A ring-transformation/ring-annulation strategy for the synthesis of the DHFR inhibitor, TNP-351: A correction

Full text of DOI:10.1021/jo961230s

J . Org. Chem. 1996, 61, 7973-7974
7973
Sch em e 1
A Rin g-Tr a n sfor m a tion /Rin g-An n u la tion
Str a tegy for th e Syn th esis of th e DHF R
In h ibitor , TNP -351: A Cor r ection
Edward C. Taylor* and Zhenmin Mao
Department of Chemistry, Princeton University,
Princeton, New J ersey 08544
Received J uly 1, 1996
In a recent paper,1 we described a versatile synthesis
of 2-substituted 4-aminopyrrolo[2,3-d]pyrimidines (3) by
the reaction of a variety of 2-amino-3-cyanofurans (2)
with amidines (1). The reaction proceeds by a ring-
opening, ring-recyclization sequence of reactions through
which the starting furan 2-amino nitrogen becomes the
pyrrole nitrogen of the final product, and one of the
amidine nitrogens becomes N-1 of the fused pyrimidine
ring. Among the compounds prepared by this strategy
was the 2,4-diaminopyrrolo[2,3-d]pyrimidine 3a , which
we had incorrectly identified as the DHFR inhibitor TNP-
3512 (Scheme 1). The latter, however, has a three-carbon
(propyl) bridge between the pyrrole and benzene rings
(i.e., 3b) rather than the two-carbon (ethyl) bridge found
in its lower homologue 3a .3 We report in this paper a
successful total synthesis of TNP-351 by the ring-opening,
ring-recyclization strategy (Scheme 2).
Sch em e 2
Thus, 4-(4′-carbomethoxyphenyl)butyraldehyde (4)4 was
converted to the R-hydroxy ketone 5 by a mixed benzoin
condensation with paraformaldehyde, catalyzed by N-
ethylbenzothiazolium bromide in the presence of triethyl-
amine.5 Base-catalyzed condensation of 5 with malono-
nitrile then provided methyl 4-[3-(2-amino-3-cyanofur-
4-yl)propyl]benzoate (6), which was condensed with
guanidine to give the pyrrolo[2,3-d]pyrimidine 7. Hy-
drolysis of 7 to the corresponding benzoic acid 8, peptide
coupling with diethyl L-glutamate to give 9, and final
saponification as previously described2 then provided
TNP-351 (3b) in an overall yield of 10% from 4, compared
with the original 11-step, 16% yield of TNP-351 by Miwa.2
Exp er im en ta l Section
Meth yl 4-(5-Hyd r oxy-4-oxop en tyl)ben zoa te (5). A etha-
nol solution (10 mL) of aldehyde 44 (4.12 g, 20 mmol), paraform-
aldehyde (600 mg, 20 mmol), N-ethylbenzothiazolium bromide
(878 mg, 3.6 mmol), and triethylamine (364 mg, 3.6 mmol) was
heated at 65 °C for 20 h. The solvent was removed under
reduced pressure, and the residue was chromatographed with
hexane/EtOAc (7/3). Fractions containing the product were
combined and evaporated under reduced pressure to give 5 (2.5
g, 53%) as a colorless oil which solidified upon standing: 1H
NMR (CDCl3) δ 2.01 (m, 2H), 2.42 (t, 2H, J ) 7.3 Hz), 2.71 (t,
2H, J ) 7 Hz), 3.05 (s, 1H, br), 3.91 (s, 3H), 4.22 (s, 2H), 7.23 (d,
2H, J ) 8 Hz), 7.96 (d, 2H, J ) 8 Hz). Anal. Calcd for
15 h. Solvent was removed under reduced pressure, the residue
was dissolved in EtOAc (300 mL), and the resulting solution was
passed through a short silica gel column. Evaporation of the
eluate under reduced pressure gave 6 (2.23 g, 94%) as a white
solid: 1H NMR (CDCl3) δ 1.94 (m, 2H), 2.42 (t, 2H, J ) 7.6 Hz),
2.72 (t, 2H, J ) 7.6 Hz), 3.91 (s, 3H), 4.62 (s, 2H, br), 6.56 (s,
1H), 7.24 (d, 2H, J ) 7.9 Hz), 7.95 (d, 2H, J ) 7.9 Hz). Anal.
