The Discovery of OSI-906, a Small-molecule Inhibitor of the Insulin-like Growth Factor-1 and Insulin Receptors - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 87

N Cl

b c

O

N

N

N

N R

H

OH

20 (R = H)
21 (R = Ph)

a

22 23

N Cl

N Cl

d e f

N

N

N N

O NH

NH 2

24

25

N N

Cl Cl

h, i

N g N

N N OSI-906

N N

O

26 27

j k

AQIP PQIP

Scheme 4.4 Linear synthesis of imidazo[1,5-a]pyrazine-derived IGF-IR inhibitors:
AQIP, PQIP, and OSI-906.(a) PhLi, THF, 0 1C; then sulfur, MeOH,
70 1C; (b) SeO 2 , 160 1C (42% three-step yield); (c) nBuLi, tetra-
methylpiperidine, 2-chloropyrazine, THF, 78 1C; (d) SOCl 2 , CHCl 3 ,
rt; then potassium phthalimide; then NH 2 NH 2 , EtOH, rt; (e) 3-methy-
lenecyclobutanecarboxylic acid, EDC, HOBT, DIEA, CH 2 Cl 2 ; (f)
POCl 3 , DMF, MeCN, 55 1C; (g) NMO, cat. K 2 OsO 4 , THF/H 2 O, rt; then
NaIO 4 , THF/H 2 O (3:1), 0 1C - rt (88% two-step yield); (h) 3M
MeMgCl in THF, N 2 , 78 1C - rt, 1 h; (i) NH 3 , iPrOH, stainless steel
Parr apparatus, 110 1C, 15 h (61% two-step yield); (j) 9-BBN, THF, 0 1C
- rt (62%); then NH 3 , iPrOH, 110 1C, 24 h (51%); then Ts 2 O, pyridine,
CH 2 Cl 2 , 40 1C - rt (53%); then azetidine, THF, 50 1C; (k)
Na(OAc) 3 BH, THF, N-methylpiperizine, DCE, rt; then NH 3 , iPrOH,
110 1C, 24 h.

in the presence of EDC/HOBT afforded amide 25 in 88% yield, which was
subsequently cyclized to imidazopyrazine 26 in 93% yield with POCl 3 and
DMF in acetonitrile. Imidazopyrazine 26 proved to be a versatile intermediate
and was used to synthesize several analogs, including AQIP, PQIP, and OSI-
906. 39,35-37 For the synthesis of AQIP, hydroboration of 8-chloroimidazopyr-
azine 26 with 9-BBN, followed by oxidative cleavage, afforded a 5:1 ratio of