H. Harada, A. Fujii, O. Odai
Mar 1, 2004
Citations
1
Influential Citations
7
Citations
Journal
Organic Process Research & Development
Abstract
(2R)-[3-(2-Aminopropyl)-1H-indol-7-yloxy]acetic acid (2) is the left-hand side segment of AJ-9677, which is a potent and selective human and ratâ3-adrenergic receptor agonist. Herein, we describe the process development of a scaleable synthetic route to the correspondingN,N-diethylacetamide derivative 3 of 2 from 7-benzyloxy-1H-indole (4). Reaction of the indole Grignard reagent 12 generated from 4 and methylmagnesium bromide with the N-Fmoc-D-alanyl chloride 22, followed by reduction of the resulting crude 3-acylindole 26 with NaBH4 in a mixture of MeCN and 2-PrOH at refluxing temperature and subsequent treatment with oxalic acid gave the oxalate of the N-deprotected product, (2R)-3-(2-aminopropyl)-7-benzyloxy-1Hindole [(R)-7] as a crystalline material in 60% yield. After N-protection of the (R)-7 by Boc group, the (2R)-3-[2-(Bocamino)propyl]-1H-indole 30 was hydrogenated to provide the (2R)-3-(2-aminopropyl)-7-hydroxy-1H-indole 31, which was subsequently alkylated with ClCH2CONEt2 to give 32 in 91% yield. Finally, treatment of 32 with oxalic acid afforded the desired 3 in 79% in >99% ee. Introduction â-Adrenergic receptors ( â-ARs) have been subclassified as â1-, â2-, and â3-ARs. The â3-AR has been shown to mediate various pharmacological and physiological effects such as lipolysis in white adipocytes, thermogenesis in brown adipocytes, and relaxation of urinary bladder detrusor tissue. 2-5 Potent and selective â3-AR agonists are potential drugs for the treatment of obesity, non-insulin dependent (Type-II) diabetes, frequent urination, and related diseases. At the beginning of 1990 and on the basis of results obtained from random screening for rat â3-AR agonists, we found a novel 3-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-1H-indole (1). In the course of our studies on the structure-activity relationships of1, a potent and selective human and ratâ3-AR agonist {3-[(2R)-[[(2R)-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1 H-indol-7-yloxy}acetic acid (AJ-9677) was finally selected as a promising clinical candidate. 6 The earlier original synthetic route to AJ-9677 from the 7-benzyloxy-1H-indole7 (4) via the diastereomers 9 and10 is shown in Scheme 1. 6 However, this synthetic route has several limitations for large-scale preparation of AJ-9677, for example, the use of LiAlH4, multisteps, low overall yield, and tedious silica gel column chromatography separation of the key diastereomer 10, which is obtained from reaction of the racemic 3-(2-aminopropyl)-7-benzyloxy-1 H-indole (7) with the commercially available ( R)-3-chlorostyrene oxide (8) and successive protection of the aminoethanol moiety of 9 using N,N′-carbonyldiimidazole (CDI). Production of a large amount of AJ-9677 is required for the development needs of toxicology, formulation, and pharmacology studies. To meet this production requirement, a process development of a scaleable synthetic route to the left-hand side segment of AJ-9677, (R)-[3-(2-aminopropyl)-1H-indol-7-yloxy]acetic acid (2) is essential. In this contribution, we describe an efficient process used to provide kilogram quantities of the optically activeN,N-diethylacetamide analogue 3 of 2. Results and Discussion Sato and Kozikowski 8 and Isobe et al .9 have reported a novel tryptophan synthesis via Lewis acid-promoted coupling * Corresponding author. Telephone: +81-6-6337-5904. Fax:+81-6-63387656. E-mail: hiroshi-harada@dainippon-pharm.co.jp. (1) Arch, J. R. S.; Ainsworth, A. T.; Cawthorne, M. A.; Piercy, V.; Sennitt, M. V.; Thody, V. E.; Wilson, C.; Wilson, S. Nature1984, 309, 163. (2) Weyer, C.; Gautier, J. F.; Danforth, E., Jr. Diabetes Metab. 