
be successful. For the same reason, removal of in situ generated DMSO, with a stricter limit of
detection (<100 ppm), proving necessary. Finally, a less energy consuming procedure would be
highly desirable.
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Seeking for alternative methods for the selective N-methylation of amides we came across a
report by Taylor et al., where (chloromethyl)dimethylchlorosilane was employed for the
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chemoselective methylation of amides and heterocycles. According to the proposed mechanism,
the initial activation of the nitrogen atom by hexamethyldisilazine (HMDS, Scheme 3), is
followed by a transilylation event to intermediate 12 and, thereafter, an intramolecular O-
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alkylation to the stabilized imidate 13. The desired N-alkylation product 14, comprising a
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pentacoordinate silicon atom, is effected after a Chapman-type rearrangement. The authors
found out that treatment of this silicon species with CsF afforded the N-methylated amides 15 in
good yields. They also demonstrated that the reaction sequence can operate equally well in the
presence of other nucleophiles.
Scheme 3. The proposed mechanism by Pestunovich et al. for the selective N-methylation of
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amides using (chloromethyl)dimethylchlorosilane
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In fact, we envisioned that the nitrogen atom of the carbamate substituent at C2 position could
react intramolecularly with the pentacoordinated silicon atom in 16a leading to a cyclic
intermediate (Scheme 4; suggested structure 16b), thus offering additional stabilization to the
system. Our hypothesis was further supported by analogous examples in the literature involving
suitable tethered sulfonamides that served as nucleophiles that eventually led to similar cyclic
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products.
Scheme 4. N-Methylation of 4 using (chloromethyl)dimethylchlorosilane. Proposed structures of
intermediates 16.
To test our theory we applied the suggested experimental conditions directly on the hydroxy-
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pyrimidone compound 4 (Scheme 4). Thus, refluxing of an acetonitrile solution of the latter
with HMDS for 3 h and then, addition of (chloromethyl)dimethylchlorosilane and further heating
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for 16 h gave a new compound as evidenced by TLC. By solvent exchange to diglyme and
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heating at 160 C, in the presence of CsF, we were pleased to find out that the desired N-
methylated product was afforded in 65% isolated yield. We were even more excited to note that
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the undesirable O-methylated pyrimidone 6, was below the detection limit by HPLC analysis
(0.01% w/w based on signal-to-noise = 3 criterion).
This initial achievement, although quite encouraging, called for improvement in many aspects of
the process (solvents, temperature, cost of reagents etc). Much effort was expended to these
factors, to deliver a much more industrially friendly process with an upgraded efficiency (78%
isolated yield). In particular, reaction time for the first step was shortened, while the desilylation
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step could be conducted in a solvent of much lower boiling point (THF; 65 C). We found that the
more manufacturing friendly solvent ethyl acetate could be employed for this purpose. Ethyl
acetate also resulted in a simplified work up process. Furthermore, we were happy to discover
that KF, a much more economical source of fluoride anions, could be utilized as the desilylation
agent instead of the costly CsF.
Scheme 5. The silylation-amidation-desilylation sequence on 4
As a further development to our process, we were keen to explore the possibility of carrying out
the N-4-fluorobenzylamide formation step before the desilylation event; thus combining two
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steps without any isolation of intermediates (Scheme 5). Hence, starting material 4 was treated
successively with HMDS and (chloromethyl)dimethylchlorosilane in boiling acetonitrile,
followed by solvent exchange to methanol and addition of 4-fluorobenzylamine and
triethylamine as base. Upon exposure to these conditions, the initially formed intermediate
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16(a or b) was fully converted within 30 mins to a new compound 17(a or b), which was then
subjected to desilylation with KF after a second solvent exchange to ethyl acetate. A simple
acidic work-up afforded the desired N-methylated amide 8 in 75-80% yield after
recrystallization. Once again, optimization of the process revealed that the desilylation step could
be carried out by direct addition of solid KF in the amidation reaction mixture in hot MeOH. The
formation of a colorless precipitate is indicative of the completion of the reaction. Demineralized
water is then added to the slurry and stirred for 1 h further. Crude amide 8 was collected as a
colorless solid by filtration under vacuum. To our delight, once again, HPLC analysis of 8
showed no detected O-methyl isomer 9, though, contamination by small amounts (3-4%) of non-
methylated compound 7 was observed, which was partially removed after recrystallization (0.5-
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a
Scheme 6. Completion of the synthesis of raltegravir. BDL; below detection limit (0.01% w/w
based on signal-to-noise = 3 criterion)
Despite the presence of trace amounts of 7, the material produced by the method described above
was able to ultimately deliver our pharmaceutical compound in superior quality. According to
our synthetic plan (Scheme 6), the advanced intermediate 8, was deprotected to free amine 18
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using catalytic hydrogenation under acidic conditions (glycolic acid). When this transformation
was first reported, it was mentioned that the resulting amine was obtained in its dihydrate form, a
fact that necessitated the use of excess (2.2 equivs) of the expensive heterocyclic carboxylic acid
5
potassium salt 19 to force the following amidation reaction to completion. Utilizing our
modified isolation conditions, amine 18 is reproducibly accessed with much lower water content
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(< 1.5% by Karl-Fischer titration).
