A highly efficient Suzuki-Miyaura methylation of pyridines leading to the drug pirfenidone and its CD3 version (SD-560)

Article abstract of DOI:10.1039/c7gc01740e

Efficient introduction of methyl or methyl-d₃ into aromatic and heteroaromatic systems still presents a synthetic challenge. In particular, we were in search of a non-cryogenic synthesis of the 5-CD₃ version of pirfenidone (4d, also known as Pirespa, Esbriet or Pirfenex), one of the two drugs approved to date for retarding idiopathic pulmonary fibrosis (IPF), a serious, rare and fatal lung disease, with a life expectancy of 3-5 years. The methyl-deuterated version of pirfenidone (4e, also known as SD-560) was designed with the objective of attenuating the rate of drug metabolism, and our goal was to find a green methylation route to avoid the environmental and economic impact of employing alkyllithium at cryogenic temperatures. The examination of several cross-coupling strategies for the introduction of methyl or methyl-d₃ into methoxypyridine and pyridone systems culminated in two green and nearly quantitative Suzuki-Miyaura cross-coupling routes in the presence of RuPhos ligand: the first, using commercially available methyl boronic acid or its CD₃ analog and the second, employing potassium methyl trifluoroborate or CD₃BF₃K, the latter obtained by a new route in 88% yield. This led, on a scale of tens of grams, to the synthesis of pirfenidone (4d) and its d₃ analog, SD-560 (4e), at 99% isotopic purity.

Full text of DOI:10.1039/c7gc01740e

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A Highly Efficient Suzuki-Miyaura Methylation of Pyridines Leading to the Drug
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DOI: 10.1039/C7GC01740E
Pirfenidone and to its CD3 Version (SD-560)
Eliezer Falb‡*, Konstantin Ulanenko‡, Andrey Tor‡, Ronen Gottesfeld‡, Michal Weitman§, Michal Afri§, Hugo Gottlieb§
and Alfred Hassner§
‡Discovery & Product Development, Global Innovative R&D, Teva Pharmaceutical Industries Ltd., 12 Hatrufa St., PO
Box 8077, Kiryat Sapir 42504 Netanya, Israel; §Department of Chemistry, Bar-Ilan University, Ramat Gan 52900, Israel
*E-mail: eliezer.falb@teva.co.il
Abstract: Efficient introduction of methyl or methyl-d3 into aromatic and heteroaromatic systems still presents a
synthetic challenge. In particular, we were in search of a non-cryogenic synthesis of the 5-CD3 version of pirfenidone
(4d, also known as Pirespa®, Esbriet® or Pirfenex®), one of the two drugs approved to date for retarding idiopathic
pulmonary fibrosis (IPF), a serious, rare and fatal lung disease, with life expectancy of 3-5 years. The methyl-deuterated
version of pirfenidone (4e, also known as SD-560) was designed with the objective of attenuating the rate of drug
metabolism, and our goal was to find a green methylation route to avoid the environmental and economic impact of
employing alkyllithium at cryogenic temperatures. Examination of several cross-coupling strategies for introduction of
methyl or methyl-d3 into methoxypyridine and pyridone systems culminated in two green and nearly quantitative
Suzuki-Miyaura cross-coupling routes in the presence of RuPhos ligand: the first, using commercially available methyl
boronic acid or its CD3 analog; and the second, employing potassium methyl trifluoborate or CD3BF3K, the latter
obtained by a new route in 88% yield. This led, on a scale of tens of grams, to pirfenidone (4d) and its d3 analog, SD-560
(4e), at 99% isotopic purity.
Introduction:
Pyridines are a ubiquitous class of compounds important in biological applications and human medicine1. Pirfenidone (5-
methyl-1-phenyl-2-pyridone), 4d2, is an important drug approved for treatment of idiopathic pulmonary fibrosis (IPF), a
serious, rare and fatal lung disease, and its methyl deuterated form, 4e, has been shown in nonclinical and clinical
studies to have a higher peak and total exposure compared to non-deuterated pirfenidone at equal doses. With both 4d
and 4e as effective, robust, controlled and green synthetic targets, we examined known and new routes toward this
goal. Two major approaches come to mind: one involves introduction of deuterium into an existing 5-substituted
pyridone, while the second option is introduction of deuterated methyl (CD3) into pyridine systems. The second
approach has the advantage of providing an efficient synthesis of both pirfenidone 4d and its CD3 analog, 4e. Extensive
synthetic work by Auspex Pharmaceuticals and Concert Pharmaceuticals in recent years has focused on interconversion
of a 5-substituent on a pyridine into a 5-CD3 group leading to SD-560 (4e) as an example of the first approach (Schemes
1 and 2).
