Preparation of 8-substituted xanthine CVT-124 precursor by late stage pyrimidine ring closure

Article abstract of DOI:10.1021/jo015925r

To develop a novel route for the scaleable synthesis of the chiral xanthine CVT-124 (1, aka. BG9719), a method for the late stage pyrimidine ring closure of the nitrogen-protected endo 2-norbornenyl imidazole 3 was developed. The three-component coupling of benzylamine, 2-cyanoglycine ethyl ester (4), and methyl 5-norbornene-2-carboximidate hydrochloride (5) was demonstrated to achieve 3 in 23-46% isolated yields. The imidazole 3 was then elaborated to construct the N-benzyl xanthine 2 as a 1:1 mixture of exo and endo isomers, which were separable at this stage by chromatography. The nitrogen-protected endo xanthine 2 is a key intermediate in the synthesis of CVT-124.

Full text of DOI:10.1021/jo015925r

188
J . Org. Chem. 2002, 67, 188-193
P r ep a r a tion of 8-Su bstitu ted Xa n th in e CVT-124 P r ecu r sor by La te
Sta ge P yr im id in e Rin g Closu r e
R. J ason Herr,* Paul F. Vogt, Harold Meckler, and Michael P. Trova
Medicinal Chemistry and Chemical Development Departments, Albany Molecular Research, Inc.,
P.O. Box 15098, Albany, New York 12212-5098
Steven R. Schow†
Medicinal Chemistry Department, CV Therapeutics, 3172 Porter Drive, Palo Alto, California 94304
Russell C. Petter
Medicinal Chemistry Department, Biogen, Inc., Fourteen Cambridge Center,
Cambridge, Massachusetts 02142
rjasonh@albmolecular.com
Received J uly 13, 2001
To develop a novel route for the scaleable synthesis of the chiral xanthine CVT-124 (1, aka. BG9719),
a method for the late stage pyrimidine ring closure of the nitrogen-protected endo 2-norbornenyl
imidazole 3 was developed. The three-component coupling of benzylamine, 2-cyanoglycine ethyl
ester (4), and methyl 5-norbornene-2-carboximidate hydrochloride (5) was demonstrated to achieve
3 in 23-46% isolated yields. The imidazole 3 was then elaborated to construct the N-benzyl xanthine
2 as a 1:1 mixture of exo and endo isomers, which were separable at this stage by chromatography.
The nitrogen-protected endo xanthine 2 is a key intermediate in the synthesis of CVT-124.
In tr od u ction
Resu lts a n d Discu ssion
The chiral xanthine CVT-124 (1, aka. BG9719) is a
potent and selective adenosine A1 receptor antagonist
that recently entered Phase II clinical trials by a col-
laborative effort between CV Therapeutics, Inc., and
Biogen, Inc. This target has previously been made by two
different research groups1,2 and was constructed using
the classical methods of xanthine synthesis, i.e., ring
closures to form the imidazole ring in the final steps
(Scheme 1).
As part of a program to develop a novel and scaleable
route for the chiral synthesis of xanthine 1, one plan was
to devise a method for the late stage ring closure of endo
2-norbornyl imidazole 3 to the corresponding nitrogen-
protected xanthine 2 (Scheme 2). This imidazole was
envisioned to arise from the three-component coupling
of benzylamine, 2-cyanoglycine derivative 4, and the endo
norbornenyl imidate hydrochloride 5. This route was to
be developed in such a way that the arrangement of
substituents around the heterocyclic ring of 3 would be
unambiguous and was partially based on a recently
reported synthesis.3
Develop m en t of New Ch em istr y: Th e Mod el Sca f-
fold . In order to investigate this new chemistry, a model
study was undertaken using an isopropyl moiety in place
of the norbornenyl ring. Thus, ethyl cyanoglyoxylate-2-
oxime (6) was reduced according to literature precedent4
to 2-cyanoglycine ethyl ester (4) in yields comparable to
those of known procedures (Scheme 3).3-5 Amine 4 was
then condensed with methyl 2-methylpropionimidate
hydrochloride (7)6 in refluxing chloroform. The resulting
slurry was filtered, and the filtrate was subjected to a
second condensation reaction with benzylamine in re-
fluxing chlororform.3 After purification by flash column
chromatography and recrystallization, the desired 2-iso-
propyl imidazole 8 was isolated in 43% yield. By achiev-
ing the synthesis in this fashion, the N-benzyl protecting
group resides on the N-1 imidazole nitrogen unambigu-
ously. It should be noted that the use of chloroform, while
(3) (a) Ahn, H.-S.; Bercovici, A.; Boykow, G.; Bronnenkant, A.;
Chackalamannil, S.; Chow, J .; Cleven, R.; Cook, J .; Czarniecki, M.;
Domalski, C.; Fawzi, A.; Green, M.; Gu¨ndes, A.; Ho, G.; Laudicina,
M.; Lindo, N.; Ma, K.; Manna, M.; McKittrick, B.; Mirzai, B.; Nechuta,
T.; Neustadt, B.; Puchalski, C.; Pula, K.; Silverman, L.; Smith, E.;
Stamford, A.; Tedesco, R. P.; Tsai, H.; Tulshian, D.; Vaccaro, H.;
Watkins, R. W.; Weng, X.; Witkowski, J . T.; Xia, Y.; Zhang, H. J . Med.
Chem. 1997, 40, 2196. (b) See also: Mackenzie, G.; Wilson, H. A.; Shaw,
G.; Ewing, D. J . Chem. Soc., Perkin Trans. 1 1988, 2541.
(4) De Meester, J . W. G.; van der Plas, H. C.; Middelhoven, W. J . J .
