Efficient pyridinylmethyl functionalization: Synthesis of 10,10-bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (DMP 543), an acetylcholine release enhancing agent

Article abstract of DOI:10.1021/jo9804339

2-Fluoro-4-methylpyridine (3) is efficiently functionalized by chlorination, hydrolysis and methane-sulfonylation into the novel alkylating agent 7. This mesylate is used for the bisalkylation of anthrone under carefully defined conditions to prepare the cognition enhancer drug candidate 1. This process proceeds in up to 37% overall yield and is adaptable for large scale synthesis.

Full text of DOI:10.1021/jo9804339

7
718
J . Org. Chem. 2000, 65, 7718-7722
Efficien t P yr id in ylm eth yl F u n ction a liza tion : Syn th esis of
1
0,10-Bis[(2-flu or o-4-p yr id in yl)m eth yl]-9(10H)-a n th r a cen on e (DMP
5
43), a n Acetylch olin e Relea se En h a n cin g Agen t†
‡
J aan A. Pesti,* George F. Huhn, J ianguo Yin, Yide Xing, and J oseph M. Fortunak
Chemical Process R&D Department, The DuPont Pharmaceuticals Company, DuPont Chambers Works,
Process Research Facility, Deepwater, New J ersey 08023-0999
Richard A. Earl§
Chemical and Physical Sciences Department, The DuPont Pharmaceuticals Company,
Experimental Station, Wilmington, Delaware 19880-0500
jaan.a.pesti@dupontpharma.com
Received March 9, 1998
2
-Fluoro-4-methylpyridine (3) is efficiently functionalized by chlorination, hydrolysis and methane-
sulfonylation into the novel alkylating agent 7. This mesylate is used for the bisalkylation of
anthrone under carefully defined conditions to prepare the cognition enhancer drug candidate 1.
This process proceeds in up to 37% overall yield and is adaptable for large scale synthesis.
Alzheimer’s disease is the most frequently encountered
age-associated dementia, striking about 10% of those over
1
,2
6
5 and rising to about 50% for those over 85. It is a
particularly distressing affliction for both victims and
their families, as symptoms usually progress through
memory impairment, loss of motor coordination, and
eventually death. Currently approved therapeutic agents
are limited to tacrine, whose benefit-to-risk ratio is not
3
4
high, and the recently approved donepezil. The need
for more effective treatments continues to drive intense
5
research in this direction. In this paper, we present an
of both core and pendant groups led to an analogue
possessing an anthrone core approximately 10 times as
potent. However, DuP 996 was readily metabolized by
efficient and practical synthesis for DuPont’s lead com-
pound in this area: DMP 543 (1). Our objective was the
development of a safe, inexpensive and environmentally
cognizant synthesis that would permit the preparation
of kilogram lots of this drug candidate. This would allow
timely preparation of drug substance for safety assess-
ment, formulation development, and clinical studies. The
potentiality to adapt this synthesis for eventual com-
mercial production was also desirable.
9
N-oxidation of the pyridinylmethyl pendant groups, lead-
ing to short plasma residence times of the parent drug.
Attenuation of the process was necessary to increase in
vivo duration of these neurotransmitter release enhanc-
ing agents. It seemed likely that fluoro substituents in
the ortho position of the pyridine rings would reduce both
the nitrogen’s basicity and susceptibility to N-oxidation.
This hypothesis led to the design of 1.10
As part of a program to develop compounds that might
reduce cholinergic system dysfunction by acetylcholine
release enhancement, DuP 996 (2, linopirdine) was found
to be active both in vivo and in vitro.6 Further variation
The most expeditious synthesis of 1 would be the
bisalkylation of anthrone with a properly functionalized
-8
2
-fluoropyridine. 2-Fluoro-4-methylpyridine (3), the only
*
Current address and to whom correspondence should be ad-
dressed: DuPont Pharmaceuticals Company, Chemical Process R&D
Department, DuPont Experimental Station, Wilmington, DE 19880-
(7) Cook, L.; Nickolson, V. J .; Steinfels, G. F.; Rohrbach, K. W.;
0
336. Tel.: (302) 695-3189. Fax: (302) 695-3167. Email: jaan.a.pesti@
DeNoble, V. J . Drug Dev. Res. 1990, 19, 301-314.
dupontpharma.com.
(8) (a) Chorvat, R. J .; Earl, R. A.; Zaczek, R. Drugs Future 1995,
20, 1145-1162. (b) Zaczek, R.; Chorvat, R. J .; Earl, R. A.; Tam, S. W.
Alzheimer Dis. 1994, 252-255.
†
Reported in part at the 216th National Meeting of the American
Chemical Society, Boston, MA, August 23-27, 1998.
