Reversible carboxamide-mediated internal activation at C(6) of 2-chloro-4-anilino-1H-pyrrolo[2,3-d]pyrimidines

Article abstract of DOI:10.1021/jo8020693

(Chemical Equation Presented) A synthetic route to bisanilino-1H-pyrrolo[2, 3-d]pyrimidines has been discovered, wherein the C(6)-chloride reactivity is necessarily enhanced via reversible acid-catalyzed internal activation of the pyrimidine ring by a C(1′)-carboxamide moiety. Subsequent selective nucleophilic displacements at C(6) and C(1′) constitute a one-pot tandem protocol for the rapid assembly of bisanilino-1H-pyrrolo[2,3-d]pyrimidines.

Full text of DOI:10.1021/jo8020693

SCHEME 1. Synthesis of Carboxamides 4 and 57
Reversible Carboxamide-Mediated Internal
Activation at C(6) of
2-Chloro-4-anilino-1H-pyrrolo[2,3-d]pyrimidines
Stanley D. Chamberlain, Roseanne M. Gerding,
Huangshu Lei, Ganesh Moorthy, Samarjit Patnaik,
Aniko´ M. Redman, Kirk L. Stevens, Joseph W. Wilson,
Bin Yang, and J. Brad Shotwell*
GlaxoSmithKline, Oncology R&D, 5 Moore DriVe, Research
Triangle Park, North Carolina 27709
jbs26900@gsk.com
ReceiVed September 18, 2008
been aided by straightforward chemical syntheses wherein 2,4-
dichloropyrimidines are versatile starting materials, allowing
sequential derivatization of both chlorides via SNAR displace-
ments with functionalized anilines. We recognized the potential
for the corresponding 4,6-bisanilino-1H-pyrrolo[2,3-d]pyrim-
idines to bind to kinases in an analogous manner, with a 3-point
contact to the kinase hinge, and expected that chemical
diversification of known dichloro-pyrrolopyrimidine 1 via
sequential chloride displacements would proceed smoothly in
analogy to chemistry reported for 2,4-dichloropyrimidines.1-6
We were especially interested in 1H-pyrrolo[2,3-d]pyrimidines2
containing side-chain carboxamides and herein describe our
successful synthetic efforts toward this class of potential kinase
inhibitors.
A synthetic route to bisanilino-1H-pyrrolo[2,3-d]pyrimidines
has been discovered, wherein the C(6)-chloride reactivity is
necessarily enhanced via reversible acid-catalyzed internal
activation of the pyrimidine ring by a C(1′)-carboxamide
moiety. Subsequent selective nucleophilic displacements at
C(6) and C(1′) constitute a one-pot tandem protocol for the
rapid assembly of bisanilino-1H-pyrrolo[2,3-d]pyrimidines.
Dichloride 1 was prepared according to previous reports8 and
readily derivatized by acid- or base-mediated addition of anilines
2 and 3 to afford C(4)-substituted pyrrolopyrimidines 4 and 5
in reasonable yields (Scheme 1). Exposure of 4 to aniline 6
and hydrochloric acid, quenching with ammonium hydroxide,
and subsequent detosylation, afforded C(6) derivative 8 in good
yield. In contrast, chloride 5 proved refractory toward acid-
catalyzed, electrophilic aromatic substitution, and preparation
of 9 using palladium-catalyzed methods proved extremely
capricious (Scheme 2).
Structures possessing aminopyrimidines are remarkably gen-
eral in their ability to potently inhibit a variety of protein kinases
via a direct 2-point interaction with the kinase hinge. Potent
inhibition of a number of anticancer/anti-inflammation kinase
targets including AurA/B,1 IGF-1R/IR,2 FAK,2 VEGF,3 ALK,2
SYK,4 IKK,5 and JAK6 by 2,4-bisanilino pyrimidines is well-
documented. The development of this class of inhibitors has
In general, pyrrolopyrimidines are much more resistant toward
SNAR displacements than corresponding simple pyrimidine
substrates, with their reduced electrophilicity apparently a result
of the electronic impact of the pendant pyrrole. As such, within
(1) Burdick, D.; Liang, J. Pyrimidine Kinase Inhibitors. WO 2007/120339
A1, December 15, 2006.
