Organic Process Research & Development 1999, 3, 389−393
Articles Process Development of a Novel Non-Xanthine Adenosine A1 Receptor Antagonist Atsuhiko Zanka,* Ryoichi Uematsu, Yasuhiro Morinaga, Hironobu Yasuda, and Hiroshi Yamazaki Technological DeVelopment Laboratories, Fujisawa Pharmaceutical Co. Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka, 532-8514, Japan
Abstract: (+)-(R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-piperidine ethanol (FK453) is a novel, potent adenosine A1 receptor antagonist for the regulation of renal function. The development of a reliable process suitable for large scale manufacture is described. A Horner-Emmons reaction and a 1,3-dipolar cycloaddition were successfully scaled up to afford ethyl (E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloylate, with excellent regioselectivity and stereoselectivity. Process improvements and optimization of each step permitted elimination of column chromatography, resulting in a straightforward, practical synthesis of FK453.
Introduction In recent years adenosine A1 receptor antagonists have attracted much attention due to their potential therapeutic usefulness for the regulation of renal function.1 The discovery of Bay n 1468, 32 whose potent effects were attributed to selective adenosine A1 receptor antagonistic properties, prompted efforts to find novel and selective adenosine receptor antagonists. In our previous papers, we described a pilot scale synthesis of the adenosine A1 receptor antagonist, FK838 (2).3 This drug has characteristic features related to both diuretic and antihypertensive effects.4 On the other hand, FK453 (1) has been developed mainly focusing on its more potent regulatory effects on renal function.5 For the purpose of complete pharmacological and toxicological evaluation of FK453 (1), we needed to develop a manufacturing process suitable for a large scale synthesis (Figure 1). Early synthetic efforts aimed at supplying FK453 (1) in gram quantities for the initial pharmacological screening utilized the synthesis outlined in Scheme 1.6 These methods (1) Daly, J. W. J. Med. Chem. 1982, 25, 197. (2) Meyer, H.; Hortsmann, H.; Moller, E.; Grathoff, B. Eur. Pat. 412215 1981. (3) (a) Zanka, A. Org. Process Res. DeV. 1998, 2, 60. (b) Zanka, A.; Hashimoto, N.; Uematsu, R.; (b) Okamoto, T. Org. Process Res. DeV. 1998, 2, 320. (4) (a) Horiai, H.; Kohno, Y.; Minoura, H.; Takeda, M.; Nakano, K.; Hanaoka, K.; Kusunoki, T.; Otsuka, M.; Shimomura, K. Can. J. Physiol. Pharmacol. 1994, 72, P17.3.9. (b) Takeda, M.; Kohno, Y.; Esumi, K.; Horiai, H.; Ohtsuka, M.; Shimomura, K.; Imai, M. Jpn. J. Pharmacol. 1994, 64, O-376. (5) Terai, T.; Kita, Y.; Kusunoki, T.; Andoh, T.; Nagatomi, I.; Horiai, H.; Akahane, A.; Shiokawa, Y.; Yoshida, K. Eur. J. Pharmacol. 1995, 279, 217. (6) Akahane, A.; Katayama, H.; Mitsunaga, T.; Kita, Y.; Kusunoki, T.; Terai, T.; Yoshida, K.; Shiokawa, Y. Bioorg. Med. Chem. Lett. 1996, 6, 2059.
