A Robust Kilo-Scale Synthesis of Doravirine

Article abstract of DOI:10.1021/acs.oprd.6b00163

Doravirine is non-nucleoside reverse transcriptase inhibitor (NNRTI) currently in phase III clinical trials for the treatment of HIV infection. Herein we describe a robust kilo-scale synthesis for its manufacture. The structure and origin of major impurit

Full text of DOI:10.1021/acs.oprd.6b00163

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Full Paper
A Robust Kilo-Scale Synthesis of Doravirine
Louis-Charles Campeau, Qinghao Chen, Danny Gauvreau, Mélina Girardin, Kevin M. Belyk,
Peter E. Maligres, Guoyue Zhou, Chaozhan Gu, Wei Zhang, Lushi Tan, and Paul Denis O'Shea
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00163 • Publication Date (Web): 05 Jul 2016
Downloaded from http://pubs.acs.org on July 6, 2016
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A Robust KiloꢀScale Synthesis of Doravirine
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LouisꢀCharles Campeau*,†,‡, Qinghao Chen†, Danny Gauvreau‡, Mélina Girardin‡, Kevin
Belyk†, Peter Maligres†, Guoyue Zhouǁ, Chaozhan Guǁ, Wei Zhangǁ, Lushi Tan†, Paul D. O’Shea‡
†Process Research and Development, Merck Research Laboratories, 126 E. Lincoln Ave.
Rahway New Jersey 07065.
‡Process Research and Development, Merck Frosst Center for Therapeutic Research, 16711
Trans Canada Highway, Kirkland, Quebec, Canada ́ H9H 3L1.
ǁWuXi AppTec Co., Ltd., No. 1 Building, #288 FuTe ZhongLu, WaiGaoQiao Free Trade Zone,
Shanghai 200131, China
*Corresponding Author: louisꢀcharles_campeau@merck.com
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TOC Abstract
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Cl
I
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Cl
CN
O
H
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Cl
CN
O
Cl
CN
O
O
Cl
NH
F
Me
N
F3C
H
O
O
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N
N
N
O
O
F3C
N
N
NH
NH
F3C
F3C
Cl
H
N
Doravirine
O
N
NH
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ABSTRACT Doravirine is nonꢀnucleoside reverse transcriptase inhibitor (NNRTI) currently in
phase III clinical trials for the treatment of HIV infection. Herein we describe a robust kiloꢀscale
synthesis for its manufacture. The structure and origin of major impurities were determined and
their downstream fateꢀandꢀpurge studied. This resulted in a reꢀdesign of the route to introduce
the key nitrile functionality via a copper mediated cyanation which allowed all impurities to be
controlled to an acceptable level. The improved synthesis was scaled to prepare ~100 kg batches
of doravirine to supply all preꢀclinical and clinical studies up to phase III. The synthesis affords
high quality material in a longest linear sequence of 6 steps and 37% overall yield.
