Synthesis of the novel tetrahydropyrazolo[3,4- c ]pyridin-5-one scaffold

Article abstract of DOI:10.1055/s-0034-1379504

We report an efficient synthesis of the novel 1,4,6,7-tetra-hydropyrazolo[3,4-c]pyridin-5-one scaffold with the potential for incorporation of alkyl or aryl substituents at the C-3 and N-6 positions. The route utilises a Dieckmann condensation to install the lactam ring, followed by a hydrazine cyclisation to build the fused pyrazole ring.

Full text of DOI:10.1055/s-0034-1379504

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 228–232
letter
228
N. J. Howe et al.
Letter
Synlett
Synthesis of the Novel Tetrahydropyrazolo[3,4-c]pyridin-5-one
Scaffold
Nicholas J. Howe*
Kevin Blades
O
R2
O
R1
R2
N2H4⋅H2O
O
N
O
LHMDS, THF
reflux
R2
Gillian M. Lamont
EtOH, reflux
N
O
O
N
N
N
R1
R1
OH
AstraZeneca Oncology Innovative Medicines, Mereside,
Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
nick.howe@astrazeneca.com
H
MeO
R1 = propyl, phenyl, 2,4-dimethoxybenzyl
R
2 = methyl, phenyl, 4-methylphenyl, 3-cyanophenyl
Received: 09.10.2014
Accepted after revision: 30.10.2014
Published online: 02.12.2014
O
NH2
DOI: 10.1055/s-0034-1379504; Art ID: st-2014-d0847-l
N
N
N
Abstract We report an efficient synthesis of the novel 1,4,6,7-tetra-
hydropyrazolo[3,4-c]pyridin-5-one scaffold with the potential for incor-
poration of alkyl or aryl substituents at the C-3 and N-6 positions. The
route utilises a Dieckmann condensation to install the lactam ring, fol-
lowed by a hydrazine cyclisation to build the fused pyrazole ring.
O
O
N
4
OMe
Key words pyrazole, lactam, Dieckmann condensation, hydrazine
Br
Indazoles and azaindazoles are important heterocyclic
cores for exploration as drug scaffolds.1 In comparison with
indazole (1) and, to a lesser extent, 6-azaindazole (2), the
analogous fused pyrazole-lactam 3 is a significantly less lipo-
philic scaffold for structural elaboration, as demonstrated
by their ClogP values2 (Figure 1).
N
N
N
F
O
N
5
N
4
4
3
3
4
O
5
3
5
5
N2
NH 1
2
Figure 2 Biologically active compounds based on fused pyrazole-lact-
am scaffolds
N 2
N 1
N
N 1
HN
6
6 N
6
7
H
7
H
7
1
2
3
Duplantier et al. described the synthesis of 4,5,6,7-tetra-
hydropyrazolo[3,4-c]pyridin-7-ones6 (Scheme 1) proceed-
ing via keto ester 6, which underwent a Dieckmann con-
densation with sodium methoxide to give the vinylogous
acid 7, which then underwent cyclisation with an aryl hy-
drazine to give a mixture of the two 4,5,6,7-tetrahydropyra-
zolo[3,4-c]pyridin-7-one regioisomers. It should be noted
that the authors only reported the synthesis of compounds
bearing alkyl substituents at the C-3 position of the core.
We have been successful in developing a similar ap-
proach to the synthesis of 6,7-dihydro-1H-pyrazolo[3,4-c]-
pyridin-5(4H)-ones 8 (Table 1). The success of this new
route required finding reliable conditions for formation of
the γ-keto acid intermediates 10. Initial attempts focussed
on reaction of an aryllithium species (derived from the aryl
ClogP 1.6
ClogP 0.9
ClogP –1.7
Figure 1 Generic indazole, 6-azaindazole and 1,4,6,7-tetrahydropyra-
zolo[3,4-c]pyridin-5-one scaffolds
Compounds based on core 3 should also have improved
aqueous solubility compared with analogous compounds
based on cores 1 and 2, as a result of their reduced planari-
ty.3 Compounds with fused pyrazole-lactam cores are
known to be biologically significant, and examples include
Apixaban (4), which is an inhibitor of blood coagulation fac-
tor Xa,4 and 5 (Figure 2), which was recently reported as
having antitumour activity.5 The synthesis of substituted
1,4,6,7-tetrahydropyrazolo[3,4-c]pyridin-5-one (3) was re-
quired for an AstraZeneca medicinal chemistry project and
this paper describes how it was achieved.