The next step, the direct peptide coupling of free amine 18 with the chloride derived from salt
9, has been the center of interest for other research groups, as it represents the shortest path to
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raltegravir free phenol. In their patent published in 2012, Mylan Pharmaceuticals reported the
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use of TMSCl, among other agents, for the transient protection of the phenolic group in 18 and
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the trapping of excess water. Their process utilized more than 6 equivalents of TMSCl in order
to reduce the loading of 19 to 1.5 equivalents (compared to the 2.2 previously reported).
According to our assessment, the same result could be achieved using HMDS (2.0 equivs) as the
silylating agent. However, we observed that a portion of salt 19 (approximately 20%) was lost to
an undesirable reaction with HMDS. After much experimentation, we discovered that the
employment of 0.8 equivalents of HMDS in the presence of catalytic amounts of p-
toluenesulfonic acid could lead to a more controllable protection of hydroxyl group in compound
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18. This improvement restricts the requirement in salt 19 to as low as 1.25 equivalents. Under the
optimized conditions raltegravir free phenol is obtained in very high purity (>99.8%) by
precipitation from the reaction mixture. Finally, a typical treatment with EtOK (Scheme 6), led
to the respective potassium salt as a colorless solid, whose specifications met all the standards of
pharmacopeia with respect to the specific API.
In conclusion, we have successfully implemented and extensively modified a previously reported
methodology for the selective N-methylation of a common pyrimidone-type intermediate of
raltegravir, employing (chloromethyl)dimethylchlorosilane as silylating agent and KF as an
inexpensive source of fluoride anion for the desilylation step. The method has been properly
adjusted to reduce the safety and environmental risks and to fit for multikilogram production.
Furthermore, for the rest of the synthesis, the shortest path, which involves Cbz deprotection and
direct coupling with the oxadiazoloyl moiety, has been followed. Problems associated with water
removal and wasteful use of expensive salt 19 have been addressed to eventually deliver
raltegravir potassium salt (1) in high overall yield and excellent purity.
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EXPERIMENTAL DETAILS
General Remarks. All grade quality reagents commercially available were used without further
purification. All reactions were monitored on commercial available pre-coated TLC plates (layer
thickness 0.25mm) of Kieselgel 60 F254. Compounds were visualized by use of UV lamp or/and
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Seebach stain solution and heating. NMR spectra were recorded on a 500 MHz spectrometer ( H:
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00 MHz, C: 126 MHz). Chemical shifts are given in ppm and J in Hz using residual solvent as
an internal reference. IR spectra were recorded on an FTIR instrument as indicated. Mass spectra
were obtained by electro spray technique, positive mode (ES-MS). Melting points were
determined with a capillary apparatus and are uncorrected.