Scheme 1: WO 2015/112701, WO 2012/122165 A2, WO 2008/157786 A1 Route3
The atom economy of using heavy atom reagents such as thionyl chloride, isobutyl chloroformate and phosphorus
tribromide to enable the introduction of the three deuterium atoms is low for Scheme 1. Furthermore, the use of
expensive and dangerous LiAlD4 under cryogenic conditions and quenching of the reaction intermediates with D2O
are additional complications in large scale synthesis where convergence, brevity, safety, efficiency, robustness, and
economics are critical parameters to optimise.
Scheme 2: WO 2009/035598 A1Route4
1

Green Chemistry
Page 2 of 9
Similarly, in Scheme 2, reduction of the nitrile found in 6-hydroxynicotinonitrile with highly flammable deuterium gas
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for a long period of time is not practical and does not meet the safety requirements to allow process development to
DOI: 10.1039/C7GC01740E
4e.
An example of the second approach to 4e4,5 involves methylation of 1a to 2b with methyl-d3 iodide (CD3I). It requires
cryogenic metalation with BuLi and is therefore not energy-efficient. Moreover, the free bases 2a and 2b are viscous
liquids and volatile and therefore must be derived and isolated as HCl salts. While examining this scheme we found
1b to be very reactive, giving rise to des-methyl 2c, which is very difficult to separate from 2a, and to bipyridine 2d.
Consequently, the atom economy of reaction of 1a with CH3I/CD3I via lithiation with hazardous BuLi is low and the
whole process does not meet most of the principles of green chemistry6.
Scheme 3: WO 2009/035598 A14 and WO 2015/171345 A15 Route
A recent report by Liao7 et al describes an effective Negishi8 procedure for the methylation of aryl halides with CD3I,
including the synthesis of SD-560 from 3c at 70% overall yield; this approach required a special Ni catalyst in a glove
box, a large excess of THF and volatile CD3I on a scale of 100s of mg (Scheme 4):
Scheme 4: L. Hu, X. Liu and X. Liao, Angew. Chem., 2016, 128, 9895-9899
It is clear that efficient functionalization of pyridines, such as methylation and deuteriomethylation under non-cryogenic
conditions still represents a major challenge. Herein, we report our efforts involving methyl cross-coupling of 5-bromo-
2-methoxy pyridine (1a) or of N-phenyl pyridone (4a) which ultimately led to a high yielding, simple, fast and green
process that is amenable to plant manufacturing of pirfenidone (4d) and its deuterated analog (4e), with 99% isotopic
purity.
Results and Discussion:
The synthesis of 4d and 4e via "methylation-first" (Scheme 3) of 1a-1c through low molecular weight intermediates 2a
and 2b and their unstable/hygroscopic HCl salts has some operational and environmental drawbacks; 2a and 2b sublime
on drying, and therefore, they are difficult to isolate and store, and the pyrophoric nature of the BuLi used in the
halogen exchange to give 1b enhances the accident potential of the process. Furthermore, in the sequence 1a->2b->
3b->4e methylation with an expensive deuterated reagent in the first step of the process is much less economically
efficient than a "methylation-last" process. Hence, we examined a new route to 4d-e (Schemes 5, 6 and 7), taking
advantage of heavy halogen and crystallinity of 3c9-3e10,11, obtained in nearly quantitative yield by hydrolysis of the
methyl ether of 1a and 1c, simply by heating in aqueous HCl followed by neutralization and filtration. Next, pyridones,
3c-3e, underwent N-phenylation via the Chan-Lam-Evans conditions to furnish 4a12-4c13,14 in high yields. With the latter
in hand, we addressed the challenge of introducing the CH3 and CD3 groups, respectively, into position 5 in compounds
4d and 4e.
Scheme 5: Preparation of halo-N-phenylpyridones, 4a-c
2

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Green Chemistry
We employed two methodologies for “methylation last”: 1) introducing a methyl via metalatiDoOnI:w10i.t1 o/rCg7aGnCo0m174e0tEallic
h03V9iew Article Online
reagents, under non-cryogenic conditions, followed by trapping the C-metal active species of 4a-c with electrophilic
methyl; 2) transition metal catalyzed cross coupling between 4a-c and a methyl partner. The first methodology has the
advantage of side-stepping the cryogenic lithiation; however, it still produces unnecessary derivatization and waste.
