An efficient synthesis of 2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-5-((2,2-methylpro pyl)carbamoyl)benzoic acid: A factor VIIa inhibitor discovered by the Ono Pharmaceutical Company

Article abstract of DOI:10.1016/S0040-4039(00)01016-9

A small molecule factor VIIa inhibitor has recently been reported by the Ono Pharmaceutical Company. Herein, we outline an efficient and convergent, synthetic route that relies upon a palladium-catalyzed Stille coupling reaction as a key step for the synt

Full text of DOI:10.1016/S0040-4039(00)01016-9

Tetrahedron Letters 41 (2000) 6041±6044
An ecient synthesis of
2-(3-(4-amidinophenylcarbamoyl)naphthalen-2-yl)-
5-((2,2-methylpropyl)carbamoyl)benzoic acid:
a factor VIIa inhibitor discovered by the
Ono Pharmaceutical Company
Je€rey T. Kohrt,* Kevin J. Filipski, Stephen T. Rapundalo, Wayne L. Cody and
Jeremy J. Edmunds
Departments of Chemistry and Biochemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co.,
Ann Arbor, MI 48105, USA
Received 9 May 2000; revised 5 June 2000; accepted 6 June 2000
Abstract
A small molecule factor VIIa inhibitor has recently been reported by the Ono Pharmaceutical Company.
Herein, we outline an ecient and convergent, synthetic route that relies upon a palladium-catalyzed Stille
coupling reaction as a key step for the synthesis of the inhibitor. # 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: Factor VIIa; anticoagulant; palladium catalyzed cross-coupling; Stillie coupling.
It is the abnormal coagulation and inappropriate thrombus formation within blood vessels that
precipitates many acute cardiovascular diseases. As a result, there has been an intense e€ort to
discover small molecule anticoagulants that work to speci®cally inhibit serine proteases in the
blood coagulation cascade. The direct inhibition of thrombin has been intensively investigated
leading to the development of potent and selective inhibitors, but clinical trials have met with
disappointing results.1,2 The speci®c inhibition of factor Xa, which is a key enzyme in the
production of thrombin and subsequent formation of a blood clot, has also received increased
attention owing to its central position in linking the extrinsic and intrinsic coagulation
pathways.1,2
Recently, the extrinsic clotting system has been recognized as the major pathway for activation
of coagulation.3 Formation of a blood clot via the extrinsic pathway results from vascular injury
* Corresponding author. E-mail: je€rey.kohrt@wl.com
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01016-9

6042
and exposure of cell surface tissue factor (TF) to circulating factor VII (FVII) forming an FVII/
TF complex. This complex activates FVII to factor VIIa (FVIIa) which, when combined with
tissue factor in the presence of Ca2+ and phospholipids, ultimately converts factor X into factor
Xa.3
Due to the importance of FVIIa in the hemostasis/thombosis balance, its inhibition is believed
to be useful as a treatment for disease states associated with the extrinsic system such as acute
myocardial infarction, stroke, disseminated intravascular coagulation (DIC) and thrombolytic
disease.3a Also, the speci®c inhibition of FVIIa, while interrupting thrombus formation, should
not e€ect the function of normal hemostasis.4 Thus, speci®c inhibitors of FVIIa may reduce the
risk of hemorrhagic complications observed with current heparin and warfarin therapies. Despite
its signi®cant role in coagulation, few small molecule FVIIa inhibitors have been reported.5
Recently, the Ono Pharmaceutical Company reported that 2-(3-(4-amidinophenylcarbamoyl)-
naphthalen-2-yl)-5-((2,2-methylpropyl)carbamoyl)benzoic acid±methane sulfonate 1 was a potent
inhibitor of FVIIa with an IC50 of 12 nM.5b As part of our program to develop small molecule
anticoagulants, inhibitor 1 was prepared to evaluate the potential of a FVIIa inhibitor as a
pharmaceutical agent. Unfortunately it was not evident from the Ono patent application5b as to
how certain key intermediates were prepared or, in fact, the actual synthetic strategy that was
utilized for construction of the inhibitor. Therefore, it was necessary to develop an independent
synthesis of 1. In this communication, we report the implementation of an ecient, scalable and
convergent synthetic strategy for the preparation of 1 that relies on a palladium-catalyzed Stille
coupling reaction of the naphthyliodide 2 with organostannane 3 (Fig. 1).6
Figure 1.
Chemistry: The synthesis of 1 started with the esteri®cation of commercially available 5-
formylsalicylic acid 4 under literature conditions to form the corresponding methyl ester,7 which
was then converted to tri¯ate 5 with tri¯ic anhydride under standard conditions.8 Oxidation of
the aldehyde to the carboxylic acid with a bu€ered solution of sodium hypochlorite followed by a
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexa¯uorophosphate (BOP) mediated
amide coupling with isobutylamine provided the amide 6 in a 95% yield over two-steps.9 Tri¯ate
6 was converted to trimethylstannane 3 in excellent yield via palladium-catalyzed coupling with
hexamethylditin (Scheme 1).10
Formation of the naphthyliodide 2 started with 3-amino-2-napthanoic acid which was sub-
jected to Sandmeyer conditions to form the iodo-acid 9.11 The coupling of 9 and 4-aminobenzo-
nitrile required vigorous dehydrating conditions12a in which catalytic 4-dimethylaminopyridine
(DMAP) was found necessary for formation of amide 2 (Scheme 2). Standard carbodiimide, BOP