Methyl
2-(2-(((benzyloxy)carbonyl)amino)propan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-
dihydropyrimidine-4-carboxylate (5). A 500 ml 3-necked round bottom flask, equipped with a
reflux condenser and a thermometer is charged with 15.0 g (41.5 mmol) methyl 2-
(
2(((benzyloxy)carbonyl)amino)propan-2-yl)-5,6-dihydroxy-1,6dihydropyrimidine-4-carboxylate
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(
4) and 150 ml acetonitrile under inert atmosphere at 20-30 C. To the resulting suspension is
added with stirring 8.7 ml HMDS (41.5 mmol; 1.0 equiv) (suspension turns into clear solution)
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and mixture is heated at 80 C for 1 h. While still hot, 6.0 ml (chloromethyl)-
dimethylchlorosilane (45.7 mmol, 1.10 equivs) is added and heating is maintained for 2 h.
Reaction progress is monitored by TLC (DCM/MeOH= 95/5; double development). Upon
completion, the volatiles are evaporated off and the residue is further dried under high vacuum
for at least 30 min. To the residue is added 75 ml EtOAc and the mixture is heated and stirred
o
until a clear solution arises (approximately 60 C). 3.0 g KF (51.9 mmol; 1.25 equivs) is added
and stirring is maintained for approximately 1h. Upon completion, 50 ml demineralized water is
added. After stirring for 10 min, the mixture is left to settle. The upper organic phase is collected
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and washed with 50 ml water, then dried over anhydrous Na SO , filtered and evaporated down
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4
to afford 5 as off-white solid (12.1 g; 78% yield; >98% purity).
Benzyl (2-(4-((4-fluorobenzyl)carbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-
-yl)propan-2-yl)carbamate 8. A 2 L 3-necked round bottom flask, equipped with a mechanical
stirrer, a reflux condenser and a thermometer is charged with 150.0 g (0.42 mol) methyl 2-
0
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2
(2(((benzyloxy)carbonyl)amino)propan-2-yl)-5,6-dihydroxy-1,6dihydropyrimidine-4-carboxylate
o
(
4) and 0.75 L acetonitrile under inert atmosphere at 20-30 C. To the resulting suspension is
added with stirring 87 ml HMDS (0.42 mol; 1.0 equiv), the suspension slowly turns into a clear
o
solution and the mixture is heated at 80 C for 1 h. While still hot, 60.4 ml (chloromethyl)-
dimethylchlorosilane is added over 10-15 min and heating is maintained for 2 h. Reaction
progress is monitored by TLC (DCM/MeOH= 95/5; double development). Upon completion, the
mixture is evaporated down and the residue is further dried under vacuum for at least 30 min. To
the residue is added 0.75 L MeOH and the mixture stirred until a clear solution arises. 69.7 ml
(0.50 mol; 1.20 equivs) Et N is added followed by 57.2 ml (0.50 mol; 1.20 equivs) 4-F-
3
o
benzylamine and the resulting mixture is heated to 65 C for 1 h. While still hot, KF (30.8 g;
0.53 mol; 1.25 equivs) is added in one portion and heating maintained for 1-2 h. Upon
completion of the desilylation, a colorless solid precipitates from the reaction mixture. Reaction
is cooled down to ambient temperature and 1.12 L demineralized water is added and the slurry is
stirred for 1 h. Crude Benzyl (2-(4-((4-fluorobenzyl)carbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-
dihydropyrimidin-2-yl)propan-2-yl)carbamate (8) is afforded by filtration under vacuum. The
wet cake is washed with 0.45 L MeOH/H O (1:2) and pulled dry on the filter for 1 h. The
2
o
colorless solid is collected and dried further under vacuum at 30 C for 10 h. After
recrystallization with MeOH/H O= 3:1, pure 8 is obtained as colorless solid (159.8 g, 82%). IR
2
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(
film) 3346, 3237, 3145, 1712, 1674, 1533 cm , H-NMR (500 MHz, CDCl ) δ 11.89 (br, 1 H),
3
7
.77 (br, 1 H), 7.32-7.29 (m, 7H), 7.06-7.03 (m, 2 H), 5.21 (s, 1H), 5.00 (s, 1H), 4.56 (d, J = 6.0
1
3
Hz, 2H), 3.64 (s, 3H), 1.66 (s, 6 H), C-NMR (125 MHz, CDCl ) δ 168.4, 163.3 (d, J =246
3
CF
10
11
12
13
14
15
16
17
18
19
20
21
22
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53
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56
57
58
59
60
Hz), 161.4, 150.9, 133.1, 129.5, 129.4, 128.7, 128.2, 115.7 (d, J =21 Hz), 57.3, 42.4, 32.9, 28.0,
CF
1
9
+
F-NMR (470 MHz, CDCl ) δ -114.5 (br s), HRMS (ESI) calculated for C H FN O (M+H)
3
24 25
4
5
469.1887, found 469.1880.