C
13H16O4: C, 66.09; H, 6.83. Found: C, 66.17; H, 6.94.
Meth yl 4-[3-(2-Am in o-3-cya n ofu r -4-yl)p r op yl]ben zoa te
(6). A mixture of malononitrile (603 mg, 9.13 mmol) and
triethylamine (922 mg, 9.13 mmol) in MeOH (10 mL) was added
to a solution of the R-hydroxy ketone 5 (1.96 g, 8.3 mmol) in
MeOH (30 mL), and the resulting solution was stirred at rt for
Calcd for
C16H16N2O3‚0.1H2O: C, 67.17; H, 5.71; N, 9.79.
Found: C, 66.80; H, 5.62; N, 10.16.
Meth yl 4-[3-(2,4-Dia m in o-7H-p yr r olo[2,3-d ]p yr im id in -5-
yl)p r op yl]ben zoa te (7). To a solution of guanidine-free base
(1.5 mmol, from 143 mg of guanidine hydrochloride and 81 mg
of sodium methoxide) in anhydrous MeOH (30 mL) was added
aminonitrile 6 (284 mg, 1 mmol), and the mixture was refluxed
for 30 h. The solvent was removed under reduced pressure, and
the residue was chromatographed on silica gel with 5% MeOH/
CH2Cl2. The fractions containing the product were combined
(1) Taylor, E. C.; Patel, H. H.; J un, J .-G. J . Org. Chem. 1995, 60,
6684.
(2) Miwa, T.; Hitaka, T.; Akimoto, H.; Nomura, H. J . Med. Chem.
1991, 34, 555.
(3) For the first reported synthesis of 3a , see: Shih, C.; Gossett, L.
S. Heterocycles 1993, 35, 825.
(4) Taylor, E. C.; Harrington, P. M. J . Org. Chem. 1990, 55, 3222.
(5) Matsumoto, T.; Ohishi, M.; Inoue, S. J . Org. Chem. 1985, 50,
603.
S0022-3263(96)01230-3 CCC: $12.00 © 1996 American Chemical Society

7974 J . Org. Chem., Vol. 61, No. 22, 1996
Notes
and evaporated under reduced pressure to give 7 (150 mg, 42%)
as a light brown solid: 1H NMR (CDCl3) δ 2.02 (m, 2H), 2.66 (t,
2H, J ) 7.6 Hz), 2.75 (t, 2H, J ) 7.6 Hz), 3.91 (s, 3H), 4.58 (s,
2H, br), 4.84 (s, 2H, br), 6.50 (s, 1H), 7.24 (d, 2H, J ) 7.9 Hz),
give 9 as a gummy solid (145 mg, 62%). Recrystallization from
aqueous MeOH gave a white solid: mp 134 °C dec; 1H NMR
(DMSO-d6) δ 1.16 (t, 3H, J ) 7 Hz), 1.21 (t, 3H, J ) 7 Hz), 1.79-
2.14 (m, 4H), 2.41 (t, 2H, J ) 7 Hz), 2.65 (t, 2H, J ) 7.2 Hz),
2.70 (t, 2H, J ) 7 Hz), 4.05 (q, 2H, J ) 7 Hz), 4.11 (q, 2H, J )
7Hz), 4.24 (m, 1H), 5.35 (s, 2H), 5.92 (s, 2H), 6.42 (s, 1H), 7.29
(d, 2H, J ) 8 Hz), 7.81 (d, 2H, J ) 8 Hz), 8.66 (d, 1H, J ) 7.3
Hz), 10.38 (s, 1H, br). Anal. Calcd for C25H32N6O5‚H2O: C,
58.35; H, 6.66; N, 16.33. Found: C, 58.71; H, 6.42; N, 16.53.
