First synthesis of methyl 2-amino-6-methoxynicotinate using a combination of microwave and flow reaction technologies

Article abstract of DOI:10.1055/s-0030-1259283

The synthesis of methyl 2-amino-6-methoxynicotinate, a valuable building block for the preparation of fused 2-pyridones, is reported. The optimized synthesis includes sequential microwave-induced regioselective 6-methoxylation, esterification, followed by microwave-induced reaction with p- methoxybenzylamine, and final deprotection under flow reaction hydrogenation conditions. Two key steps in the reported synthesis are a microwave-induced methoxylation and a microfluidic hydrogenation that afford improved regioselectivity and purity profile of the reaction products. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259283

LETTER
203
First Synthesis of Methyl 2-Amino-6-Methoxynicotinate Using a Combination
of Microwave and Flow Reaction Technologies
First Synthesis of
M
y
e
thyl 2-A
m
o
ino-6-Metho
r
xynicoti
g
nate y Jeges,a Tamas Meszaros,a Tamas Szommer,a Jozsef Kovacs,a Tamas Nagy,a,1 Dmytro Tymoshenko,*b
Nader Fotouhi,c Paul Gillespie,c Agnieszka Kowalczyk,c Robert A. Goodnow Jr.c
a
AMRI Hungary, Zahony u. 7, 1031 Budapest, Hungary
AMRI, 26 Corporate Circle, Albany, NY 12203, USA
Roche Research Center, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 0711, USA
b
c
E-mail: dmytro.tymoshenko@amriglobal.com
Received 30 August 2010
known in the literature and is not commercially avail-
Abstract: The synthesis of methyl 2-amino-6-methoxynicotinate, a
valuable building block for the preparation of fused 2-pyridones, is
reported. The optimized synthesis includes sequential microwave-
induced regioselective 6-methoxylation, esterification, followed by
microwave-induced reaction with p-methoxybenzylamine, and fi-
nal deprotection under flow reaction hydrogenation conditions.
Two key steps in the reported synthesis are a microwave-induced
methoxylation and a microfluidic hydrogenation that afford im-
proved regioselectivity and purity profile of the reaction products.
able.11
We herein report the synthesis of methyl 2-amino-6-meth-
oxynicotinate (4), a valuable building block for the syn-
thesis of medicinally relevant compounds, starting from
commercially available 2,6-dichloronicotinic acid (5).
The synthesis of 2-amino-6-methoxynicotinate starts
from the preparation of 2-chloro-6-methoxynicotinic acid
(6) by direct methoxylation of commercial 2,6-dichloron-
icotinic acid (5, Scheme 2). Our preliminary experiments
as well as reports found in the literature revealed poor re-
gioselectivity of the process.12–15 In our hands the typical
reaction mixture obtained from the reaction of 5 with so-
dium methoxide in methanol consisted of 2-chloro-6-
methoxynicotinic acid (6), 6-chloro-2-methoxynicotinic
acid (7), and 2,6-dimethoxynicotinic acid (8), with the
predominant product being the undesired regioisomer 7.
Hirokawa and co-workers12 previously reported similar
results for the reaction of methyl 2,6-dichloronicotinate
with sodium ethoxide in nonpolar media, although in al-
coholic and polar aprotic medium (DMF) the reverse regio-
selectivity was observed. The regioisomer formation (1:1)
was previously reported for 2-substituted derivatives of
benzyl alcohol,13 while in the case of {2,2-dimethyl-6-
(9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-
methanol14 predominant formation of the 2-isomer was
observed. Switching to the use of potassium methoxide,
formed in situ from potassium tert-butoxide in methanol,
results in improved predominant formation of the 6-meth-
oxy derivative 6,11 but requires extremely long reaction
times.15
Key words: 2-pyridone, microwave, microfluidic reaction, cy-
clization, hydrogenation
2-Pyridone 1 (Scheme 1) is a valuable structural motif in
a variety of biologically relevant molecules. Both substi-
tuted and fused 2-pyridone core motifs are known as a
promising class of inhibitors of HIV-1 non-nucleoside re-
verse transcriptase,2 DNA gyrase,3,4 and bacterial topo-
isomerase,5 as noncompetitive inhibitors of MAPK
kinase,6 as ligands for the benzodiazepine binding site of
the GABAA receptor,7 and as 5-HT1A/5-HT2A receptor
ligands.8 The importance of pyridones in natural products
and ring-construction methodologies has been reviewed
recently.9
Fused pyridones 2 are of particular interest in our quest for
new medicinally important building blocks, and retrosyn-
thetically they can be derived from 2-amino-6-methoxy-
nicotinate (4) through methoxy pyridine derivatives 3
(Scheme 1). We envisaged that the ortho-aminocarboxy-
pyridine fragment can be further elaborated into a variety
of heterocyclic systems10 fused to the 2-pyridone ring.