2-(2-Aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-
dihydropyrimidine-4-carboxamide 18. A slurry suspension of 500 g (1.07 mol) Benzyl (2-(4-
(4-fluorobenzyl)carbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2yl)
(
carbamate 8, 190 ml (2.13 mol) glycolic acid (67% w/w) and 25g 5% Pd/C (50% w/w) in 5 L
methanol was hydrogenated at 130 psi for 3-4 h. The reaction mixture was transferred to a 20 L
glass reactor and diluted with 10 L MeOH, filtered through celite bed and washed with 0.5 L
o
MeOH. The combined filtrates ware concentrated to a total volume of 5.5 L at 25-28 C and
neutralized by 325 ml Et N. The formed crystalline solid is collected by filtration, rinsed with
3
0.5L MeOH and dried under vacuum to afford 325 g (0.97 mol; 91% yield, 99.6% purity) of 2-
(2-Aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-
o
-1 1
carboxamide (18). mp 190.6-190.8 C, IR (film) 3666, 3199,2978, 1639, 1551, 1509 cm , H-
NMR (500 MHz, DMSO-d ) δ 10.16 (br, 1 H), 7.33-7.30 (m, 2H), 7.14-7.10 (m, 2H), 4.45 (d, J
6
1
3
= 6.0 Hz, 2H), 3.68 (s, 3H), 1.56 (s, 6H), C-NMR (125 MHz, DMSO-d ) δ 168.1, 162.1 (d,
6
J =243 Hz), 160.2, 135.6, 129.3 (d, J = 8 Hz), 123.2, 115.0 (d, J = 22 Hz), 55.9, 48.6, 41.3,
CF
CF
CF
1
9
3
3.1, 28.2, F-NMR (470 MHz, CDCl ) δ -116.2 (tt), HRMS (ESI) calculated for C H FN O
3 16 19 4
3
+
(M+H) 335.1419, found 335.1417.
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Raltegravir (1) free phenol. A mixture of oxadiazole potassium salt 19 (238.5 g, 1.43 mol),
o
acetonitrile (1.2 L), and DMF (7.4 ml) was cooled to -5 C and oxalyl chloride (115.2 ml, 1.34
o
mol) is added over 30 min. The resulting slurry was aged at 0-5 C for 1 h and then cooled
0
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o
to -10 C. A slurry of 2-(2-Aminopropan-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-
1,6-dihydropyrimidine-4-carboxamide (18) (300 g, 0.90 mol) and THF (3L) was stirred at room
temperature and HMDS (148.5 ml, 0.72 mol) is added dropwise over a period of 5 min. To the
resulting suspension 5.13 g p-TsOH (26.8 mmol) was added in one portion. The reaction mixture
o
o
was heated at 60-65 C for 2 h, then cooled down to around -5 C and N-methylmorpholine
o
(
296.4 ml, 2.69 mol) was added. The resulting solution was aged at -5 C for 20-30 min. The
oxadiazole acid chloride, prepared above, was added dropwise to the amine containing slurry
o
reaction mixture at -5 C over 45 min. Reaction is monitored with HPLC and after completion
o
2
0% aq. potassium hydroxide (1.50 L) was added and the reaction mixture is stirred at 5 C for
1
h. HCl 2N (1.11 L) was added over 10-15 min to adjust the pH at 3-4 and the reaction mass is
o
warmed at 15 C. 11.25 L water was added slowly over 1 h. The resulting white suspension was
o
aged at 15 C for 1 h and filtered. The cake was washed with 0.90 L H O/acetonitrile (2.5:1) and
2
0.90 L water. The colorless solid is dried further to afford raltegravir free phenol (337 g, 84%