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229
N. J. Howe et al.
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O
OEt
Cl
Et
Et
O
O
NaOH, benzene
reflux
Et2MgBr
98%
N
O
N
O
O
Ph
Ph
NH
O
Ph
OEt
6
Et
NaOMe
MeOH
reflux
72%
N
N
N
Ph
F
O
Et
HCl⋅H2N
N
54%
H
F
O
OH
NaOMe, EtOH, reflux
+
N
Ph
Et
O
N
N
F
7
N
Ph
O
14%
Scheme 1 Synthetic route to 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-7-ones6
bromide through lithium–bromine exchange with n-BuLi)
with succinic anhydride to go straight to the desired γ-keto
acid.7
With the γ-keto esters 9 in hand, the corresponding
γ-keto acids 10 were formed by base hydrolysis and were
then coupled using propanephosphonic cycloanhydride
(T3P) with amino esters 11 to give amide products 12. Due
to its reduced nucleophilicity, methyl 2-(phenylamino)ace-
tate required two equivalents of acid and overnight stirring
for the reaction to proceed, but even then the yield of 12f
was moderate (63%; Table 1). Intermediates 12 were then
subjected to a Dieckmann condensation with LHMDS at re-
flux. The resulting vinylogous acid intermediates 13 were
then heated to reflux with hydrazine in ethanol to give 6,7-
dihydro-1H-pyrazolo[3,4-c]pyridin-5(4H)-ones 8. The com-
bined yields for these two final steps varied from 66% (8e)
to 21% (8f). The Dieckmann condensations generally gave
just one major product; however, the cyclisation with
methyl 2-(4-oxo-N,4-diphenylbutanamido)acetate gave an
equal amount of an unknown regioisomer, which could not
be separated from desired 13f. Upon reaction with hydra-
zine, 8f precipitated out of the reaction mixture. The hydra-
zine reactions were generally complete within 24 h; how-
ever, cyclisation of the intermediate hydrazones proceeded
more slowly when electron-withdrawing substituents were
present (Table 1, 8c and 8f). The final cyclisation was also
attempted with vinylogous acid 13a and methyl- and aryl-
hydrazines (Table 2). The reaction with methylhydrazine
gave an inseparable mixture of regioisomers, but it is as-
sumed that 14a is the major regioisomer by analogy to the
reactions of phenylhydrazine and 2-pyridylhydrazine,
This approach did not yield the desired product, so, after
attempting a palladium-catalysed approach,8 our attention
turned to the reaction of an organometallic species with an
acid chloride to form the desired ketone. Organolithium
species were deemed too reactive and incompatible with
the desired functionalities (e.g., ester, nitrile) so we investi-
gated the use of organocuprate species. These were pre-
pared by transmetallation of an organozinc or organomag-
nesium species using commercial copper cyanide–lithium
chloride complex.9
The cuprate derived from (3-ethoxy-3-oxopropyl)zinc
bromide reacted with benzoyl chloride or 4-methylbenzoyl
chloride to give the corresponding γ-keto esters in 71 and
77% yield, respectively (Scheme 2). Reaction of this same al-
kylcuprate with 3-cyanobenzoyl chloride, however, failed
to give any γ-keto ester. An alternative method was used in
this case; the aryl Grignard of 3-bromobenzonitrile was
formed, transmetallated with CuCN·2LiCl and subsequently
reacted with methyl 4-chloro-4-oxobutanoate to give the
desired γ-keto ester in 84% yield. This method is suited to
electron-deficient aryl bromides such as 3-bromobenzoni-
trile. However, more electron-rich aryl bromides (e.g., bro-
mobenzene or 4-bromotoluene) are less suited to this
method because they undergo bromine–magnesium ex-
change only very slowly.10
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 228–232

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N. J. Howe et al.