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Keywords: nonꢀnucleoside reverse transcriptase inhibitor (NNRTI), Doravirine, CꢀH
Borylation, Cyanation
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Introduction. Highly active antiretroviral therapy (HAART) is the standard of care for the
treatment of HIV infection.1 A critical component of this treatment is often a nonꢀnucleoside
reverse transcriptase inhibitor (NNRTI).2 Efavirenz is a first generation NNRTI3 which has been
coꢀformulated with tenofovir disoproxil fumarate and emtricitabine both nucleoside reverse
transcriptase inhibitors (NRTI), as a onceꢀaꢀday fixedꢀdose combination (Atripla®). This firstꢀ
line therapy reached a premier market position given its proven efficacy, tolerability and
convenient dosing regimen.4 However, neurocognitive side effects,5 teratogenicity,6 and
complications of hyperlipidemia7 have been associated with efavirenz treatment. Coupled with
the emergence of clinical resistance to first generation NNTRIs, there is a critical need for the
development of a superior, second generation of these lifeꢀsaving medications.8
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Results and Discussion. Our discovery efforts toward this goal identified doravirine (1) as a
potential second generation NNRTI, and this compound has advanced into Phase III clinical
trials.9 To support its preclinical and early clinical development, we required a robust and
practical synthesis suitable for kiloꢀscale deliveries. Our retrosynthetic approach to 1 leveraged
the discovery chemistry strategy used to establish the triazolinone pharmacophore via lateꢀstage
alkylation of pyridone intermediate 2. Early synthetic evaluation of a lateꢀstage methylation of
readily accessible penultimate revealed formation of several distinct impurities in the active
pharmaceutical ingredient (API) which would have to be reduced to meet our target
specifications (Scheme 1). For milligramꢀscale synthesis, this was only possible using tedious
HPLC purification. LCMS revealed that these impurities fall into two classes; those resulting
from monoꢀ and bisꢀmethylation. Only two isomers of the monoꢀmethylated impurities, along
with two bisꢀmethylated impurities were typically observed and the extent to which each formed
largely depended on the methyl iodide charge and reaction conditions. However, one impurity
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was identified as a bisꢀCN doravirine 3, which we tracked to the upstream pyridone synthesis. In
fact, close examination of the lot of pyridone 2 which had been used to synthesize the material in
discovery chemistry, revealed presence of bisꢀcyanopyridone 2-CN (Scheme 2). After extensive
crystallization studies at the penultimate and final steps failed to identify adequate conditions for
the removal 3,10 we set out to develop a route to pyridone 2 in which formation of this bisꢀcyano
impurity would be limited to <0.5% area by HPLC.
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With this critical knowledge, we first set out to address the robustness of the sequence and
develop a process which could be rapidly scaled to kilogram quantities to help accelerate the
development of doravirine.
Scheme 1. Synthetic Strategy and Impurities for doravirine Chemical Process
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Pyridone Synthesis. The original route to pyridone 2 (scheme 2), was largely limited by the
availability of 1,3,5ꢀsubstituted benzene raw materials. To achieve differentiated substitution, 1ꢀ
bromoꢀ3ꢀchloroꢀ5ꢀfluorobenzene was selected. This arene underwent a selective SNAr reaction
with methoxide, the product of which was converted to the phenol using boron tribromide.9
Elaboration to the cyanation precursor 4 was then straightforward via two successive substitution
reactions on 2ꢀchloroꢀ3ꢀfluoroꢀ4ꢀtrifluoromethyl pyridine. Several palladium catalysts were
screened for the cyanation of 4,11 some of which showed ~1 % bisꢀcyano impurity in a smallꢀ
scale controlled gloveꢀbox environment. This protocol called for reduction of the Pd (II) preꢀ
catalyst with zinc dust and use of Zn(CN)2 as the cyanide source. However, while these optimal
conditions led to a high yield, >1% HPLC of bisꢀcyanation impurity 2-CN on laboratory scale,
outside the gloveꢀbox environment. Given that we intended to target a specification <1% of 2-
CN and that this impurity tended to enrich in the endꢀgame an alternative approach was sought.
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Scheme 2. Original Route to Pyridione 2
We then explored copper mediated cyanation reactions, hoping to achieve better selectivity;
however attempts at cyanation of the aryl bromide with copper cyanide underscored the
difficulty of this transformation. Screening of solvent and temperature revealed that at <90 ºC, no
reaction occurred. Increasing the temperature to >130 ºC afforded ~70% conversion overnight
with formation of several impurities including the bisꢀcyano 2-CN.
