A scaleable synthesis of methyl 3-amino-5-(4-fluorobenzyl)-2- pyridinecarboxylate

Article abstract of DOI:10.1021/op7001326

A scaleable synthesis of methyl 3-amino-5-(4-fluorobenzyl)-2- pyridinecarboxylate (1b), starting from 5-bromo-2-methoxypyridine (8) and 4-fluorobenzaldehyde (9), is described. Key steps in the process include lithium-bromine exchange of 8, addition of the

Full text of DOI:10.1021/op7001326

Organic Process Research & Development 2007, 11, 899–902
A Scaleable Synthesis of Methyl 3-Amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate
Eric E. Boros,* Svetlana A. Burova, Greg A. Erickson, Brian A. Johns, Cecilia S. Koble, Noriyuki Kurose,† Matthew J. Sharp,
Elie A. Tabet, James B. Thompson, and Matthew A. Toczko
GlaxoSmithKline Research & DeVelopment, FiVe Moore DriVe, Research Triangle Park, North Carolina 27709, U.S.A.
Abstract:
Results and Discussion
Efficient placement of the fluorobenzyl group in 1 was a
desirable feature of any new synthesis, and commercially
available 5-bromo-2-methoxypyridine (8)5 appeared well-suited
for this purpose. We assumed that metal–halogen exchange of
8 and trapping of the resulting organometallic species with
benzyl acceptor synthons would yield the desired 5-benzylpy-
ridine structure. In addition, the C-2 oxygen of 8 might direct
nitration to the 3-pyridyl position and later be converted to a
leaving group suitable for alkoxycarbonylation chemistry. Along
these lines, we worked towards a more development-friendly
synthesis of 7a,b starting from pyridine 8.
A scaleable synthesis of methyl 3-amino-5-(4-fluorobenzyl)-2-
pyridinecarboxylate (1b), starting from 5-bromo-2-methoxypyri-
dine (8) and 4-fluorobenzaldehyde (9), is described. Key steps in
the process include lithium–bromine exchange of 8, addition of
the resulting lithiate to aldehyde 9, regioselective nitration of pyr-
idone 12, and Pd-catalyzed alkoxycarbonylation of bromopyridine
15b. Overall yield of the five-stage synthesis was 23%; intermedi-
ates 10, 12, 13, 15b, and final product 1b ·HCl were isolated as
filterable solids. Compounds 1a,b are important intermediates in
the synthesis of 7-benzylnaphthyridinones (e.g., 2) and related
HIV-1 integrase inhibitors.
Lithium-bromine exchange of 8 was initially explored with
n-BuLi in THF at -78 °C; reaction of the resulting 5-lithio
species with 4-fluorobenzaldehyde afforded the desired alcohol
10 in good yield. When this reaction was examined at higher
temperatures (-20 °C) in THF, the 5-lithio species was unstable
and reacted with the bromobutane generated during the reaction.
However, when the reaction was performed in tert-butyl methyl
ether (TBME), the 5-lithiopyridine was stable below -18 °C
(reaction maintained between -32 and -18 °C), and upon
addition of 4-fluorobenzaldehye, clean conversion to 10 was
observed; the product was crystallized from 2,2,4-trimethyl-
pentane/TBME following workup and was isolated in 74%
yield.
The original conversion of alcohol 10 to benzylpyridine
11 was achieved by silane-hydride transfer6 with TFA/
triethylsilane in refluxing 1,2-dichloroethane; O-demethy-
lation of 11 in refluxing HBr/acetic acid then afforded
pyridone 12. Since both reduction7 of electron-deficient
benzylic alcohols and O-demethylation8 of 2-methoxypy-
ridines are known to occur in the presence of large
excesses of TMSI, we decided to combine conditions for
in situ TMSI formation (TMSCl/NaI)7 with silane hydride
transfer conditions (TFA/triethylsilane)6 in an attempt to
“telescope” conversion of 10 to 12. Remarkably, when
10 was subjected to these conditions at 70 °C in
acetonitrile, clean conversion to 12 occurred in excellent
yield (Scheme 2).
