An improved synthesis of a novel α1A partial agonist including a new two-step synthesis of 4-fluoropyrazole

Article abstract of DOI:10.1016/j.tetlet.2010.03.080

This Letter outlines a new two-step process for the synthesis of 4-fluoropyrazole and its application in an improved synthesis of 4-fluoro-1-[5-fluoro-1-(1H-imidazol-2-yl)-indan-4-ylmethyl]-1H-pyrazole. The original synthesis of 4-fluoro-1-[5-fluoro-1-(1H-imidazol-2-yl)-indan-4-ylmethyl]-1H-pyrazole is also described.

Full text of DOI:10.1016/j.tetlet.2010.03.080

Tetrahedron Letters 51 (2010) 2849–2851
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An improved synthesis of a novel a1A partial agonist including a new
two-step synthesis of 4-fluoropyrazole
*
Katherine England , Helen Mason, Rachel Osborne, Lee Roberts
Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter outlines a new two-step process for the synthesis of 4-fluoropyrazole and its application in an
improved synthesis of 4-fluoro-1-[5-fluoro-1-(1H-imidazol-2-yl)-indan-4-ylmethyl]-1H-pyrazole. The
original synthesis of 4-fluoro-1-[5-fluoro-1-(1H-imidazol-2-yl)-indan-4-ylmethyl]-1H-pyrazole is also
described.
Received 22 December 2009
Revised 9 March 2010
Accepted 19 March 2010
Available online 25 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Compound 1 as a single enantiomer has been identified as a
potent, partial agonist of the a1A adrenergic receptor (Ki 5 nM,
EC50 9 nM, Emax 60%).1
chlorination and displacement with NaCN gave nitrile 6. Hydroly-
sis of the methyl ester to the carboxylic acid, activation with CDI
and reduction with NaBH4 gave the benzyl alcohol which was con-
verted into intermediate 8 through chlorination and displacement
with 4-fluoropyrazole. Treatment of the nitrile with a saturated
solution of ethanolic HCl followed by reaction with aminoacetalde-
hyde dimethyl acetal and ring closure under acidic conditions fur-
nished the target molecule. The active enantiomer was
subsequently separated by chiral HPLC.
A more direct route was required to deliver 1 on gram scale for
follow-up studies. Although benzoic acid 2 was protected as the
methyl ester in the first step of the original route, the methyl ester
was incompatible with intramolecular Friedel–Crafts step (f) and
therefore had to be hydrolysed to the acid in step (e) and subse-
quently re-introduced. It was envisaged that 1 could be synthes-
ised more efficiently by installing the 4-fluoropyrazole moiety
early in the synthesis, thus avoiding several functional group inter-
conversions and reducing the overall number of steps.
Retrosynthetically, we anticipated that the imidazole ring could
be introduced via Negishi coupling of vinyl triflate 17, which would
be derived from indanone 16 (Scheme 2). We expected that synthe-
sis of the indanone ring could be achieved either by Rh-catalysed
cyclocarbonylation2 of trimethylsilyl acetylene intermediate 15, or
by intramolecular Friedel–Crafts cyclisation of the corresponding
propionic acid 14. In a closely related analogue, where the 4-fluoro-
pyrazole ring had been replaced with a methoxy group, we had suc-
cessfully formed the indanone ring through Rh-catalysed
cyclocarbonylation of a trimethylsilyl acetylene intermediate,1
however, the Friedel–Crafts approach had proved unsuccessful due
to displacement of the methoxy group by chloride.
The key obstacle to this new synthetic strategy was the synthesis
of 4-fluoropyrazole in sufficient quantity to enable its introduction
at the beginning of the route. Although several routes to 4-fluoropy-
razole have been reported in the literature, most suffer from limita-
tions that would preclude their use on large scale (lengthy syntheses
HN
N
*
F
N
F
N
1
We required compound 1 as a single enantiomer on gram scale
to assess its potential use as a treatment for stress urinary
incontinence.
In this communication, the original synthesis of 1 and subse-
quent improvements to the route which enabled the synthesis of
1 to be performed on gram scale are described. The original route
to 1 (Scheme 1) was designed to allow the exploration of the struc-
ture activity relationship (SAR) of the series. Intermediate 6 con-
tains two synthetic handles (the methyl ester and cyano groups)
which were utilised for late-stage functionalisation when explor-
ing the SAR.
Compound 1 was initially synthesised on milligram scale in 17
steps.1 Commercially available benzoic acid 2 was protected as the
methyl ester with MeI and subsequently converted into cinnamic
ester 3 via Heck coupling. Hydrogenation of the double bond, acidic
cleavage of the tert-butyl ester and basic hydrolysis of the methyl
ester gave diacid 4. Intramolecular Friedel–Crafts cyclisation was
achieved via conversion into the diacyl chloride in the presence
of AlCl3. The resulting indanonyl acyl chloride was treated with
MeOH to give 5. Reduction of the ketone with NaBH4 followed by
* Corresponding author. Tel.: +44 1304 640 957.
E-mail address: katherine.england@pfizer.com (K. England).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.080