While being fascinated with the broad synthetic potential
of compound 4, we were surprised to discover that it is un-
In our hands, similar results were obtained for the reaction
between acid 5 and potassium methoxide, but, when the
R
O
R
R
R
O
MeO
N
H
1
H2N
N
OMe
N
O
N
OMe
H
2
3
4
Scheme 1 Retrosynthetic route of 2-pyridones
SYNLETT 2011, No. 2, pp 0203–0206
x
x.
x
x.
2
0
1
0
Advanced online publication: 23.12.2010
DOI: 10.1055/s-0030-1259283; Art ID: S05610ST
© Georg Thieme Verlag Stuttgart · New York

204
G. Jeges et al.
LETTER
O
O
O
O
MeO–
HO
HO
HO
HO
+
+
conditions
MeO
N
OMe
Cl
N
Cl
MeO
N
Cl
Cl
N
OMe
5
6
7
8
Scheme 2 Direct methoxylation of 2,6-dichloronicotinic acid
reaction was microwave irradiated at 300 W, a significant ed insufficient 17–25% conversion of 9 after 24 hours
enhancement in both overall yield (ca. 90% yields of the reflux (10 equiv of amine, 1,4-dioxane).
crude mixture of 6, 7, and 8) as well as regiochemistry was
We further examined the deprotection of compounds
observed, giving 6 in 85–90% (1H NMR analysis). Al-
13a,b to obtain the final product 4. The first attempt was
though neither this mixture nor the corresponding mixture
performed in EtOH in an autoclave under hydrogen pres-
of esters produced in 92–95% yields after simple esterifi-
sure (3 bar) in the presence of 10% of Pd/C. In the case of
cation with SOCl2/MeOH (Scheme 3, structures of esters
benzyl derivative 13a these reaction conditions were in-
sufficient for the required deprotection; only trace
amounts of product 4 were detected (HPLC-MS analysis)
after 2 days at either ambient temperature or 70 °C. Nev-
ertheless, these reaction conditions were successfully em-
ployed for the deprotection of 13b, affording 85% isolated
derived from 7 and 8 omitted for clarity purposes) are sep-
arable under chromatography conditions, the crude prod-
uct 9 was sufficiently pure to be used directly in the
amination step (see Supporting Information for a typical
LC-MS trace of the mixture).
Contrary to known amination chemistry using yield of the product after 48 hours (25 °C) to 30 hours
methylamine14 and p-trifluoromethylbenzylamine,16 our (70 °C) reaction time. Implementation of H-Cube® tech-
initial approach involving the reaction of crude chloro- nology for the deprotection of either 13a or 13b under
intermediate 9 with ammonia proved to be problematic. flow-reaction hydrogenation conditions18 was explored to
Thus, reactions with ammonia in EtOH at reflux at atmo- optimize the reaction conditions.18 Conducting the reac-
spheric pressure or in an autoclave at 4 bar did not result tion in ‘controlled mode’17d at 40 °C resulted in no prod-
in the formation of the 2-aminopyridine product; only uct formation for debenzylation of 13a. Similarly, the
starting material 9 was recovered.