yield; 98.7% purity). This material was optionally recrystallized from 7.5 L H O/acetonitrile
2
(2.5:1) to deliver raltegravir free phenol in 99.7% purity (recrystallization yield 91%). mp 141.0-
o
-1 1
145.2 C. IR (film) 3583, 3492, 3340, 3302, 1703, 1686, 1637, 1597, 1505 cm , H-NMR (500
MHz, DMSO-d ) δ 12.24 (s, 1 H), 9.90 (s, 1H), 9.12 (t, J = 6.4 Hz, 1 H), 7.41-7.38 (m, 2 H),
6
13
7
.19-7.15 (m, 2 H), 4.51 (d, J = 6.4 Hz, 2 H), 3.48 (s, 3 H), 2.56 (s, 3 H), 1.74 (s, 6 H), C-NMR
(
125 MHz, DMSO-d ) δ 168.4, 165.8, 162.3 (d, J =241 Hz), 158.6, 158.1, 152.6, 151.8, 145.8,
6
CF
1
34.9, 129.7 (d, J =6 Hz), 129.5 (d, J =6 Hz), 124.5, 115.5, 57.6, 41.7, 33.1, 27.1, 10.9, 10.7,
CF CF
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F-NMR (470 MHz, CDCl ) δ -115.7 (tt), HRMS (ESI) calculated for C H FN O 445.1636
3
20 21
6
5
found 445.1631
Raltegravir (1) potassium salt. To a suspension of raltegravir free phenol (100 g, 0.23 mol) in
10
11
12
13
14
15
16
17
18
19
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EtOH (1.0 L) a solution of KOH (17.7 g) in 0.75 L H O was added slowly over a period of 30
2
min. To the reaction mixture 1.0 L EtOH was then added over 30 min. The reaction was stirred
o
at 25 C for 90 min. A colorless solid was formed that was collected by filtration and rinsed with
o
0
.5 L EtOH. The cake was dried further for 10 h at 50 C under vacuum to afford raltegravir
o
potassium salt (1) (95.0 g, 88% yield, 99.8% purity). mp 267.2-267.6 C. IR (film) 3416, 3259,
-1 1
1
697, 1639, 1572, 1536, 1509, 1486 cm , H-NMR (500 MHz, DMSO-d ) δ 11.68 (s, 1 H), 9.75
6
(s, 1H), 7.34-7.31 (m, 2 H), 7.13-7.10 (m, 2 H), 4.45 (d, J = 6.0 Hz, 2 H), 3.40 (s, 3 H), 2.56 (s, 3
1
3
H), 1.70 (s, 6 H), C-NMR (125 MHz, DMSO-d ) δ167.3, 165.9, 165.4, 161.9 (d, J =242 Hz),
6
CF
1
59.9, 158.6, 157.4, 151.9, 137.9, 137.1 (d, J =3 Hz), 129.0 (d, J =8 Hz), 122.4, 114.9 (d,
CF CF
19
J =22 Hz), 57.2, 40.9, 32.1, 26.9, 10.7. F-NMR (470 MHz, CDCl ) δ -116.7 (br s).
CF
3
ASSOCIATED CONTENT
1
13
19
H, C and F NMR spectra of compounds 8, 18 and 1 are listed in the Supporting Information.
Experimental details of the performed HPLC method and the chromatograms of compound 8 and
final API raltegravir (1) potassium salt are also included. The following files are available free of
charge.
1
13
19
H, C and F NMR spectra (file type, i.e., PDF)
AUTHOR INFORMATION:
Corresponding Author
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th
*
Address: Pharmathen S.A. 9 km Thessaloniki-Thermi, Thessaloniki, 57001, Greece.
Phone: +30 2310 477600. E-mail: cstathakis@pharmathen.com; hkoftis@pharmathen.com.
ABBREVIATIONS
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
0
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0
API, Active Pharmaceutical Ingredient; DMAD, dimethyl acetylenedicarboxylate; NMP, N-
methyl-2-pyrrolidone; DMSO, dimethylsulfoxide; HPLC, high performance liquid
chromatography;
HMDS,
hexamethyldisilazine;
THF,
tetrahydrofuran;
TMSCl,
trimethylchlorosilane; TLC, thin layer chromatography.