Heterocycl. Chem. 1987, 24, 441.
(5) (a) Brown, T.; Shaw, G. J . Chem. Soc. 1980, 2310. (b) Shaw, G.;
Wilson, D. V. J . Chem. Soc. 1962, 2937. (c) Hosmane, R. S.; Lim, B. B.
Tetrahedron Lett. 1985, 26, 1915.
(6) McElvain, S. M.; Venerable, J . T. J . Am. Chem. Soc. 1950, 72,
1661.
* To whom correspondence should be addressed at Medicinal
Chemistry Department, Albany Molecular Research, Inc., P.O. Box
15098, 21 Corporate Circle, Albany, NY 12212-5098. Phone: (518) 464-
0279 ext 2435. Fax: (518) 257-2025.
† Present address: Telik, Inc., 750 Gateway Blvd., South San
Francisco, CA 94080.
(1) (a) Moore, A. G.; Schow, S. R.; Lum, R. T.; Nelson, M. G.; Melville,
C. R. Synthesis 1999, 7, 1123. (b) Pfister, J . R.; Belardinelli, L.; Lee,
G.; Lum, R. T.; Milner, P.; Stanley, W. C.; Linden, J .; Baker, S. P.;
Schreiner, G. J . Med. Chem. 1997, 40, 1773.
(2) (a) Shimada, J .; Suzuki, F.; Nonaka, H.; Ishii, A. J . Med. Chem.
1992, 35, 924. (b) Suzuki, F.; Shimada, J .; Mizumoto, H.; Karasawa,
A.; Kubo, K.; Nonaka, H.; Ishii, A.; Kawakita, T. J . Med. Chem. 1992,
35, 3066.
10.1021/jo015925r CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/07/2001

8-Substituted Xanthine CVT-124 Precursor
J . Org. Chem., Vol. 67, No. 1, 2002 189
Sch em e 1
Sch em e 2
Sch em e 4
potassium carbonate at 70 °C in DMF to produce 11 in a
comparable yield.8
Ap p lica tion of New Ch em istr y: Con str u ction of
th e en d o-Nor bor n en yl System . This synthetic route
was then applied toward the construction of the CVT-
124 core 2, with the initial emphasis on building the
2-norbornenyl imidazole 3. First, methyl imidate hydro-
chloride 5 was prepared via the Pinner reaction9 between
5-norbornene-2-carbonitrile (12) and methanol in ether-
eal HCl in 82% yield (Scheme 5). Use of the commercially
available starting material 12 (a 1:1 mixture of endo and
exo isomers) resulted in a 1:1 mixture of methyl imidate
epimers from the Pinner reaction. Following the chem-
istry developed for the model system, we treated imidate
5 with cyanoglycine ester 4 in chloroform and filtered the
mixture after it was stirred for 1 h at reflux. The filtrate,
containing the intermediate cyanoglycine imidate 13, was
treated with benzylamine and refluxed for an additional
17 h. The solution was then cooled, concentrated, and
purified by flash chromatography to produce N-1-benzyl
imidazole 3 in 46% isolated yield.
Sch em e 3
not a solvent of choice for commercial-scale production,
could be replaced with isopropyl acetate to furnish 8 in
a somewhat diminished overall yield (24%).
Literature precedent demonstrated that pyrimidines
may be constructed from the ring closure of 4(5)-amino-
5(4)-carboxy imidazoles (Scheme 4).7 Thus, to build the
model xanthine ring system 11, imidazole 8 was coupled
with n-propyl isocyanate to produce unsymmetrical urea
9 in 68% isolated yield. This was followed by the
equilibrium deprotonation of the N-propyl urea nitrogen
of 9 by treatment with sodium methoxide in refluxing
methanol to provide xanthine 10 in 91% isolated yield.
Finally, N-alkylation of xanthine 10 with sodium hydride
and 1-bromopropane proceeded to afford bis-propyl model
compound 11 in 62% isolated yield. Alkylation of xan-
thine 10 with 1-bromopropane was also achieved with
On a small scale, it was also found that a practical
purification of 3 could be achieved without a lengthy
chromatography. When a small amount of the crude
reaction mixture (about 2 g) from the bis-condensation
was filtered through a short plug of silica gel, eluting with
methanol/methylene chloride (5:95), fairly clean imida-
zole was isolated upon concentration of the filtrate. When
this residue was dissolved in 2 N HCl solution, washed
repeatedly with ether, and then made basic with 2 N
(8) Sakai, R.; Konno, K.; Yamamoto, Y.; Sanae, F.; Takagi, K.;
Hasegawa, T.; Iwasaki, N.; Kakiuchi, M.; Kato, H.; Miyamoto, K. J .
Med. Chem. 1992, 35, 4039.
(9) (a) Pinner, A.; Klein, F. Ber. 1877, 10, 1889. (b) Moreau, R. C.;
Reynaud, P. Bull. Soc. Chim. Fr. 1964, 2997. (c) Cooper, F. C.;
Partridge, M. W. J . Chem. Soc. 1952, 5036.
(7) (a) Bridson, P. K.; Wang, X. Synthesis 1995, 855. (b) Edenhofer,
A. Helv. Chim. Acta. 1975, 58, 2192. (c) See also: Shaw, G. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Ed.; Elsevier
Science, Ltd.: Exeter, 1996; Vol. 7, Chapter 7.11, p 397.

190 J . Org. Chem., Vol. 67, No. 1, 2002
Herr et al.