‡
Present address: Decision Sight Inc., 122 Broadbent Rd., Wilm-
(9) Earl, R. A.; Myers, M. J .; J ohnson, A. L.; Scribner, R. M.;
Wuonola, M. A.; Boswell, G. A.; Wilkerson, W. W.; Nickolson, V. J .;
Tam, S. W.; Brittelli, D. R.; Chorvat, R. J .; Zaczek, R.; Cook, L.; Wang,
C.; Zhang, X.; Lan, R.; Mi, B.; Wenting, H. Bioorg. Med. Chem. Lett.
1992, 2, 851-854.
ington, DE 19810.
§
Present address: Nitromed Inc., 12 Oak Park Dr., Bedford, MA
0
1730.
1) Farlow, M. R. Alzheimer Dis. Assoc. Disord. 1994, 8, (suppl. 2),
(
s50-s57.
(10) (a) Teleha, C. A.; Wilkerson, W. W.; Earl, R. A. Int. Pat. 1994,
241131; Chem. Abstr. 1995, 122, 105859. (b) Zaczek, R.; Chorvat, R.
J .; Saye, J . A.; Pierdomenico, M. E.; Maciag, C. M.; Logue, A. R.; Fisher,
B. N.; Rominger, D. H.; Earl, R. A. J . Pharm. Exp. Ther. 1998, 285,
724-730. (c) Earl, R. A.; Zaczek, R.; Teleha, C. A.; Fisher, B. N.;
Maciag, C. M.; Marynowski, M. E.; Logue, A. R.; Tam, S. W.; Tinker,
W. J .; Huang, S. M.; Chorvat, R. J . J . Med. Chem. 1998, 41, 4615-
4622.
(
(
(
2) Davidson, B. Drug Market Dev. 1997, 8, 229-235.
3) Hollister, L.; Gruber, N. Drugs Aging 1996, 8, 47-55.
4) Kawakami, Y.; Inoue, A.; Kawai, T.; Wakita, M.; Sugimoto, H.;
Hopfinger, A. J . Bioorg. Med. Chem. Lett. 1996, 4, 1429-1445.
(
5) Brennan, M. B. Chem. Eng. News 1997, 75, 29-35.
(6) Nickolson, V. J .; Tam, S. W.; Myers, M. J .; Cook, L. Drug Dev.
Res. 1990, 19, 285-300.
1
0.1021/jo9804339 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Efficient Pyridinylmethyl Functionalization
J . Org. Chem., Vol. 65, No. 23, 2000 7719
Sch em e 1a
Sch em e 2
this system, particularly with regard to reaction ef-
ficiency, safety, cost, and environmental issues.
Intriguingly, the presence of water increased the
chlorination rate, as did increasing the flux of incandes-
cent light but with less effect. Assuming that water
reacted with either NCS or chlorine originating from NCS
to produce traces of acid,16 which was hypothesized to
be catalyzing the chlorination, we added 3 mol % of acetic
acid. Gratifyingly, the optimum reaction time dropped
1
7
from 8 to 2 h and the solution yields increased to g70%.
There were fewer side-products, and light was no longer
necessary. The process was optimized further to lead to
large scale production; however, the use of acetonitrile
as solvent and acid-catalyzed rate enhancement re-
mained the key improvements.
a
Reagents: (a) NCS, benzoyl peroxide, CH3COOH, CH3CN, 65-
7
9
6
5%; (b) K2CO3, H2O, 65-70%; (c) CH3SO2Cl, (CH3CH2)3N, EtOAc,
0-95%; (d) NaI, THF; (e) anthrone, lithium tert-butoxide, THF,
5-75%.
18
The role of acid catalysis in this radical-initiated
reaction (benzoyl peroxide is still required) is worth
discussing. Two possible initial reactions would be pro-
tonation of either NCS or 3. Pyridinium ion formation
could lead via a formal prototropic rearrangement to
equilibrium with the unstable tautomer 3* which should
be quickly chlorinated,19 (Scheme 2). Similar mechanisms
are proposed for other heterocycles with benzylic methyl
groups.20 Alternatively, the presence of traces of acid or
water in solutions of NCS will result in the formation of
suitably commercially available starting material, seemed
to be a good candidate for functionalization of the benzylic
position. The optimized process is described in Scheme
1
. Our initial research was directed toward chloride 4,
which would be a precursor to the alkylating agent, iodide
1
1
8
.