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In light of the challenges associated with the synthesis of 2, we elected to evaluate an
alternative substrate for cyanation which would enable the use of milder and hopefully more
selective cyanation conditions. Early proofꢀofꢀconcept for this strategy was quickly achieved
using commercially available 3ꢀchloroꢀ5ꢀiodoꢀphenol. Treatment of iodoꢀpyridone 5 with CuCN
in DMF or NMP at 120ºC readily afforded complete conversion to the desired pyridone with no
observed formation of the bisꢀcyano impurity.12 The corresponding palladiumꢀcatalyzed protocol
led to significant amounts of a desꢀchloro impurity so we opted to move forward with the
copperꢀmediated protocol. Due to its limited availability on bulk scale, the development of a
scalable synthesis of 3ꢀchloroꢀ5ꢀiodoꢀphenol was required, which we envisioned via metaꢀ
selective CꢀH borylationꢀoxidation of 3ꢀiodoꢀchlorobenzene.13 Initially, we employed 4,4´ꢀdiꢀ
tertꢀbutylꢀ2,2´ꢀbipyridyl (dtbpy) as the ligand in the iridiumꢀcatalyzed borylation.14 The high cost
and long lead time for this ligand led us to examine alternative bipyridyl ligands for this
transformation and we were delighted to find that the simple 2,2´ꢀbipyridyl was a suitable
replacement. Moreover, we were also able to reduce the iridium loading from the initial 1.5ꢀ3.0
mol% to 0.8ꢀ1.0 mol%. By running the borylation as a concentrated solution in cyclohexane, the
subsequent oxidation step could be run as a throughꢀprocess. After a solvent switch from
cyclohexane to acetone, the pinacol boronate intermediate solution is cooled and a 25 wt%
aqueous oxone solution is added while maintaining the temperature between 0ꢀ10ºC.15 After
workꢀup and carbon treatment, the phenol could be directly used in the subsequent step as a
solution in NMP. This process was readily executed on an 85 kg batch to afford the desired
phenol in 94% assay yield. The two subsequent steps were adapted from the original route,
continuing as a through process. First, 3ꢀchloroꢀ5ꢀiodophenol was coupled with pyridine 2ꢀ
chloroꢀ3ꢀfluoroꢀ4ꢀtrifluoromethylpyridine by carbonateꢀmediated SNAr , affording 5 in 91%
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assay yield on 65 kg scale. Hydrolysis of chloropyridine 5 to pyridone 6 could be accomplished
using either sodium or potassium hydroxide but the latter resulted in agglomeration of potassium
salts and was not amenable to large scale synthesis. In contrast, the use of sodium hydroxide
provided a reaction mixture that remained a wellꢀagitated slurry throughout the course of the
reaction. Pyridone 6 could then be isolated directly by addition of aqueous HCl to the mixture,
and the crude solid was reꢀcrystallized from ethyl acetate and nꢀheptane to provide compound 6
in 87% yield and 99% purity over the 3ꢀstep through process. Cyanation of of iodopyridone 6
using the aforementioned CuCN process in NMP at 105ꢀ110 °C provided full conversion to
nitrile 2. We found that controlling the temperature below 110 ºC was beneficial to the overall
impurity profile of 2. Following a buffered ammonia workꢀup to remove copper salts, the
pyridone could be isolated via crystalization from an NMP solution by addition of water. The
process was successfully executed on 92 kg scale and final pyridone 2 was isolated in 87% yield
from 6 and 99.1% purity. The bisꢀcyano pyridone impurity 2-CN could not be detected in
material obtained from this route.
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Scheme 3. Improved Synthesis of Pyridone 2.
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Triazolinone and End-Game. When considering options for incorporation of the Nꢀ
methyltriazolinone moiety, we were mindful of the fact that we could readily procure large
quantities of desꢀmethylated triazinolinone which is an intermediate in the manufacturing
process of another Merck product, EMEND®.16 The bulk availability of this intermediate for
early deliveries prompted us to explore a twoꢀstep process, where we first introduced the
heterocycle and then affixed the methyl group in the final step. Desꢀmethyl doravirine 7 was
readily prepared by alkylation of pyridone 2 with triazolinone chloride and potassium carbonate
in DMF at ꢀ10 ºC.17 Material which meets specifications, including complete rejection of the
triazolinone chloride, can be obtained by reꢀcrystallization from acetonitrile/water in 81%
isolated yield. This protocol was executed on 122 kg scale batches.