(2) (a) Liu, T.; LaFortune, T.; Honda, T.; Ohmori, O.; Hatakeyama, S.; Meyer,
T.; Jackson, D.; Groot, J.; Yung, W. Mol. Cancer Ther. 2007, 6, 1357. (b) Galkin,
A.; Melnick, J.; Kim, S.; Hood, T.; Nanxin, L.; Lintog, L.; Xia, G.; Steensma,
R.; Chopiuk, G.; Wan, Y.; Ding, P.; Liu, Y.; Sun, F.; Schultz, P.; Gray, N.;
Warmuth, M. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 270. (c) Imbach, P.;
Kawahar, E.; Konishi, K.; Matsuura, N.; Miyake, T.; Ohmori, O.; Roesel, J.;
Teno, N.; Umemura, I. Pyrimidine Derivatives. WO 2006/021454 A2, August
27, 2004. (d) Garcia-Echeverria, C.; Kanazawa, T.; Kawahara, E.; Masuya, K.;
Matsuura, N.; Miyake, T.; Ohmori, O.; Umemura, I.; Steensma, R.; Chopiuk,
G.; Jiang, J.; Wan, Y.; Ding, Q.; Zhang, Q.; Gray, N.; Karanewsky, D. 2,4-
Pyrimidinediamines Useful in the Treatment of Neoplastic Diseases, Inflammatory
and Immune System Disorders. WO 2005/016894 A1, September 24, 2003.
(3) (a) Sammond, D.; Nailor, K.; Veal, J.; Nolte, R.; Wang, L.; Knick, V.;
Rudolph, S.; Truesdale, A.; Nartey, E.; Stafford, J.; Kumar, R.; Cheung, M.
Bioorg. Med. Chem. Lett. 2005, 15, 3519. (b) Kumar, R.; Knick, V.; Rudolph,
S.; Johnson, J.; Crosby, R.; Crouthamel, M.; Hopper, T.; Miller, C.; Harrington,
L.; Onori, J.; Mullin, R.; Gilmer, T.; Truesdale, A.; Epperly, A.; Boloor, A.;
Stafford, J.; Luttrell, D.; Cheung, M. Mol. Cancer Ther. 2007, 6, 2012.
(4) Atkinson, F.; Campos, S.; Harrison, L.; Parr, N.; Patel, V.; Vitulli, G.
1H-Indazol-4-yl-2,4-pyrimidinediamine Derivatives. WO 2007/085540 A1, June
9, 2006.
(5) Wagnon, J.; Nguefack, J.; Jegham, S.; Bosch, M.; Bouaboula, M.;
Casellas, P.; Tonnerre, B.; Olsen, J.; Mignani, S. Novel 2,4-Dianilinopyrimidine
Derivatives, The Preparation Thereof, Their Use as Medicaments, Pharmaceutical
Compositions and, in Particular, as IKK Inhibitors. WO 2007/006926 A2,
November 25, 2005.
(6) Hui, L.; Argade, A.; Tso, K.; Thota, S.; Carroll, D.; Sran; A.; Copper,
R.; Singh, R.; Bhamidipati, S.; Masuda, E.; Taylor, V. Compositions and Methods
for Inhibition of the JAK Pathway. WP 2007/098507 A2, October 19, 2006.
(7) TFE ) trifluoroethanol.
(8) Gore, P.; Patel, V. K.; Walker, A.; Woodrow, M. Pyrrolopyrimidine
Derivatives as Syk Inhibitors and Their Preparation, Pharmaceutical Composi-
tions, and Use in the Treatment of Inflammatory and Allergic Diseases. WO
2007042298 A1, April 19, 2007.
10.1021/jo8020693 CCC: $40.75
Published on Web 11/11/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9511–9514 9511

SCHEME 2. Apparent Reduced Reactivity of 5 Toward
Chloride Displacements
SCHEME 4. Isolation and Reactivity of Key Intermediate
11
carboxamide at N(5).9 Interestingly, tetracyclic 12 can be
intercepted by a variety of primary amines, in addition to
ammonia, to afford the corresponding secondary amide products
(13-15). This constitutes a general route to bisanilino-1H-
pyrrolo[2,3-d]pyrimidines, wherein the reduced reactivity of the
C(6) chloride is enhanced via reversible internal activation of
the pyrimidine ring by the C(1′) carboxamide, with a concomi-
tant elimination of ammonia and acylation of the N-5 pyrimidine
nitrogen.
SCHEME 3. Reversible Internal Activation at C(6)
We postulated that the in situ formation of chloride 11
accounts for the inherent differences in reactivity between 4
and 5 because the constraint inherent in lactam 5 would prevent
intramolecular activation by N(5). Also noteworthy, trifluoro-
ethanol proved uniquely efficient in its ability to promote the
conversion of 4 f 12.10 This suggests a key alcoholysis event
could precede the formation of 11.11 This further accounts for
the loss of reactivity for 5 since the opening of the lactam by
trifluoroethanol would leave a high, effective concentration of
a primary amino group more disposed toward displacement of
a transient trifluoroethyl ester than the N(5) nitrogen.