Introduction
Alkyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylates 1
are useful intermediates in the synthesis of 7-benzyl-4-hydroxy-
1,5-naphthyridin-2(1H)-ones (e.g., 2) and related HIV-1 inte-
grase inhibitors1–3 (eq 1). The original synthesis of 1a2 (Scheme
1, practical for medicinal chemistry purposes, posed several
feasibility issues with large-scale applications. These concerns
included the moderate instability of aldehyde intermediate 3
(prepared in 2 steps from 1-fluoro-4-iodobenzene) and the
formation of unwanted regioisomer 7b from ring opening of
pyridine carboxylic anhydride 6 with ethanol (ratio 7a:7b ≈ 7:
3). Moreover, Curtius rearrangement of 7a,b with diphe-
nylphosphoryl azide (DPPA) and TEA, although uneventful on
a multigram scale, generates potentially dangerous acyl azide
intermediates.4 For these reasons, an alternate route to 7a,b was
developed (Scheme 2) for kilogram-scale applications.
* To whom correspondence should be addressed. Fax: 919-315-0430. E-mail:
eric e. boros@gsk.com.
† Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
(1) For a recent review of HIV integrase inhibitors, see: Pommier, Y.;
Johnson, A. A.; Marchand, C. Nat. ReV. Drug DiscoVery 2005, 4, 236–
248.
(2) Johns, B. A.; Boros, E. E.; Kawasuji, T.; Koble, C. S.; Kurose, N.;
Murai, H.; Sherrill, R. G.; Weatherhead, J. G. Chem. Abstr. 2005,
143, 248371 (WO 05077050, August 25, 2005) .
(3) Murai, H.; Endo, T.; Kurose, N.; Taishi, T.; Yoshida, H. Chem. Abstr.
2004, 140, 287278 (WO 04024693, March 25, 2004) .
(4) Curtius rearrangements have the capacity to be performed on limited
scale, if necessary, under carefully controlled conditions; acyl azide
intermediates are explosive hazards and their isolation should be
avoided, see: am Ende, D. J.; DeVries, K. M.; Clifford, P. J.; Brenek,
S. J. Org. Process Res. DeV. 1998, 2, 382–392.
(5) Starting materials and selected reagents (sources and approximate cost):
compd 8 ($825.00/kg; Synthon Chemicals); compd 9 ($60.00/kg;
ABCR); phosphorous oxybromide was purchased from Lancaster
Synthesis ($2.31/g).
10.1021/op7001326 CCC: $37.00
Published on Web 09/01/2007
2007 American Chemical Society
Vol. 11, No. 5, 2007 / Organic Process Research & Development
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899

Scheme 1
Scheme 2
Regioselective nitration of pyridone 12 was a critical step
and debenzylation of 12. Byproduct 14 was completely removed
in the aqueous filtrate.
in the synthesis of 1. Although 2-pyridones are easily nitrated,9
there was some concern that the fluorophenyl ring of 12 might
undergo competing nitration.10 Although both sulfuric acid and
TFA were examined as solvents for nitration of 12, TFA gave
a considerably cleaner product. Nitration of 12 was ac-
complished with 90% HNO3 in TFA (2.7 vol) at 72 °C and
was relatively selective (70–80%) for the 3-pyridyl position.
Little or no nitration of the fluorophenyl ring was observed.
After dilution of the reaction mixture with water, the product
13 crystallized from the reaction mixture and was isolated in
61% yield. The major byproduct of this reaction was the 5-nitro-
2-pyridone 14 (20–30%), a result of apparent ipso-nitration11
We next explored conversion of 13 to “activated” pyridines
15a,b suitable for carbonylation chemistry. Treatment of
pyridone 13 with neat POCl3 at 112 °C easily afforded
2-chloropyridine 15a. Unfortunately, the rate of CO insertion
of 15a was sluggish; therefore, rather than optimizing CO
insertion of the chloropyridine, we opted to investigate reaction
with the corresponding 2-bromopyridine 15b.
