Process for making benzoxazepin compounds
Processes are described for the preparation of PI3K inhibitor, GDC-0032, Formula I, having the structure: and intermediates useful for the preparation of I.
1. A process for preparing (2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide I, having the structure:
and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, comprising:
(a) reacting IV and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to form 22
(b) reacting 22, a palladium catalyst, and III to form 23
(c) reacting 23 with an aqueous basic reagent to form II
and
(d) reacting II with an acyl activating reagent, followed by ammonia to give I.
2. The process of claim 1 wherein IV is prepared by reacting 17:
with a brominating reagent.
3. The process of claim 1 wherein the palladium catalyst is selected from PdCl 2 (PPh 3 ) 2 , Pd(t-Bu) 3 , PdCl 2 dppf CH 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(OAc)/PPh 3 , Cl 2 Pd[(Pet 3 )] 2 , Pd(DIPHOS) 2 , Cl 2 Pd(Bipy), [PdCl(Ph 2 PCH 2 PPh 2 )] 2 , Cl 2 Pd[P(o-tol) 3 ] 2 , Pd 2 (dba) 3 /P(o-tol) 3 , Pd 2 (dba)/P(furyl) 3 , Cl 2 Pd[P(furyl) 3 ] 2 , Cl 2 Pd(PMePh 2 ) 2 , Cl 2 Pd[P(4-F-Ph) 3 ] 2 , Cl 2 Pd[P(C 6 F 6 ) 3 ] 2 , Cl 2 Pd[P(2-COOH-Ph)(Ph) 2 ] 2 , Cl 2 Pd[P(4-COOH-Ph)(Ph) 2 ] 2 , and encapsulated catalysts Pd EnCat™ 30, Pd EnCat™ TPP30, and Pd(II)EnCat™ BINAP30.
4. The process of claim 1 wherein palladium is removed from I with a solid adsorbent palladium scavenger.
5. The process of claim 4 wherein the solid adsorbent palladium scavenger is selected from silica gel, controlled-pore glass, and low crosslinked polystyrene.
6. The process of claim 1 wherein III is prepared by:
(a) reacting V with a 2-hydroxyethylation reagent to form 14
and
(b) reacting 14 with an aqueous basic reagent to form V.
7. The process of claim 1 wherein III is prepared by:
(a) reacting 28 with acetamidine to form 29
and
(b) reacting 29 with isopropyl hydrazine and an acidic reagent to form III.
8. The process of claim 1 wherein III is prepared by reacting 28 with N′-isopropylacetohydrazonamide 6 to form III
9. The process of claim 7 wherein 28 is prepared by:
(a) reacting 11 with hydroxylamine to form 24
(b) reacting 24 with ethyl propiolate to form 25
(c) heating 25 to form 26
(d) reacting 26 with a 2-hydroxyethylation reagent to form 27
and
(e) reacting 27 with an aqueous basic reagent to form 28.
10. A compound selected from the structures: