WAY-315193

WAY-315193

7-Fluoro-1-[(1S,2R)-1-(3-fluorophenyl)-2-hydroxy-3-(methylamino)propyl]-3,3-dimethylindolin-2-one Hydrochloride

Drugs that possess norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition, have been used for multiple indications including major depressive disorder, attention deficit hyperactivity disorder, stress urinary incontinence, vasomotor symptoms, and pain disorders such as diabetic neuropathy and fibromyalgia.1 In the search for new candidates with improvements in both potency and selectivity, one of the lead compounds in the 1-(3-amino- 2-hydroxy-1-phenylpropyl)indolin-2-one series, WAY-315193 (1), was identified.2

Paper

Organic Process Research & Development 2009, 13, 880–887

Large-Scale Synthesis of a Selective Inhibitor of the Norepinephrine Transporter:
Mechanistic Aspects of Conversion of Indolinone Diol to Indolinone Aminoalcohol
and Process Implications
Asaf Alimardanov,* Alexander Gontcharov, Antonia Nikitenko, Anita W. Chan, Zhixian Ding, Mousumi Ghosh,
Mahmut Levent, Panolil Raveendranath,† Jianxin Ren, Maotang Zhou, Paige E. Mahaney,‡ Casey C. McComas,‡
Joseph Ashcroft, and John R. Potoski
Wyeth Research, 401 North Middletown Road, Pearl RiVer, New York 10965, U.S.A., and Wyeth Research, 500 Arcola Road,
CollegeVille, PennsylVania 19426, U.S.A.

TREATMENT OF GYNECOLOGICAL DISORDERS
WAY-315193 (Wyeth Pharmaceuticals)

Development of a scalable synthesis of WAY-315193 is described.
Use of LiHMDS as a base and Ti(O-i-Pr)4 as a Lewis acid was optimal for efficient and reproducible addition of indolinone anion to epoxyalcohol. Conversion of indolinone diol to indolinone aminoalcohol was achieved via monotosylationmethylamination.
The possibility of selective formation of the amidine side product, as well as its utilization for alternative selective preparation of the target aminoalcohol, was demonstrated.

The synthetic route used initially for preparation of 1 is shown in Scheme 1. The key step of the synthesis was the
Sharpless epoxidation of fluorocinnamic alcohol 3 which selectively introduced both relative and absolute configurations at the C-2 and C-3 positions. At the early stages of the project, allylic alcohol 3 was prepared in two steps from commercially available fluorocinnamic acid 2 by treatment with MeI in the presence of Cs2CO3 in acetone, followed by DIBAL reduction at -78 °C. The epoxide 4 was opened with the sodium salt of dimethylfluoroindolinone in DMF to afford the diol. The diol 6 was further elaborated into the final aminoalcohol hydrochloride 1 in 30-34% yield via tosylation with p-toluenesulfonyl chloride (TsCl) in pyridine, isolation of the intermediate monotosylate, treatment with MeNH2, and conversion to HCl salt. Dimethylfluoroindolinone was prepared by reduction and bis-methylation of 7-fluoroisatin by a process developed earlier as described in a prior publication.3

white solid (58% yield). Mp 209-212 °C.
[R]D25°)+10.7°.

1H NMR (D2O, 400 MHz) δ: 7.40-7.25 (m,3H), 7.16-6.97 (m, 4H), 5.47-5.25 (2H, broad m), 3.27-3.20
(2H, broad m), 2.76 (s, 3H), 1.37 (s, 3H), 1.24 (broad s, 3H).
ES+ MS, m/z 361 (MH+). Anal. Calc’d for C20H23ClF2N2O2:C, 60.53; H, 5.84; N, 7.06. Found: C, 60.43; H, 5.69; N, 6.84.
Sn content: <1 ppm. Enantiomeric purity: 99.1% ee. Chiral SFCanalysis conditions: column: Chiralcel OF 250 mm × 4.6 mm;mobile phase: 30% ethanol, 0.4% diethylamine in CO2; detection wavelength: 254 nm; 2 mL/min, 40 °C.

* Corresponding author. E-mail: alimara@wyeth.com.
† Deceased.
‡ Wyeth Research, Collegeville, PA.
(1) (a) For a review on norepinephrine reuptake inhibitors, see: Babu,R. P. K.; Maiti, S. N. Heterocycles 2006, 69, 539. (b) Krell, H. V.;Leuchter, A. F.; Cook, I. A.; Abrams, M. Psychosomatics 2005, 46,379. (c) Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown,M. T.; Wong, E. H. W. CNS Drug ReV. 2004, 10, 23. (d) McCormack,
P. L.; Keating, G. M. Drugs 2004, 64, 2567.
(2) Kim, C. Y.; Mahaney, P. E.; Trybulski, E. J.; Zhang, P.; Terefenko,E. A.; McComas, C. C.; Marella, M. A.; Coghlan, R. D.; Heffernan,G. D.; Cohn, S. T.; Vu, A. T.; Sabatucci, J. P.; Ye, F. Phenylaminopropanol
Derivatives and Methods of Their Use. U.S. Patent 7,517,899,2009.

(3) Wu, Y.; Wilk, B. K.; Ding, Z.; Shi, X.; Wu, C. C.; RaveendranathP.; Durutlic, H. Process for the Synthesis of Progesterone ReceptorModulators. U.S. Patent Publ. Appl. US 2007/027327, 2007.
(4) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (b) For a recent example of large-scale asymmetric epoxidation, see: Henegar,
K. E.; Cebula, M. Org. Process Res. DeV. 2007, 11, 354.

(5) (a) For indolinone deprotonation for epoxide opening, see: Proudfoot,J. R.; Regan, J. R.; Thomson, D. S.; Kuzmich, D.; Lee, T. W.;Hammach, A.; Ralph, M. S.; Zindell, R.; Bekkali, Y. Preparation ofPropanol and Propylamine Derivatives and Their Use as Glucocorticoid Ligands. WO 2004/063163, 2004. (b) Gillman, K.; Bocchino, D. M.
Preparation of Monosaccharides Prodrugs of Fluorooxindoles Useful in Treatment of Disorders Which are Responsive to the Opening of Potassium Channels. U.S. Patent Publ. Appl. US 2004/0152646, 2004.
(c) For amide deprotonation for epoxide opening, see: Albanese, D.; Landini, D.; Penso, M. Tetrahedron 1997, 53, 4787. (d) Chan, W. N.; Evans, J. M.; Hadley, M. S.; Herdon, H. J.; Jerman, J. C.; Morgan,H. K. A.; Stean, T. O.; Thompson, M.; Upton, N.; Vong, A. K. J. Med.Chem. 1996, 39, 4537.
(6) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218.
(7) (a) Smith, J. G. Synthesis 1984, 629. (b) Parker, R. E.; Isaacs, N. S.Chem. ReV. 1959, 59, 737.

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