PMB deprotection resulted in only 9% of 4 being ob-
served by LC-MS analysis. Switching to ‘full hydrogena-
tion mode’17d yielded 9%, 34%, and 87% conversion of
the PMB derivative 13b at 25 °C, 40 °C, and 70 °C, re-
spectively, whereas a mediocre 41% conversion of 13a to
4 was obtained at 70 °C under similar hydrogenation con-
ditions. Based on our experimental observations, the use
of the PMB-protected aniline 13b was chosen as the pre-
ferred intermediate in this synthesis due to its ease of re-
moval of protecting group compared to the analogous
benzyl group 13a. The optimized reaction conditions for
the preparation of 4 involved the hydrogenolysis of 13b
(H-Cube®, full hydrogenation mode at 70 °C), which af-
forded 87–90% isolated yields in repeated syntheses of
the target compound.
Microwave conditions (ammonium hydroxide, EtOH, mi-
crowave at 300 W, 100 °C, 5 h) resulted in 60–70% con-
version of the starting material, but the product was
identified as a mixture of 10, 11, and 12 (26%, 60%, and
14%, respectively, based on HPLC-MS result). Therefore
we set out to develop an alternate synthetic route. Upon
reaction of crude 9 with benzylamine or p-methoxybenzyl-
amine (10 equiv of amine, 1,4-dioxane, microwave at 300
W, 170 °C, 2 h) the corresponding derivatives 13a,b were
obtained in moderate to good isolated yields (45% and
67%, respectively) with excellent (>97% LC-MS and
NMR) purities after purification by column chromatogra-
phy. Similar reactions under conventional heating provid-
O
O
O
MeOH, SOCl2
RNH2
MeO
MeO
HO
Cl
N
OMe
N
Cl
N
OMe
HN
R
OMe
6
9
13a R = Bn
13b R = PMB
NH3, conditions
O
H2, Pd/C
O
O
O
HO
H2N
H2N
+
H2N
MeO
H2N
+
N
OMe
H2N
N
OMe
Cl
N
OMe
N
OMe
10
11
12
4
Scheme 3 Preparation of methyl 2-amino-6-methoxynicotinate on alternate synthetic route
Synlett 2011, No. 2, 203–206 © Thieme Stuttgart · New York

LETTER
First Synthesis of Methyl 2-Amino-6-Methoxynicotinate
205
O
O
O
MeO
EtOOCHNSCHN
14
HN
MeO
H2N
SCNCOOEt
97%
EtONa
99%
N
OMe
HS
N
N
OMe
N
OMe
4
15
Scheme 4 Synthesis of the fused 2-pyridone system
Thompson, S.-A.; Wafford, K.; Dawson, G. R.; Pike, A.;
Sohal, B.; Tsou, N. N.; Ball, R. G.; Castro, J. L. J. Med
Chem. 2002, 45, 1887.
In an additional proof of concept experiment, 4 was trans-
formed into 7-methoxy-2-mercaptopyrido[2,3-d]pyrimi-
din-4(3H)-one (15, Scheme 4),19 thus demonstrating the
utility of 2-amino-6-methoxynicotinate in the synthesis of
the fused 2-pyridone systems. The synthetic sequence in-
volved reaction with ethoxycarbonyl isothiocyanate,20
followed by cyclization of the intermediate thiourea 14
into 7-methoxy derivative 15.21
(8) Mokrosz, J. L.; Duszynska, B.; Paluchowska, M. H.;
Charakchieva-Minol, S.; Mokrosz, M. J. Arch. Pharm.
(Weinheim, Ger.) 1995, 328, 623.
(9) Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9,
1757.
(10) For recent examples of cyclization based on 2-amino-
nicotinic acid, see: (a) 1,8-Naphthyridin-4(1H)-ones:
Bilokin, M. D.; Yushchenko, D. A.; Pivovarenko, O. V.;
Pivovarenko, V. G. Ukr. Bioorg. Acta 2008, 6, 13. (b) 3,4-
Dihydro-4-oxopyrido[2,3-d]pyrimidines: Storelli, S.;
Verzijl, D.; Al-Badie, J.; Elders, N.; Bosch, L.; Timmerman,
H.; Smit, M. J.; De Esch, I. J. P.; Leurs, R. Arch. Pharm.
