A facile two-step synthesis of 3-fluoro-6-methoxyquinoline

Article abstract of DOI:10.1021/op800198b

A facile two-step synthesis of 3-fluoro-6-methoxyquinoline is described. p-Anisidine was heated at reflux with 2-fluoromalonic acid in the presence of phosphorus oxychloride to produce 2,4-dichloro-3-fluoro-6-methoxyquinoline. This was followed by hydrogenolysis to produce 3-fluoro-6-methoxyquinoline.

Full text of DOI:10.1021/op800198b

Organic Process Research & Development 2008, 12, 1273–1275
A Facile Two-Step Synthesis of 3-Fluoro-6-methoxyquinoline
Bryan Li,* Zhijun Zhang, and Michael Mangano
Research-API, Pharmaceutical Sciences, Pfizer Global R&D Groton Laboratories, Eastern Point Road,
Groton, Connecticut 06340, U.S.A.
Abstract:
A facile two-step synthesis of 3-fluoro-6-methoxyquinoline is
described. p-Anisidine was heated at reflux with 2-fluoromalonic
acid in the presence of phosphorus oxychloride to produce 2,4-
Figure 1
dichloro-3-fluoro-6-methoxyquinoline. This was followed by hy-
drogenolysis to produce 3-fluoro-6-methoxyquinoline.
Schlosser et al.,5 in which an aniline is condensed with methyl
2-fluoro-3-methoxyacrylate, required cryogenic conditions and
the use of gaseous dichlorofluoromethane. Alternatively, Michael
addition of N-tosylanilines to acrolein, followed by cyclization
and thermal elimination, provides a convenient synthesis of
quinolines.6 Unfortunately, this method could not be adapted
for the 3-fluoroquinoline synthesis as the requisite starting
material, 2-fluoroacrolein, polymerized rapidly even under cold
storage.
We considered the functionalization of chloroquinolines.
Heteroaromatic chlorides are efficient ortho-metalation directing
groups and readily removed via catalytic hydrogenolysis.7 With
this in mind, we initially embarked on the directed ortho-
lithiation8 of chloroquinolines 2a and 2b9(Scheme 2), followed
by addition of (PhSO2)2NF as an electrophile. Unfortunately,
this approach did not produce a meaningful yield of the desired
3-fluorinated products (3).10
In parallel to these lithiation studies, we investigated the
synthesis of 2,4-dichloro-3-fluoroquinolines (3b) via an annu-
lation approach, (Scheme 3). Analogous to the well-precedented
synthesis of 2,4-dichloroquinoline,11 p-anisidine was heated at
reflux with 2-fluoromalonyl chloride, which was generated in
situ by treating 2-fluoromalonic acid (4)12 with phosphorus
oxychloride. This process proved to be successful, and dichlo-
rofluoroquinoline 3b was obtained in ∼60% yield. Removal
Introduction
As an important class of alkaloids, quinoline compounds are
of pharmaceutical interest due to their wide range of biological
activities.1 Several examples in the medicinal chemistry litera-
ture have demonstrated that fluorinated quinolines display
improved performance relative to that of their des-fluoro
analogues, which has resulted in the development of new
pharmaceutical candidates incorporating fluoroquinolines.2 We
recently engaged in a program to develop a method for the
preparation of 6-methoxy-3-fluoroquinoline (1, Figure 1). This
communication describes the kilogram-scale synthesis of 1.
The Schiemann reaction (fluorination of anilines with
NOBF4; see steps 6/7 in Scheme 1) remains one of the most
common methods to introduce fluorines into heteroaromatic
compounds.3 When we engaged in this project, the only known
preparation of 1 in the literature was a seven-step synthesis
(Scheme 1)4 that employed a Schiemann reaction in the final
step. The chemistry was not deemed suitable for scale-up
because of efficiency issues and some high-energy transforma-
tions (steps 2 and 6/7). We considered several alternative
methods for the fluorination of quinolines. The method of
* To whom correspondence should be addressed. Fax: 1(860)715-1448.
E-mail: bryan.li@pfizer.com.
(5) Maevers, U.; Berruex, F.; Schlosser, M. Tetrahedron 1996, 52 (9),
3223–3228.
(1) Michael, J. P. Nat. Prod. Rep. 2007, 24 (1), 223–246.
(2) (a) Takahashi, K.; Kamiya, M.; Sengoku, Y.; Kohda, K.; Kawazoe,
Y. Chem. Pharm. Bull. 1988, 36 (11), 4630–4633. (b) Kamiya, M.;
Sengoku, Y.; Takahashi, K.; Kohda, K.; Kawazoe, Y. Basic Life Sci.