Sch em e 5
Con clu sion s
To develop a novel and scaleable route for the synthesis
of the endo xanthine CVT-124 (1, aka. BG9719), a method
was devised for the late stage pyrimidine ring closure of
2-norbornenyl imidazole 3 to the 8-substituted nitrogen-
protected xanthine precursor 2. The imidazole scaffold 3
was in turn prepared by a three-component coupling of
methyl 5-norbornene-2-carboximidate hydrochloride (5),
2-cyanoglycine ethyl ester (4), and benzylamine. Imida-
zole 3 was then elaborated to construct xanthine 2 as a
1:1 mixture of exo and endo isomers, which were sepa-
rable by flash chromatography. The N-benzyl endo
compound 2b is a key component in the synthesis of CVT-
124 (1), and this process should therefore be amenable
to the preparation of chiral 1 from the requisite chiral
endo imidate 5. Precursor 5 is accessible from known (-)-
(1S,2S)-5-norbornene-2-carboxylic acid (18, Scheme 5)11
by straightforward chemistry via primary amide 14.12,13
It should be mentioned that work was developed to
provide an alternative route to the preparation of 1,
which is currently prepared by a more classical route
similar to the chemistry described in Scheme 1.14
NaOH solution, the clean imidazole 3 could be collected
by vacuum filtration as a white solid. The ratio of exo/
endo isomers was unchanged from 12 (1:1, as confirmed
by 1H NMR analyses), even after chromatography or acid/
base extraction purifications. Interestingly, the major
byproduct from the condensation reaction was found to
be amide 14 (Scheme 5), which was formed by the
hydrolysis of imidate 5. This compound was found to be
insoluble in cold chloroform, which allowed for its quick
removal from the crude reaction mixture and simplified
the chromatographic purification process.
Exp er im en ta l Section
The 1:1 epimeric mixture of imidates 3 was elaborated
to xanthine scaffold 2 on the basis of the chemistry
developed in the model system (Scheme 6). Imidazole 3
was treated with n-propyl isocyanate and triethylamine
in refluxing toluene overnight to produce the unsym-
metrical urea 15 in 61% isolated yield. While a chro-
matographic purification allowed for a greater isolated
yield of urea 15, it was found that treatment of the crude
reaction residue with cold ether was sufficient to provide
consistent amounts of clean 15 by simple precipitation.
Cyclization of 15 to xanthine 16 with sodium methoxide
was achieved in less than 2 h in refluxing methanol. In
this case, the crude reaction residue was diluted with
aqueous HCl solution and extracted with methylene
chloride to ultimately provide 16 as a colorless oil in 96%
isolated yield. Xanthine 16 was N-alkylated under the
standard conditions8 with 1-bromopropane and potas-
sium carbonate at 70 °C in DMF to produce a 1:1 epimeric
mixture of 2-norbornenyl xanthines 2a and 2b. It was
found that the two isomers could be separated at this
stage by chromatography to produce roughly equal
amounts of the exo isomer 2a (in 50% isolated yield) and
the requisite endo isomer 2b (in 43% isolated yield).
Gen er a l P r oced u r es. All nonaqueous reactions were
performed under a dry atmosphere of nitrogen. Reagents
purchased from commercial sources were used as received,
unless noted otherwise. Anhydrous solvents were obtained
1
from commercial sources and used as received. The H NMR
spectrum of endo N-3-benzyl derivative 17 (made indepen-
dently) was supplied for comparison by CV Therapeutics, Inc..
Proton magnetic resonance spectra were obtained on a Bruker
AC 300 MHz NMR instrument, using either tetramethylsilane
or chloroform as an internal reference. Thin-layer chromatog-
raphy was performed using 1′′ × 3′′ in. Analtech GF 350 silica
gel plates with a fluorescent indicator. Visualization of TLC
plates was realized by observation under a UV lamp, in iodine
(10) For other recent examples of regioselective N-3 alkylation of
similar xanthines, see: (a) Akguen, H.; Balkan, A.; Guenay, S.; Erol,
K.; Boydag, S. Eur. J . Med. Chem. 1997, 32, 175. (b) Avasthi, K.;
Chandra, T.; Rawat, D. S.; Bhakuni, D. S. Indian J . Chem., Sect. B
1996, 35, 437. (c) Del Guidice, M. R.; Borioni, A.; Mustazza, C.; Gatta,
F.; Dionisotti, S.; Zocchi, C.; Ongini, E. Eur. J . Med. Chem. 1996, 31,
59. (d) Mueller, C. E.; Sandoval-Ramirez, J . Synthesis 1995, 1295.
(11) For current large-scale synthesis of the chiral endo 5-nor-
bornene-2-carboxylic acid 18, see: (a) Poll, T.; Sobczak, A.; Hartmann,
H.; Helmchen, G. Tetrahedron Lett. 1985, 26, 3095. (b) Chang, H. X.;
Zhou, L.; McCargar, R. D.; Mahmud, T.; Hirst, I. Org. Proc. Res. Dev.
1999, 3, 289 and references therein.
(12) For recent examples of aliphatic carboxylic acid to primary
amide conversions, see: (a) J osse, O.; Labar, D.; Marchand-Brynaert,
J . Synthesis 1999, 404. (b) Wang, W.; McMurray, J . S. Tetrahedron
Lett. 1999, 40, 2501. (c) Muller, G. W.; Shire, M. G.; Wong, L. M.;
Corral, L. G.; Patterson, R. T.; Chen, Y.; Stirling, D. I. Bioorg. Med.
Chem. Lett. 1998, 8, 2669. (d) Boeckman, R. K., J r.; Connell, B. T. J .
Am. Chem. Soc. 1995, 117, 12369. (e) Fernandez, F.; Lopez, C.;
Hergueta, A. R. Tetrahedron 1995, 51, 10317.