Bromination of 13 was initially performed with POBr35 in
toluene; however, significant solubility problems were encoun-
tered with this solvent. By changing the solvent to 1,2-
dichloroethane we were able to obtain efficient bromination of
13 with POBr3 at 84 °C; this procedure provided 2-bromopy-
ridine 15b in 74% yield.
(6) (a) For reductions of substituted benzhydrol derivatives with TFA/
triethylsilane, see: Waterlot, C.; Hasiak, B.; Couturier, D.; Rigo, B.
Tetrahedron 2001, 57, 4889–4901. (b) Barda, D. A.; Wang, Z-Q.;
Britton, T. C.; Henry, S. S.; Jagdmann, G. E.; Coleman, D. S.; Johnson,
M. P.; Andis, S. L.; Schoepp, D. D. Bioorg. Med. Chem. Lett. 2004,
14, 3099–3102.
Various conditions were examined for CO insertion12 of 15b;
the most effective ones included methanol as solvent or co-
solvent. Efficient methyl ester formation was achieved with
Pd(OAc)2, (o-tolyl)3P, and TEA in MeOH/DMSO at 50 °C
under an atmosphere of carbon monoxide. Following workup,
an EtOAc solution of 16 was carried directly to the final
reduction step without isolation.
(7) Moderately electron-deficient benzyl alcohols may be reduced with
TMSI generated in situ; see: Cain, G. A.; Holler, E. R. Chem. Commun.
2001, 1168–1169.
(8) For O-demethylation of heteroaromatic methyl ethers with TMSI, see:
McBriar, M. D.; Guzik, H.; Shapiro, S.; Xu, R.; Paruchova, J.; Clader,
J. W.; O’Neill, K.; Hawes, B.; Sorota, S.; Margulis, M.; Tucker, K.;
Weston, D. J.; Cox, K. Bioorg. Med. Chem. Lett. 2006, 16, 4262–
4265.
Remarkably, hydrogenation of the nitro group in 16 was one
of the more difficult reactions to optimize. Although this reaction
(9) For nitration of 2-pyridones in sulfuric acid, see: Burton, A. G.; Halls,
P. J.; Katritzky, A. R. Tetrahedron Lett. 1971, 12, 2211–2212.
(10) Aromatic nitration of ethyl 4-fluorophenylacetate in sulfuric acid is
reported; see: Kuse, M.; Doi, I.; Kondo, N.; Kageyama, Y.; Isobe, M.
Tetrahedron 2005, 61, 5754–5762.
(12) For examples of Pd-catalyzed methoxycarbonylation of 2-bromopy-
ridine derivatives, see: Ducharme, Y.; Friesen, R. W.; Blouin, M.;
Cote, B.; Dube, D.; Ethier, D.; Frenette, R.; Laliberte, F.; Mancini,
J. A.; Masson, P.; Styhler, A.; Young, R. N.; Girard, Y. Bioorg. Med.
Chem. Lett. 2003, 13, 1923–1926.
(11) Tashiro, M.; Yamato, T.; Fukata, G.; Fukuda, Y. J. Org. Chem. 1981,
46, 2376–2379.
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proceeded cleanly at atmospheric pressure, the rate was slow
and significant buildup of hydroxylamine intermediate was
observed. For example, hydrogenation of 16 in aqueous
HCl–MeOH with Pd on carbon catalyst required 9 days for
complete reaction. Moreover, after 2 days, the product mixture
consisted of 3% desired amine 1b and 97% of the corresponding
hydroxylamine intermediate. Interestingly, we discovered that
by adding a small amount of iron powder to the reaction
mixture, hydrogen uptake was enhanced to the point where little
or no hydroxylamine intermediate was observed.13,14 Acceptable
hydrogenation rates were achieved with Pd on carbon catalyst
and addition of catalytic quantities of iron powder (Pd:Fe )
40:1) in EtOAc at 65 °C. Under these conditions, hydrogenation
was complete in 8 h, and product 1b was isolated as a
hydrochloride salt in 77% yield (from 15b).