1990, 52, 441–446. (c) Arakawa, H.; Mano, E.; Hakoda, N.; Yoshinari,
T.; Nakagawa, S.; Okura, A. Anti-Cancer Drug Des. 1996, 11 (3),
221–229. (d) Saeki, K.; Kadoi, M.; Kawazoe, Y.; Futakuchi, M.;
Tiwawech, D.; Shirai, T. Biol. Pharm. Bull. 1997, 20 (1), 40–43. (e)
Horchler, C. L.; McCauley, J. P.; Hall, J. E.; Snyder, D. H.; Moore,
W. C.; Hudzik, T. J.; Chapdelaine, M. J. Bioorg. Med. Chem. 2007,
15 (2), 939–950. (f) Kamal, A.; Satyanarayana, M.; Devaiah, V.;
Rohini, V.; Yadav, J. S.; Mullick, B.; Nagaraja, V. Lett. Drug Des.
DiscoVery 2006, 3 (7), 494–502. (g) Hoeglund, I. P. J.; Silver, S.;
Engstroem, M. T.; Salo, H.; Tauber, A.; Kyyroenen, H.-K.; Saarenketo,
P.; Hoffren, A.-M.; Kokko, K.; Pohjanoksa, K.; Sallinen, J.; Savola,
J.-M.; Wurster, S.; Kallatsa, O. A. J. Med. Chem. 2006, 49 (21), 6351–
6363.
(6) Tokuyama, H.; Sato, M.; Ueda, T.; Fukuyama, T. Heterocycles 2001,
54 (1), 105–108.
(7) Marzi, E.; Bobbio, C.; Cottet, F.; Schlosser, M. Eur. J. Org. Chem.
2005, 10, 2116–2123.
(8) Marsais, F.; Godard, A.; Queguiner, G. J. Heterocycl. Chem. 1989,
26 (6), 1589–1594. (b) Cottet, F.; Marull, M.; Lefebvre, O.; Schlosser,
M. Eur. J. Org. Chem. 2003, 8, 1559–1568. (c) Leleu, S.; Papamicael,
C.; Marsais, F.; Dupas, G.; Levacher, V. Tetrahedron: Asymmetry
2004, 15 (24), 3919–3928. (d) Riego, E.; Bayo, N.; Cuevas, C.;
Albericio, F.; Alvarez, M. Tetrahedron 2005, 61 (6), 1407–1411.
(9) 2-Chloro-6-methoxyquinoline is commercially available or conve-
niently prepared: Inglis, S. R.; Stojkoski, C.; Branson, K. M.;
Cawthray, J. F.; Fritz, D.; Wiadrowski, E.; Pyke, S. M.; Booker, G. W.
J. Med. Chem. 2004, 47 (22), 5405–5417.
(10) Trace amount of the desired product (<5%) was observed by LC/
MS. The starting materials mostly decomposed. The investigation of
this approach was limited to reaction conditions of LDA or LiTMP
at-60 °C, then (PhSO2)2NF addition.
(11) Lee, B. S.; Chu, S.; Lee, B.-S.; Chi, D. Y.; Song, Y. S.; Jin, C. Bioorg.
Med. Chem. Lett. 2002, 12 (5), 811–815. (b) Prakash, G.; Arul
Rajendran, S. P. Heterocycl. Commun. 2001, 7 (4), 353–358.
(12) Prepared from the commercially available dimethyl 2-fluoromalonate.
(3) Roe, A.; Hawkins, G. F. J. Am. Chem. Soc. 1949, 71, 1785–1786.
(4) (a) El Ahmad, Y.; Leconte, J. P.; Malpart, J.; Mignani, S.; Mutti, S.;
Tabart, M. Fr. Demande FR2862301, A120050520. 2005; Chem. Abstr.
2005, 142, 481961. (b) Miller, W. H.; Pendrak, I.; Seefeld, M. A.
PCT Int. Appl. WO2006002047. 2006; Chem. Abstr. 2006, 144,
108362.
10.1021/op800198b CCC: $40.75
Published on Web 10/25/2008
2008 American Chemical Society
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Scheme 1
Scheme 2
Scheme 3
was stirred at room temperature for 16 h. The reaction was
monitored with TLC (10% EtOAc/hexanes, I2 visualization).