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Screening of base and solvent for the final methylation step immediately revealed that the
highest levels of conversion to product could be obtained in DMAc or DMSO (Figure 1). This is
most likely due to the very low solubility of pyridone 2 in many organic solvents. Closer
examination of reaction profile led us to choose potassium carbonate as the base for the final
coupling which provided endꢀofꢀreaction streams with 76% purity on screening scale at room
temperature. Moving from DMAc to NMP as the reaction solvent further enhanced the process,
providing a similar reaction profile while enabling direct isolation of the crude compound after
addition of water, and obviating the need for an aqueous workꢀup. To reach an optimal balance
between yield and formation of the bisꢀmethylated impurities, we elected to not drive the
reaction to completion and instead opted to quench the reaction once >90% conversion was
reached. Additional bisꢀmethylated impurities were observed when the reaction was carried out
at 40 ºC, keeping the reaction between 5ꢀ10 ºC provided optimal balance of reaction time and
purity profile.
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Figure 1. Base and Solvent Screen for Final Methylation Step.a
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40 40 70 90
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a% conversion measured by HPLC analysis using 1.05 equiv. of MeI and 3.0 equiv. of base at
0.2 M.
At the end of reaction, filtration of the heterogeneous base followed by direct crystallization of
the API by addition of ~1.5 volumes of water afforded the crude API (1) with 89ꢀ90% HPLC
purity. The main impurity in the crude material is a bisꢀmethylated impurity at ~5% HPLC.
There are three other main impurities, 1 bisꢀmethylated and 2 monoꢀmethylated regionꢀisomers.
The API could then be recrystallized from NMP:EtOH (~8:1) at ~75 ºC which yields doravirine
in 69% yield and high purity (99.1%). This improved endꢀgame process was executed on 130 kg
batches to afford >92 kg of API per batch.
Scheme 4. Doravirine EndꢀGame and Final Recrystallization.
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Cl
CN
O
Cl
CN
O
Cl
CN
O
Cl
H
1) MeI, K2CO3, NMP
1) K2CO3, DMF, -10ºC
N
H
Me
N
+
O
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N
2) NMP:EtOH (8:1)
69%
2) MeCN/Water recryst.
81%
NH
N
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N
O
O
NH
N
N
NH
NH
F3C
F3C
F3C
7
Doravirine (1)
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Conclusion. In summary, we developed a robust, scalable synthesis of doravirine. The focus
of our strategy was to enable rapid acceleration of doravirine into preclinical and clinical
development. With this in mind, we developed a process that leveraged existing knowledge for
the triazolinone fragment. We identified the structure and origin of major impurities and were
able to develop a robust process which either eliminated or purged these to acceptable levels,
delivering material in greater than 99% purity. The process was quickly developed on labꢀscale
to supply initial preclinical drug substance and was then scaled up to provide material on >90 kg
batches of final API.