Cross-coupling under transition metal catalysis is much greener, but despite of numerous protocols utilizing boronic
acids/esters that have been disclosed for alkenylation and alkynylation, there are only limited examples for sp3-
hybridized electrophiles, and even fewer for CH3 electrophile, and coupling often proceeds with unsatisfactory yields
due to sluggish reaction rates and/or generation of undesired side products.
Methylation of 4a-c with Turbo Grignard15 or Ate complexes16 in the presence or absence of CuCN•2LiCl using different
methylation reagents and addition regimens as well as different concentrations of the metalating agents, did not enable
us to meet our goal. The reaction of 4a with Turbo Grignard, followed by methylation, resulted mostly in
dehalogenation to 5, with substantial dimerization to 6 and only minor amounts of the desired 4d (Table 1-2, see the
ESI). Moreover, 1,4 iPrMg addition to 4c gave 21% of 7, while addition to 4a followed by methylation gave 6% 8, and 4%
of a unique rearrangement product 917 (Scheme 6). Therefore, the lack of selectivity and high susceptibility (Table 1-2,
ESI) and the overall low atom economy calls into question the efficiency of these organometallic agents in a green route
to 4d-e.
Scheme 6: Products in reaction between halo-N-phenylpyridones (4a-c) and Turbo-Grignard or Ate complexes followed
by methylation
In spite of the problems encountered with the Turbo Grignard and Ate complexes in obtaining pirfenidone, 4d, in high
yield and without side products, via methylation of 4a-c (methodology 1 of halogen-metal exchange), we also examined
methyl cross-coupling of 1a and 1c under Pd catalysis, as well as Stille coupling18 with the Bu3Sn derivative of 1a and
Negishi coupling8,19, using CH3ZnI20. In all cases 2a was accompanied by 2c and by homo-coupling product 2d. In the best
case, 44% of 2a and 55% of 2d were obtained using the InterMune patent21 conditions employed on a different
pyridone system.
Finally, we turned to Suzuki-Miyaura cross-coupling (SMC)22 with 4a-c, as one of the mildest and most appealing
methods for the introduction of an alkyl group into various functionalized arenes. This is true also from the perspective
of green chemistry since the nontoxic inorganic byproducts can be readily removed by simple workup, after the
coupling of the organoboron reagent. We examined methyl coupling of 4a-c, in which Me-B(OH)2, the pinacol ester of
methylboronic acid or trimethylboroxine (TMB)23 serve as the boron coupling partner, using either PdCl2(dppf)24 or
Pd(PPh3)4 catalysis, in THF or 1,2-dimethoxyethane (DME) or DME/water mixtures and K2CO3 or Na2CO3 or KF as the
base, under inert atmosphere at reflux temperature. Reactions were monitored by TLC and HPLC, and the most
promising ones were worked up, purified and the structures confirmed by NMR. Again, as with 1a and 1c, cross-coupling
presented a major challenge with "dimerization" of the halo-(phenyl)pyridones into 6 and dehalogenation to 5
concomitant to the desired "methylation". With 4a and Pd(PPh3)4 and MeB(OH)221, phenyl ring transfer occurred to
generate 1025, in addition to 5 and 6. 10 was isolated and characterized, 5 was independently synthesized from pyridin-
2-ol, 3f, as shown in Scheme 5 and was found to be identical to 5 isolated from SMC. In addition, oxidation of the
catalyst to triphenyl phosphine oxide and its subsequent adhesion to the highly conjugated aromatic products resulted
in complex mixtures of 4d, 5, 6 and 10 (Scheme 7), which were difficult to purify and impractical to pursue further.