2850
K. England et al. / Tetrahedron Letters 51 (2010) 2849–2851
O
a, b
c, d, e
f, g
F
F
I
CO2H
2
F
CO2tBu
F
CO2H
CO2Me
5
CO2Me
3
CO2H
4
HN
N
CN
CN
CN
h, i, j
k, l, m
n
o, p, q, r
*
F
F
F
F
CO2Me
N
N
Cl
N
F
F
N
6
7
8
1
Scheme 1. Original route to 1. Reagents and conditions: (a) MeI, DBU, acetone, 99%; (b) tert-butyl acrylate, Pd(OAc)2, P(o-tol)3, Et3N, MeCN, 45 °C, 98%; (c) 50 psi H2, Pd/C,
EtOH, 89%; (d) TFA, CH2Cl2, quant.; (e) LiOH, H2O, THF, quant.; (f) (COCl)2, AlCl3, cat. DMF, CH2Cl2, 15 °C to rt; (g) MeOH, 15 °C to rt, 83% over two steps; (h) NaBH4, MeOH,
quant.; (i) SOCl2, CH2Cl2, quant.; (j) NaCN, DMSO, 63%; (k) LiOH, H2O, THF, quant.; (l) CDI, THF, NaBH4, quant.; (m) SOCl2, CH2Cl2, 0 °C to rt, quant.; (n) 4-fluoropyrazole, NaH,
THF, 5–80 °C, 58%; (o) HCl, EtOH, 5 °C, quant.; (p) aminoacetaldehyde dimethyl acetal, MeOH, quant.; (q) HCl, H2O, reflux, 80%; (r) chiral HPLC, 81%.
requiring cryogenic conditions or ozone-depleting dichlorofluorom-
ethane).3–5 The shortest route that does not employ cryogenic
conditions is a four-step synthesis from sodium fluoroacetate which
provides 4-fluoropyrazole in 19% overall yield (Scheme 3).6
good yield. Our modified procedure used P(o-tol)3 as a cheaper
alternative to the Tedicyp ligand, and replaced DMF with acetoni-
trile to facilitate subsequent solvent removal.
Intermediates 14 and 15 were used to investigate two routes to
the indanone in parallel. The first (Rh-catalysed cyclocarbonylation
of the trimethylsilyl acetylene 15)1,2 was unsuccessful, however,
We envisaged that condensation of fluoroaminoacrolein inter-
mediate 10 with hydrazine would deliver 4-fluoropyrazole directly
and would provide a shorter alternative to converting 10 into the
fluoromalonaldehyde. Pleasingly, the reaction proceeded cleanly
and rapidly under acidic conditions, furnishing 4-fluoropyrazole
in only two steps and in identical overall yield (Scheme 4).7
With this novel, short, scalable route to 4-fluoropyrazole in
hand, we then decided to explore the synthesis of the indanone
derivative 16 (Scheme 5). Benzylic bromination of 2-fluoro-6-iodo-
toluene 12 followed by displacement with 4-fluoropyrazole affor-
ded intermediate 13. This was subsequently converted into
trimethylsilyl acetylene 15 by Sonogashira coupling and to propi-
onic acid 14 by a modified one-pot procedure reported by Doucet
and Santelli.8 Heck coupling of intermediate 13 with acrolein eth-
ylene acetal followed by hydrolysis gave the propionic acid 14 in
H
O
F
H
O
F
H
O
O
F
H
N
O
F
N
H
ONa
F
ONa
NMe2
Scheme 3. A reported four-step synthesis of 4-fluoropyrazole.
H
N
O
F
H
a
b
O
N
F
ONa
F
NMe2
9
10
11
Scheme 4. Improved 4-fluoropyrazole synthesis. Reagents and conditions: (a) (i)
(COCl)2, DMF; (ii) Et3N; (iii) K2CO3 (aq), 0–80 °C, 24%; (b) H2NNH2Á2HCl, EtOH, 55 °C,
HN
N
77%.
*
F
N
F
F
F
1
F
N
TMS
N
F
N
OTf
O
15
c
O
a,b
F
F
N
N
F
I
F
I
F
17
N
N
N
N
12
F
F
13
16
d
f
N
N
e
16
O
CO2H
F
F
O
N
N
N
F
F
N
14
F
CO2H
F
Scheme 5. Approaches to indanone intermediate 16. Reagents and conditions: (a)
NBS, benzoyl peroxide, CCl4, reflux, 75%; (b) 4-fluoropyrazole, NaH, THF, reflux, 95%;
(c) trimethylsilyl acetylene, Pd(PPh3)4, Et3N, CuI, DMF, 78%; (d) acrolein ethylene
acetal, Pd(OAc)2, P(o-tol)3, Et3N, MeCN, 120 °C; (e) NaOH (aq), 80 °C, 79%; (f) (i)
(COCl)2, CH2Cl2, cat. DMF, 0 °C to rt; (ii) AlCl3, 84%.
TMS
N
N
N
N
F
F
15
14
Scheme 2. Retrosynthetic strategy to a key vinyl triflate intermediate.