EXPERIMENTAL PROCEDURES
Preparation of 3-chloro-5-iodo phenol. 1ꢀchloroꢀ3ꢀiodobenzene (75.0 kg, 314.5 mol) was
dissolved in cyclohexane (950 L) in a glassꢀlined vessel under nitrogen and the mixture was
degassed by reducing pressure and backꢀfillingwith nitrogen. Bis(pinacolato) diboron is then
charged (96.0 kg 468.2 mol) along with bis(1.5ꢀcyclooctadiene) diꢀµꢀmethoxydiridium(I) (1.0
kg, 1.6 mol, 0.005 equiv.) and 4,4’ꢀbypyridine (0.98 kg, 6.3 mol, 0.02 equiv.). The mixture is
further degassed for 20 minutes before raising the temperature between 50ꢀ55 ºC. The mixture is
aged for 12ꢀ20h until HPLC analysis showed less than 2% remaining starting material. The
reaction mixture is then solvent switched to acetone keeping the temperature below 40 ºC to final
volume of ~1000 L. After cooling back to 0ꢀ10 ºC, 20.5 w% aqueous oxone solution (718.0 kg,
237.5 mol) is added slowly over 9ꢀ10h keeping the temperature between 0ꢀ10 ºC. After addition,
the reaction was complete and an aqueous 10% NaHSO3 quench is then added over 30 minutes at
the same temperature. Upon further stirring for 30 minutes, the reaction was concentrated to
~1200 L. Ethyl acetate (750 L) is added to the mixture which is stirred for 30 minutes between
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20ꢀ30 ºC. Stirring was stopped and the aqueous layer was separated. The organic layer was
filtered via 9.0 kg of activated charcoal. The charcoal was further washed with ethyl acetate (200
L). The organic layer was then washed with water (400 L) and concentrated and azeotroped with
nꢀheptane. The solution in finally solvent switched to NMP resulting in a 10.4 weight % NMP
solution of known 3ꢀchloroꢀ5ꢀiodo phenol (75.3 kg, 94.1% assay yield, 98.5% LCAP) which
could be used directly in the next step. Spectral data was consistent with what is already
reported.
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Preparation of 6 (3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridin-2-ol). 3ꢀchloroꢀ5ꢀ
iodo phenol (83.4 kg, 331.7 mol) as a ~10 w% solution in NMP is diluted with further NMP
(~250 L) to a final approximate volume of 1000 L. Potassium carbonate (66.8 kg, 483.3 mol) and
2ꢀchloroꢀ3ꢀfluoroꢀ4ꢀtrifluoromethylpyridine (65.5 kg, 328.3 mol) are then charged and the
reaction is heated between 45ꢀ55 ºC for 12 h after which point HPLC analysis showed >99%
conversion. The reaction is cooled between 20ꢀ25 ºC and water (1000 L) and then nꢀheptane
(~850 L) were added while keeping the temperature constant. This mixture was stirred for 2.5h,
the layers were then separated and the aqueous layer was backꢀextracted with nꢀheptane (~850
L). The combined organic layers were then washed with water (675 L, twice). The resulting nꢀ
heptane solution was assayed to contain compound 5 in 91.6% assay yield (130.4 kg, 301.8 mol)
and 92.1 % LCAP. The solution is then concentrated under reduced pressure and finally solvent
switched to tꢀBuOH (to a final volume between 4ꢀ6X) keeping the temperature under 45 ºC. To
this tꢀBuOH solution is added solid sodium hydroxide (61.7 kg, 1542 mol) and the mixture is
heated between 65ꢀ75 ºC for 38h. After cooling, water (~750 L) is added keeping the
temperature between 25ꢀ35 ºC. The mixture’s pH is then adjusted to 6ꢀ7 using 2N HCl in two
portions while keeping the temperature between 25ꢀ35 ºC. More water is then added (900 L)
resulting in complete precipitation of crude 6 (supernatant <0.5 LCAP). The solid is filtered and
the cake washed with 165 L of water and then 110 L of nꢀheptane. Analysis of mother liquors
revealed only 0.1 LCAP of pyridone 6. The wet cake was then recharged into the vessel along
with ethyl acetate (1400 L). The mixture is heated between 75ꢀ80 ºC until all solids were
dissolved and then concentrated at atmospheric pressure to a final volume between 280ꢀ480 L.
