An improved synthesis of YC-1

Article abstract of DOI:10.1055/s-1998-1882

A concise synthesis of YC-1 has been achieved in ten-fold enhanced yield over the previously reported method. This new, flexible strategy should readily allow the automated parallel synthesis of analogues.

Full text of DOI:10.1055/s-1998-1882

October 1998
SYNLETT
1065
An Improved Synthesis of YC-1
David W. Gordon
Discovery Chemistry Department, Pfizer Central Research, Sandwich, Kent, CT13 9NJ, UK
Received 24 July 1998
12
Abstract: A concise synthesis of YC-1 has been achieved in ten-fold
enhanced yield over the previously reported method. This new, flexible
strategy should readily allow the automated parallel synthesis of
reduction with
a
commercially available
solution of lithium
borohydride in THF at ambient temperature furnished YC-1 whose mp,
H-NMR and mass spectrum were all consistent with those reported in
1
#
6
analogues.
the patent.
Indazole derivatives have been shown to possess a wide range of
1
2
pharmacological effects including hypocholesterolemic, analgesic and
3
anti-inflammatory activity. Moreover, the indazole moiety is present in
the marketed anti-inflammatory drugs Bendazac and Benydamine.
More recently, 1-benzyl-3-(5 -hydroxymethyl-2-furyl)indazole (YC-1),
4
/
an NO-independent, superoxide-sensitive activator of soluble guanylate
5
cyclase has been the subject of much pharmacological interest since a
6
recent patent described its role in inhibition of blood platelet
aggregation. Where synthesised (rather than being bought or gifted),
YC-1 has been prepared by the route reported in this patent, as outlined
in scheme 1.
Scheme 2
We have since discovered that conversion of bromofuran 7 to its
13
trimethylstannane 8 and isolation of the latter prior to Stille coupling,
as shown in scheme 3, increases the conversion of 4 to 3 to 52%, thereby
improving the overall yield of YC-1 to 37%, though no further
optimisation studies have been performed with respect to choice of
catalyst, nature of solvent or effect of temperature and length of heating.
Scheme 3
In summary, we have realised a concise synthesis of YC-1 accompanied
by an order of magnitude improvement in the overall yield compared
with the previous method of choice. In addition, our flexible strategy
should be more amenable to the high-speed parallel synthesis of 1,3-
disubstituted indazoles, either in solution or by tethering the parent
indazolinone to a solid support via the benzo-fused ring. Results will be
reported in due course.
Scheme 1
The 4-step sequence starts with a heterogenous Friedel-Crafts reaction
involving prolonged heating in carcinogenic carbon tetrachloride. The
ensuing ketone 1 is converted to its benzyl hydrazone 2 and the crude
mixture of isomers oxidatively cyclised to indazole 3 following a
protocol attributed to Yoshina, Tanaka & Kuo. Finally, reduction of the
ester function with a dispersion of commercially inaccessible calcium
Acknowledgement: I thank Dr Tony Wood of Pfizer Central Research
for the opportunity to pursue this research and for his encouragement
and helpful discussion.
7
borohydride in refluxing THF gives YC-1 in less than 4% overall yield.
We chose, as an alternative, a cross-coupling strategy that attaches the
furyl moiety directly to the indazole nucleus - see scheme 2.
References and Notes:
Commercial 3-indazolinone
4
has previously been benzylated
# During the course of the preparation of this manuscript, a series of
8
14
selectively at N in near-quantitative yield. We successfully repeated
German patents was published
demonstrating cross-coupling
1
this reaction, then converted the benzylindazolinone product 5 to its
methodology for the synthesis of 3-heteroarylindazoles. However, the
use of indazole triflates, though alluded to, was not exemplified, whilst
experimental details of the synthesis and yield of YC-1 were not given.
9
triflate 6 under standard conditions in excellent yield. 6 underwent
10
11
Stille coupling with 7 , mediated by hexamethylditin. Ultimately,