Scheme 7: Phenyl ring transfer from Pd catalyst into the skeleton of N-Ph-5-bromopyridone (4a)
3

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Page 4 of 9
View Article Online
DOI: 10.1039/C7GC01740E
In his recent instructive review26, Molander highlighted the importance of organotrifluoroborates (R-BF3K) for
increasing the chemical diversity in transition-metal-catalyzed cross-couplings, also with sp3 carbon. Apparently, R-BF3K
serve as stable, slow release reservoirs for boronic acids, which tune their release to match the rate of the trans-
metalation, hence minimising protodeboronation, 2c and 5 in our case, and other side reactions, such as homo-
couplings, e.g., compounds 2d and 6. Molander's group did not ignore simple methylation. In fact, preparation of
MeBF3K was reported in 200327 and it was used for methylation with various halo-aryl/heteroaryl substances28, but not
with pyridone systems. MeBF3K is air-stable, more atom-economical than most organo-borons and water-soluble,
thereby minimizing the amount of organic solvent, enabling higher throughput and non-toxic waste of boron salts. For
the synthesis of 4d we used commercially available MeBF3K; however, for its deuterated form, CD3BF3K, commercial
supply is limited to sporadic availability of small quantities at a premium cost; hence, we prepared it from deuterated
boronic acid (CD3B(OH)2) by reaction with commercially available, inexpensive, potassium hydrogen fluoride (KHF2) at
1
88% yield and excellent purity as determined by H, 13C, 11B (δ (D2O) 5.91 ppm, q, J = 65 Hz) and 19F (δ (D2O) -132.39
ppm, q, J = 65 Hz) NMR and HRMS29.
Scheme 8: Facile preparation of deuterated version of Molander's potassium methyltrifluoroborate reagent
With the two reagents in hand, we applied Molander's set of conditions on 4a. The reaction, monitored by HPLC,
showed complete disappearance of the starting material and formation of 4d, with less than 0.5% of 5 and 6, each,
within 6-7 hours. To our delight, for the first time near quantitative methylation of 4a to furnish 4d and 4e, at 97% and
90% (Scheme 9) respective isolated yields, was achieved and without the loss of deuterium for 4e; the latter was
obtained at more than 99% isotopic purity (based on mass spectra and NMR data; see ESI).
Scheme 9: Suzuki-Miyaura cross-coupling (SMC) in a "methylation-last" route to pirfenidone (4d) and SD-560 (4e)
Alternatively, 4d was also obtained by the "methylation-first" route (Scheme 3 vs. Scheme 10) but instead of introducing
the CH3/CD3 via cryogenic lithiation (Scheme 3, overall yield of 32%) 1a was coupled under SMC conditions via 2a and
2b, isolated as the HCl salts, followed by OMe cleavage to 3a and 3b, and Chan-Lam phenylation to provide 4d in overall
yield of 58%.
Scheme 10: SMC and "methylation-first" route to pirfenidone and SD-560
It should be pointed out that there is only one report by Blum30 et al on Pd-catalyzed methylation of 1a which led to 2a
in 68% yield, but it was carried out with bis[μ-[2-(dimethylamino)ethanolato-N,O:O]] tetramethyldiindium. The latter is
not commercially available or easy to prepare31, mainly because it requires trimethylindium, which is pyrophoric and
needs to be handled with the utmost care and caution. Most other reported routes32 leading to 2-methoxy-5-
methylpyridine (2a) or to 5-methyl-2-pyridone (3a) involves a pyridine which already incorporates the 5-methyl
substituent, and are thus not suitable for effective introduction of a 5-CD3 group.
We showed that these SMC conditions (5% of Pd (OAc)2 and 10% of 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl
(RuPhos))33 ligand are general for alkylation of bromomethoxypyridine 1a as well as of bromopyridone 4a. Using i-
4

Page 5 of 9
Green Chemistry
butyl34-, cyclopropyl35-, vinyl36- and trans-1-propenyl37-trifluoroborates K salts resulted in mo
DdOeIr:a1t0e 3o9/Ch7iGghC01y7i4e0ldE of
.10tView Article Online
alkylated products 2e-2h38 and 4f39, 4g40, 4h41, 4i42, as shown in Scheme 11 and Table 1.
Scheme 11: SMC route for alkylated and alkenylated N-phenylpyridones and pyridines
Table 1: Synthesis of N-phenylpyridones and pyridines via Scheme 11
%
% Conversion
(in HPLC
for the free base)
Isolated
Yield
Cpd. No.
Structure
Conversion
(in HPLC)
Yield
66%
98%
98%
85%
Cpd. No.