There are a variety of potential short routes to
1
2
R-chloropicolines from picolines; however, the majority
of these feature N-oxides as prominent intermediates and
were unlikely to form efficiently from electron-deficient
rings such as 3. Most of the remaining one-step proce-
dures require chlorine gas,13 presenting operational
hazards in our scale-up facilities that we decided to
forego. Ultimately, the answer arose from classical radi-
cal-catalyzed chlorination, namely N-chlorosuccinimide
1
6,21
hydrogen chloride and then molecular chlorine,
and
such conditions are known to accelerate the benzylic
chlorination of toluene.21
However, further experiments suggested the tautomer
3
* was not involved. Since 3 is very weakly basic, any
1
4
(NCS)/benzoyl peroxide/carbon tetrachloride/heat/light
pyridinium ion would be in extremely low concentration
which produced an acceptable product mixture of 3, 4,
and 5 (60-65% yield of 4) if halted once 4 had attained
its maximum concentration at 85-90% reaction. How-
ever, since chlorinated solvents are generally unaccept-
able in commercial processes, we were pleased to discover
that acetonitrile could be substituted for carbon tetra-
chloride using the reaction conditions described above.
A literature search revealed that non-chlorinated solvents
2
2
in the presence of acetic acid. Indeed, no signal shifts
occurred in the 1H or CNMR spectra of 3 upon the
13
addition of either acetic acid-d
or deuterium chloride/deuterium oxide to chloroform-d
solutions.23 Furthermore, as cited before, since the chlo-
4 3
to acetonitrile-d solutions
3
(
16) Adam, J .; Gosselain, P. A.; Goldfinger, P. Nature 1953, 171,
7
04-705.
are rarely used for benzylic or allylic chlorination with
(17) In contrast, ring halogenation by N-halosuccinimides by a
NCS.15 Acetonitrile turns out to be a superior solvent in
broad range of acid catalysts is known: Bovonsombat, P.; McNelis, E.
Synthesis 1993, 237-241 and references within.
(18) Acetonitrile is also an infrequently cited but useful solvent for
(
11) The corresponding bromide was a similarly poor alkylating
agent of anthrone; Earl, R. A. unpublished research.
12) (a) For a review, see: Mathes, W.; Schuly, H. Angew. Chem.,
ring brominations by N-bromosuccinimide: (a) Carreno, M. C.; Ruano,
J . L. G.; Sanz, G.; Toledo, M. A.; Urbano, A. J . Org. Chem. 1995, 60,
5328-5331. (b) Oberhauser, T. J . Org. Chem. 1997, 62, 4504-4506.
(19) Hyperconjugative effects have been correlated with unexpected
pK values of some picolines: Brown, H. C.; Mihm, X. R. J . Am. Chem.
a
Soc. 1955, 77, 1723-1726.
(
Int. Ed. Engl. 1963, 2, 144-149. (b) Newkome, G. R.; Puckett, W. E.;
Kiefer, G. E.; Gupta, V. K.; Xia, Y.; Coreil, M.; Hackney, M. A. J . Org.
Chem. 1982, 47, 4116-4120, ref 8 therein.
(13) (a) By chlorine in water: Nishimura, Y.; Itou, Y.; Morino, A.;
(20) Such a mechanism would be analogous to that reported for
the bromination of 2-(dibromomethyl)quinoline in acetic acid/sodium
acetate: (a) Brown, B. R.; Hammick, D. L.; Thewlis, B. H.; Walbridge,
D. J . J . Chem. Soc. 1953, 1369-1372. (b) Smalley, R. K. In Quinolines
Part 1; J ones, G., Ed.; J . Wiley and Sons: New York, 1977, pp 622-
623. The condensation of 2-methylthiazole with benzaldehydes in acetic
acid: (c) Van Arnum, S. D.; Ramig, K.; Stepsus, N. A.; Dong, Y.; Outten,
R. A. Tetrahedron Lett. 1996, 37, 8659-8662.
Nishihara, K.; Kawamura, S. Eur. Pat. Appl. 557 967 A1; Chem. Abstr.
994, 120, 30680. (b) By chlorine in acetic acid/sodium acetate but
forms the trichloride: Brown, B. R.; Hammick, D. L.; Thewlis, B. H.
J . Chem. Soc. 1951, 1145-1149. (c) by chlorine in acetonitrile:
Gunther, A. US Pat. 1993 5,198,549. Chem. Abstr. 1992, 116, 83696.
1
(
14) Newkome, G. R.; Kiefer, G. E.; Xia, Y.-J . Synthesis 1984, 676-
79.
15) Literature searches using the Beilstein and Chemical Abstracts
6
(
(21) Adam, J .; Gosselain, P. A.; Goldfinger, P. Bull. Soc. Chem. Belg.
1956, 65, 523-532.
online databases only located three examples of NCS benzylic/allylic
chlorination in unchlorinated solvents (the first two references feature
substrates wherein the chlorinated position possessed additional
activation toward chloride): (a) Vaz, A. D. N.; Schoellmann, G. J . Org.
Chem. 1984, 49, 1286-1288. (b) Vilsmaier, E.; D o¨ rrenb a¨ cher, R.;
M u¨ ller, L. Tetrahedron 1990, 46, 8103-8116. (c) Hebbelynck, M. F.;
Martin, R. H. Bull. Soc. Chem. Belg. 1959, 59, 193-207.