(13) For relevant examples of primary amide to imidate conversions,
see: (a) Brutsche, A.; Hartke, K. Liebigs Ann. Chem. 1992, 921. (b)
Confalone, P. N.; Pizzolato, G. J . Am. Chem. Soc. 1981, 103, 4251. (c)
Nakajima, N.; Saito, M.; Ubukata, M. Tetrahedron Lett. 1998, 39, 5565.
(14) (a) Dowling, J . E.; Kumaravel, G.; Petter, R. C. U.S. Pat. Appl.
WO 01/34604 A2 (2000). (b) Kiesman, W. F.; Dowling, J . E.; Ensinger,
C. L.; Kumaravel, G.; Petter, R. C.; Chang, H. X.; Lin, K. C. U.S. Pat.
Appl. WO 01/34610 A1 (2000).
1
Interestingly, the H NMR spectrum of the endo N-1-
benzyl isomer 2b was similar, but not identical to the
1H NMR spectrum of endo N-3-benzyl xanthine 17, which
was prepared by dissolving metal deprotection of 2b
followed by direct N-alkylation with benzyl bromide and
sodium hydride in DMF. In this case, the regiochemistry
of the alkylation is such that the benzyl group approaches
from the least hindered side of pyrimidine to provide the
N-3 positional isomer 17 selectively, as expected.3,10
Comparison of the spectral data of 2b and 17 helped to
prove the structural assignments unambiguously.

8-Substituted Xanthine CVT-124 Precursor
J . Org. Chem., Vol. 67, No. 1, 2002 191
Sch em e 6
vapors, or by dipping in commercial phosphomolybdic acid
solution, followed by warming. Infrared spectra were obtained
as KBr pellets and obtained on a Perkin-Elmer Spectrum 1000
FT-Infrared Spectrophotometer. CI Mass spectroscopic analy-
ses were performed on a Shimadzu QP-5000 GC/Mass Spec-
trometer (methane) by direct injection. Melting points were
obtained either by differential scanning calorimetry (DSC)
using a Perkin-Elmer model DSC-4 instrument or by using
an electrothermal instrument and are uncorrected. Elemental
analyses were performed by Quantitative Technologies, Inc.,
Whitehouse, NJ .
129.0, 128.3, 127.0, 60.6, 47.0, 42.2, 27.1, 22.7, 21.3, 14.2, 11.2;
IR (KBr) 3377, 3969, 1711, 1661, 1508 cm-1; CI MS m/z 373
(M + H)+.
1-n -P r op yl-3,9-d ih yd r o-9-ben zyl-8-(2-m eth yleth yl)-1H-
p u r in e-2,6-d ion e (10). Sodium methoxide (0.20 mL, 0.53
mmol, 25% in methanol) was added to a solution of 9 (0.098 g,
0.26 mmol) in anhydrous methanol (2 mL) at room tempera-
ture under nitrogen, and the mixture was heated at reflux to
stir for 80 min. The mixture was cooled to room temperature,
and the solvent was removed under reduced pressure. The
foamy residue was diluted with 10% HCl solution (3 mL) and
extracted with chloroform (3 × 20 mL). The combined organic
extracts were washed with brine and dried (MgSO4), and the
solvent was removed under reduced pressure to produce 10
as a white solid (0.078 g, 91% yield): mp 255-260 °C; TLC Rf
Eth yl 5-Am in o-2-(2-m eth yleth yl)-1-ben zyl-1H-im id a -
zole-4-ca r boxyla te (8). A mixture of 2-cyanoglycine ethyl
ester (4,3-5 2.66 g, 21 mmol) and methyl 2-methylpropionimi-
date hydrochloride (7,6 2.60 g, 18 mmol) in anhydrous chloro-
form (10 mL) was heated at reflux under nitrogen and stirred
for 60 min. The mixture was cooled to room temperature and
filtered through a short plug of Celite (10 g), rinsing the solid
support with chloroform (30 mL). The filtrate was charged with
benzylamine (2.3 mL, 21 mmol), and the mixture was heated
to reflux for 17 h. The reaction mixture was cooled to room
temperature, and the solvent was removed under reduced
pressure to produce a red oil. This residue was purified by flash
column chromatography on silica gel, eluting with methanol/
methylene chloride (2:98), to produce the partially purified
imidazole as a yellow solid (1.81 g). Recrystallization of this
solid with ethyl acetate/hexanes produced the purified product
8 (0.495 g, 10% yield). A second impure fraction from the flash
column chromatography was also recrystallized with ethyl
acetate/hexanes to yield additional 8 (0.849 g, 16% yield). The
mother liquors from the two recrystallizations were combined,
and the solvents were removed under reduced pressure. The
resulting residue was then purified by flash column chroma-
tography on silica gel, eluting with methanol/methylene
chloride (1:99), to produce additional 8 (0.860 g, 17% yield).
The total amount of isolated product 8 was 2.20 g (43% yield):
1H NMR (CDCl3) δ 1.32 (d, 6H, J ) 6.9 Hz), 1.40 (t, 3H, J )
2.4 Hz), 2.92 (m, 1H), 4.43 (q, 2H, J ) 3.3 Hz), 4.65 (br s, 2H),
5.02 (s, 3H), 7.06 (m, 2H), 7.39 (m, 3H); 13C NMR (CDCl3) δ
165.0, 147.6, 145.7, 134.8, 129.3, 128.5, 110.5, 59.9, 45.6, 26.4,
21.4, 14.7; CI MS m/z 288 (M + H)+.
