US 12,071,422 B2
Process for synthesis of quinazoline compounds
Rene Lebl, Graz (AT); Ngiap Kie Lim, Dublin, CA (US); Roland Christoph Meier, Ueken (CH); Ugo Jonathan Orcel, Basel (CH); Joerg Sedelmeier, Basel (CH); Jeff Shen, Foster City, CA (US); Lauren Elizabeth Sirois, San Francisco, CA (US); Jacob C. Timmerman, Redwood City, CA (US); Etienne Trachsel, Basel (CH); Nicholas Andrew White, San Francisco, CA (US); Jie Xu, San Mateo, CA (US); Haiming Zhang, San Mateo, CA (US); Stephan Bachmann, Allschwil (CH); Thomas Michael Bass, Fremont, CA (US); Raphael Bigler, Aarau (CH); Johannes Adrian Burkhard, Millbrae, CA (US); Kyle Bradley Pascual Clagg, San Francisco, CA (US); Francis Gosselin, San Mateo, CA (US); Chong Han, Foster City, CA (US); Dainis Kaldre, Lorrach (DE); Sean M. Kelly, San Mateo, CA (US); Sebastian Herold, Bad Saeckingen (DE); and Christian Leitner, Eiken (CH)
Assigned to Genentech, Inc., South San Francisco, CA (US); and Hoffmann-La Roche Inc., Little Falls, NJ (US)
Filed by Genentech, Inc., South San Francisco, CA (US); and Hoffmann-La Roche Inc., Little Falls, NJ (US)
Filed on Feb. 3, 2023, as Appl. No. 18/164,302.
Claims priority of provisional application 63/307,529, filed on Feb. 7, 2022.
Prior Publication US 2023/0250074 A1, Aug. 10, 2023
Int. Cl. C07D 401/04 (2006.01); B01J 23/44 (2006.01); B01J 23/755 (2006.01)
CPC C07D 401/04 (2013.01) [B01J 23/44 (2013.01); B01J 23/755 (2013.01)] 48 Claims
 
1. A process for the synthesis of a compound of formula (I);

OG Complex Work Unit Chemistry
or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof, wherein
X1 and X3 are each independently hydrogen or halogen;
R1 is hydrogen or PG1;
each R2 is independently halogen, cyano, unsubstituted C1-6 alkyl, unsubstituted C1-6 cyanoalkyl, or unsubstituted C1-6 haloalkyl;
R3 is hydrogen, halogen, R3A-substituted or unsubstituted C1-3 alkyl, R3A-substituted or unsubstituted C1-3 haloalkyl, or R3A-substituted or unsubstituted cyclopropyl;
R3A is halogen, OH, CN, unsubstituted C1-3 alkyl or unsubstituted C1-3 haloalkyl;
R4 is R4A_substituted or unsubstituted C1-3 haloalkyl;
R4A is unsubstituted C1-3 alkyl;
n is 1 or 2;
each PG is independently an amino protecting group; and
PG1 is an amino protecting group;
wherein the process comprises
(a) contacting a compound of formula (II)

OG Complex Work Unit Chemistry
wherein X2 is halogen;
with an organomagnesium compound thereby forming a compound of formula (IIa):

OG Complex Work Unit Chemistry
(b) transferring the compound of formula (IIa) of step (a) to a continuous stirred tank reactor (CSTR) comprising a zinc compound at a temperature of about −20° C. to 20° C. thereby synthesizing a compound of formula (IIb); and

OG Complex Work Unit Chemistry
wherein m is 0, 1, or 2;
p is 1, 2, or 3; and
X2 is halogen or OPiv;
(c) contacting the compound (IIb) of step (b) with a compound of formula (III),

OG Complex Work Unit Chemistry
wherein X4 is halogen,
a transition metal catalyst precursor, and a chiral ligand, thereby synthesizing a compound of formula (I).