1999, 25, 11. (3) Kordik, C. P.; Reitz, A. B.J. Med. Chem. 1999, 42, 181. (4) Weber, A. E.Annu. Rep. Med. Chem. 1998, 33, 193. (5) Dow, R. L.Exp. Opin. InVest. Drugs1997, 6, 1811. (6) Harada, H.; Hirokawa, Y.; Suzuki, K.; Hiyama, Y.; Oue, M.; Kawashima, H.; Yoshida, N.; Furutani, Y.; Kato, S. Bioorg. Med. Chem. Lett. 2003, 13, 1301. (7) Harada, H.; Fujii, A.; Kato, S. Synth. Commun. 2003, 33, 507. (8) Sato, K.; Kozikowski, A. P.Tetrahedron Lett.1989, 30, 4073. (9) Nishikawa, T.; Kaji, S.; Wada, K.; Ishikawa, M.; Isobe, M. Synthesis2002, 1658. Organic Process Research & Development 2004, 8, 238−245 238 • Vol. 8, No. 2, 2004 / Organic Process Research & Development 10.1021/op0341869 CCC: $27.50 © 2004 American Chemical Society Published on Web 02/12/2004 reaction of indole with the optically active aziridine carboxylate ester. To extend the application of this synthesis, we examined the reaction of 7-benzyloxy-1 H-indole (4) with racemic 2-methylaziridines as C-3 units having different N-protecting groups. Initial attempts at reaction of the indole Grignard reagent 12generated from4 and methylmagnesium bromide with 1-benzyloxycarbonyl (Cbz)-2-methylaziridine (13) in the presence of Lewis acids, such as Me 2S/CuBr, BF3‚Et2O, or Zn(OTf)2 failed to afford the expected 3-aziridine ring-opening product 15. Only the inefficient regioisomer 16 of 15 was obtained in 20 -30% yield, and4 was recovered in ca. 50% yield. A similar reaction between 12 and 1-(4-toluenesulfonyl) (Ts)-2-methylaziridine ( 14) under the same conditions and silica gel purification of the reaction mixture afforded the 3-aziridine ring-opening product 17 in only ca. 30% yield together with a large amount of by-products (Scheme 2). To improve the yield, other methods were tried. Although a large number of synthetic routes to 3-acylindoles using Friedel -Crafts acylation11-13 and Vilsmeier acylation14 have been reported, reaction of the indole Grignard reagent with acid chlorides is the most general and useful method. 15 Ames et al. have reported the preparation of 3-(2-amino-1-hydroxyethyl)-5-hydroxy-1 H-indole from 5-benzyloxy-1H-indole using the reaction of indolylmagnesium iodide with benzyloxycarbonylglycinyl chloride and subsequent reduction of the resulting 3-acylindole with LiBH4. Although the yield of this preparation was relatively low, we focused our attention on the nucleophilic substitution reaction of the indole Grignard reagent 12 with acid chlorides. At the outset of our synthesis, reaction of 12 with acetyl chloride as a simple acid chloride was examined. Treatment of 12generated from4 and methylmagnesium bromide with acetyl chloride in CH2Cl2 along with a small amount of Et 2O needed for methylmagnesium bromide under ice-cooling or at room temperature and subsequent silica gel column purification produced the expected 3-acetyl-7-benzyloxy-1 Hindole (18) in ca. 80% yield (Scheme 3). On the basis of this good result, reaction of the D-alanyl chlorides19-22 having differentN-protecting groups with12was performed. The requiredD-alanyl chlorides19-22 were prepared in a usual manner from the readily available N-protectedD(10) Ezquerra, J. Tetrahedron Lett.1996, 37, 683. (11) Amat, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J. J. Org. Chem.1994, 59, 10. (12) Nakatsuka, S.; Teranishi, K.; Goto, T. etrahedron Lett.1994, 35, 2699. (13) Yang, C. X.; Patel, H. H.; Ku, Y.-Y.; Shah, R.; Sawick, D. Synth. Commun. 1997, 27, 2125. (14) Anthony, W. C.J. Org. Chem.1960, 25, 2049. (15) Heacock, R. A.; Kas ˇpárek, S.AdV. Heterocycl. Chem. 1969, 10, 43. (16) Ames, D. E.; Bowman, R. E.; Evans, D. D.; Johes, W. A. J. Chem. Soc. 1956, 1984. Scheme 1