US 12,172,982 B2
Synthesis of quinazoline compounds
Ngiap-Kie Lim, Dublin, CA (US); Jeff Shen, Foster City, CA (US); Lauren Elizabeth Sirois, San Francisco, CA (US); Jacob C. Timmerman, San Mateo, 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); Raphael Bigler, Basel (CH); Kyle Bradley Pascual Clagg, San Francisco, CA (US); Antonio Giovanni Dipasquale, San Bruno, CA (US); Francis Gosselin, San Mateo, CA (US); Ugo Jonathan Orcel, Basel (CH); and Roland Christoph Meier, Basel (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 Aug. 10, 2021, as Appl. No. 17/398,345.
Claims priority of provisional application 63/064,746, filed on Aug. 12, 2020.
Prior Publication US 2022/0081413 A1, Mar. 17, 2022
Int. Cl. C07D 401/04 (2006.01); C07D 401/14 (2006.01)
CPC C07D 401/14 (2013.01) 52 Claims
 
1. A process for the preparation of a compound or a solvate, tautomer, stereoisomer, or salt thereof of formula;

OG Complex Work Unit Chemistry
wherein;
X0 is hydrogen, halogen, OR5A, or R5-substituted or unsubstituted C1-6 haloalkyl;
X1 is hydrogen or halogen;
X3 is hydrogen, halogen, R6-substituted or unsubstituted C1-3 alkyl, R6-substituted or unsubstituted C1-3 haloalkyl, R6-substituted or unsubstituted C1-3 alkoxy, or R6-substituted or unsubstituted cyclopropyl;
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 C3-6 cycloalkyl;
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;
R5 is halogen, cyano, OH, NO2, R5A-substituted or unsubstituted C1-6 alkyl, R5A-substituted or unsubstituted C1-6 haloalkyl, R5A-substituted or unsubstituted C1-6 cyanoalkyl, R5A-substituted or unsubstituted C3-6 cycloalkyl, R5A-substituted or unsubstituted 3-6 membered heterocycle, R5A-substituted or unsubstituted phenyl, or R5A-substituted or unsubstituted 6 membered heteroaryl;
R5A and R5B are each independently R5C-substituted or unsubstituted C1-6 alkyl, R5C-substituted or unsubstituted C1-6 haloalkyl, R5C-substituted or unsubstituted C3-7 cycloalkyl; R5C-substituted or unsubstituted 3-7 membered heterocycle; R5C-substituted or unsubstituted C5-7 aryl, or R5C-substituted or unsubstituted C5-7 heteroaryl;
R5C is independently halogen, OH, CN, NO2, R5D-substituted or unsubstituted C1-6 alkyl, R5D-substituted or unsubstituted C1-6 haloalkyl, R5D-substituted or unsubstituted C3-7 cycloalkyl; R5D-substituted or unsubstituted C3-7 heterocycle; R5D-substituted or unsubstituted C5-7 aryl, or R5D-substituted or unsubstituted C5-7 heteroaryl;
R5D is independently halogen, OH, CN, NO2, unsubstituted C1-6 alkyl, unsubstituted C1-6 haloalkyl, unsubstituted C3-7 cycloalkyl; unsubstituted C3-7 heterocycle; unsubstituted C5-7 aryl, or unsubstituted C5-7 heteroaryl;
R6 is halogen, OH, CN, NO2, unsubstituted C1-6 alkyl, unsubstituted C1-6 haloalkyl, or unsubstituted C3-7 cycloalkyl;
n is 0, 1, or 2;
each PG is independently Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) or Cbz (carbobenzyloxy); and
PG1 is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) or Cbz (carbobenzyloxy);
the process comprising the steps:
(a) contacting a compound of formula (II)

OG Complex Work Unit Chemistry
wherein X2 is halogen;
with (i) an organomagnesium compound selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl) (di-n-butyl) magnesiate) and (ii) a zinc complex selected from the group consisting of ZnCl2, ZnBr2, ZnI2, Zn(OAc)2, and Zn(OPiv)2; and
(b) contacting the mixture of step (a) with (i) a compound of formula (III),

OG Complex Work Unit Chemistry
wherein X4 is halogen;
(ii) a Pd catalyst precursor selected from the group consisting of Pd(OAc)2, PdCl2, PdCl2(MeCN)2, Pd(benzonitrile)2Cl2, Pd(dba)2, Pd2(dba)3, Pd(PPh3)4, Pd(PCy3)2, Pd(PtBu3)2, Pd(TFA)2, [Pd(allyl)Cl]2, [Pd(cinammyl)Cl]2, [PdCl(crotyl)]2, PdCl(η5-cyclopentadienyl), or [(η3-allyl)(η5-cyclopentadienyl) palladium (II)]; and (iii) a chiral ligand comprising a compound of formula:

OG Complex Work Unit Chemistry
wherein
Y is O or NR7;
R7 and R8 are independently unsubstituted C1-6 alkyl;
R12 and R13 are each independently R14-substituted or unsubstituted C1-6 alky, R14-substituted or unsubstituted C3-7 cycloalkyl, R14-substituted or unsubstituted aryl, or R14-substituted or unsubstituted C5-7 heteroaryl; and
each R14 is independently unsubstituted C1-4 alkyl;
thereby synthesizing a compound of formula

OG Complex Work Unit Chemistry