Letter
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O
EtO
ZnBr
O
O
O
EtO
HO
CuCN⋅2LiCl, –15 °C
NaOH
Cl
R
R
R
O
O
R = H (a)
R = Me (b)
9a (71%)
9b (77%)
10a (97%)
10b (97%)
1. i-PrMgCl⋅LiCl, 0 °C
2. CuCN⋅2LiCl, 0 °C
3.
O
O
O
Cl
MeO
CN
HO
CN
Br
CN
MeO
NaOH
94%
O
84%
O
O
9c
10c
Scheme 2 Synthesis of γ-keto acid intermediates 10
Table 1 Synthetic Route to 6,7-Dihydro-1H-pyrazolo[3,4-c]pyridin-5(4H)-ones 8
O
HO
R2
O
OMe
Br
O
R1
R2
N
O
O
10a–c
T3P, base, r.t.
H
NH2
O
O
N
R1
R1
OMe
OMe
(a) R1 = DMB
(b) R1 = Ph
11a (53%)
11b (63%)
12a–f
LHMDS, THF
reflux
R2
N2H4⋅H2O
O
O
O
EtOH, reflux
R2
N
N
N
H
R1
N
R1
OH
8a–f
13a–f
Entry
R1
R2
Isolated yield (%)
12
13
8
a
b
c
d
e
f
DMBa
Ph
88
83
82
98
85
63
74
54
70
57
79
50
71
82
58
88
83
43
DMBa
DMBa
DMBa
Prc
4-MeC6H4
3-NCC6H4
Meb
Ph
Ph
Ph
a DMB = 2,4-dimethoxybenzyl.
b Commercial levulinic acid was used.
c Commercial methyl 2-(propylamino)acetate was used.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 228–232

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Table 2 Reaction of Vinylogous Acid 13a with Substituted Hydrazines
H
MeO
O
N
MeO
O
NH2
MeO
O
R
N
R
N
OH
N
EtOH, heat
N
N
N
N
O
OMe
OMe
R
OMe
13a
14
15
Entry
R
Yield of 14 (%)
Yield of 15 (%)
a
b
c
Me
54a
60b
78b
14a
Ph
11c
2-pyridyl
negligible
a Regioisomers not separable; the ratio was determined based on 1H NMR spectroscopic analysis.
b Isolated and the structure was confirmed by ROESY NMR.
c Determined by LC–MS analysis.
where it was possible to isolate the major regioisomer and
this was confirmed in both cases as the 2-substituted pyra-
zole (Table 2, 14b and 14c). It is postulated that when the R2
group is phenyl, as in 13a, the vinylogous acid exists pre-
dominantly as the tautomer shown in Table 2, which may
explain the regioselectivity observed on reaction with sub-
stituted hydrazines.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379504.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
(1) For examples, see: (a) Howard, S.; Amin, N.; Benowitz, A. B.;
Chiarparin, E.; Cui, H.; Deng, X.; Heightman, T. D.; Holmes, D. J.;
Hopkins, A.; Huang, J.; Jin, Q.; Kreatsoulas, C.; Martin, A. C. L.;
Massey, F.; McCloskey, L.; Mortenson, P. N.; Pathuri, P.; Tisi, D.;
Williams, P. A. ACS Med. Chem. Lett. 2013, 4, 1208. (b) Disalvo,
D.; Kuzmich, D.; Mao, C.; Razavi, H.; Sarko, C.; Swinamer, A. D.;
Thomson, D.; Zhang, Q. PCT Int. Appl WO 2009134666 A1,
23.04.2009; Chem. Abstr. 2009, 151, 528758. (c) Cook, B. N.;
Disalvo, D.; Fandrick, D. R.; Harcken, C.; Kuzmich, D.; Lee, T.