10 (0.92 kg, 3.94 mol, 1 equiv), CH3CN (9.2 L), NaI (2.37 kg,
15.8 mol, 4 equiv), and triethylsilane (945 mL, 5.92 mol, 1.5
equiv). Trifluoroacetic acid (477 mL, 6.19 mol, 1.57 equiv) was
added at a rate that maintained the temperature below 30 °C;
TMSCl (2.5 L, 19.7 mol, 5 equiv) was added, and the batch
was heated at 70 °C for 3 h. Upon cooling to 55 °C, a solution
of 0.8 M Na2SO3 (4.6 L) was added, and the mixture was
distilled to a final volume of 12 L. A solution of 0.15 M Na2SO3
(4.6 L) was added, and the mixture was stirred at room
temperature overnight. A solution of 1.4 M K2CO3 solution (6
L) was added, and the mixture was cooled to 0 °C. The resulting
solid was collected by filtration and washed with water and
TBME. The filter cake was dried to afford 12 as a tan solid
(749 g, 93% yield): 1H NMR (DMSO-d6, δ) 3.62 (s, 2H), 6.24
(d, 1H, J ) 9.3 Hz), 7.08 (dd, 2H, JHF ) 9 Hz, JHH ) 9 Hz),
7.26–7.19 (m, 4H), 11.39 (br s, 1H); ES+ MS 204 (M + H+,
100); mp 145–147 °C. Anal. Calcd for C12H10FNO·(0.1 H2O):
C, 70.30; H, 5.01; N, 6.83. Found: C, 70.24; H, 4.91; N, 6.78.
5-[(4-Fluorophenyl)methyl]-3-nitro-2(1H)-pyridinone (13).
A 20-L jacketed glass laboratory reactor equipped with me-
chanical stirrer, Na2SO3 scrubber (to remove NOx gases), and
reflux condenser was charged with TFA (4 L), 12 (1.484 kg,
7.30 mol, 1 equiv) and 90% HNO3 (618 mL, 14.6 mol, 2 equiv).
The batch was heated at 72 °C for 1.5 h and then cooled to 24
°C. Water (14.8 L) was added, and the mixture was stirred for
2 h. The mixture was filtered, and the filter cake was washed
with water and dried to afford 13 as a yellow-orange solid (1.11
kg, 61% yield): 1H NMR (DMSO-d6, δ) 3.76 (s, 2H), 7.11 (dd,
2H, JHF ) 8.6 Hz, JHH ) 8.6 Hz), 7.30 (dd, 2H, JHF ) 5.7 Hz,
JHH ) 8.6 Hz), 7.80 (d, 1H, J ) 2.4 Hz), 8.31 (d, 1H, J ) 2.4
Hz), 12.76 (br s, 1H); ES+ MS 249 (M + H+, 100); mp
265–266 °C (dec). Anal. Calcd for C12H9FN2O3 ·(0.1 H2O): C,
57.65; H, 3.71; N, 11.20. Found: C, 57.63; H, 3.59; N, 11.15.
2-Bromo-5-[(4-fluorophenyl)methyl]-3-nitropyridine (15b).