Aiming to prepare and isolate 11 as a valuable activated
synthetic intermediate, we found treatment of dichloride 1 with
anthranilic acid under standard conditions, followed by exposure
to oxalyl chloride, afforded 11 that is stable and isolable as the
HCl salt (Scheme 4).12 Interestingly, 11 is extremely reactive
toward a variety of anilines exclusively at C(6) and afforded
the corresponding displacement products in <2 h at 80 °C or
upon stirring at room temperature for 16 h. This enhanced
reactivity at C(6) is consistent with acid-catalyzed, intramo-
lecular cyclization (i.e., 4 f11) functioning as a key step in
the one-pot formation of tetracyclic 12 from 4 (Scheme 3).
We envisioned the exploitation of this internal C(6)-chloride
activation for the synthesis of 10, as well as for other molecules
lacking a primary carboxamide moiety, would be possible via
manipulation of the carboxamide following the activation step.
the pyrrolopyrimidine series, we were quite surprised at the
reactivity differences between 4 and 5. Whereas 4 apparently
reactsanalogouslytotherelatedpyrimidinesreportedelsewhere,1-6
5 has a reactivity profile more consistent with other literature
reports of pyrrolopyrimidines.8 In our hands, a number of
molecules related to 4, but lacking a carboxamide moiety at
C(1′), proved completely refractory to SNAR displacements,
consistent with the reduced electrophilicity of pyrrolopyrim-
idines in general, but inconsistent with the reactivity of 4.
Therefore, the reactivity of 4 was an outlier among a variety of
similarly substituted pyrrolopyrimidines we investigated and
suggested a unique mechanism by which the primary carboxa-
mide moiety (present in 4) directly participated in the C(6)-
chloride displacement.
(9) Although this general tetracyclic substructure has appeared in several
communications, it has not been exploited as a general means of activating
electron-rich pyrimidines or related substrates. See: (a) Vasudevan, A.; Mavan-
dadi, F.; Chen, L.; Gangjee, A. J. Org. Chem. 1999, 64, 634. (b) Querioz, M.;
Begouin, A.; Ferreira, I.; Kirsch, G.; Calhelha, R.; Barbosa, S. Eur. J. Org. Chem.
2004, 3679. (c) El-Bahaie, S.; El-Deeb, A.; Assy, M. Pharmazie 1991, 46, 26.
(d) Abdel-Fattah, A.; Aly, A.; Gad, F.; Hassan, N.; El-Gazzar, A. Phosphorus,
Sulfur Silicon Relat. Elem. 2000, 163, 1.
(10) Additionally screened were 2-propanol, tert-butanol, DMF, and hexaflu-
oroisopropanol.
(11) Products arising from alcoholysis of the amide and ring opening of 11
by trifluoroethanol can sometimes be observed in the reacting mixtures prior to
quenching with ammonia or another base.
Analysis of unquenched reacting mixtures by LCMS sug-
gested a discrete intermediate was involved in the conversion
of 4 to 7. Exposure of carboxamide 4 to HCl and aniline 6 at
80 °C for 12 h, followed by isolation prior to quenching with
ammonium hydroxide, affords stable and isolable tetracyclic 12
(Scheme 3), wherein displacement of the C(6) chloride has been
accompanied by concomitant intramolecular cyclization of the
(12) Additionally, tetracyclic 11 could be isolated by exposure of 4 to HCl
in trifluoroethanol and as a component of reaction mixtures quenched prematurely
with saturated aqueous sodium bicarbonate.