6043
Scheme 1. Conditions: (i) H2SO4, MeOH, re¯ux, 24 h, 78%; (ii) Tf2O, 2,6-lutidine, CH2Cl2, ^78ꢀC±rt, 5 h, 65%; (iii)
NaClO2, H2O2, NaH2PO4, H2O, MeCN, 0ꢀC±rt, 18 h; (iv) isobutylamine, diisopropylethylamine, BOP, DMF, rt, 4 h,
95% (two-steps); (v) hexamethylditin, LiCl, PdCl2(PPh3)2, THF, re¯ux, 14 h, 75%
and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa¯uorophosphate/1-hydroxy-7-
azabenzotriazole (HATU/HOAT)12b mediated amide coupling reactions failed to yield any of the
desired product.
Scheme 2. Conditions: (i) H2SO4, H2O, NaNO2, 100±110ꢀC; (ii) Kl, H2SO4, H2O, 100ꢀC±rt, 75% (two-steps); (iii) 4-
aminobenzonitrile, PCl3, DMAP, xylenes, 150ꢀC, 1.5 h, 71%
Using a palladium-catalyzed Stille coupling procedure which relied upon the use of both
catalytic copper(I) iodide and triphenylarsine, stannane 3 and iodo-amide 2 were coupled to form
10 in 55% yield.6 Failure to use both copper(I) iodide and triphenylarsine resulted only in trace
yields of the coupled product. Completion of the synthesis required conversion of the nitrile into
Scheme 3. Conditions: (ii) 2, Pd2(dba)3, Ph3As, Cul, DMF, 60ꢀC, 6 h, 55%; (iii) NH2OH±HCl, MeOH, 12 h, rt; (iv)
TFA, TFAA, 4 h, 100% (two-steps); (v) RaNi, H2, Et3N, MeOH, 14 h; (vi) LiOH, MeOH, THF, H2O (1:1:1), rt, 4 h,
62% (two-steps)

6044
an amidine which was accomplished via a high yielding, two-step procedure for the formation of
tri¯uoromethyloxadiazole 11 followed by a Raney nickel-catalyzed hydrogenation.13 The ®nal
hydrolysis of the methyl ester with lithium hydroxide and puri®cation of the resulting amidino-
carboxylic acid by reversed-phase preparative HPLC revealed the inhibitor 1, as a tri¯uoroacetate
salt, in a combined 62% yield over the ®nal two steps (Scheme 3).
Scheme 3 allows for facile preparation of the factor VIIa inhibitor 1 in quantities sucient for
further pharmacological evaluation. The above structure was fully characterized by high-resolution
proton NMR, mass spectrometry, and CHN combustion analysis as the tri¯uoroacetate salt.14
When synthetic 1 was tested in our in-vitro assay for FVIIa/TF inhibition, an IC50 of 9 nM with a
Ki of 6.4 nM was determined, which compared favorably with the published values.5b
References
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(c) Jakobsen, P.; Worsaae, H. WO 9948878, 1999, Chem. Abstr. 1999, 131, 243274.
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D. C.; Murray, C. K. J. Org. Chem. 1986, 51, 277.
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Caprino, J. Am. Chem. Soc. 1993, 115, 4397.
13. Menzler, S.; Bikker, J. A.; Horwell, D. C. Tetrahedron Lett., 1998, 39, 7619.
14. 2-(3-(4-Amidinophenylcarbamoyl)naphthalen-2-yl)-5-((2,2-methylpropyl)carbamoyl)benzoic acid±tri¯uoromethane
acetate 1: HPLC (% A: 0.1% TFA:H2O; B: 0.1% TFA:CH3CN; gradient: 20±86% B over 22 min; Vydac
218TP54) Rt=12.5 min; 1H NMR (400 MHz, CDCl3) ꢀ: 9.11 (broad s, 2H) 8.86 (broad s, 2H), 8.65 (1H, t,
J=5.8 Hz), 8.31 (1H, s), 8.26 (1H, s), 8.08±7.96 (3H, m), 7.78±7.70 (5H, m), 7.64±7.60 (2H, m), 7.39 (1H, d, J=8.0
Hz), 3.06 (2H, broad t, J=6.4 Hz), 1.84 (1H, m), 0.86 (6H, d, J=6.6 Hz); MS (APCI) m/e=509 (M+1)+, 492
(M^OH)+, 448 (M^H2O,CO, NH3)+; anal. calcd for C30H28N4O4±1.10 (C2F3O2)±0.7 (H2O): % C=59.81, %
H=4.75, % N=8.66, % F=9.70, % H2O=1.95. Found: % C=59.61, % H=4.78, % N=8.59, % F=9.67, %
H2O=1.94.