A 20-L jacketed glass laboratory reactor equipped with me-
chanical stirrer, caustic scrubber, and reflux condenser was
charged with 13 (931 g, 3.75 mol, 1 equiv) and 1,2-dichloro-
ethane (5.6 L). A solution of POBr3 (1.18 kg, 4.13 mol, 1.1
equiv) in 1,2-dichloroethane (2.9 L) was added, and the mixture
was heated at 84 °C for 3 h. Additional POBr3 (96 g, 0.33 mol,
0.088 equiv) was added, and heating was continued for 2 h at
which point the mixture was cooled to ambient temperature
and then to 2 °C. A solution of 2 M NaOH (10.2 L) was added
over 30 min, maintaining the temperature below 20 °C. The
organic phase was separated, filtered through celite, and washed
with water (3 L). The organic layer was separated and distilled
to a final volume of 3.9 L at which point it was cooled to 56
°C and diluted with 2,2,4-trimethylpentane (10 L). The mixture
was heated to 80 °C and then cooled slowly to -15 °C. The
resulting solids were collected by filtration, and the filter cake
was washed with 2,2,4-trimethylpentane. Further drying of the
filter cake provided 15b as a sand-like solid (843 g, 72% yield):
1H NMR (DMSO-d6, δ) 4.05 (s, 2H), 7.12 (dd, 2H, JHF ) 8.7
Hz, JHH ) 8.7 Hz), 7.33 (dd, 2H, JHF ) 5.6 Hz, JHH ) 8.7 Hz),
8.37 (d, 1H, J ) 2 Hz), 8.62 (d, 1H, J ) 2 Hz); ES+ MS 313
(M + H+, 100), 311 (M + H+, 100); mp 80–82 °C. Anal. Calcd
for C12H8BrFN2O2: C, 46.33; H, 2.59; N, 9.00; Br, 25.68.
Found: C, 46.38; H, 2.53; N, 8.86; Br, 25.52.
In summary, a scaleable synthesis of 1b was developed
starting from pyridine 8 and aldehyde 9. A 0.523 kg batch of
1b·HCl was prepared in 5 stages and 23% overall yield.
Compounds 1a,b are important intermediates in the synthesis
of 7-benzylnaphthyridinones (e.g., 2) and related HIV-1 inte-
grase inhibitors.
Experimental Section
(4-Fluorophenyl)[6-(methyloxy)-3-pyridinyl]methanol (10).
A 20-L jacketed glass laboratory reactor (graduated volume )
20 L; quench volume ca. 30 L) equipped with mechanical stirrer
and reflux condenser was charged with 8 (1.25 kg, 6.64 mol, 1
equiv) and TBME (12 L). The solution was cooled to -32 °C.
A solution of 2.5 M n-BuLi in hexanes (2.7 L, 6.64 mol, 1
equiv) was added over 30 min while maintaining the temper-
ature below -18 °C. The mixture was stirred for 60 min at
-32 °C. 4-Fluorobenzaldehyde (9) (0.64 L, 6.04 mol, 0.91
equiv) was then added to the lithiate over 30 min while
maintaining the temperature below -23 °C. After stirring for
30 min, the batch was warmed to 0 °C and quenched with 1 M
HCl (8.6 L). The phases were separated and the aqueous layer
was extracted twice with TBME (8.6 and 3.4 L). All combined
organic phases were washed with water (2 L), distilled to a
final volume of 9 L, and then diluted with 2,2,4-trimethylpentane
(12 L). Distillation was continued to a final volume of 12.5 L
at which point the batch was cooled to ambient temperature
and then to -10 °C. The resulting precipitate was collected by
filtration, washed with 2,2,4-trimethylpentane, and dried to
1
afford 10 as a light tan solid (1.05 kg, 74% yield): H NMR
(CDCl3, δ) 3.91 (s, 3H), 5.80 (s, 1H), 6.70 (d, 1H, J ) 8.6
Hz), 7.02 (dd, 2H, JHF ) 8.7 Hz, JHH ) 8.7 Hz), 7.33 (dd, 2H,
JHF ) 5.5, JHH ) 8.6 Hz), 7.51 (dd, 1H, J ) 2.5 and 8.6 Hz),
8.12 (d, 1H, J ) 2.5 Hz); AP+ MS 234 (M + H+, 100);
hydroxylic proton not observed.
5-[(4-Fluorophenyl)methyl]-2(1H)-pyridinone (12). A 20-L
jacketed glass laboratory reactor equipped with mechanical
stirrer, caustic scrubber, and reflux condenser was charged with
(13) Metal salts (including iron) have potential to eliminate hydroxylamine
accumulation during aromatic nitro group reductions; see: Baumeister,
P.; Blaser, H. U.; Studer, M. Catal. Lett. 1997, 49, 219–222.