(Weinheim, Ger.) 2007, 340, 281. (c) 4-Chloropyrido[2,3-
d]pyrimidine: Echeverria, M.; Mendivil, B.; Cordeu, L.;
Cubedo, E.; Garcia-Foncillas, J.; Font, M.; Sanmartin, C.;
Palop, J. A. Arch. Pharm. (Weinheim, Ger.) 2006, 339, 182.
(d) 3-Benzimidazolo-2-pyridinamine and 1H-imidazo[4,5-
c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine: Bamford, M. J.;
Alberti, M. J.; Bailey, N.; Davies, S.; Dean, D. K.; Gaiba, A.;
Garland, S.; Harling, J. D.; Jung, D. K.; Panchal, T. A.; Parr,
C. A.; Steadman, J. G.; Takle, A. K.; Townsend, J. T.;
Wilson, D. M.; Witherington, J. Bioorg. Med. Chem. Lett.
2005, 15, 3402. (e) 1H-Pyrido[2,3-b]azepine-5,8-dione:
Kunick, C.; Lauenroth, K.; Wieking, K.; Xie, X.; Schultz,
C.; Gussio, R.; Zaharevitz, D.; Leost, M.; Meijer, L.; Weber,
A.; Jorgensen, F. S.; Lemcke, T. J. Med. Chem. 2004, 47,
22. (f) Imidazo[1,2-a]pyridine-8-carboxamide: Masurier,
N.; Moreau, E.; Lartigue, C.; Gaumet, V.; Chezal, J.-M.;
Heitz, A.; Teulade, J.-C.; Chavignon, O. J. Org. Chem.
2008, 73, 5989.
In summary, we report herein the first synthesis of methyl
2-amino-6-methoxynicotinate (4) and proved its utility in
the synthesis of fused 2-pyridone systems. The key fea-
tures of the four-step process are microwave-induced
regioselective 6-methoxylation, esterification, and se-
quential microwave-induced reaction with p-methoxy-
benzylamine followed by deprotection under flow-
reaction hydrogenation conditions. The microwave-in-
duced and microfluidic steps are advantageous and time-
saving while maintaining the desired regioselectivity and
improving the purity profile of the product. Further prep-
arations of fused heterocyclic systems based on 4 are in
progress and will be reported in due course.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors thank Dr. Brian T. Gregg (AMRI) for his valuable com-
ments and helpful discussions.
(11) (a) Direct copper-catalyzed amination of 2,6-dichloro-
nicotinic acid results in 4.5% of 2-amino-6-chloroderivative.
Its further alcoholysis gives corresponding 6-ethoxy- and
6-isopropoxy-2-aminonicotinic acids: Nakamoto, K.;
Matsukura, M.; Tanaka, K. EP 1782811, 2007.
References and Notes
(1) Current address: EGIS Gyógyszergyár Nyrt., Keresztúri út
30-38, 1106 Budapest, Hungary
(2) Medina-Franco, J. L.; Martinez-Mayorga, K.; Juarez-
Gordiano, C.; Castillo, R. ChemMedChem 2007, 2, 1141.
(3) Shen, L. L.; Tanaka, S. K.; Chu, D. T. W. Curr. Pharm.
Design 1997, 3, 169.
(b) Synthetic applications of the title compound were
described recently without preparative details: Chen, Q.;
Feng, Y.; Wang, Z.; Yue, B.; Zhuang, W. CN 1701031,
2010.
(12) Hirokawa, Y.; Horikawa, T.; Kato, S. Chem. Pharm. Bull.
2000, 48, 1847.
(4) Kim, O. K.; Barrett, J. F.; Ohemeng, K. Exp. Opin. Investig.
(13) Lee, J.; Kirincich, S. J.; Smith, M. J.; Wilson, D. P.; Follows,
B. C.; Wan, Z.-K.; Joseph-Mccarthy, D. M.; Erbe, D. V.;
Zhang, Y.-L.; Xu, W.; Tam, S. Y. WO 081960, 2005.
(14) Plourde, R. Jr.; Shaver, S. R.; Douglass, J. G. III.; Watson,
P. S.; Boyer, J. L.; Tu, C.; Abreo, M. A.; Alfaro-Lopez, L. J.;
Feng, Y.; Harvey, D. F.; Khasanova, T. V. US 267134, 2005.