W.-H.; Liu, P.; Lord, J.; Mao, C.; Neu, J.; Raudenbush, B. C.;
Razavi, H.; Reeves, T. J.; Song, J. J.; Swinamer, A. D.; Tan, Z. PCT
Int. Appl WO 2010036632 A1, 22.05.2009; Chem. Abstr.; 2010,
152, 429699.
To allow the potential for further derivatisation11 of the
1,4,6,7-tetrahydropyrazolo[3,4-c]pyridin-5-one core, it was
demonstrated that the DMB protecting group could be
removed by heating 8b with trifluoroacetic acid to give the
N-H lactam 16 in 58% yield (Scheme 3).
TFA, anisole
150 °C
O
MeO
O
N
N
HN
N
58%
(2) ClogP values were calculated by using clogPv4.3 (Biobyte), see:
Leo, A. J. Chem. Rev. 1993, 93, 1281.
N
N
H
H
OMe
(3) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.
(4) Pinto, D. J. P.; Orwat, M. J.; Koch, S.; Rossi, K. A.; Alexander, R. S.;
Smallwood, A.; Wong, P. C.; Rendina, A. R.; Luettgen, J. M.;
Knabb, R. M.; He, K.; Xin, B.; Wexler, R. R.; Lam, P. Y. S. J. Med.
Chem. 2007, 50, 5339.
8b
16
Scheme 3 Deprotection of 2,4-dimethoxybenzyl protecting group
We have developed an efficient route12–14 to a novel tet-
rahydropyrazolo[3,4-c]pyridin-5-one scaffold. This ap-
proach allows for alkyl or aryl substituents to be incorpo-
rated at the C-3 and N-6 positions. Further structural diver-
sity can be achieved by the use of suitable protection on
the lactam nitrogen, such as the DMB group. This allows the
N-1/N-2 and N-6 positions on this scaffold to be further
elaborated, once the core has been constructed.
(5) Zhuang, C.; Miao, Z.; Wu, Y.; Guo, Z.; Li, J.; Yao, J.; Xing, C.;
Sheng, C.; Zhang, W. J. Med. Chem. 2014, 57, 567.
(6) Duplantier, A. J.; Andresen, C. J.; Cheng, J. B.; Cohan, V. L.;
Decker, C.; DiCapua, F. M.; Kraus, K. G.; Johnson, K. L.; Turner, C.
R.; UmLand, J. P.; Watson, J. W.; Wester, R. T.; Williams, A. S.;
Williams, J. A. J. Med. Chem. 1998, 41, 2268.
(7) For examples, see: (a) Barbosa, J.; Carson, K. G.; Gardyan, M. W.;
Healy, J. P.; Han, Q.; Mabon, R.; Pabba, P.; Tarver, J.; Terranova, K.
M.; Tunoori, A.; Xu, X. U.S. Pat. Appl US 20120302562 A1,
23.05.2012; Chem. Abstr. 2012, 158, 37391. (b) Kono, Y.; Ochiai,
K.; Takita, S.; Kojima, A.; Eiraku, T.; Kishi, T. Jpn. Kokai Tokkyo
Koho JP 2009040711 A, 2009; Chem. Abstr. 2009, 150, 260203.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 228–232

232
N. J. Howe et al.
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O
Pd(PPh3)2Cl2, K3PO4⋅H2O
toluene, 100 °C, 1 h
O
Cl
OH
+
OMe
B
OMe
200 mg; 63%
O
OH
O
Scheme 4 γ-Keto ester formation by palladium catalysis8
(8) Wang, Y.; Przyuski, K.; Roemmele, R. C.; Hudkins, R. L.; Bakale,
R. P. Org. Process Res. Dev. 2013, 17, 846; Pd-catalysed coupling
gave the desired γ-keto ester in 63% yield (Scheme 4); however,
on 10-fold scale-up to 13 mmol, the yield dropped to 39%. We
were unable to obtain a robust, scalable procedure by using this
methodology.