9512 J. Org. Chem. Vol. 73, No. 23, 2008

SCHEME 5. Synthesis of Key Lactam 10
mixture was treated with DIEA (90 mL) and heated to reflux for
16 h. The reaction mixture was then further concentrated by
distilling more volatiles off (400 mL over 4 h), then continued
heating at reflux overnight. The resulting mixture was cooled to
room temperature and concentrated under reduced pressure to obtain
a thick oil, which was diluted with EtOAc (1.3 L), then sequentially
washed with a 1 N HCl solution (2 × 500 mL) and a saturated
NaHCO3 solution (500 mL). Further dilution of the separated
organic layer with a saturated NaCl solution (500 mL) led to the
formation of a thick precipitate. The entire mixture was filtered,
and the solid was washed with Et2O. The solid was dried overnight
in a vacuum oven at 60 °C to obtain 2-({2-chloro-7-[(4-methylphe-
nyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoic acid
17 as a yellow solid (61.63 g, 92%): 1H NMR (400 MHz, DMSO-
d6) δ ppm 11.34 (s, 1 H), 8.30 (d, J ) 8.2 Hz, 1 H), 7.97 (d, J )
8.4 Hz, 2 H), 7.85-7.93 (m, 1 H), 7.72 (d, J ) 3.8 Hz, 1 H), 7.57
(t, J ) 7.2 Hz, 1 H), 7.44 (d, J ) 8.2 Hz, 2 H), 7.13 (t, J ) 7.6 Hz,
1 H), 6.69 (d, J ) 4.0 Hz, 1 H), 2.33 (s, 3 H); 13C NMR (400
MHz, DMSO-d6) δ ppm 21.11, 102.38, 105.33, 119.28, 121.96,
123.32, 124.38, 127.73, 130.19, 131.07, 133.66, 133.96, 139.75,
146.28, 150.34, 153.64, 154.08, 169.42; IR (KBr pellet) 3410, 1624,
1576, 1560, 1388, 1284, 1260, 1188, 1164, 1147, 670, 578 cm-1
;
HRMS m/e calcd for C20H16ClN4O4S (M + H)+ 443.05753, found
443.05750.
5-Chloro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]py-
rimido[6,1-b]quinazolin-7(3H)-one (11). A slurry of 2-({2-chloro-
7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-
yl}amino)benzoic acid 17 (33.05 g, 71.7 mmol) and THF (1000
mL) was treated with a few drops of DMF and oxalyl chloride
(12.55 mL, 143 mmol). The resulting fine slurry was stirred at rt
for 3 h, then maintained at ∼5 °C for 17 h, without stirring. The
cold slurry was filtered, the solid washed with cold THF, then dried
in a vacuum oven at rt to obtain 5-chloro-3-[(4-methylphenyl)sul-
fonyl]pyrrolo[2′,3′:4,5]-pyrimido[6,1-b]quinazolin-7(3H)-one hy-
drogen chloride salt 11 as a pale yellow solid (∼34.6 g, quantitative
Accordingly, aniline 18 added efficiently to dichloride 1, and
subsequent exposure to oxalyl chloride afforded tetracyclic
bromide 20. Treatment of 20 with trimethoxy aniline 6, followed
by dilution with warm methanol, efficiently promoted tandem
C(6)-chloride displacement and subsequent methanolysis to
afford ester 21 in good overall yield. With the requisite C(6)
aniline in place, cyanation and treatment with cobalt borohy-
dride13 gave lactam 9 in excellent yield. Basic hydrolysis
afforded the target pyrrolopyrimidine 10 (Scheme 5).
In summary, we have developed an efficient protocol for the
rapid assembly of a variety of carboxamides containing bisa-
nilinopyrrolopyrimidines (8, 10, and 13-15). The reduced
reactivity of the C(6) chloride relative to related pyrimidine
substrates has been overcome through reversible internal activa-
tion of the pyrrolopyrimidine ring by the C(1′) carboxamide
via tetracyclic 11 and 20. As such, this approach does not rely
on an SNAR displacement at C(6); rather, a tandem intramo-
lecular cyclization/aniline displacement, followed by nucleo-
philic addition at C(1′), is employed. This allows a means of
both amide diversification and restoration of the pyrimidine ring.
Careful synthetic design has allowed the exploitation of this
reversible internal activation in the context of final molecules
not possessing primary carboxamide moieties (e.g., 10).
1
yield ∼100%): H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (s,
3H), 7.07 (d, 4.21 Hz, 1H), 7.34 (d, J ) 4.21 Hz, 1H), 7.47 (d,
8.06 Hz, 2H), 7.53-7.63 (m, 1H), 7.78-7.90 (m, 1H), 8.00 (d, J
) 8.42 Hz, 2H), 8.18 (dd, J ) 7.78 Hz, 1.74 Hz, 1H), 9.28 (d, J
) 8.42 Hz, 1H); 13C NMR (400 MHz, DMSO-d6) δ ppm (single
aryl resonance unresolved) 21.12, 93.83, 104.27, 119.97, 121.52,
121.82, 126.61, 127.11, 127.84, 130.05, 134.16, 138.18, 145.49,
145.89, 151.72, 154.23, 158.42; IR (CDCl3 solution) 1723, 1625,
1602, 1387, 1181, 1167, 1157 cm-1; HRMS m/e calcd for
C20H13ClN4O3S (M + H)+ 425.0475, found 425.0475.
3-[(4-Methylphenyl)sulfonyl]-5-{[3,4,5-tris(methyloxy)phenyl]-
amino}pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (12).