(15) Hirokawa, Y.; Fujiwara, I.; Suzuki, K.; Harada, H.;
Yoshikawa, T.; Yoshida, N.; Kato, S. J. Med. Chem. 2003,
46, 702.
Drugs 2001, 10, 199.
(5) Li, Q.; Mitscher, L. A.; Shen, L. L. Med. Res. Rev. 2000, 20,
231.
(6) Spicer, J. A.; Rewcastle, G. W.; Kaufman, M. D.; Black,
S. L.; Plummer, M. S.; Denny, W. A.; Quin, J. III.;
Shahripour, A. B.; Barrett, S. D.; Whitehead, C. E.; Milbank,
J. B. J.; Ohren, J. F.; Gowan, R. C.; Omer, C.; Camp, H. S.;
Esmaeil, N.; Moore, K.; Sebolt-Leopold, J. S.;
Pryzbranowski, S.; Merriman, R. L.; Ortwine, D. F.;
Warmus, J. S.; Flamme, C. M.; Pavlovsky, A. G.; Tecle, H.
J. Med. Chem. 2007, 50, 5090.
(16) Guiadeen, D.; Hale, J. J.; Kothandaraman, S. WO 130527,
2008.
(17) (a) Kovacs, I.; Jones, R.; Otvos, Z.; Urge, L.; Dorman, G.;
Darvas, F. In Heterogeneous Catalysis Research Progress;
(7) Collins, I.; Moyes, C.; Davey, W. B.; Rowley, M.;
Bromidge, F. A.; Quirk, K.; Atack, J. R.; McKernan, R. M.;
Synlett 2011, No. 2, 203–206 © Thieme Stuttgart · New York

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LETTER
reaction mixture concentrated to dryness under reduced
Gunther, M. B., Ed.; Nova Science Publisher, Inc.: New
York, 2008, 395. (b) Jones, R. V.; Godorhazy, L.; Varga, N.;
Szalay, D.; Urge, L.; Darvas, F. J. Comb. Chem. 2006, 8,
110. (c) Spadoni, C.; Jones, R.; Urge, L.; Darvas, F. Chem.
Today 2006, 38. (d) Clapham, B.; Wilson, N. S.;
Michmerhuizen, M. J.; Blanchard, D. P.; Dingle, D. M.;
Nemcek, T. A.; Pan, J. Y.; Sauer, D. R. J. Comb. Chem.
2008, 10, 88.
pressure. The residue obtained was purified by column
chromatography on silica with hexanes–EtOAc eluent by
gradient method from 4:1 to 1:1. The fractions were
concentrated under reduced pressure and the residue was
triturated with diethyl ether to afford compounds 13a,b.
Methyl 6-Methoxy-2-(benzylamino)nicotinate (13a)
Yield 45%. 1H NMR (400 MHz, CDCl3): d = 8.51 (br s, 1 H),
7.99 (d, J = 8.5 Hz, 1 H), 7.35 (d, J = 7.5 Hz, 2 H), 7.30 (t,
J = 7.5 Hz, 2 H), 7.23 (t, J = 7.5 Hz, 1 H), 5.95 (d, J = 8.5
Hz, 1 H), 4.73 (d, J = 5.8 Hz, 2 H), 3.85 (s, 3 H), 3.81 (s, 3
H). 13C NMR (100 MHz, CDCl3): d = 168.0, 166.5, 158.8,
142.3, 139.9, 128.4, 127.4, 126.9, 98.0, 97.8, 53.4, 51.3,
44.8. ESI-HRMS: m/z calcd for C15H16N2O3 [M + H]+:
273.1234; found: 273.1234. Anal. Calcd for C15H16N2O3: C,
66.16; H, 5.92; N, 10.29. Found: C, 66.40; H, 5.98; N, 10.14.