(9) (a) For transmetallation of ArMg species with CuCN·2LiCl, see:
Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.
(b) For transmetallation of ArZn species with CuCN·2LiCl, see:
Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem. Int. Ed.
2004, 43, 1017.
(10) Shi, L.; Chu, Y.; Knochel, P.; Mayr, H. J. Org. Chem. 2009, 74,
2760; In this paper, they report that 50% Br–Mg exchange with
i-PrMgCl·LiCl at 0 °C occurs in 2.3 min for 3-bromobenzonitrile,
1.9 days for bromobenzene and 2.4 days for 4-bromotoluene.
(11) For conditions for lactam N-alkylation and N-arylation, see Ref.
6. For the conversion of silyl-protected lactams into N-alkyl
cyclic imines, see: Hua, D. H.; Miao, S. W.; Bharathi, S. N.;
Katsuhira, T.; Bravo, A. A. J. Org. Chem. 1990, 55, 3682.
ride cyanide (1 M in THF, 3.74 mL, 3.74 mmol) at 0 °C, with
stirring at this temperature for 10 min and then the mixture
was cooled to –50 °C under nitrogen and methyl 4-chloro-
4-oxobutanoate (0.418 mL, 3.30 mmol) in anhydrous THF (2
mL) was added. The reaction was stirred at –50 °C for 10 min
and then warmed to r.t. gradually overnight. The reaction
mixture was quenched by addition of sat. aq NH4Cl (30 mL) and
then extracted with EtOAc (3 × 20 mL). The combined organic
phases were washed with water (20 mL), brine (20 mL), dried
(MgSO4), filtered and concentrated under vacuum to afford a
brown oil (1.0 g). The crude product was purified by flash silica
chromatography (EtOAc–heptane, 0 to 100%). Pure fractions
were evaporated to dryness to afford methyl 4-(3-cyanophe-
nyl)-4-oxobutanoate (395 mg, 84%) as a white foamy solid. 1H
NMR (400 MHz, CDCl3): δ = 2.80 (t, J = 6.5 Hz, 2 H), 3.30 (t,
J = 6.5 Hz, 2 H), 3.71 (s, 3 H), 7.59–7.65 (m, 1 H), 7.85 (dt, J = 7.7,
1.4 Hz, 1 H), 8.20 (dt, J = 7.9, 1.4 Hz, 1 H), 8.24–8.28 (m, 1 H). 13
C
NMR (101 MHz, CDCl3): δ = 27.9, 33.5, 51.9, 113.4, 117.9, 129.7,
131.8, 132.0, 136.1, 137.4, 173.0, 196.1. HRMS: m/z calcd for
(12) Formation of γ-Keto Esters; Typical Procedure for Ethyl 4-
Oxo-4-phenylbutanoate(9a): A multi-necked round-bottomed
flask was dried with a hot-air gun under vacuum and then
purged with nitrogen and cooled. To this flask was added
(3-ethoxy-3-oxopropyl)zinc(II) bromide (0.5 M in THF, 7.50 mL,
3.75 mmol), which was cooled to –15 °C under nitrogen.
Benzoyl chloride (0.419 mL, 3.57 mmol) was added followed by
copper(I) dilithium dichloride cyanide (1 M in THF, 3.75 mL,
3.75 mmol). The reaction mixture was warmed to r.t. and
stirred at this temperature for 3 h. The reaction was quenched
by addition of sat. aq NH4Cl (80 mL) and filtered. The filtrate
was extracted with EtOAc (2 × 50 mL) and the combined organ-
ics were washed with brine (40 mL), dried (MgSO4), filtered,
and concentrated under vacuum to afford an orange oil (900
mg). The crude product was purified by flash silica chromatog-
raphy (EtOAc–heptane, 0 to 30%). Pure fractions were evapo-
rated to dryness to afford ethyl 4-oxo-4-phenylbutanoate (0.53
g, 71%) as a colourless liquid. 1H NMR (400 MHz, CDCl3): δ = 1.26
(t, J = 7.2 Hz, 3 H), 2.76 (t, J = 6.7 Hz, 2 H), 3.31 (t, J = 6.7 Hz,
2 H), 4.16 (q, J = 7.1 Hz, 2 H), 7.43–7.50 (m, 2 H), 7.53–7.60 (m,
1 H), 7.95–8.01 (m, 2 H). 13C NMR (101 MHz, CDCl3): δ = 14.2,
28.4, 33.4, 60.6, 128.1, 128.6, 133.2, 136.7, 172.9, 198.1. HRMS:
m/z calcd for C12H14O3: 206.0943; found: 206.0926.