The reaction suspension was stripped to ∼135 mL. Water (67.5
mL) and MTBE (450 mL) were added. After cooling to 0 °C,
concentrated HCl (66 mL, 37%, 0.66 mol) was added. The
organic layer was separated, and the aqueous layer was extracted
with MTBE (3 × 225 mL). The organic layers were combined,
dried with sodium sulfate, and concentrated to give the product
as a white solid (36.1 g, 99%). 1H NMR (400 mHz, CDCl3) δ
(ppm) 5.4 (d, J ) 2.1 Hz, 1H), 5.31 (d, J ) 2.1, 1H), 5.15 (br,
4H). MS m/z (M - H)+ 120.88.
2,4-Dichloro-3-fluoro-6-methoxyquinoline (3b). Labora-
tory Scale. To phosphorus oxychloride (210 mL) was added
fluoromalonic acid (35 g, 0.287 mol, portionwise. The mixture
was heated at reflux for 30 min to completely dissolve
fluoromalonic acid and then cooled to 60 °C. After p-anisidine
(35.3 g, 0.287 mol) was added slowly, the mixture was heated
at reflux for 2 h, and then ∼100 mL of phosphorus oxychloride
was removed by distillation. The resulting mixture was cooled
to RT and poured onto ice (350 g) and stirred for 30 min.
Ammonium hydroxide (300 mL, 28-30%) was added to adjust
the pH to 10. The suspension was stirred for 2 h before it was
filtered. The filter cake was washed with water. After drying,
the solid was regranulated in MTBE (200 mL) for 2 h. An off-
white solid was collected and dried under vacuum at 45 °C to
produce the first crop product (12.4 g). The filtrate was
concentrated and exchanged with ethyl acetate to a volume of
∼150 mL. Hexanes (150 mL) were added. The suspension was
granulated for 2 h. Filtration of the slurry and drying under full
vacuum gave the second crop product (19.6 g). The filtrate was
chromatographed, eluting with 5% ethyl acetate in hexanes to
produce additional product as the third crop (10.2 g). The
combined crops were 42.2 g, 60% yield. 1H NMR (400 MHz,
CDCl3) δ 7.91 (d, J ) 9.1 Hz, 1H), 7.38 (dd, J ) 9.1, 2.9 Hz,
1H), 7.32 (d, J ) 2.9 Hz, 1H), 3.98 (s, 3H). MS m/z 246.1 (M
+ H)+; HRMS m/z Calcd for C10H7NOFCl2(M + H)+ 245.9889,
Found: 245.9889.
of the chlorine by transfer hydrogenolysis or Raney nickel
provided 1 in good yields. This protocol was subsequently
executed on more than one kilogram scale.13
While 2-fluoromalonic acid derivatives are known to react
with amidines, ureas, or guanidines to produce 5-fluorouracils
or other pyrimidines,14 their applications in Friedel-Crafts
acylation/cyclocondensation reactions have not been docu-
mented in the literature. The findings reported herein demon-
strate a new approach to the syntheses of 3-fluoroquinolines.
This method may be amenable for syntheses of other com-
pounds possessing the 3-fluoropyridine fragment.
Experimental Section
2-Fluoromalonic Acid (4). To dimethyl 2-fluoromalonate
(45 g, 0.3 mol, LR) was added methanol (675 mL), water (45
mL), and lithium hydroxide (15.3 g, 0.63 mol). The mixture
(13) More robust isolation methods for both the intermediate 3b and the
final product will need to be explored for multikilogram-scale reactions.
(14) Fuchigami, T.; Yamanochi, A.; Tanaka, M.; Sakai, K.; Yamada, K.
Jpn. Kokai Tokkyo Koho: JP 61205261. 1986; Chem. Abstr. 1987,
106, 18608. (b) Takaoka, A.; Ibrahim, M.; Kamal, K. S. R. F.;
Ishikawa, N. Nippon Kagaku Kaishi 1985, 11, 2169–2176. (c)
Schostarez, H. J. PCT Int. Appl. WO 9208705. 1992; Chem. Abstr.
1991, 117, 90319. (d) Kawada, M.; Uesugi, Y.; Yamashita, T.; Terao,
H.; Kondo, K.; Uchiumi, J.; Ohara, S. Jpn. Kokai Tokkyo Koho:
JP06239839. 1994; Chem. Abstr. 1995, 122, 81393.