(22) Compared to 4-picoline, an ortho fluorine atom decreases the
3
5,36
basicity of 3 by ∼6 pK
a
units to ∼0.2.
a
The pK of acetic acid is only
3
7
4.8.
(23) Chemical shifts have been recorded for other pyridines under
such conditions as an indicator of protonation: Corey, E. J .; Zheng, G.
Z. Tetrahedron Lett. 1998, 39, 6165-6154.

7
720 J . Org. Chem., Vol. 65, No. 23, 2000
Pesti et al.
rination of toluene is accelerated by acid, the presence
of a pyridine ring for the purposes of tautomerization is
not required for acid induced rate increase. Our exami-
nation of the generality of this reaction toward other
picolines led to similar conclusions regarding the choice
of mechanism. All of the isomers of 2-fluoropicoline
reacted at similar rates, including those that cannot
achieve an intermediate analogous to 3*. The effect of
acid seemed to be exclusive of the positional substitution
of the substrate. In general, the acid induced effect on
rate was remarkably similar for methyl-substituted
ortho-halo picolines but was not noted for more basic
picolines or quinolines. The selective nature of the effect
of acid may be due to additional activation toward either
chlorination or radical formation that the ortho-halo
picolines may possess under these specific conditions, as
compared to other nitrogen heterocycles that may be
protonated under the reaction conditions. However, the
principal role of the acid seems to be reaction with NCS,
not 3. Further discussion expanding the prototrophic
rearrangement mechanism and the effect on other mol-
ecules is relegated to the Supporting Information along
with additional chlorination data and experimental
results.
namely chloride 4, iodide 8, and the corresponding
bromide and tosylate. Care in the selection of the reaction
conditions was required since the dialkylation of an-
throne is often accompanied by O-alkylation.26 The initial
samples of 1 destined for safety assessment studies were
made from 4 and anthrone under phase transfer condi-
tions.2
6b,c,27
Unfortunately, these alkylations proceeded in
variable yields and purities. An improved process con-
sisted of prior treatment of the crude chlorination mix-
1
0c
ture (3/4/5) with sodium iodide in acetone.
Only
monochloride 4 reacted to form iodide 8. Subsequent
reaction of this halogenated mixture with the anion of
anthrone prepared with sodium hydride in THF formed
crude 1 on a several hundred gram scale (neither 3 or 5
reacted under these conditions). However, purification
required tedious chromatography and repeated recrys-
tallization to achieve >99% purity. The use of 8 for
bisalkylation, prepared from 7 rather than 4, led to a
cleaner reaction profile and improved overall yield.
Alternatively, the addition of catalytic or stoichiometric
NaI to a mixture of anthrone anion and the chlorination
mixture produced 8 in situ from 4, but as was detected
later, this also catalyzed the formation of impurities. All
of these reactions formed a mixture of 1, O,C -dialkylated,
and mono O-alkylated side-products, as determined by
mass, 13C NMR, and H NMR spectroscopies. However,
particularly difficult to remove were the two largest
impurities: 10,10′-bianthrone (9) and 1,2-di(2-fluoro-4-
pyridyl)ethylene (10).
Despite improved chlorination conditions, 4 was still
produced as a mixture with 3 and 5. The mixture was
carried forward without further purification as only 4
reacts with the anion of anthrone after in situ conversion
to the iodide with sodium iodide (alkylation as the
chloride provided much lower yields of the product).
However this reaction produced numerous impurities
that were laborious to remove. An analogue of 4 of
improved alkylating characteristics and greater stability
1
(4 decomposed upon storage) was required. This led to
the evaluation of the mesylate 7, readily prepared from
the benzylic alcohol 6.
Hydrolysis of the chlorination mixture of 3, 4, and 5
in aqueous potassium carbonate at reflux selectively and
completely converted 4 into 6 in 1 h while 3 and 5
remained unaffected. Isolation was expedient: 6 re-
mained in the aqueous solution, permitting complete
separation of 3 and 5 as an oily layer. Extraction of the
heptane-washed aqueous solution with ethyl acetate
isolated 6 in 65-70% yield. Considering the highly
impure chlorinated starting mixture and the simple
workup, the product is remarkably pure (g98% LC area).
While bianthrone is a trace contaminant of commercial
anthrone, we found that the presence of sodium iodide
also promoted its formation, possibly via a radical
2
8,29
coupling of the enolates induced by iodine oxidation.
The olefin 10 could arise from deprotonation of either 7
or 8, followed by S 2 alkylation onto another molecule
N
of 7 or 8 and elimination of HX.30 We found that 10
formed in 43% crystallized yield by the reaction of 7,
sodium iodide and potassium tert-butoxide in THF. These
observations suggested we minimize the exposure of the
alkylating agent to base and of anthrone anion to sodium
iodide to suppress formation of sideproducts. Implemen-
tation of these conditions directly led to our optimized
process.