The mixture is cooled between 50ꢀ70 ºC followed by slow addition of nꢀheptane (1500 L). The
mixture is cooled between 15ꢀ25 ºC for 1.5ꢀ2 h and filtered. The wet cake was washed with 90 L
of nꢀheptane and was then dried under vacuum at 45ꢀ55 ºC for 20h affording 107.8 kg of
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pyridone 6 (85.3% yield, 99.9 LCAP). 1H NMR (400 MHz, DMSOꢀd6) δ 12.69 (br. s., 1H), 7.58
(d, J = 6.8 Hz, 1H), 7.53 (t, J = 1.6 Hz, 1H), 7.29 (dd, J = 1.4, 2.3 Hz, 1H), 7.09 (t, J = 2.0 Hz,
1H), 6.47 (d, J = 6.9 Hz, 1H); 13C NMR (101 MHz, DMSOꢀd6) δ 157.34, 156.78, 140.83,
134.51, 133.83, 130.85, 130.61 (q, JCꢀF = 31.2 Hz), 123.11, 121.84 (q, JCꢀF = 274.7 Hz), 115.57,
99.87 (q, JCꢀF = 5.0 Hz), 95.12; 19F NMR (377 MHz, DMSOꢀd6) δ ꢀ62.06 (s, 1F); HRMS [M +
H]+ for C12H7ClF3INO2 calcd, 415.9157; found, 415.9159; mp 221.68ꢀ223.25 °C.
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Preparation of 2 (3-chloro-5-((2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-
yl)oxy)benzonitrile). Pyridone 6 (92.0 kg, 221.4 mol) is dissolved in NMP (450 L). Copper (I)
Cyanide (35.7 kg, 390.8 mol) is then added to the mixture which is then heated between 105ꢀ110
ºC for 40h. HPLC analysis revealed >99% conversion. The mixture was cooled between 20ꢀ30
ºC and 1800 L of 2ꢀMeTHF is added along with 500 L of MTBE. To this mixture is added
ammonia buffer (460 L, H2O/NH4Cl/NH3=9.4/4.0/3.8). The aqueous layer was separated and the
organics were washed three more times with the ammonia buffer (270ꢀ350 L). Finally the
organics were concentrated to an approximate volume of 220ꢀ300 L (NMP:MTBE:2ꢀ
MeTHF=16.1:0.5:91.0 w%). 250 L of NMP is added to the mixture which was concentrated
further until NMP w% was ~85%. The mixture was then heated between 50ꢀ60 ºC to dissolve all
solids. After cooling between 30ꢀ40 ºC, 130 L of water was added slowly. After the addition, the
temperature was dropped to 10ꢀ20 ºC and the slurry was stirred for 1h and filtered. The wet
caked was rinsed with 0.5 volume of NMP:water (2:1), then 2 volumes of water. Finally the wet
cake was charged with 700 L of water into a vessel and the slurry was stirred at 50ꢀ60 ºC for 4h.
After cooling to 10ꢀ20 ºC and aging for 3h, the slurry was filtered and the wet cake washed with
200 L of water. The cake was dried under vacuum at 50ꢀ65 ºC for 28h resulting in 63.4 kg
(89.6% yield, 99.1 LCAP) of pyridone 2. Spectral data was consistent with what is already
reported.18
Preparation of 7(3-chloro-5-((2-oxo-1-((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-4-
(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile). Pyridone 2 (121 kg, 386.5 mol)
is dissolved in DMF (475 L) and cooled between ꢀ10ꢀ10 ºC. To this solution is added potassium
carbonate (106.9 kg, 773.5 mol) followed by 5ꢀchloromethylꢀ2,4ꢀdihydroꢀ[1,2,4] triazolꢀ3ꢀone
(54.4 kg, 407.4 mol) as a solution DMF (235 L) over 7ꢀ9h. After aging for a futher 0.5ꢀ1h, HPLC
analysis revealed >97% conversion. 4N HCl is then added (230 L) slowly while keeping the
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temperature between 10ꢀ30 ºC, followed by 600 L of water. pH analysis revealed the pH to be
~8. The mixture was aged for another 2h at this pH which was then further reduced to between
5ꢀ6 by addition of more 4N HCl (100 L) and water (615 L). The resulting slurry was aged at
between 10ꢀ30 ºC for 10h and then the solids filtered. The wet cake is filtered and washed with