1066
1.
LETTERS
SYNLETT
Oiji, Y.; Naito, N.; Yada, S., Japanese Patent 48054063, 1973;
9.
Procedure for triflate : Triflic anhydride (8.4 mmoles) was added
6
to a stirred suspension of
(6.8 mmoles) and pyridine (16.9
5
Chem. Abstr., 1974, 80, 47989.
mmoles) in dry dichloromethane (12ml) under nitrogen with ice-
bath cooling. The reaction mixture was warmed to ambient
temperature overnight then filtered through a short column of
2.
3.
4.
5.
Kuroda, T.; Goto, H.; Ishikawa, T., Japanese Patent 50130759,
1975; Chem. Abstr., 1976, 85, 46631.
Banno, K.; Kuwahata, T.; Ikeda, T.; Nakagawa, K.; Dohi, T.,
silica gel. Triflate
immediately in the subsequent cross-coupling reaction. H NMR
was isolated as an oil (95%) and used
6
1
Japanese Patent 48048467, 1973; Chem. Abstr., 1973, 79, 92214.
th
(300MHz, CDCl ) δ 5.55 (2H, s), 7.30 (8H, m), 7.72 (1H, d).
The Merck Index 11 ed., Budavari, S., Ed.; Merck & Co., Inc.:
3
Rahway, NJ, monographs 1042 and 1136 respectively.
10. Purchased from Sigma-Aldrich Library of Rare Chemicals.
11. Standard procedure for cross-coupling: Pd(PPh ) (0.8 mmoles)
Recent citations include: Friebe, A.; Koesling, D., Molecular
Pharmacology, 1998, 53, 123. Wegener, J.; Gath, I.; Forstermann,
U.; Nawrath, H., Br. J. Pharmacol., 1997, 122, 1523. Wegener, J.;
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Chem. Abstr., 1996, 125, 33633. Yu, S.; Cheng, Z.; Guh, J.; Lee,
F-Y.; Kuo, S-C., Biochem. J. 1997, 322, 951.
3 4
was added to a stirred suspension of 6 (8.1 mmoles), 7 (8.1
mmoles), (Me Sn) (8.1 mmoles) and LiCl (25 mmoles) in dioxan
3
2
(50ml) and the reaction mixture stirred at reflux under nitrogen
overnight. On cooling, an equal volume of saturated aqueous KF
solution was added and the mixture vigorously stirred at rt for 1
hour. Upon filtration through celite, the filtrate was diluted
(EtOAc), washed (brine), dried (MgSO ), concentrated and
4
chromatographed (0% - 20% EtOAc in hexane) to give ester 3
(37%), whose physical and spectroscopic data matched those in
6
the patent.
12. Purchased from Sigma-Aldrich Co. Ltd.
13. Procedure for stannane : following the procedure for cross-
8
6.
7.
8.
Kuo, S-C.; Lee, F-Y.; Teng, C-M., European Patent EP667345,
coupling, above, but with the omission of LiCl, was isolated as
8
1995; Chem. Abstr., 1995, 123, 340113.
1
an oil: H NMR (300MHz, CDCl ) δ 0.54 (9H, m), 3.85 (3H, s),
6.64 (1H, d), 7.18 (1H, d); MS (thermospray) m/z 307 (MNH ),
m/z 289 (MH ), each with expected Sn isotope pattern.
3
+
Yoshina, S.; Tanaka, A.; Kuo, S-C., Yakugaku Zasshi, 1978, 98,
204; Chem. Abstr., 1978, 89, 43221.
4
+
Soga, T.; Niwa, H.; Okada, K.; Umezawa, S.; Japanese Patent
14. DE 19649460, 1998; DE 19642323, 1998; DE 19642322, 1998;
DE 19642320, 1998; DE 19642319, 1998.
JP49007278, 1974; Chem. Abstr., 1974, 80, 108517.