K. England et al. / Tetrahedron Letters 51 (2010) 2849–2851
2851
Me2NO2SN
HN
N
N
O
OTf
*
a
c
d,e,f
F
F
F
F
N
N
N
N
N
N
N
N
F
F
F
F
16
17
20
1
ZnCl
N NSO2NMe2
b
N
NSO2NMe2
18
19
Scheme 6. Introduction of the imidazolyl moiety. Reagents and conditions: (a) Tf2O, DTBMP, CH2Cl2, 93%; (b) (i) n-BuLi, THF; (ii) ZnCl2; (c) Pd(PPh3)4, THF, 50 °C, 61% over two
steps; (d) HCl (aq), EtOH, reflux, 79%; (e) 50 psi H2, Pd/C, EtOH, 81%; (f) chiral HPLC, 81%.
7. Representative procedure to 10: A suspension of 5.00 g of sodium fluoroacetate
the second (intramolecular Friedel–Crafts cyclisation of the propi-
onic acid 14) proceeded in good yield to afford indanone 16.
(0.05 mol, 1 equiv) (Caution: very toxic) in DMF (35 mL) was cooled to 0 °C and
9.62 mL of oxalyl chloride (0.11 mol, 2.2 equiv) was added dropwise over
As expected, the indanone was readily converted into the imid-
azole 1. Facile conversion of indanone 16 into vinyl triflate 17 fol-
lowed by formation of the imidazolylzinc intermediate 19 and
Negishi coupling, cleavage of the sulfonyl urea unit and hydroge-
nation of the olefin gave 1 as a racemic mixture. The enantiomers
were resolved using chiral HPLC to deliver 1 on gram scale as a sin-
gle enantiomer for further characterisation (Scheme 6).
Experience with a closely related analogue indicates that asym-
metric hydrogenation of the olefin could deliver compound 1 in
enantioenriched form.9 By analogy with the absolute stereochem-
istry of the active enantiomer of this analogue, we anticipate that
the active enantiomer of 1 also has R stereochemistry.
40 min. The reaction mixture was stirred at room temperature for 30 min,
heated to 60 °C for a further 30 min, then cooled to 0 °C. Et3N (13.9 mL, 0.10 mol,
2 equiv) was added dropwise over 20 min. The reaction mixture was stirred at
0 °C for 30 min then at 50 °C for 30 min. The reaction mixture was cooled to 0 °C
and 10 mL of ice water was added followed by 65 mL of saturated K2CO3
solution, portion wise. The reaction mixture was heated at 80 °C for 30 min, then
cooled to room temperature, diluted with a minimum volume of H2O to dissolve
the precipitate, 350 mL of brine was added and the aqueous extracted with
CH2Cl2 (3 Â 300 mL). The combined organics were dried over Na2SO4 and
concentrated in vacuo to give a brown oil that was purified by flash column
chromatography (neat EtOAc) to give 1.4 g (24%) of 10 as a brown oil.
Representative procedure to 11: 448 mg of hydrazine dihydrochloride (4.3 mmol,
1 equiv) was added to a solution of 500 mg of 10 (4.3 mmol, 1 equiv) in 1 mL of a
40% v/v solution of EtOH in H2O and the resulting solution heated at 55 °C for
20 min. The reaction mixture was cooled to room temperature, basified to pH 9
with a saturated solution of NaHCO3 and extracted with Et2O (3 Â 30 mL). The
organics were combined, dried over MgSO4 and most of the solvent removed by
distillation to give 366 mg of 11 as a yellow oil (77% product by mass).
8. Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron 2004, 60, 11533–11540.
9. Asymmetric hydrogenation of a closely related analogue (150 psi H2, RuCl2[(S)-
BINAP], MeOH, 80 °C) resulted in an ee of 47%.
In conclusion, we have developed a new, elegant two-step syn-
thesis of 4-fluoropyrazole that enabled its early introduction in the
synthesis of 1, reducing the number of linear steps from 17 to 8
and delivering 1 on gram scale as a single enantiomer.
References and notes
HN
HN
N
N
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1530.
4. (a) Hanamoto, T.; Iwamoto, Y.; Yamada, K.; Anno, R. J. Fluorine Chem. 2007, 128,
1126–1130; (b) Hanamoto, T.; Koga, Y.; Kido, E.; Kawanami, T.; Furuno, H.;
Inanaga, J. Chem. Commun. 2005, 2041–2043.
Cl
Cl
MeO
MeO
5. Molines, H.; Wakselman, C. J. Org. Chem. 1989, 54, 5618–5620.
6. (a) Reichardt, C.; Halbritter, K. Justus Liebigs Ann. Chem. 1975, 470–483; (b)
Reichardt, C.; Halbritter, K. Justus Liebigs Ann. Chem. 1970, 99–107.