Methyl 6-Methoxy-2-(4-methoxybenzylamino)-
nicotinates (13b)
(18) Optimization experiments were performed using 0.05 M
solutions of 13a,b in EtOH using a 30 mm 10% Pd/C
CatCart® cartridge. Two modes have been tested at the given
temperatures: (a) controlled mode, 30 bar, liquid flow rate 1
mL/min, hydrogen flow rate 2 N mL/min (b) full hydro-
genation mode, atmospheric pressure, liquid flow rate 1 mL/
min, hydrogen flow rate 30 N mL/min.
(19) Biological activities and medicinal applications have been
reported for 2-mercaptopyrido[2,3-d]pyrimidin-4 (3H)-
ones: (a) El-Gazzar, A.-R. B. A.; Hafez, H. N. Bioorg. Med.
Chem. Lett. 2009, 19, 3392. (b) El-Gazzar, A.-R. B. A.;
Hafez, H. N. Acta Chim. Slov. 2008, 55, 359.
Yield 67%. 1H NMR (300 MHz, CDCl3): d = 8.43 (br s, 1 H),
7.98 (d, J = 8.5 Hz, 1 H), 7.28 (d, J = 8.8 Hz, 2 H), 6.85 (d,
J = 8.8 Hz, 2 H), 5.95 (d, J = 8.5 Hz, 1 H), 4.66 (d, J = 5.7
Hz, 2 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 3.79 (s, 3 H). 13C NMR
(100 MHz, CDCl3): d = 168.0, 166.5, 158.7, 158.6, 142.3,
131.9, 128.7, 113.9, 97.9, 97.7, 55.3, 53.4, 51.3, 44.3. ESI-
HRMS: m/z calcd for C16H18N2O4 [M + H]+: 303.1340;
found: 303.1339. Anal. Calcd for C16H18N2O4: C, 63.57; H,
6.00; N, 9.27. Found: C, 63.85; H, 6.02; N, 9.37.
(20) Sbardella, G.; Bartolini, S.; Castellano, S.; Artico, M.;
Paesano, N.; Rotili, D.; Spadafora, C.; Mai, A.
ChemMedChem 2006, 1, 1073.
(21) Experimental Procedures for the Preparation of Methyl
2-Amino-6-methoxynicotinate (4) and Fused
Pyrimidines 14 and 15
Procedures and analytical data for 2-chloro-6-
methoxynicotinic acid (6) and methyl 2-chloro-6-
methoxynicotinate (9), as well as methyl 2-[3-
Methyl 2-Amino-6-methoxynicotinate (4)
Asolution ofmethyl6-methoxy-2-(4-methoxybenzylamino)
nicotinate (4.0 g, 13.23 mmol) in EtOH (25 mL) was
hydrogenated in an H-Cube instrument over a 70 mm 10%
Pd/C CatCart column under full hydrogenation mode (ref.
18) and column temperature 70 °C. The solvent was
removed under reduced pressure to afford 2.3 g (95%) of the
title compound. 1H NMR (300 MHz, DMSO-d6): d = 7.93 (d,
J = 8.5 Hz, 1 H), 7.27 (br s, 2 H), 6.01 (d, J = 8.5 Hz, 1 H),
3.82 (s, 3 H), 3.76 (s, 3 H). 13C NMR (100 MHz, DMSO-d6):
d = 167.6, 166.6, 159.7, 142.2, 99.7, 98.3, 53.5, 51.4. ESI-
HRMS: m/z calcd for C8H10N2O3 [M + H]+: 183.0764;
found: 183.0764.
(ethoxycarbonyl)thioureido]-6-methoxynicotinate (14) and
7-methoxy-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4
(1H)-one (15) can be found in the Supporting Information.
Methyl 6-Methoxy-2-(benzylamino)nicotinates 13a,b
A 100 mL Milestone microwave reaction vessel was charged
with crude methyl 2-chloro-6-methoxynicotinate (9, 6.50 g,
32.2 mmol), 1,4-dioxane (128 mL), and benzylamine or 4-
methoxybenzylamine (0.32 mol, 10 equiv). The vessel was
capped and the reaction mixture was microwave irradiated at
170 °C for 2 h using a Milestone MicroSYNTH T640
Microwave instrument. The vessel was cooled to r.t. and the
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