REFERENCES
1
For a recent review see: Lesbats, P.; Engelman, A. N.; Cherepanov, P. Chem. Rev. 2016, 116,
1
2730–12757.
2
(a) Mouscadet, J. F.; Delelis, O.; Marcelin, A.G.; Tchertanov, L. Drug resist. updat. 2010, 13,
1
39–150. (b) Cocohoba, J.; Dong, B. J. Clinical therapeutics. 2008, 30, 1747–1765.
3
Pommier, Y.; Johnson, A. A.; Marchand, C. Nat Rev Drug Discov. 2005, 4, 236–248.
4
(a) Crescenzi, B.; Gardelli, C.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.;
Petrocchi, A.; Poma, M.; Rowley, M. J.; Scarpelli, R.; Summa, V. PCT Int. Appl.
WO2003035077 A2 20030501, 2003. (b) 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.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore,
G.; Scarpelli, R.; Stillmock, K.; Witmer, M. V.; Rowley, M. J. J. Med. Chem. 2008, 51, 5843–
5
855.
5
Belyk, K. M.; Morrison, H. G.; Jones, P.; Summa, V. PCT Int. Appl. WO2006060712 A2
20060608, 2006.
6
(
a) Humphrey, G. R.; Miller, R. A.; Maligres, P. E.; Weissman S. PCT Int. Appl.
WO2009088729 A1 20090716, 2009. (b) Humphrey, G. R.; Pye, P. J.; Zhong, Y.-L.; Angelaud,
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R.; 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, 73-83.
7
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NMP belongs to Class 2 in the classification of Organic solvents (ICH Q3C, guideline for
residual solvents, 2016).
8
Bassindale, A. R.; Parker, D. J.; Patel, P.; Taylor, P. G. Tetrahedron Lett. 2000, 41, 4933-
4936
9
(a) Yoder, C. H.; Ryan, C. M.; Martin, G. F.; Ho, P. S. J. Organomet. Chem. 1980, 190, 1-7.
(b) Kalikhman, I. D.; Albanov, A. I.; Bannikova, O. B.; Belousova, L-I.; Voronkov, M. G.;
Pestunovich, V. A.; Shipov, A. G.; Kramarova, E. P.; Baukov, Y. I. J. Organomet. Chem. 1989,
361, 147-155. (c) ref. 8.
1
0
Chapman A. W. J. Chem. Soc., Trans., 1925, 127, 1992-1998.
1
1
For analogous example see: Shipov, A. G.; Kramarova, E. P.; Fang, H.; Arkhipov, D. E.;
Nikolin, A. A.; Bylikin, S. Y.; Negrebetsky, V. V.; Korlyukov, A. A.; Voronina, N. A.;
Bassindale, A. R.; Taylor, P.G.; Baukov, Y. I. J. Organomet. Chem. 2013, 741ꢀ742, 114-121:
1
2
Although acetonitrile belongs to Class 2 of organic solvents, as NMP does, its removal to the
dictated limits is much more effective.
1
3
The exact structure of the intermediate could not be unambiguously determined by common
spectroscopic techniques (NMR, HPLC and LC-MS) due to the inherent instability of both
suggested compounds.
14
Intermediate 17 also proved too labile for its structure to be identified.
1
5
Under these reaction conditions, the formation of 7 in crude 8 seemed inevitable.
Suppression of impurity 7 was achieved by using TMSCl/Et N in place of HMDS, however the
3
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material thus produced was of diminished purity. Efforts to improve the impurity profile of 8
obtained by the aforementioned modification are currently underway.
1
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The deprotected amine 18 was found to be free of the corresponding non-methylated
impurity (< 0.1% by HPLC).
1
7
Precipitation of compound 18 from a more dilute methanolic solution allows for more
effective reduction of water content from the precipitate. For more details see experimental part.
1
8
Dandala, R.; Vellanki, S. R. P.; Balusu, R. B.; Javvaji, R. R.; Ravi, M. R. Indian Patent
Office IN/736/CHE/2012 20120228, 2012.
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graphical abstract
1
73x47mm (300 x 300 DPI)
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