This method is a considerable improvement over the
existing procedure for the preparation of 624 and may
provide a general method for the preparation of hydroxy-
alkylpyridines from alkylpyridines.
Reaction of 6 with methanesulfonyl chloride/triethyl-
amine in ethyl acetate produced the mesylate 7 in 88-
9
5% yield. This compound was cleanly and nearly quan-
titatively converted to the iodide 8 upon treatment with
sodium iodide in acetone. Unlike the corresponding
tosylate,25 7 was crystalline, easy to purify and stable.
More importantly, as we found later, mesylate 7 im-
proved the subsequent conversion to 1.
(
26) (a) Branz, S. E.; Carr, J . A. Synth. Commun. 1986, 16, 441-
4
51 and references therein. (b) Majumdar, K. C.; Chattopadhyay, S.
K. Synthesis 1988, 552-553 and references therein. (c) Majumdar, K.
C.; Khan, A. T.; Chattopadhyay, S. K. J . Chem. Soc., Perkins Trans.
1
990, 2219-2223.
(27) Willner, I.; Halpern, M. Synthesis 1979, 177.
Besides 7, a variety of alkylating agent candidates for
anthrone were available to us for the preparation of 1,
(28) Anthrone will dimerize in the presence of oxidants: (a) Bradley,
W.; Watkinson, J . J . Chem. Soc. 1956, 319-323. (b) Arndt, F.;
Schlatter, J . M. Chem. Ber. 1954, 87, 1336-1339.
(24) A less convenient preparation of 6 is the reduction of 2-fluoro
(29) Iodine catalyzes the cross-coupling of enolates via a radical
mechanism: Belletire, J . L.; Spletzer, E. G.; Pinhas, A. R. Tetrahedron
Lett. 1984, 25, 5969-5972.
isonicotinic acid: Atsuyuki, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya,
C.; Watanabe, M.; Yokoyama, K. Chem. Pharm. Bull. 1990, 38, 2446-
2
458.
(30) This finding is analogous to the reaction of 4-(chloromethyl)-
pyridine with sodium hydride: Crispino, G. A.; Breslow, R. J . Org.
Chem. 1992, 57, 1849-1855.
(25) Prepared in a manner similar to the mesylate 7 using tosyl
chloride in 90% yield.

Efficient Pyridinylmethyl Functionalization
J . Org. Chem., Vol. 65, No. 23, 2000 7721
When a solution of anthrone with 3 equiv of lithium
tert-butoxide31 in THF was mixed with a solution of
grade and were not further purified. All reactions were carried
out under a positive pressure of nitrogen unless otherwise
specified. Reagents and solvents were used as received unless
otherwise noted. Reagent and intermediate quantities and
yields are all corrected for purity. If a weight % purity was
not obtained, the area % purity was assumed to be equivalent
for the purposes of calculations. 2-Fluoro-4-methylypridine was
purchased from Lancaster Chem. Co. HPLC conditions: Zor-
bax 4.6 mm × 15 cm RX C18 column at 1.00 mL/min at 40 °C
mesylate 7 plus 0.5 equiv of sodium iodide in THF, 87-
9
2% solution yields of 1 were achieved after 1-2 h.
Significantly, the formation of 9 and 10 were now largely
suppressed (<1% LC area %), and a subsequent cyclo-
hexane reslurry of the isolated solids removed nearly all
of both contaminants. An aqueous workup produced 1 of
3
and 260 nm. Solvent A: water. Solvent B: CH CN. Solvent
∼
90% purity which was further refined by treatments
with absorbents and 2-propanol recrystallizations, with-
out chromatography, to yield 1 of >99.9% purity.
program: A/B 60/40 at t ) 0 min, 40/60 at t ) 10 min, 15/85
at t ) 15 min, 40/60 at t ) 18 min, 60/40 at t ) 20 min.
Retention times (min): 1, t
) 6.1; 6, t ) 1.7; 7, t ) 2.6; 8, t
-(Ch lor om eth yl)-2-flu or op yr id in e (4). A mixture of 3
R
) 8.2; 3, t
R
) 3.5; 4, t ) 4.1; 5,
R
A final hurdle arose from the various polymorphic
forms of 1.32 Currently, 14 polymorphs have been char-
acterized by X-ray diffraction powder pattern spectros-
copy.33 The appearance of a new, crystalline form during
a late stage campaign was unexpected. Furthermore, we
were no longer able to prepare the other crystalline
forms, even though the appearance of this new high
melting form occurred over 300 miles from our develop-
mental laboratories! This is an example of the phenom-
enon of “disappearing polymorphs”.34 We have subse-
quently accepted this new crystal as our preferred
t
R
R
R
R
) 5.2.