Structure
4f
4g
4h
4i
81.5%
100%
100%
100%
2e
2f
99.71%
65%
60%
38%
44%
80.27%
100%
N
O
Ph
2g
2h
95.5%
Finally, to our pleasant surprise, when the Suzuki-Miyaura methyl cross-coupling conditions (5% mol Pd(OAc)2 catalysis
and K2CO3, but also requiring 5-10% mol Buchwald's RuPhos ligand), were used with greener and less expensive Me-
B(OH)2 or with its deuterated version (CD3B(OH)2, Scheme 12), 2a and 2b, were obtained in moderate to good yields
and within ca. 3 h. The lower yields in the route starting with 1a may be attributed to the volatility of intermediates 2.
Scheme 12: SMC with Me/CD3B(OH)2 and 1a in presence of Buchwald's RuPhos ligand
By using the "methyl last" route, these new coupling conditions, provided even higher overall yields in the synthesis of
pirfenidone 4d and its deuterated form 4e (scheme 13) than via the "methyl first" route.
Scheme 13: SMC with Me/CD3B(OH)2 and 4a in presence of Buchwald's RuPhos Ligand
We followed the progress of methylation of 4a via SMC with CH3/CD3B(OH)2 by HPLC (Fig. 1 and 2, ESI), which clearly
showed the consumption of 4a and formation of 4d and 4e in high yield and essentially devoid of side products, within
2 hours, unlike the poor results obtained by Scheme 7. The bromo pyridine 4a was found to be the most effective
substrate for SMC under the conditions of scheme 13, even with 1% mol of Pd(OAc)2, leading to almost full conversion
to 4d, while 4b and 4c gave only 67% and 7.8% respective conversion. 4a was fully consumed under catalysis of 5%
mol Pd2(dba)3/5% mol RuPhos (instead of Pd(OAc)2/RuPhos) to give 90% of isolated 4d (see Table 3 in ESI).
5

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View Article Online
DOI: 10.1039/C7GC01740E
Schemes 3, 10 and 13, which are the most practical for further process development for plant production (excluding
Schemes 1, 2 and 4), were examined based on a set of green chemistry parameters (Table 2) to enable a more
calculated/quantitative/objective discrimination between the three routes before commencing the next stage of
process development, including avoiding chromatographic purification and improving the crystallization procedure43.
While most of the calculations are based on accepted and known methods in the pharmaceutical industry, some are
our own internal methods.
Table 2: Quantitative green evaluation of the operational routes to pirfenidone and its deuterated analog SD-560
Scheme 3*
Methylation 1st via
lithiation
Scheme 13^
Methylation last via
SMC
Scheme 10*
Methylation 1st via SMC
Green Index
Overall Yield
PMI [g/g]
32%!
257
38%
147
273
9.5
58%
130
23%
104
95
84%
56
Atom Economy
E-Factor
41%
28
Total Solvents
Class 4 (Dioxane)
44
0
0
Class 3 (DCM, Pyridine, n-
Hexane)
41
46
15
Class 2 (Toluene, MTBE)
130
1.5
91
21
1
6
0
Class 1 (Butanol)
Water
27
23
5-Bromo-2-Methoxy pyridine
input for 1kg DS
Methylation reaction volume
[L/kgDS]
3.17
55
1.74
26
1.21
8
Methylation reaction
Temperature
Duration of methylation
-50
87
6h
87
3h
14.5h
!Based on 70% of volataile 2a after its filtration and before complete drying; *Each calculation contains all the stages required to synthesise pirfenidone from 1a;
^calculated for SD-560, 4e from 1a; PMI (Process Mass index) - All input materials required for one gram of product; Atomic Efficiency - ratio between MW of the
product to MWs of all raw materials and reagents x 100; E-factor - ratio between input material mass without product mass to product mass44; Class 4 -
forbidden; Class 3 - undesirable; Class 2 - usable; Class 1 - preferable - according to our internal classification45
The SMC procedures show significant reduction of the environmental footprint. Thus, in Scheme 10, still with the
“methylation-first” strategy, replacing the cryogenic step (BuLi/MTBE/-55°C protocol) with Molander’s MeBF3K, there
is a marked improvement in almost all the green parameters. Moreover, in Scheme 13, employing the “methylation-
last” strategy, with CD3B(OH)2 and Buchwald’s RuPhos ligand, all the green parameters are reduced, mainly due to
higher yield and ca. 6 fold reduction of solvent volume, especially class 3 solvents, which saves waste treatment. The
fact that the methylation with an expensive deuterated reagent is done at the end of the process with significant
energy conservation reduces both environmental footprint as well as production costs. From the operational point of
view an important benefit in Scheme 13 is its higher throughput in less manufacturing time, which yields more active
pharmaceutical ingredient (API) in a reduced number of batches under the same construction costs with fewer
human working hours and release analysis, in the plant environment.