Eth yl 5-[[(n -P r op yla m in o)ca r bon yl]a m in o]-2-(2-m eth -
yleth yl)-1-ben zyl-1H-im id a zole-4-ca r boxyla te (9). n-Pro-
pyl isocyanate (0.20 mL, 2.1 mmol) was added to a mixture of
8 (0.200 g, 0.70 mmol) and triethylamine (0.29 mL, 2.08 mmol)
in anhydrous toluene (4 mL) at room temperature under
nitrogen, and the reaction mixture was heated at reflux to stir
for 14.5 h. The mixture was cooled to room temperature; the
solvent was removed under reduced pressure, and the residue
was purified by flash column chromatography on silica gel,
eluting with ethyl acetate/hexanes (1:1), to produce 9 as a
white solid (0.175 g, 68% yield): 1H NMR (CDCl3) δ 0.86 (t,
3H, J ) 8.9 Hz), 1.27 (q, 3H, J ) 7.2 Hz), 1.39 (m, 6H), 2.97
(m, 1H), 3.11 (m, 3H), 4.15 (q, 2H, J ) 10.5 Hz), 4.30 (q, 2H,
J ) 9.1 Hz), 5.00 (s, 2H), 6.63 (br s, 2H), 7.16 (m, 2H), 7.35
(m, 3H); 13C NMR (CDCl3) δ 161.6, 154.5, 153.7, 135.2, 130.1,
1
(50% ethyl acetate/hexanes) ) 0.50; H NMR (CDCl3) δ 0.86
(t, 3H, J ) 10.5 Hz), 1.27 (d, 6H, J ) 7.1 Hz), 1.56 (m, 2H),
2.91 (m, 1H), 3.87 (m, 2H), 5.31 (m, 2H), 7.01 (m, 2H), 7.33
(m, 3H); 13C NMR (CDCl3) δ 157.2, 153.7, 153.2, 138.4, 134.5,
129.1, 128.3, 125.6, 114.9, 46.2, 42.4, 29.7, 26.4, 21.4, 21.1, 11.3;
IR (KBr) 2967, 1717, 1663, 1577, 1453 cm-1; CI MS m/z 327
(M + H)+, 145.
1,3-Dip r op yl-3,9-d ih yd r o-9-b en zyl-8-(2-m et h ylet h yl)-
1H-p u r in e-2,6-d ion e (11). Meth od A. Sodium hydride (0.020
g, 0.46 mmol, 60% dispersion in oil) was added to a solution
of 10 (0.150 g, 0.46 mmol) in anhydrous acetonitrile (5 mL) at
room temperature under nitrogen, after which the suspension
was charged with 1-bromopropane (0.10 mL, 0.92 mmol) and
N,N-dimethylformamide (2 mL). The reaction mixture was
stirred at room temperature for 3 h, after which it was heated
at reflux to stir for 3.5 h. The mixture was cooled to room
temperature and diluted with water (20 mL). The aqueous
mixture was extracted with ethyl acetate (3 × 20 mL), and
the combined organic extracts were washed with brine and
dried (MgSO4). The solvent was removed under reduced
pressure, and the residue was purified by flash column
chromatography on silica gel, eluting with ethyl acetate/
hexanes (1:1), to produce 11 as a clear oil (0.105 g, 62% yield):
mp 95-105 °C; TLC Rf (50% ethyl acetate/hexanes) ) 0.30;
1H NMR (CDCl3) δ 0.92 (t, 3H, J ) 6.0 Hz), 1.06 (t, 3H, J )
10.8 Hz), 1.27 (d, 6H, J ) 4.0 Hz), 1.65-1.85 (m, 4H), 2.94 (m,
1H), 4.09 (m, 2H), 4.34 (t, 2H, J ) 6.0 Hz), 5.23 (s, 2H), 7.14
(m, 2H), 7.34 (m, 3H); 13C NMR (CDCl3) δ 157.2, 155.4, 154.8,
147.9, 136.7, 129.1, 128.1, 127.0, 118.1, 70.6, 45.6, 43.2, 27.2,
22.2, 22.1, 21.7, 11.6, 10.8; IR (KBr) 2967, 1699, 1559, 1531,
1487 cm-1; CI MS m/z 369 (M + H)+, 279, 229.
Meth od B. A mixture of 10 (0.148 g, 0.45 mmol), potassium
carbonate (0.075 g, 0.54 mmol), and 1-bromopropane (0.10 mL,
0.66 mmol) in anhydrous N,N-dimethylformamide (3 mL) was
heated at reflux under nitrogen to stir for 1 h. The mixture
was cooled to room temperature and diluted with ether. This
organic solution was washed with water (6 × 10 mL) and dried
(MgSO4). The solvents were removed under reduced pressure
to produce 11 as a colorless oil, which solidified upon standing
1
(0.103 g, 62%). The H NMR and IR spectra, TLC, and CI MS
analyses were identical to the data obtained from Method A.

192 J . Org. Chem., Vol. 67, No. 1, 2002
Herr et al.
