Processes for preparing aminopyrimidine compounds
Provided herein are improved processes for preparing aminopyrimidine compounds of Formula (I). The disclosed processes advantageously proceed through a β-diketoester intermediate of Formula (A) and avoid the direct linking of a pyrimidine and phenyl moieties. The disclosed methods significantly increase yield of the desired compounds and simplifies the synthetic route.
1 . A process for preparing a compound of Formula (IIa):
said process comprising:
a′) contacting a compound of Formula (A)
wherein
R 1a is CH 3 ;
R 2a is CN;
R 1b , R 2b , and R 3 are each H;
R 4 is selected from the group consisting of C1-C8 alkyl and C3-C8 cycloalkyl, each of which is optionally substituted with from 1 to 6 members independently selected from the group consisting of F and Cl;
with a guanidine reagent in 2,2,2-trifluoroethanol to obtain a compound of Formula (B)
wherein said guanidine reagent is guanidine HCl or guanidine carbonate;
and contacting the compound of Formula (B) with a halogenation agent to form a compound of Formula (Ia)
wherein X is Cl or Br and the halogenation agent is POCl 3 , PSCl 3 , SOCl 2 , (COCl) 2 , PCl 5 , PBr 3 , N-chlorosuccinimide (NCS), or N-bromosuccinimide (NBS);
b′) converting said compound of Formula (Ia) to a compound of Formula (Ca);
and
c′) combining said compound of Formula (Ca) with a compound of Formula (D),
to produce said compound of Formula (IIa).
2 . The process according to claim 1 , wherein step b′) comprises
b′-1) contacting the compound of Formula (Ia) with triisopropylsilylacetylene under Sonogashira coupling conditions to produce an intermediate of Formula (Ca′):
and
b′-2) contacting the compound of Formula (Ca′) with a desilylating reagent to produce said compound of Formula (Ca).
3 . The process according to claim 2 , wherein said Sonogashira coupling conditions comprise a palladium catalyst and a copper co-catalyst.
4 . The process according to claim 2 , wherein said Sonogashira coupling conditions further comprise an amine base.
5 . The process according to claim 4 , wherein the amine base is triethylamine or N,N-diisopropylethylamine.
6 . The process according to claim 2 , wherein said desilylating reagent is selected from the group consisting of tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), sodium tetrachloroaurate (III), and acetyl chloride.
7 . The process according to claim 1 , wherein step c′) further comprises a copper catalyst.
8 . The process in accordance with claim 1 , wherein R 4 is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, and 2,2,2-rifluoroethyl.
9 . The process in accordance with claim 1 , wherein contacting the compound of Formula (B) with a halogenation agent is carried out in a polar aprotic organic solvent.
10 . The process in accordance with claim 9 , wherein said polar aprotic organic solvent is selected from the group consisting of acetonitrile, DMF, DMSO, NMP, and combinations thereof.
11 . The process in accordance with claim 9 , wherein the halogenation agent is POCl 3 ; X is Cl; said guanidine reagent is guanidine carbonate; and said polar aprotic organic solvent is acetonitrile.
12 . The process in accordance with claim 1 , wherein contacting the compound of Formula (B) with a halogenation agent is conducted at a temperature of about 67-83° C.
13 . The process in accordance with claim 1 , wherein said compound of Formula (A), said guanidine reagent, and 2,2,2-trifluoroethanol are heated to reflux temperature.
14 . The process in accordance with claim 1 , wherein, prior to contacting the compound of Formula (B) with a halogenation agent, said compound of Formula (B) is triturated with an organic solvent to remove a byproduct of Formula (i)
15 . The process in accordance with claim 14 , wherein said organic solvent is selected from the group consisting of ethanol, methanol, acetonitrile, dichloromethane, ethyl acetate, and methyl tert-butyl ether.
16 . The process in accordance with claim 9 , wherein contacting the compound of Formula (B) with a halogenation agent is conducted with a base additive.
17 . The process in accordance with claim 16 , wherein said base additive is selected from the group consisting of trimethylamine, diisopropylethylamine, dimethylaniline, benzyltrimethylammonium chloride, and benzyltriethylammonium chloride.
18 . The process in accordance with claim 1 , wherein the compound of Formula (A) is prepared by:
i) contacting a compound of Formula (a)
with a halogenation agent to prepare a compound of Formula (b)
wherein
Y is a halogen; and
ii) combining the compound of Formula (b) with a compound of Formula (c)
in the presence of a base to form a compound of Formula (A).
19 . The process in accordance with claim 18 , wherein the compound of Formula (a) is prepared by:
i) contacting a compound of Formula (a′y)
with a cyanation reagent to prepare a compound of Formula (a′x)
or
ii) contacting the compound of Formula (a′y) with a Grignard reagent and CO 2 to give the compound of Formula (a′x).