270 L of water. The solids were then dried under vacuum at 65ꢀ75 ºC for 12h resulting in 193.7
kg of crude product. The crude solid was then reꢀdissolved in a 19:1 mixture of MeCN:H2O
(3000 L) by heating the mixture to 80ꢀ90 ºC. The solution is then concentrated to 330ꢀ400 L and
another 2500 L of MeCN is added. Distillation is continued back down to a volume of 330ꢀ400 L
at which point, the slurry is cooled and aged for 10h at a temperature between 10ꢀ30 ºC. The
slurry is then filtered and the wet cake washed with 100 L of MeCN. The solids were dried under
vacuum at 65ꢀ75 ºC for 12h affording the desired penultimate triazolone intermediate in 81%
yield (130.6 kg, 99.7 LCAP). 1H NMR (400 MHz, DMSOꢀd6) δ 11.47 (br. s., 1H), 11.40 (s, 1H),
7.93 (d, J = 7.3 Hz, 1H), 7.75 (t, J = 1.5 Hz, 1H), 7.58 (dd, J = 1.2, 2.3 Hz, 1H), 7.51 (t, J = 2.1
Hz, 1H), 6.66 (d, J = 7.3 Hz, 1H), 5.02 (s, 2H); 13C NMR (101 MHz, DMSOꢀd6) δ 157.25,
156.20, 155.97, 142.52, 140.09 (q, JCꢀF = 2.0 Hz), 137.74, 134.97, 130.17 (q, JCꢀF = 31.2 Hz),
126.53, 121.70 (q, JCꢀF = 274.7 Hz), 121.16, 118.37, 116.96, 113.70, 99.96 (q, JCꢀF = 4.0 Hz),
44.90; 19F NMR (376 MHz, DMSOꢀd6) δ ꢀ62.24 (s, 1F); HRMS [M + H]+ for C16H10ClF3N5O3
calcd, 412.0419; found, 412.0415; mp 148.46ꢀ156.11 °C
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Preparation of Doravirine (1) (3-chloro-5-((1-((4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-
triazol-3-yl)methyl)-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile).
The triazolone intermediate (130.6 kg, 317.2 mol), NMP (850L), potassium carbonate (65.9 kg,
477.5 mol) and water (5 L) were charged to the vessel and degassed with N2. The mixture was
cooled to 5ꢀ10 ºC and methyl iodide (50.9 kg, 381.2 mol) is added over 0.5h. The mixture is then
aged for 34h after which point the reaction had reached ~90% conversion. The mixture was
filtered over 15 kg of celite and the cake washed with 375 L of NMP. The resulting filtrate was
added over 2.5h to water (2400 L) at 20ꢀ25 ºC and the slurry was aged for 24ꢀ30h at 20ꢀ30 ºC.
The slurry is then filtered and the wet cake washed with 2000 L of water. The wet cake is then
taken up in 450 L of EtOH and heated to 70ꢀ80 ºC for 1.5ꢀ2h. After cooling to 5ꢀ10 ºC the solid
was filtered, rinced with EtOH and dried under vacuum to afford 105.4 kg of crude Doravirine.
The crude solid is then recrystallized by slow addition of EtOH (45 L) to a 80ꢀ95 ºC solution of 1
in NMP (320 L), then seeding with crystalline 1 (121 g) and further addition of EtOH (13 L).
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The mixture was cooled to between 70ꢀ80 ºC and aged for 2h. Then 1400 L of EtOH is added.
After aging for 1h the mixture is cooled to between 5ꢀ10 ºC 7h. The slurry is then filtered and
rinsed with cold EtOH (45 L). The solids were dried in a vacuum under reduced pressure
between 50ꢀ75 ºC for 17h affording pure Doravirine 1 in 68.3% overall yield (92.3 kg, 99.1
LCAP). Spectral data was consistent with what is already reported.18
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Supporting Information.
Full spectral data for all new compounds (PDF)
ACKNOWLEDGMENT
We thank Smita Debnath (Merck Frosst), Guoyin Yin (WuXi) and Jing Xu (Merck) for
analytical support. We thank Benjamin Sherry and Steven Oliver for helpful discussion during
the preparation of the manuscript.
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