Meth yl 5-Nor bor n en e-2-ca r boxim id a te Hyd r och lor id e
(5, 1:1 Exo/En d o Mixtu r e). Hydrogen chloride gas (about 3
equiv, by weight) was introduced into a solution of 5-nor-
bornene-2-carbonitrile (12, 55 g, 462 mmol) and anhydrous
methanol (19 mL, 462 mmol) in anhydrous diethyl ether (300
mL) at 0 °C over a 1 h period through a gas inlet tube below
the surface of the reaction mixture. The gas flow was termi-
nated, and the reaction mixture was stirred for 1 h, after which
the mixture was placed in the freezer for 3 days. The
precipitate was collected by vacuum filtration and washed with
anhydrous diethyl ether (100 mL). The solids were dried
overnight (30 mmHg vacuum, 50 °C) to produce 5 as an off-
white solid (71.4 g, 82% yield): mp (DSC) 181 °C; 1H NMR
(CDCl3) δ 6.31 (dd, 1H, J ) 3.1, 5.8 Hz), 6.20 (t, 2H, J ) 3.5
Hz), 5.91 (dd, 1H, J ) 2.5, 5.8 Hz), 4.32 (s, 3H), 4.23 (s, 3H),
3.53 (s, 1H), 3.16 (s, 1H), 3.03 (s, 1H), 2.87-2.84 (m, 1H), 2.13-
2.06 (m, 1H), 1.66-1.60 (m, 3H), 1.54-1.43 (m, 5H); 13C NMR
(CDCl3) δ 182.7, 181.7, 178.5, 177.2, 139.8, 138.6, 138.5, 138.1,
136.1, 132.4, 131.2, 61.0, 60.7, 50.3, 48.2, 48.1, 47.3, 46.8, 46.6,
46.4, 44.6, 44.3, 43.2, 42.9, 42.8, 42.6, 42.1, 41.8, 37.6, 31.3,
and the precipitate was collected by vacuum filtration and
washed with ether (30 mL). The filtrate solution was concen-
trated to a volume of about 50 mL and cooled at 0 °C to stand
for 1 h. The resulting precipitate was collected by vacuum
filtration and washed with cold ether (10 mL). The two crops
of solids were combined and dried overnight (30 mmHg
vacuum, 50 °C) to produce 15 as an off-white powder (5.0 g,
61% yield): mp 168-170 °C; TLC Rf (50% ethyl acetate/
hexanes) ) 0.51; 1H NMR (CDCl3) δ 7.37-7.31 (m, 6H), 7.13-
7.08 (m, 4H), 6.31-6.27 (m, 1H), 6.20-6.05 (m, 2H), 5.95-
5.90 (m, 1H), 5.15-4.90 (m, 4H), 4.32-4.18 (m, 4H), 3.40-
3.30 (m, 1H), 3.25-3.20 (m, 1H), 3.20-3.10 (m, 4H), 3.10-
2.95 (m, 2H), 2.95-2.80 (m, 2H), 2.70-2.60 (m, 1H), 2.40-
2.30 (m, 1H), 1.95-1.85 (m, 2H), 1.55-1.40 (m, 4H), 1.40-
1.35 (m, 4H), 1.35-1.20 (m, 6H), 0.95-0.75 (m, 6H); 13C NMR
(CDCl3) δ 161.9, 154.9, 154.7, 154.5, 152.4, 151.2, 138.8, 137.7,
136.1, 135.5, 132.3, 129.2, 128.5, 127.6, 127.3, 60.8, 60.7, 50.0,
47.8, 47.4, 46.9, 46.4, 42.8, 42.5, 42.2, 37.3, 31.8, 31.1, 23.0,
22.9, 14.5, 11.5, 11.4; IR (KBr) 3356, 2967, 2875, 1718, 1665,
1508 cm-1; CI MS m/z 423 (M + H)+, 364. The 1H NMR
spectrum was consistent with a 1:1 mixture of the exo and
endo structures.
30.8, 30.1, 30.0; IR (KBr) 3378, 3194, 2974, 1655, 1405 cm-1
;
CI MS m/z 275 (M + H)+, 152, 138. The 1H NMR spectrum
was consistent with a 1:1 mixture of the exo and endo
structures.
1-n -P r op yl-3,9-d ih yd r o-9-ben zyl-8-[2-n or bor n -5-en yl]-
1H-p u r in e-2,6-d ion e (16, 1:1 Exo/En d o Mixtu r e). Sodium
methoxide (8.7 mL, 40 mmol, 25% in methanol) was added to
a solution of 15 (1:1 exo/endo mixture, 3.4 g, 8.0 mmol) in
anhydrous methanol (80 mL) at room temperature under
nitrogen, and the reaction mixture was heated at reflux to stir
for 1.5 h. The mixture was cooled to room temperature, and
the solvent was removed under reduced pressure. The residue
was charged with 2 N HCl solution (50 mL) and extracted with
methylene chloride (2 × 100 mL). The combined organic
extracts were washed with brine (1 × 100 mL) and dried
(MgSO4). The solvent was removed under reduced pressure
to produce a colorless oil, which crystallized upon standing to
produce 16 as an off-white solid (2.9 g, 96% yield): mp (DSC)
235 °C; TLC Rf (5% methanol/chloroform) ) 0.56; 1H NMR
(CDCl3) δ 7.40-7.30 (m, 6H), 7.10-6.95 (m, 4H), 6.30-6.25
(m, 1H), 6.20-6.05 (m, 2H), 5.85-5.80 (m, 1H), 5.35 (s, 2H),
5.28 (d, 2H, J ) 8.8 Hz), 3.90-3.80 (q, 4H, J ) 7.3 Hz), 3.66
(s, 4H), 3.23-3.10 (m, 2H), 3.10-2.90 (m, 2H), 2.73 (s, 1H),
2.55-2.45 (m, 1H), 2.31-2.25 (m, 1H), 2.09-1.99 (m, 1H),
1.95-1.78 (m, 1H), 1.65-1.45 (m, 2H), 1.45-1.28 (m, 2H), 0.92
(t, 3H, J ) 7.2 Hz), 0.86 (t, 3H, J ) 7.2 Hz); 13C NMR (CDCl3)
δ 138.7, 137.6, 135.6, 132.0, 129.2, 128.5, 126.1, 125.6, 49.8,
47.6, 46.7, 46.5, 46.1, 42.5, 42.0, 36.6, 36.4, 31.7, 31.0, 21.1,