Kilo Laboratory Scale. To phosphorus oxychloride (7.0 L)
in a 12 L glass reactor equipped with a mechanical stirrer,
condenser, and thermometer was added fluoromalonic acid
(1109 g, 9.09 mol) portionwise. The mixture was heated at
reflux for 30 min to completely dissolve fluoromalonic acid
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and then cooled to 60 °C. p-Anisidine (1119 g, 9.09 mol) was
added over a period of 1.5 h at 60-65 °C (Caution: with each
addition, there was a short duration of a rapid release of HCl
gas and a minor exotherm). The mixture was heated to reflux
(HCl gas continued to evolve during the heat-up; the reaction
should be heated up slowly). Once the reaction temperature was
>90 °C, the heating was continued for 2 h. (The final reaction
temperature will be 100-105 °C). POCl3 (1.5 L) was then
removed by vacuum distillation. The resulting mixture was
cooled to RT and slowly transferred into a 30 gal PE jug
(equipped with an agitator) that contained ice (35 kg); the
mixture stirred for 30 min. Ammonium hydroxide (30 L,
28-30%) was added to adjust the pH to 9.5-10 range. The
suspension was stirred for 2 h before it was filtered. The filter
cake was washed with water. The wet solids (3.2 kg) were
transferred to the reactor, and EtOAc (9 L) was added. The
mixture was heated to dissolve the solids, and cooled to RT.
The aqueous bottom layer was decanted (1.4 L water), and the
organic phase was treated with active carbon (200 g) and
filtered. The filtrate was concentrated to 3 L volume and cooled
to -20 °C in a freezer. The solids were collected by filtration,
rinsed twice with a mixture of EtOAc and MTBE (250 mL
each at 0-4 °C), and dried under vacuum at 35-40 °C to
produce the desired product (808 g, 36%). On large scale, it
was not deemed economical to chromatographically isolate a
second crop from the mother liquor, alhough a significant
amount of the product was present.
were collected and concentrated to dryness to yield a white solid
as the product (8.03 g, 56% yield). 1H NMR (400 MHz, CDCl3)
δ (8.64 (d, J ) 2.9 Hz, 1H), 7.98 (d, J ) 9.1 Hz, 1H), 7.65
(dd, J ) 9.1, 2.9 Hz, 1H), 7.31 (dd, J ) 9.1, 2.9 Hz, 1H), 7.01
(d, J ) 2.9 Hz, 1H), 3.92 (s, 3H). MS m/z 178.19 (M + H)+.
HRMS m/z Calcd for C10 H9NOF (M + H)+ 178.0668, Found:
178.0656.
Raney Nickel Method. To a 20 L autoclave was charged
MeOH (7 L), followed by the addition of 3b (808 g, 3.28 mol)
and 7 M NH3 in MeOH (7 L). Raney nickel (150 g) was added,
and the reaction was hydrogenated at 150 psi for 18 h. Portions
of Raney nickel were added at intervals of 18 h (150 g), 42 h
(100 g), and 50 h (50 g). The reaction was typically completed
in 50-72 h. The reaction mixture was filtered through Celite
and rinsed with MeOH (4 L) [Caution: Do not allow the filter
bed to become dry at any time]. The filtrate was concentrated,
and the resulting oil was dissolved in MTBE (600 mL). The
solution was treated with active carbon at reflux and filtered.
The hot filtrate was cooled slowly with agitation to form a thick
slurry. The mixture was further cooled to -20 °C and filtered.
The filter cake was rinsed with MTBE at -20 °C (2 × 100
mL) and dried to give the first crop of the desired product. A
second crop of the product was recovered from the mother
liquor by repeating the crystallization after concentration. Both
crops were of similar purity by HPLC (>98%), and the
combined yield was 489 g (81%). The batch size was repeated
six times to give consistent results. Analytical data were identical
to those obtained in the Pd/C reduction method.
3-Fluoro-6-methoxyquinoline (1). Pd-C Method. To 10%
Pd/C (1 g) were added methanol (300 mL) and 2,4-dichloro-
3-fluoro-6-methoxyquinoline (20 g, 0.0813 mol). After stirring
for 30 min, the mixture was filtered through Celite (Note: This
pretreatment was performed to remove an unidentified catalyst
poison). To the filtrate were added fresh Pd/C (1 g) and
ammonium formate (10 g). The reaction was stirred for 16 h at
RT. The reaction mixture was filtered. The filtrate was stripped
to dryness. The resulting residue was passed through a silica
gel plug with 5% ethyl acetate in hexanes. Product-rich fractions
Acknowledgment
We thank Cambridge Major Laboratories for scaling up the
chemistry, and we are grateful for valuable comments on the
manuscript from Dr. Martin A. Berliner.
Received for review August 5, 2008.
OP800198B
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