In summary, our vision of a highly efficient introduction of methyl or methyl-d3 at position 5 on the
1-phenylpyridine-2(1H)-one skeleton of pirfenidone (4d) and its d3-analog (4e) in ca. 90% yield and >99% isotopic
purity became reality, avoiding cryogenic lithiation of 5-bromo-2-methoxypyridine (1a, Scheme 3) or dangerous and
complex reduction strategies of introducing deuterated methyl into the pirfenidone framework (Schemes 1 and 2).
This was best accomplished via Suzuki-Miyaura cross-coupling (SMC) by a "methylation-last" strategy, which
proceeded in 90% isolated yield and with high isotopic purity, taking advantage of heavy bromo-N-phenyl pyridone
systems 4a as crystalline, easy-to-store and handle substrate for the cross-coupling using Molander's
alkyltrifluoroborate methodology and requiring only 1.3 eq. of the trifluoroborate reagent. Furthermore, the latter
methodology led us to identify a simple, nearly quantitative methylation of 4a with commercially available, d3-
methylboronic acid in the presence of Buchwald's RuPhos ligand, which we found essential for methylation of pyridine
and N-phenyl pyridone systems, via SMC. This green and essentially quantitative cross-coupling with solid Me/CD3-
B(OH)2 or Me/CD3-BF3K and cheap Pd(OAc)2 using small solvent volumes (5-6 V) of wet toluene, applicable to both lab
6

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Green Chemistry
and plant preparation of pirfenidone 4d and its deuterated version, 4e, SD-560, has several aDdOvIa: n10t.a 3e9s/Co7GveCr01t7h40eELi
10gView Article Online
route (Scheme 3), as well as over the Negishi procedure reported recently (Scheme 4)7; in the latter case, it avoids the
preparation of special Ni catalyst in a glove box, and the use of a large excess of solvent (40 V) and volatile MeI, and
hence offers a state-of-the art, high-yield, flexible, practical, scalable and simple methylation/alkylation procedure for
pyridine and pyridone systems.
In conclusion, our studies of introducing a methyl and methyl d3 into N-phenylated halo-pyridones or halo-pyridines by
several non-cryogenic methodologies, e.g. via "Turbo-Grignard" and via "Ate complexes" and via Suzuki-Miyaura cross-
methylation under Pd catalysis have demonstrated that the 12 principles of green chemistry are indeed an integral
part of the development of a robust, efficient, and easy to operate process for the manufacturing of an API with
control of impurities.
1
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21 B. O. Buckman, J. B. Nicholas, J. Y. Ramphal, K. Emayan and S. D. Seiwert, US 2014/0094456 A1.
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24 H. Hikawa and Y. Yokoyama, Tetrahedron, 2010, 66, 9552-9559.
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26 G. A. Molander, J. Org. Chem., 2015, 80, 7837-7848.
27 G. A. Molander, C.-S. Yun, M. Ribagorda and B. Biolatto, J. Org. Chem., 2003, 68, 5534-5539.
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29 D. J. Brauer, H. Bürger and G. Pawelke, J. Organometal. Chem., 1982, 238, 267-279. The IR and Raman spectra of
CD3BF3 were reported29 but not the NMR data. The spectral data were identical mutatis mutandis with CH3BF3K; the
fact that the broad singlet in the proton NMR at δ (D2O) -0.224 ppm, for the latter, is not seen for its deuterated
version, is indicative for the isotopic purity of the prepared reagent. In the carbon NMR the Me moiety of the two
reagents, at δ (D2O) 0.56 ppm, is hardly seen due to multiplicities with the B and F. HRMS indicates two stable
7

Green Chemistry
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DOI: 10.1039/C7GC01740E
boron isotopes; m/z 85.0512 and 86.0475 in relative abundance of 25% and 100%, for the CD3-BF3 anion (compared
-
to m/z 82.0322 and 83.0286 for CH3BF3 ), in a perfect match for the calculated exact mass 85.0510 and 86.0474.