To a suspension of 5-chloro-3-[(4-methylphenyl)sulfonyl]pyr-
rolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt 11 (3.0
g, 6.50 mmol) in 2,2,2-trifluoroethanol (100 mL) was added 3,4,5-
tris(methyloxy)aniline (1.31 g, 7.15 mmol), and the mixture was
heated at 80 °C for 2 h. At this time, solvents were removed under
reduced pressure to afford 3-[(4-methylphenyl)sulfonyl]-5-{[3,4,5-
tris(methyloxy)phenyl] amino}pyrrolo[2′,3′:4,5]pyrimido[6,1-b]-
quinazolin-7(3H)-one HCl salt 12 (4.2 g, 6.91 mmol) as a yellow
solidwithsufficientpurityfordirectuseinsubsequenttransformations.
N-Methyl-2-[(2-{[3,4,5-tris(methyloxy)phenyl]amino}-1H-pyr-
rolo[2,3-d]pyrimidin-4-yl)amino]benzamide (13). 3-[(4-Methylphe-
nyl)sulfonyl]-5-{[3,4,5-tris(methyloxy) phenyl]amino}pyrrolo[2′,3′:
4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt 12 (400 mg,
0.658 mmol) was suspended in THF (10 mL) and a solution of 2
M MeNH2 in THF (3.29 mL, 6.58 mmol). After stirring overnight,
the reaction mixture was diluted with ethyl acetate and washed with
water and a saturated brine solution. Organics were dried over
sodium sulfate, and solvents were removed under reduced pressure.
The residue was flushed through a SiO2 plug with 10% MeOH/
CH2Cl2 to afford intermediate N-methyl-2-[(7-[(4-methylphenyl)-
sulfonyl]-2-{[3,4,5-tris(methyloxy)phenyl]amino}-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino]benzamide (365 mg, 0.606 mmol) as a
Experimental Section
2-({2-Chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]py-
rimidin-4-yl}amino)benzoic Acid (17). A slurry of 2,4-dichloro-7-
[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine 1 (50 g,
146 mmol) and 2-aminobenzoic acid 16 (27.2 g, 175 mmol) in
i-PrOH (1200 mL) and 30 mL of DIEA were heated to reflux. After
1 h, the solution turned a clear brown color, at which time about
450 mL of volatiles was removed via distillation. The remaining
(13) Satoh, T.; Suzuki, S. Tetrahedron Lett. 1969, 52, 4555.
J. Org. Chem. Vol. 73, No. 23, 2008 9513

yellow foam (ESIMS (M + H)+ ) 603). The residue was dissolved
in dioxane (6 mL), and 2 N NaOH (4 mL) was added in a
microwave-safe vessel. The reaction was heated in a microwave at
120 °C for 15 min. The reaction was diluted with ethyl acetate,
and the organic layer was washed with water and saturated brine
solution and dried over sodium sulfate. Solvents were removed
under reduced pressure, and the residue was purified by chroma-
tography on SiO2 to afford N-methyl-2-[(2-{[3,4,5-tris(methylox-
y)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benza-
mide 13 (168 mg, 0.375 mmol, 57% yield, two steps) as a tan solid:
1H NMR (400 MHz, DMSO-d6) δ ppm 2.83 (d, J ) 4.39 Hz, 3
H), 3.62 (s, 3 H), 3.76 (s, 6 H), 6.32 (dd, J ) 3.20, 1.83 Hz, 1 H),
6.98-7.09 (m, 2 H), 7.28 (s, 2 H), 7.42-7.53 (m, 1 H), 7.75 (d, J
) 7.87 Hz, 1 H), 8.75 (d, J ) 4.58 Hz, 1 H), 8.87 (s, 1 H), 9.10
(d, J ) 8.42 Hz, 1 H), 11.34 (s, 1 H), 11.76 (s, 1 H); 13C NMR
(101 MHz, DMSO-d6) δ ppm 170.2, 156.1, 153.4, 153.3, 152.7,
141.9, 138.5, 132.5, 132.1, 128.6, 121.0, 120.9, 120.8, 119.4, 99.6,
97.9, 97.1, 60.8, 56.3, 27.0; IR (solid powder) 3410, 3305, 1582,
1509, 1485, 1451, 1413, 1238, 1130, 1003, 831, 754, 696 cm-1
;
HRMS m/e calcd for C23H25N6O4 (M + H)+ 449.19318, found
449.19302.
Acknowledgment. The authors thank Erich Baum for helpful
suggestions during the preparation of the manuscript.
Supporting Information Available: Additional experimental
details and spectroscopic characterization for 4, 5, 7-15, 17,
and 19-21. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO8020693
9514 J. Org. Chem. Vol. 73, No. 23, 2008