(14) Catalytic amounts of iron in the presence of noble metal catalysts are
known to facilitate selective hydrogenation of polynitroaromatic
compounds; see: Theodoridis, G.; Manfredi, M. C.; Krebs, J. D.
Tetrahedron Lett. 1990, 31, 6141–6144.
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Methyl
3-Amino-5-[(4-fluorophenyl)methyl]-2-pyri-
mixture was filtered through celite and the filtrate was treated
with a solution of 10% HCl (5.3 L). Most of the EtOAc was
removed by distillation (50 °C; 150–200 mmHg). The aqueous
HCl mixture was diluted with toluene (1.5 L), cooled to 2 °C
and stirred for 1 h. Filtration of the resulting solids and washing
with EtOAc afforded 1b·HCl (523 g, 77% yield) as a beige
solid: 1H NMR (HCl salt, DMSO-d6, δ) 3.86 (s, 3H), 4.01 (s,
2H), 6.90 (br, 3H), 7.15 (dd, 2H, JHF ) 8.6 Hz, JHH ) 8.6 Hz),
7.29 (dd, 2H, JHF ) 5.6 Hz, JHH ) 8.6 Hz), 7.44 (s, 1H), 7.95
(s, 1H). An analytical sample of 1b was obtained by crystal-
lization of the free amine from EtOAc: 1H NMR (free amine,
CDCl3, δ) 3.89 (s, 2H), 3.95 (s, 3H), 5.67 (br s, 2H), 6.71 (d,
1H, J ≈ 1.5 Hz), 6.98 (dd, 2H, JHF ) 8.6 Hz, JHH ) 8.6 Hz),
7.12 (dd, 2H, JHF ) 5.4 Hz, JHH ) 8.6 Hz), 7.94 (d, 1H, J ≈
1.5 Hz); ES+ MS: 261 (M + H+, 100); mp 156–158 °C. Anal.
Calcd for C14H13FN2O2: C, 64.61; H, 5.03; N, 10.76. Found:
C, 64.36; H, 5.04; N, 10.72.
dinecarboxylate Hydrochloride (1b). A 20-L jacketed glass
laboratory reactor equipped with mechanical stirrer, reflux
condenser, and Büchi gas flow apparatus (bpc 1202) was
charged with 15b (708 g, 2.28 mol, 1 equiv), 2:1 MeOH/DMSO
(7.1 L), Pd(OAc)2 (25.5 g, 0.11 mol, 4.8 mol%), tri-o-
tolylphosphine (34.6 g, 0.11 mol, 4.8 mol%), and TEA (952
mL, 6.8 mol). The Büchi press-flow apparatus was attached to
a carbon monoxide cylinder and the reaction vessel was
evacuated and purged three times with carbon monoxide. The
batch was heated at 50 °C for 18 h under carbon monoxide
atmosphere until gas uptake ceased. Upon cooling to rt, the
vessel was evacuated and purged with nitrogen. The mixture
was vacuum distilled (0.8 bar) until the batch reached 56 °C at
which point it was allowed to cool to rt. The mixture was diluted
with EtOAc (7.1 L) and the organic phase was washed three
times with water (3.5 L each). The aqueous washes were
removed and the remaining EtOAc layer containing 16 was
charged with a mixture of 10% Pd on carbon (242 g, 50% wet
Degussa E101 NE/W) and iron powder (6 g). A hydrogen
cylinder was attached to the Büchi press-flow apparatus and
the reaction vessel was evacuated and purged with hydrogen.
The reaction mixture was stirred for 8 h at 65 °C under
hydrogen atmosphere until gas uptake ceased. The reaction
vessel was evacuated and flushed with nitrogen. The hot reaction
Acknowledgment
This work was conducted as part of a research collaboration
between GlaxoSmithKline and Shionogi & Co., Ltd.
Received for review June 13, 2007.
OP7001326
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