BMS-599793

(DS003, BMS-599793)

2-(1-(2-(4-methoxy-7-(pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanoyl)piperidin-4- ylidene)-2-phenylethanenitrile

1 (DS003, BMS-599793) is a small molecule entry inhibitor that interferes with HIV infection by binding to the gp120 protein.1 The International Partnership for Microbicides (IPM) licensed 1 from Bristol-Myers Squibb (BMS) with the goal to develop it as a topical microbicide for use in resource-poor countries. Microbicides are vaginal dosage forms of potent inhibitors of HIV that women can use to prevent sexual transmission of HIV from male partners.

1 (a) Maddon, P. J.; Dalgleish, A. G.; McDougal, J. S.; Clapham, P. R.; Weiss, R. A.; Axel. R. Cell 1986, 47, 333-348. (b) McDougal, J. S.; Kennedy, M. S.; Sligh, J. M.; Cort, S. P.; Mawle, A.; Nicholson, J. K. Science 1986, 231, 382-385. (c) Moore, J. P.; Jameson, B. A.; Weiss, R. A.; Sattentau, Q. J. in Viral fusion mechanisms. ed. J. Bentz, CRC Press, Boca Raton, Fla. 1993, p. 233-289.

2-(1-(2-(4-methoxy-7-(pyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanoyl)piperidin-4- ylidene)-2-phenylethanenitrile (1, laboratory scale process). A flask was charged with acid 11 (9.29 g, 31.2 mmol), DIPEA (12.9 mL, 78 mmol), 4 (7.18 g, 36.3 mmol) and DMF (95 mL) subsequently. HATU (13.66 g, 35.9 mmol) was added to the reaction mixture over 10 minutes, which was accompanied by increase of internal temperature from 19 0C to 27 0C. After the reaction mixture was stirred at 25 0C for 3.5  h the HPLC analysis showed complete disappearance of acid 11. Ethanol (950 mL) was added and the resulting suspension was heated at reflux for 1 h. The mixture was then cooled to 25 0C and 1 was isolated by filtration and washed with ethanol (50 mL). The material was dried under vaccum at 50 0C to afford 10.58 g (71% yield) of 1 as a colorless solid.

1H NMR (300 MHz, CDCl3) 2.58-2.65 (m, 2H), 2.91-2.99 (m, 2H), 3.48-3.51(m, 1H), 3.68-3.78 (m, 2H), 3.95-3.99 (m, 1H), 4.11 (s, 3H), 7.27-7.46 (m, 5H), 8.16 (d, J = 5.1 Hz, 1H), 8.21-8.25 (m, 1H), 8.60 (s, 2H), 9.82 (d, J = 3.9 Hz, 1H), 11.75(br s, 1H).

LCMS: m/e 479.3 (M+H)+. Analysis by ICP-MS showed 16 ppm Pd, 79 ppm Fe, 102 ppm Zn. This material was found to be a mixture of two polymorphs: Form 1 and Form 2.

kilo-lab scale process including polymorph conversion

1 (84% yield) and 99.6% purity by HPLC. This material was a pure Form 1 polymorph.

1H NMR (400 MHz, CDCl3) 2.61 (t, J = 5.8 Hz, 1H), 2.65 (t, J = 5.9 Hz, 1H), 2.94 (t, J = 5.8 Hz, 1H), 2.99 (t, J = 5.9 Hz, 1H), 3.51 (t, J = 5.8 Hz, 1H), 3.72 (t, J = 5.8 Hz, 1H), 3.78 (t, J = 6.0 Hz, 1H), 3.98 (t, J = 6.0 Hz, 1H), 4.12, 4.12 (two s, 3H), 7.29-7.47 (m, 5H), 8.16, 8.18 (two s, 1H), 8.23, 8.25 (two d, J = 3.1 Hz,  1H), 8.60-8.63 (m, 2H), 9.83, 9.84 (two d, J = 1.4 Hz, 1H), 11.76, 11.78 (two br s, 1H);

13H NMR (100 MHz, CDCl3) 30.3, 31.0, 33.7, 34.3, 41.7, 42.0, 46.0, 46.3, 56.8, 111.4, 115.0 (2C), 117.7 (2C), 120.9, 124.2, 128.9 (2C), 129.0, 129.1 (2C), 131.9, 132.6 (2C), 133.9 (2C), 136.6, 142.2, 143.4, 143.7 (2C), 151.1, 151.3, 154.8, 166.4, 166.5, 185.6

Anal. Calcd for C27H22N6O3: C, 67.77; H, 4.63; N, 17.56. Found: C, 67.84; H, 4.64; N, 17.56.

1H NMRPREDICT

13C NMR PREDICT

Synthetic Process Development of BMS-599793 Including Azaindole Negishi Coupling on Kilogram Scale

Abstract

A new approach to the synthesis of 1 (DS003, BMS-599793), a small-molecule HIV entry inhibitor, is described. The initial medical chemistry route has been modified by rearranging the sequence of synthetic steps followed by replacement of the Suzuki coupling step by the Negishi conditions. Acylation of the resulting azaindole 7 under the Friedel–Crafts conditions is studied using monoesters of chlorooxalic acid in the presence of aluminum chloride. Polymorphism of 1is also investigated to develop conditions suitable for preparation of the desired Form 1 of the target compound. The new route is further optimized and scaled up to establish a new process that is applied to the synthesis of kilogram quantites of the target active pharmaceutical ingredient.

////////BMS-599793, BMS 599793