30 N. Jaber, H. Schumann and J. Blum, J. Heterocyclic Chem., 2003, 40, 565-567.
31 T. Maeda and R. Okawara, J. Organometal. Chem., 1972
, 39, 87-91.
32 T. Hayashi, H. Iwamura and T. Fujita, J. Agric. Food Chem. 1990, 38, 1965-1971; (b) S. Stavber and M. Zupan,
(a)
Tetrahedron Lett., 1990, 31, 775-776; (c) G. S. Kumar, S. P. Ragini, A. S. Kumar and H. M. Meshram, RSC Adv., 2015,
5, 51576-51580; (d) A. P. Smith, S. A. Savage, J. C. Love and C. L. Fraser, Org. Synth., 2002, 78, 51-56; (e) J. Wysocki,
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33 R. Martin and S. L. Buchwald, Acc. Chem. Res., 2008, 41, 1461-1473.
34 The synthesis of the free base of 2e from 1a and isobutyl boronic acid was described by T. Boesen, M. Labelle, Y.
Yang, N. Saraswat, D. Dudekula, C. J. Cook, R. R. Vakiti, R. Zhang and F. Ullah in WO2016033169A1.
35 The synthesis of the free base of 2f from 5-chloro-2-methoxypyridine and potassium cyclopropyltrifluoroborate in
glovebox using Biotage microwave and n-BuPAd2 was reported by G. A. Molander and P. E. Gormisky, J. Org. Chem.,
2008, 73, 7481-7485.
36 (a) Direct Suzuki-Miyaura vinylation of boronate ester of 1a with vinyl tosylate and special Pd complex using
glovebox was reported by T. M. Gøgsig, L. S. Søbjerg, A. T. Lindhardt (neé Hansen), K. L. Jensen and T. Skrydstrup, J.
Org. Chem. 2008, 73, 3404–3410; (b) 2g was prepared also by Ni-catalyzed vinylation of 1a with vinyl ZnBr•MgBrCl
reported by T. Yamamoto and T.Yamakawa, J. Org. Chem., 2009, 74, 3603-3605.
37 The preparation of 2h was reported by K. Kossen, S. D. Seiwert, V. Serebryany, D. Ruhrmund, L. Beigelman, L.
Raveglia, M. Francesco, S. Vallese, I. Bianchi and T. Hu in WO 2009/149188 A1, but the compound was not isolated
and was telescoped with the next OMe hydrolysis and Chan-Lam phenylation to give 4i.
38 2e-h were isolated as HCl salts because of the volatility of the free bases.
39 4f is a new chemical entity.
40 4g was prepared earlier from 2f in 25% yield as reported in WO2009/149188A1 for example 132.
41 4h is a new chemical entity.
42 4i was prepared earlier from 2h in 15% yield as reported in WO2009/149188A1 for example 326.
43 Our route scouting campaign was focused on finding a green methylation route with complete conversion to a high
quality crude pirfenidone (4d) and its deuterated version (SD-560, 4e), the crude material was purified by Combi-
Flash chromatography to allow characterization and comparison of isolated yields with the understanding that the
current crystallization procedure demands more development and will be addressed as a part of the next step in
the process development and before pilot plant production.
44 F. Roschangar, R. A. Sheldon and C. H. Senanayake, Green Chem., 2015, 17,752-768.
45 a) D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy, S. Abou-Shehada and P. J. Dunn, Green Chem., 2016, 18,
288-296; b) D. Prat, O. Pardigon, H.- W. Flemming, S. Letestu, V. Ducandas, P. Isnard, E. Guntrum, T. Senac, S.
Ruisseau, P. Cruciani, and P. Hosek, Org. Process Res. Dev., 2013, 17, 1517−1525; c) R. K. Henderson, C. Jiménez-
González, D. J. C. Constable, S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks and A. D. Curzons, Green
Chem., 2011, 13, 854-862.
8

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Green Chemistry
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DOI: 10.1039/C7GC01740E
A Highly Efficient Suzuki-Miyaura Methylation of Pyridines Leading to the Drug Pirfenidone and to its CD3
Version (SD-560)
Eliezer Falb, Konstantin Ulanenko, Andrey Tor, Ronen Gottesfeld, Michal Weitman, Michal Afri, Hugo Gottlieb
and Alfred Hassner
The first methylation/deuteromethylation in green and nearly quantitative Suzuki-Miyaura routes to
Pirfenidone and its d3 analog SD-560, at 99% isotopic purity.