C12H11NO3: 217.0739; found: 217.0753.
(13) Dieckmann Condensation and Subsequent Hydrazine Cycli-
sation; Typical Procedure for 3-Phenyl-6-propyl-6,7-di-
hydro-1H-pyrazolo[3,4-c]pyridin-5(4H)-one (8e): (i) Lithium
bis(trimethylsilyl)amide (1 M in THF, 1.46 mL, 1.46 mmol) was
added to a solution of methyl 2-(4-oxo-4-phenyl-N-propylbuta-
namido)acetate (386 mg, 1.32 mmol) in anhydrous THF (4 mL)
under nitrogen. The reaction mixture was heated at reflux for
30 min. After cooling to r.t., the reaction was diluted with 1 M
citric acid (20 mL) and CH2Cl2 (50 mL). The organics were
washed with brine (50 mL), dried (MgSO4), filtered, and the
crude product was purified by flash silica chromatography
(MeOH–CH2Cl2, 0 to 8%). Pure fractions were evaporated to
dryness to afford 4-benzoyl-5-hydroxy-1-propyl-1,6-dihydro-
pyridin-2(3H)-one (13e; 272 mg, 79%) as a pale-yellow oil,
which solidified on standing. (ii) Hydrazine hydrate (0.097 mL,
2.01 mmol) was added to a solution of 4-benzoyl-5-hydroxy-1-
propyl-1,6-dihydropyridin-2(3H)-one (260 mg, 1.00 mmol) in
ethanol (5 mL). The reaction was heated to reflux for 24 h. After
cooling to r.t., the solvent was removed under vacuum to afford
a pale-brown solid, which was triturated with EtOAc–Et2O (1:1),
filtered, and dried to afford 3-phenyl-6-propyl-6,7-dihydro-1H-
pyrazolo[3,4-c]pyridin-5(4H)-one (213 mg, 83%) as a beige
powder. 1H NMR (400 MHz, DMSO-d6): δ = 0.88 (t, J = 7.4 Hz,
3 H), 1.53–1.67 (m, 2 H), 3.37–3.47 (m, 2 H), 3.62 (t, J = 1.9 Hz,
2 H), 4.54 (s, 2 H), 7.25–7.78 (m, 5 H), 13.17 (s, 1 H). 13C NMR
(176 MHz, DMSO-d6 + CD3CO2D): δ = 11.0, 19.5, 29.8, 45.0, 48.5,
107.9, 125.7, 127.5, 128.8, 130.6, 139.2, 140.5, 166.5. HRMS:
m/z [M + H]+ calcd for C15H18N3O: 256.1450; found: 256.1460.
(14) For full experimental procedures and analytical data, please
refer to the Supporting Information.
Methyl 4-(3-Cyanophenyl)-4-oxobutanoate(9c): To dried
glassware was added 3-bromobenzonitrile (400 mg, 2.20 mmol)
in anhydrous THF (5 mL) under nitrogen. This was cooled to –10 °C
and isopropylmagnesium lithium chloride (1.3 M in THF, 2.54
mL, 3.30 mmol) was added over 10 min. The mixture was
stirred at 0 °C for 3 h, monitoring for completion of magnesiat-
ion by LC-MS of NH4Cl solution-quenched aliquots. Transmetal-
lation was carried out by addition of copper(I) dilithium dichlo-
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