4
(50.0 g, 0.441 mol), acetonitrile (250 mL), N-chlorosuccinimide
(88.4 g, 0.662 mol), benzoyl peroxide (2.15 g, 8.9 mmol), and
acetic acid (1.50 mL, 26.2 mmol) were heated at reflux for 90
1
min. LC and Η ΝΜR analysis indicated a 69% yield of 4, 17%
of 5, and 12% of remaining unreacted 3 (the yield of 4 peaked
at 71% after 80 min at reflux). The mixture was poured into
water (200 mL) and extracted with EtOAc. The organic layer
was separated, washed with 5% aqueous NaCl solution, and
concentrated in vacuo at 35 °C to 62.2 g of red oil. This mixture
was hydrolyzed as described in the next step without further
purification.
formulation form as thermal analysis indicates it to be
the most stable identified polymorph to date.33 This
An analytical sample was prepared by the chlorination of 7
as follows. A solution of 7 (3.00 g, 14.6 mmol), NaCl (9.00 g,
process is producing bulk drug in support of our ongoing
program needs.
1
54 mmol), 2 N HCl (6.0 mL), water (15 mL), and acetone (150
mL) was heated at reflux for 3 h. The cooled mixture was
diluted with water (200 mL) and EtOAc (100 mL). The organic
phase was separated, washed with water, and dried over
In summary, we have described a practical preparation
of the acetylcholine release enhancing agent 1. Of par-
ticular note is an acid-catalyzed benzylic chlorination
with NCS conducted in acetonitrile rather than the usual
chlorinated solvents, the hydrolysis of the ensuing mix-
ture of picolines which also results in an efficient
purification, the use of a mesylate as a convenient and
stable precursor to the iodide, and much improved yields/
selectivities in the bis-alkylation of anthrone enolates by
the consideration of reaction parameters. The overall
process is concise and permits progression to commercial
manufacture.
4
MgSO . The solution was concentrated in vacuo and distilled,
and the fraction boiling at 70-72 °C (3.5 mmHg) was collected
1
to yield 1.30 g (61%) of colorless oil. H NMR: 8.22 (d, J ) 5.1
Hz, 1H), 7.21 (d, J ) 5.1 Hz, 1H), 6.99 (s, 1H), 4.57 (s, 2H).
1
3
C NMR: 164.0 (d, J ) 239.2 Hz), 151.5 (d, J ) 8.1 Hz), 148.0
(
4
d, J ) 15.1 Hz), 120.6 (d, J ) 4.5 Hz), 108.8 (d, J ) 38.8 Hz),
3.2 (d, J ) 3.5 Hz). F NMR: -67.8. MS: m/e 146 (M + 1).
19
Anal. Calcd for C H ClFN: C, 49.51; H, 3.46; N, 9.62; F, 13.05.
6
5
Found: C, 49.31; H, 3.56; N, 9.32; F, 12.84.
2-F lu or o-4-p yr id in em eth a n ol (6). Impure 4 (62.2 g,
contains 0.31 mol), water (700 mL), and potassium carbonate
(56.0 g, 0.41 mol) were heated as a stirred oily suspension for
2
h (LC indicated <1% 4 remained). The mixture was cooled,
Exp er im en ta l Section
the layers were separated, and the lower, organic phase was
further extracted with water. The combined aqueous extracts
were washed with heptane and extracted with EtOAc. The
1
Gen er a l. Η ΝΜR spectra were determined at 300 MHz,
1
3
C NMR at 75.4 MHz, and 19F NMR at 282 MHz, all in CDCl
,
3
extracts were dried over MgSO
4.8 g (62%) of white solids (98 LC area %). An analytical
4
and concentrated in vacuo to
1
9
unless otherwise specified. F NMR spectra were recorded
using CFCl as an internal reference. Mass spectra (MS) were
2
3
sample was prepared by recrystallization from 1:1 EtOAc/
obtained by ammonia chemical ionization. High-resolution
mass spectral (HRMS) data possess an uncertainty of (0.1
mDa. Elemental analyses were performed at Quantitative
Technologies Inc., Whitehouse, NJ . Melting points are uncor-
rected. Solvent mixtures are defined by volume (v/v). All
solvents except for tetrahydrofuran (anhydrous) were reagent
heptane (5 mL/g) to produce colorless needles, mp 59.3-60.4
1
°
1
C. H NMR: 8.07 (d, J ) 5.1 Hz, 1H), 7.15 (d, J ) 5.1 Hz,
13
H), 6.98 (s, 1H), 4.77 (d, J ) 5.4 Hz, 2H), 4.26 (br s, 1H).
C
NMR: 164.0 (d, J ) 239.6 Hz), 157.1 (d, J ) 7.6 Hz), 146.9 (d,
J ) 14.1 Hz), 118.7 (d, J ) 4.0 Hz), 106.5 (d, J ) 37.2 Hz),
19
6
2.5 (d, J ) 3.0 Hz). F NMR: -68.8. MS: m/e 128 (M + 1).