Figure 1. Structure of adenosine A1 receptor antagonists. Scheme 1. Original route to FK453 (1)
were useful to generate FK453 (1) on a laboratory scale and were scaled up for the first manufacturing trial in a pilot plant with a few modifications. However, these methods
10.1021/op990044w CCC: $18.00 © 1999 American Chemical Society and The Royal Society of Chemistry Published on Web 09/03/1999
Vol. 3, No. 6, 1999 / Organic Process Research & Development
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Scheme 2. Route to phenylpropargyl aldehyde (5b) from trans-cinnamaldehyde
involved several shortcomings from the standpoint of largescale manufacturability. For example, the decarboxylation sequence required severe reaction conditions and column chromatography purification.3b In addition, decarboxylation and subsequent re-formylation in a synthetic process leads to a prolonged and inherently inefficient procedure. With a view to develop an alternative and efficient synthesis of FK453 (1) on a large scale, we decided to investigate a manufacturing process using phenylpropargyl aldehyde (5b). In this paper, we wish to report the results of the process development efforts for FK453 (1). Results and Discussion Phenylpropargyl aldehyde (5b) can be purchased from the Aldrich Chemical Co.; however, this agent is expensive and not available in large quantities. Therefore, we decided to investigate practical and inexpensive preparation methods amenable to a large scale operation. The synthesis of 5b from trans-cinnamaldehyde is known in the literature7 and was applied to prepare material for the scale-up trial (Scheme 2). One benefit in this method is that trans-cinnamaldehyde is inexpensive and readily available in bulk quantities. Each reaction in the process proceeded quantitatively, allowing avoiding isolation of irritant intermediates, and final purification by distillation afforded the aldehyde (5b) in satisfactory yield and quality (61% yield, 95% purity, HPLC). With an efficient preparation of aldehyde (5b) in hand, we investigated synthesis of ester (9). One of the most practical approaches to pyrazolo[1,5-a]pyridines is via 1,3dipolar cycloaddition of N-imine (4) with an acetylene. In our early studies, cycloaddition of aldehyde (5b) with N-imine (4) was investigated according to the reported method8 (Scheme 3, Route A). However, the reaction furnished tarry byproducts along with only small amounts of pyrazolopyridine (8) (20% HPLC area). As an alternative approach, we investigated the 1,3-dipolar cycloaddition of alkene (10) with N-imine (4) (Scheme 3, Route B). We investigated a practical method for the preparation of alkene (7) Allen, C. F. H.; Edens, Jr., C. O. Organic Syntheses; Wiley: New York, 1955; Collect. Vol. III, p 731. (8) (a) Anderson, P. L.; Hasak, J. P.; Kahle, A. D. J. Heterocycl. Chem. 1981, 18, 1149. (b) Huisgen. R.; Grashey, R.; Krischke, R. Tetrahedron Lett. 1962, 387. 390
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Scheme 3. Synthetic routes to the ester 9
Table 1. Horner-Emmons reaction of aldehyde (5b) and triethyl phosphonoacetatea entry
equiv of TEPAb
base (equiv)
solvent
yield (%)c of 10 from (5b)
1 2 3 4 5
1.2 1.5 1.2 1.2 1.2
KOH(1.1) KOH(1.1) KOH(1.1) KOH(1.1) tBuOK (1.2)
DMSO DMSO DMF DMA CH2Cl2
79 77 82 85 79
a Reaction was conducted at 20 °C for 2 h on a 20 g scale. c Yield was determined by quantitative HPLC. b TEPA: triethyl phosphonoacetate.
(10) on a large scale using Horner-Emmons reaction of aldehyde (5b) with triethyl phosphonoacetate, since this reagent is inexpensive and readily available in large quantities. Furthermore, the phosphate byproduct is soluble in water and easily separated from the alkene (10) by extraction. Another advantage of this reaction is the excellent (E)stereoselectivity, mainly due to stabilization of the carbanion by the ester moiety.9 These reactions are usually conducted in ethers such as THF or glyme,10 but we investigated the reaction in amides or methylene chloride as solvents, aiming for a “one-pot reaction” which would avoid isolation of the pure alkene (10), since it is an irritant and difficult to purify, and also because handling of this compound may lead to the cis-isomer via photochemical isomerization. The HornerEmmons reaction of aldehyde (5b) with triethyl phosphonoacetate proceeded smoothly in the presence of KOH, affording the trans-alkene (10) stereoselectively. As shown in Table 1, N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) gave superior yields in this step (entry 3, 4). Next, we examined the subsequent cycloaddition. As (9) Maryanoff, B. E.; Beitz, A. B. Chem. ReV. 1989, 89, 867. (10) Wadsworth, W. S., Jr. Org. React. 1977, 25, 73-253.
Table 2. 1,3-Dipolar cycloaddition of the alkene 10 with N-imine (4)a entry
equiv of 4
base (equiv)
1 2 3
1.2 1.6 2.0
4
2.0
5
2.0
6
2.0
KOH(1.2) KOH(1.6) KOH(1.0) K2CO3(0.5) KOH(1.0) K2CO3(0.5) KOH(1.0) K2CO3(0.5) tBuOK (1.0)
solvent
yield (%)b
DMSO DMSO DMSO
46 62 67
DMF
52
DMA
55
CH2Cl2