Eth yl 5-Am in o-2-[2-n or bor n -5-en yl]-1-ben zyl-1H-im i-
d a zole-4-ca r boxyla te (3, 1:1 Exo/En d o Mixtu r e). A mix-
ture of 2-cyanoglycine ethyl ester (4,3-5 11.8 g, 92 mmol) and
5 (1:1 exo/endo mixture, 19.1 g, 101 mmol) in anhydrous
chloroform (150 mL) under nitrogen was heated at reflux to
stir for 1.5 h. The mixture was cooled to room temperature
and filtered through a short plug of Celite, rinsing the solid
support with chloroform (200 mL). The filtrate was partially
concentrated to a final volume of about 150 mL and charged
with benzylamine (11.1 mL, 101 mmol), and the mixture was
heated at reflux to stir for 21 h. The mixture was cooled to
room temperature; the solvent was removed under reduced
pressure to produce an orange solid, which was purified by
flash column chromatography on silica gel, eluting with
methanol/methylene chloride (1:99), to produce 3 as a yellow
solid (14.3 g, 46% yield): mp (DSC) 249 °C; TLC Rf (5%
1
methanol/chloroform) ) 0.66, 0.60; H NMR (CDCl3) δ 7.45-
7.30 (m, 6H), 7.13-7.05 (m, 4H), 6.27-6.23 (m, 1H), 6.13-
6.07 (m, 2H), 5.92-5.85 (m, 1H), 5.15-5.03 (m, 4H), 4.71 (s,
2H), 4.62 (s, 2H), 4.42-4.28 (m, 4H), 3.23-3.18 (m, 1H), 3.10
(s, 1H), 3.02-2.85 (m, 2H), 2.53-2.47 (m, 1H), 2.40-2.33 (m,
1H), 2.13-2.00 (m, 1H), 1.83-1.78 (m, 1H), 1.70 (br s, 2H),
1.52-1.34 (m, 6H); 13C NMR (CDCl3) δ 165.2, 146.4, 146.0,
138.6, 137.6, 135.9, 135.1, 135.0, 132.4, 129.6, 128.5, 126.2,
125.9, 60.0, 49.9, 47.6, 46.9, 46.4, 45.9, 42.6, 42.1, 36.7, 36.6,
11.3; IR (KBr) 3448, 2923, 2851, 2364, 1718, 1648, 1458 cm-1
;
CI MS m/z 377 (M + H)+, 329, 311. The 1H NMR spectrum
was consistent with a 1:1 mixture of the exo and endo
structures.
31.2, 30.8, 15.0, 14.9; IR (KBr) 3413, 2977, 1670, 1455 cm-1
;
CI MS m/z 338 (M + H)+, 292, 272. The 1H NMR spectrum
was consistent with a 1:1 mixture of the exo and endo
structures.
1,3-Dip r op yl-3,9-d ih yd r o-9-ben zyl-8-exo-[2-n or bor n -5-
en yl]-1H-p u r in e-2,6-d ion e (2a ) a n d 1,3-Dip r op yl-3,9-d i-
h yd r o-9-ben zyl-8-en d o-[2-n or bor n -5-en yl]-1H-p u r in e-2,6-
d ion e (2b). A mixture of 1-bromopropane (1.4 mL, 15 mmol),
potassium carbonate (2.1 g, 15 mmol), and 16 (1:1 exo/endo
mixture, 2.9 g, 7.7 mmol) in anhydrous N,N-dimethylforma-
mide (50 mL) was heated at 70 °C under nitrogen and stirred
for 2.5 h. The mixture was cooled to room temperature and
diluted with ether (300 mL). This solution was washed with
water (2 × 100 mL) and brine (1 × 100 mL) and dried (MgSO4).
The solvent was removed under reduced pressure to produce
crude 2 as a yellow oil. The NMR spectrum of this crude
residue was consistent with the proposed structures as a 1:1
mixture of exo and endo 2-norbornenyl epimers. This oil was
then purified by flash column chromatography on silica gel,
eluting with ethyl acetate/hexanes (4:6), to first produce the
exo isomer 2a as a colorless oil, which crystallized to a white
solid upon standing (1.6 g, 50% yield): mp (DSC) 119 °C; TLC
Rf (50% ethyl acetate/hexanes) ) 0.64; 1H NMR (CDCl3) δ
7.33-7.29 (m, 3H), 7.18-7.15 (m, 2H), 6.15-6.13 (m, 1H),
6.12-6.01 (m, 1H), 5.25 (q, 2H, J ) 22.9 Hz), 4.36 (t, 2H, J )
6.5 Hz), 4.08 (t, 2H, J ) 9.1 Hz), 2.93 (s, 1H), 2.65 (s, 1H),
2.58-2.54 (m, 1H), 2.36-2.29 (m, 1H), 1.93 (d, 1H, J ) 8.5
Hz), 1.82 (q, 2H, J ) 7.2 Hz), 1.71 (q, 2H, J ) 7.5 Hz), 1.41-
1.30 (m, 2H), 1.04 (t, 3H, J ) 7.5 Hz), 0.96 (t, 3H, J ) 7.5 Hz);
An alternative, nonchromatographic method for purification
was carried out on a small scale. A 1 g sample of the crude
reaction residue (after removal of the reaction solvent) was
filtered through a plug of silica gel, eluting with methanol/
methylene chloride (1:19, 150 mL). The solvent was removed
under reduced pressure, and the residue was dissolved in 2 N
HCl solution (100 mL). This acid solution was washed with
ether (2 × 100 mL), and the aqueous layer was made basic
with 2 N NaOH solution (110 mL). The precipitate was
collected by vacuum filtration, washed with water (50 mL),
and dried overnight (30 mmHg vacuum, 60 °C) to produce 3
as a white powder. The 1H NMR spectrum was identical to
the spectrum obtained from the chromatographic purification.