6 6
Anal. Calcd for C H FNO: C, 56.69; H, 4.76; F, 14.95; N, 11.01.
(
31) Alternative bases examined included lithium diisopropylamide,
Found: C, 56.66; H, 4.63; F, 14.74; N, 11.03.
n-butyllithium, lithium isopropoxide, lithium tert-butoxide, lithium
methoxide, potassium tert-butoxide, and sodium hydride.
2-Flu or o-4-p yr id in em eth a n ol, 4-Meth ylben zen esu lfon -
a te (7). A solution of 6 (170.0 g, 1.311 mol), EtOAc (2.6 L),
and triethylamine (270.0 mL, 1.937 mol) were cooled to 0-5
(32) For an excellent monograph of polymorphism and related
crystalline species, see: J acques, J .; Collet, A.; Wilen, S. H. Enanti-
omers, Racemates, and Resolutions; Krieger Publishing Co.: Malabar,
FL, 1994.
°
C, and methanesulfonyl chloride (130.0 mL, 1.680 mol) was
added over 100 min while the temperature was maintained
at <20 °C. The reaction was aged for another 10 min (LC
indicated the area % of 6 was <1%). The reaction was mixed
with water (350 mL), and the phases were separated. The
organic layer was washed with water and saturated brine. The
(
33) Unpublished work by Dr. Michael Maurin.
(34) Dunitz, J . D.; Bernstein, J . Acc. Chem. Res. 1995, 28, 193-
2
00.
35) For 3: pK
DB program, version 4.03 to be 0.24 ( 0.10. We thank Mr. Gerald
Everlof for this calculation.
36) For 4-picoline, pK ) 6.1: Riand, J .; Chenon, M. T.; Lumbroso-
Bader, N. J . Am. Chem. Soc. 1977, 99, 6838-6845.
37) March, J . Advanced Organic Chemistry, 4th ed.; Wiley-
Interscience: New York, 1992; p 265.
38) Weinstock, L. M.; Karady, S.; Roberts, F. E.; Hoinowski, A. M.;
(
a
calculated by Advanced Chemistry Development
pK
a
2 4
solution was dried over Na SO , filtered, and concentrated in
(
a
vacuo to approximately 900 mL. This solution was diluted with
heptane (600 mL), cooled to 0-5 °C, and stirred for 2 h. The
crystals were filtered and air-dried to 251.0 g (93%) of pale
yellow crystals (>97 LC wt % purity). An analytical sample
was prepared by recrystallization from 1:1 EtOAc/heptane (15
(
(
Brenner, G. S.; Lee, T. B. K.; Lumma, W. C.; Sletzinger, M. Tetrahedron
Lett. 1975, 16, 3979-3982.
1
mL/g), mp ) 58.3-59.1 °C. H NMR: 8.27 (d, J ) 5.4 Hz, 1H),

7
722 J . Org. Chem., Vol. 65, No. 23, 2000
Pesti et al.
7
3
.20 (d, J ) 5.1 Hz, 1H), 6.98 (s, 1H), 5.26 (s, 2H), 3.10 (s,
The suspension was filtered through a pad of Celite, and the
filtrate was concentrated to 2.60 L by atmospheric distillation
and cooled to 0 °C. The crystals were filtered, washed with
cold IPA (0 °C), dried in vacuo at 50 °C, and ground in a mortar
and pestle to 283.8 g (yield 55%), LC peak area ) 99.94%, LC
1
3
H). C NMR (DMSO-d ): 163.2 (d, J ) 235.2 Hz), 150.0 (d,
6
J ) 8.6 Hz), 148.0 (d, J ) 15.6 Hz), 120.3 (d, J ) 3.5 Hz),
1
1
9
07.7 (d, J ) 38.2 Hz), 68.3 (d, J ) 3.0 Hz), 37.0. F NMR:
FNO S:
-
66.85. MS: m/e 206 (M + 1). Anal. Calcd for C
7
H
8
3
1
C, 40.96; H, 3.93; F, 9.26; N, 6.82; S, 15.62. Found: C, 41.00;
H, 3.81; F, 9.47; N, 6.70; S, 15.76.
wt % assay >99.9%, mp 169 °C. H NMR (400 MHz, DMSO-
d ): 8.42 (dd, J ) 0.9, 7.7 Hz, 2H), 7.95 (dd, J ) 1.5, 7.7 Hz,
6
1
0,10-Bis[(2-flu or o-4-p yr id in yl)m eth yl]-9(10H)-a n th r a -
2H), 7.93 (ddd, J ) 1.5, 7.7, 7.7 Hz, 2H), 7.65 (d, J ) 5.2 Hz,
2H), 7.53 (ddd, J ) 0.9, 7.7, 7.7 Hz, 1H), 6.11 (ddd, J ) 1.4,
2.3, 5.2 Hz, 2H), 5.92 (dd, J ) 1.3, 1.4 Hz, 2H), 3.95 (s, 4H).