N-[4-[3-(2,4-Dia m in o-7H -p yr r olo[2,3-d ]p yr im id in -5-yl)-
p r op yl]ben zoyl]-L-glu ta m ic Acid (3b, TNP -351). To a solu-
tion of 9 (80 mg, 0.155 mmol) in THF (2 mL) and H2O (1 mL)
was added 1 mL of 1 N NaOH. The mixture was stirred at rt
for 3 h. The THF was evaporated under reduced pressure, and
the residual solution was acidified with HOAc. The resulting
white precipitate was collected by filtration, washed successively
with water, MeOH, and ether, and dried under reduced pressure
(P2O5) to give 70 mg (88%) of 3b (TNP-351): mp 190 °C dec; 1H
NMR (DMSO-d6) δ 1.73-2.13 (m, 4H), 2.34 (t, 2H, J ) 7 Hz),
2.67 (m, 4H), 4.34 (m, 1H), 5.54 (s, 2H, br), 6.24 (s, 2H), 6.46 (s,
1H), 7.29 (d, 2H, J ) 8 Hz), 7.78 (d, 2H, J ) 8 Hz), 8.47 (d, 1H,
7.96 (d, 2H, J ) 7.9 Hz), 8.19 (s, 1H, br). Anal. Calcd for C17H19
-
N5O2‚0.4CH2Cl2: C, 58.16; H, 5.55; N, 19.49. Found: C, 58.13;
H, 5.89; N, 19.24.
4-[3-(2,4-Dia m in o-7H-p yr r olo[2,3-d ]p yr im id in -5-yl)p r o-
p yl]ben zoic Acid (8). A solution of the ester 7 (108 mg, 0.30
mmol) in a mixture of MeOH (6 mL) and 0.5 N NaOH (1 mL)
was heated under reflux for 15 h, cooled, and acidified with
glacial HOAc. The resulting precipitate was collected by filtra-
tion, washed with water, and dried in vacuo to give 8 (90 mg,
87%) as an off-white solid: 1H NMR (DMSO-d6) δ 1.84 (m, 2H),
2.69 (m, 2H), 5.37 (s, 2H, br), 5.94 (s, 2H, br), 6.42 (s, 1H), 7.29
(d, 2H, J ) 8 Hz), 7.82 (d, 2H, J ) 8 Hz), 10.38 (s, 1H, br). Anal.
Calcd for C16H17N5O2‚H2O‚0.25HOAc: C, 57.55; H, 5.85; N,
20.34. Found: C, 57.70; H, 5.35; N, 19.92.
Dieth yl N-[4-[3-(2,4-Dia m in o-7H-p yr r olo[2,3-d ]p yr im i-
d in -5-yl)p r op yl]ben zoyl]-L-glu ta m a te (9). To a suspension
of acid 8 (155 mg, 0.45 mmol) in DMF (10 mL) was added
N-methylmorpholine (NMM, 62 µL, 0.57 mmol) and 2-chloro-
4,6-dimethoxy-1,3,5-triazine (100 mg, 0.57 mmol). The resulting
solution was stirred at rt for 2 h, NMM (62 µL, 0.57 mmol) and
diethyl L-glutamate hydrochloride (140 mg, 0.59 mmol) were
added, and the mixture was stirred at rt for 4 h. Solvent was
then removed under reduced pressure, and the residue was
chromatographed on silica gel with CH2Cl2/MeOH (10/1). Frac-
tions containing the product were combined and evaporated to
J
) 7.3 Hz), 10.54 (s, 1H). Anal. Calcd for C21H24N6O5‚
1.25HOAc: C, 54.75; H, 5.67; N, 16.30. Found: C, 54.54; H,
5.83; N, 16.51.
Ack n ow led gm en t. We are grateful to Eli Lilly &
Co., Indianapolis, IN, for support of this work.
J O961230S