E t h yl 5-[[(n -P r op yla m in o)ca r bon yl]a m in o]-2-[2-n or -
bor n -5-en yl]-1-ben zyl-1H-im idazole-4-car boxylate (15, 1:1
Exo/En d o Mixtu r e). n-Propyl isocyanate (5.4 mL, 58 mmol)
was added to a solution of 3 (1:1 exo/endo mixture, 6.5 g, 19
mmol) and triethylamine (8.1 mL, 58 mmol) in anhydrous
toluene (80 mL) under nitrogen, and the reaction mixture was
heated at reflux to stir for 18 h. The mixture was cooled to
room temperature, and the solvent was removed under re-
duced pressure. The residue was charged with ether (100 mL),

8-Substituted Xanthine CVT-124 Precursor
J . Org. Chem., Vol. 67, No. 1, 2002 193
13C NMR (CDCl3) δ 157.5, 154.5, 153.7, 138.4, 136.5, 135.8,
128.7 (2), 127.8, 127.1 (2), 70.3, 47.5, 46.0, 45.4, 42.8, 41.8,
36.8, 31.4, 21.9, 21.7, 11.210.3; IR (KBr) 2968, 1701, 1555, 1483
cm-1; CI MS m/z 419 (M + H)+, 381, 353. Anal. Calcd for
C25H30N4O2: C, 71.74; H, 7.22; N, 13.39. Found: C, 71.72; H,
7.20; N, 13.20. This was followed by the endo isomer 2b as a
colorless oil, which crystallized to a white solid upon standing
(1.4 g, 43% yield): mp (DSC) 110 °C; TLC Rf (50% ethyl
acetate/hexanes) ) 0.46; 1H NMR (CDCl3) δ 7.33-7.28 (m, 3H),
7.14-7.12 (m, 2H), 6.22-6.20 (m, 1H), 5.84-5.82 (m, 1H), 5.33
(s, 2H), 4.32 (t, 2H, J ) 6.5 Hz), 4.05 (t, 2H, J ) 8.0 Hz), 3.21-
3.19 (m, 1H), 3.07 (s, 1H), 2.90 (s, 1H), 2.04-2.02 (m, 1H),
1.84-1.75 (m, 2H), 1.73-1.66 (m, 2H), 1.44-1.42 (m, 1H),
1.31-1.25 (m, 1H), 1.01 (t, 3H, J ) 7.4 Hz), 0.95 (t, 3H, J )
7.4 Hz); 13C NMR (CDCl3) δ 156.7, 152.0, 147.8, 137.2, 136.5,
132.2, 128.7 (2), 127.7, 126.5 (2), 70.2, 49.8, 46.4, 45.4, 42.8,
42.4, 37.3, 31.2, 21.8, 21.6, 11.4, 10.3; IR (KBr) 2967, 1701,
1554, 1485 cm-1; CI MS m/z 419 (M + H)+, 381, 352. Anal.
Calcd for C25H30N4O2: C, 71.74; H, 7.22; N, 13.39. Found: C,
71.60; H, 7.17; N, 13.28.
1,3-Dip r op yl-3,7-d ih yd r o-7-ben zyl-8-en d o-[2-n or bor n -
5-en yl]-1H-p u r in e-2,6-d ion e (17). Ammonia was condensed
into a solution of 2a (0.300 g, 7.0 mmol) in anhydrous
tetrahydrofuran (50 mL) at -78 °C under nitrogen to a total
volume of 100 mL. This was followed by the portionwise
addition of lithium metal (0.050 g, excess) to the point at which
the solution maintained a deep blue color for 5 min. The
mixture was diluted with methanol (20 mL), cooled to room
temperature, and diluted with saturated ammonium chloride
solution (100 mL). The mixture was then extracted with ethyl
acetate (2 × 100 mL), and the combined organic extracts were
dried (MgSO4). The solvents were removed under reduced
pressure to produce the crude xanthine as a yellow oil, which
was dissolved in anhydrous N,N-dimethylformamide (10 mL)
at room temperature under nitrogen and treated with sodium
hydride (0.035 g, 0.8 mmol, 60% dispersion in mineral oil). The
suspension was stirred at room temperature for 15 min after
which benzylamine (0.1 mL, 0.8 mmol) was added and the
mixture was stirred at room temperature for 22 h. The mixture
was diluted with water (50 mL) and extracted with ethyl
acetate (3 × 50 mL). The combined organic extracts were dried
(MgSO4), and the solvents were removed under reduced
pressure. The resulting amber oil was purified by flash column
chromatography on silica gel, eluting with ethyl acetate/
hexanes (1:3), to produce the endo N-3-benzyl positional isomer
17 as a colorless oil, which crystallized to a white solid upon
standing (0.240 g, 80% yield over two steps). The 1H NMR
spectrum (CDCl3) was identical to the known material pro-
vided by CV Therapeutics, Inc.: CI MS m/z 419 (M + H)+.
Ack n ow led gm en t. The authors acknowledge and
thank Marek G. Nelson, Ph.D., of Protein Design Labs
(formerly of CV Therapeutics, Inc.) for copies of spectral
data for compound 17 and for many helpful discussions
and Biogen, Inc., for permission to publish this body of
work. This work constitutes a six-month research effort
by Albany Molecular Research, Inc., on behalf of CV
Therapeutics, Inc., and Biogen, Inc.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all new compounds reported in this manuscript.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O015925R