cen on e (1). Two solutions are prepared. For one, 1.0 M
lithium tert-butoxide in THF (1.00 L, 1.00 mol) was added to
a solution of anthrone (70.0 g, 0.357 mol) in THF (0.70 L) at
1
3
C NMR (100.6 MHz, DMSO-d ): 181.7, 162.3 (d, J ) 235.0
6
1
5-30 °C to form lithio anthrone. The second solution was
Hz), 152.1 (d, J ) 7.6 Hz), 146.4 (d, J ) 16.0 Hz), 144.1, 134.0,
131.7, 128.5, 128.0, 126.5, 122.6, 109.7 (d, J ) 37.4 Hz), 47.9,
prepared by mixing sodium iodide (45.0 g, 0.300 mol), 7 (150.0
g, 0.731 mol), and THF (1.60 L) at 40 °C for 3 h to form a
mixture of 7/8. The lithio anthrone solution was added
dropwise over 100 min at 40-50 °C to the iodide/mesylate
solution. The reaction was aged for 1 h (the LC peak area for
47.5 (d, J ) 2.3 Hz). 19F NMR (376.1 MHz, DMSO-d
): -70.56.
O). IR
(KBr): 3060, 2946, 1665, 1602, 1556, 1475, 1452, 1407, 1321,
6
HRMS (ESI): 413.1446 (calcd 413.1465 for C26
19 2 2
H F N
-
1
1269, 1149, 931, 839, 776, 702, 645 cm . Anal. Calcd for
26 18 2 2
C H F N O: C, 75.72; H, 4.40; F, 9.21; N, 6.79. Found: C,
8
was <1%). The solution was washed with saturated aqueous
brine. Volatiles were removed in vacuo, and the residue was
diluted with toluene (1.3 L). The solution was heated to 100
75.70; H, 4.34; F, 9.21; N, 6.78.
Ack n ow led gm en t. The authors thank Drs. Robert
E. Waltermire and Philip Ma for useful discussions, Ken
Lynam for analytical assay development, Dr. Gregory
A. Nemeth and Mr. Thomas Scholz for spectral inter-
petations, Dr. Michael B. Maurin for collaboration on
the polymorph situation, Drs. Robert Chorvat, J oerg
Deerberg, and Rafael Shapiro for reviewing this manu-
script, Profs. William Berkowitz and Henry Rapoport
for helpful suggestions, and Barbara N. Fisher for
technical assistance.
°
3
C, cooled to 90 °C, and stirred with basic alumina (120 g) for
0 min. The solution was filtered through a Celite pad,
concentrated by atmospheric distillation to 500 mL, and cooled
to 25 °C to crystallize 1. Further crystallization was induced
by the dropwise addition of n-heptane (0.60 L) followed by
cooling to 0 °C for 2 h. The crystals were filtered, washed with
n-heptane and dried at 60 °C in vacuo to yield 121 g of 1 (92
LC wt %, 75% yield from anthrone).
Further manipulations were performed to attain the poly-
morphic form and purity desired to support human clinical
dosing. Two such preparations were combined (238.0 g),
dissolved in refluxing 2-propanol (IPA) (3.80 L), cooled slightly
below reflux, and filtered through a Celite pad. The solution
was concentrated by atmospheric distillation to 1.90 L and
cooled to 0 °C over 3 h. The crystals were collected by filtration,
washed with cold IPA (0 °C), and dried as above to give 208 g
of crystals. To remove anthrone, biathrone, and 15, part of this
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for 1, 4-8, 10, and 3-(chloromethyl)-2-fluoro-
pyridine, a list of the significant IR spectral peaks of 4 and 7,
1
13
the preparation, purification, and a list of the H and C NMR
spectral peaks for 5, 8, 10, and the chlorinated and hydrox-
1
13
ylated isomers of 3, the assignments of the H and C NMR
spectral peaks of 1, an expanded discussion of the chlorination
mechanism, and tables of chlorination data figures derived
from them. This material is available free of charge via the
Internet at http://pubs.acs.org.
(178.4 g) was slurried with refluxing cyclohexane (4.5 L) for 6
h, cooled to 75 °C, and filtered. The cake was washed with
cyclohexane (0.25 L) at 70 °C and dried at 60 °C in vacuo to
1
67.1 g. Material from multiple runs (327 g) derived from a
total of 1.261 mol of anthrone was dissolved in IPA (3.50 L) at
5 °C, treated with Darco G-60 (52 g), and stirred for 30 min.
7
J O9804339