Process for preparing an activin receptor-like kinase inhibitor
The present disclosure provides a method of preparing a compound represented by formula (I). The method comprises reacting in a reaction mixture a first starting material represented by formula (II) and a second starting material represented by formula (III) under Negishi conditions: to form the compound of formula (I). R is an amine protecting group; Y is Cl, Br or I; and Z is triflate, Cl, Br or I.
1 . A method of preparing a compound represented by formula (I):
comprising reacting in a reaction mixture a first starting material represented by formula (II):
and a second starting material represented by formula (III) under Negishi conditions:
to form the compound of formula (I), wherein R is an amine protecting group; Y is Cl, Br or I; and Z is Cl, Br, I or triflate.
2 . The method of claim 1 , wherein the reaction is mediated by a palladium catalyst.
3 . The method of claim 2 , wherein:
i) the first starting material of formula (II) is converted into an organozinc intermediate represented by formula (II-B):
and
ii) the organozinc intermediate of formula (II-B) is reacted with the second starting material of formula (III) in the presence of the palladium catalyst to form the compound of formula (I), wherein X is Cl, Br or I.
4 . The method of claim 3 , wherein X is Cl and Y is Br.
5 . The method of claim 3 , wherein the organozinc intermediate of formula (II-B) is reacted with the second starting material of formula (III) without isolation of the organozinc intermediate of formula (II-B).
6 . The method of claim 2 , wherein the palladium catalyst is selected from Pd(X 1 ) 2 and Pd(X 1 ) 2 Cl 2 , wherein each X 1 is independently a phosphine ligand.
7 . The method of claim 2 , wherein the phosphine ligand is selected from dtbpf, dcypf, dppf, t-BuXPhos, AdBrettPhos, SPhos, RuPhos, XPhos, BrettPhos, JackiePhos, t-BuBrettPhos, TrixiePhos, JohnPhos, t-BuDavePhos, t-BuMePhos, CyJohnPhos, DavePhos, MePhos, PhDavePhos, VPhos, PhCPhos, CPhos, EtCPhos, RockPhos, AlPhos and (t-Bu) PhCPhos.
8 . The method of claim 2 , wherein the palladium catalyst is selected from
Pd(dppe) 2 (Bis[1,2-bis(diphenylphosphino)ethane]palladium(0)),
Pd(dba) 2 (Bis(dibenzylideneacetone)palladium (0)),
CX-11 (1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) dimer),
CX-12 (1,3-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) dimer),
Pd(t-Bu 3 P) 2 (Bis(tri-tert-butylphosphine)palladium(0)), Pd(PCy 3 ) 2 (Bis(tricyclohexylphosphine)palladium(0)),
Pd(PPh 3 ) 4 (Tetrakis(triphenylphosphine)palladium(0)), Pd 2 (dba) 3 (Tris(dibenzylideneacetone)dipalladium(0)),
Pd(OAc) 2 (Palladium (II) acetate),
PdCl 2 (PPh 3 ) 2 (Dichlorobis(triphenylphosphine)palladium(II)),
PdCl 2 (Amphos) 2 (Bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II)),
Pd(MeCN) 2 Cl 2 (Bis(acetonitrile)dichloropalladium(II)),
PdCl 2 (P(o-Tol) 3 ) 2 (Dichlorobis(tri-o-tolylphosphine)palladium(II)),
Pd(dppf)Cl 2 (1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)),
Pd(MeCN) 4 (BF 4 ) 2 (Tetrakis(acetonitrile)palladium(II) tetrafluoroborate),
Pd-PEPPSI-IPent (Dichloro[1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)),
Pd-PEPPSI-IPr ([1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride), and
Pd-PEPPSI-SIPr ((1,3-Bis(2,6-Diisopropylphenyl)imidazolidene) (3-chloropyridyl) palladium(II) dichloride).
9 . The method of claim 2 , wherein the palladium catalyst is selected from Pd (MeCN) 2 Cl 2 , Pd[P(o-Tol) 3 ] 2 Cl 2 , PdCl 2 (Amphos) 2 and Pd(dba) 2 .
10 . The method of claim 2 , wherein the palladium catalyst is selected from Pd 2 (dba) 3 /P(R 1 ) 3 , Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(MeCN) 2 Cl 2 , Pd[P(o-Tol) 3 ] 2 Cl 2 , PdCl 2 (Amphos) 2 , Pd(PtBu 3 ) 2 , Pd(dppf) Cl 2 , Pd(dba) 2 , Pd 2 (dba) 3 and Pd(XPhos), wherein each R 1 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, benzyl or phenyl and wherein the benzyl or phenyl is each optionally and independently substituted with one or more groups selected from halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy.
11 . The method of claim 2 , wherein the palladium catalyst is Pd 2 (dba) 3 .
12 . The method of claim 2 , wherein the palladium catalyst is PdP(tBu) 3 .
13 . The method of claim 2 , wherein the first starting material of formula (II) is converted into the organozinc intermediate of formula (II-B) by reacting the first starting material of formula (II) with a Grignard reagent R′MgX 2 , to form an organometallic intermediate represented by formula (II-A):
and the organometallic intermediate of formula (II-A) is reacted with ZnX 2 to form the organozinc intermediate of formula (II-B), wherein R′ is a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, benzyl or monocyclic heteroaryl, wherein the phenyl, benzyl or heteroaryl is each optionally and independently substituted with one or more groups selected from halogen, C 1 -C 3 alkyl and C 1 -C 3 alkoxy group and X 2 is Cl, Br or I.
14 . The method of claim 13 , wherein the Grignard reagent is i-PrMgCl.
15 . The method of claim 13 , wherein the organometallic intermediate of formula (II-A) is reacted with ZnX 2 without isolation of the organometallic intermediate of formula (II-A).
16 . The method of claim 13 , wherein the first starting material of formula (II) is reacted with the Grignard reagent in a mixture comprising anisole.
17 . The method of claim 16 , wherein the first starting material of formula (II) is reacted with the Grignard reagent in a mixture of anisole and an ethereal solvent.
18 . The method of claim 17 , wherein the ethereal solvent is tetrahydrofuran.
19 . The method of claim 3 , wherein KOtBu in an ethereal solvent is combined with the organozinc intermediate of formula (II-B) before reaction with the second starting material of formula (III).
20 . The method of claim 19 , wherein the organozinc intermediate of formula (II-B) is combined with KOtBu in tetrahydrofuran.
21 . The method of claim 19 , wherein the reaction of the organozinc intermediate of formula (II-B) and the second starting material of formula (III) is carried out in the presence N-methyl-2-pyrollidinone.
22 . The method of claim 1 , further comprising extracting the reaction mixture after formation of the compound of formula (I) with a basic aqueous solution of N-acetyl-L-cysteine.
23 . The method of claim 1 , wherein R is selected from Fmoc (9-Fluorenylmethyl carbamate), Cbz (Benzyl carbamate), Boc (tert-butoxycarbonyl), Acetamide, benzyl, tosyl (p-Toluenesulfonamide).
24 . The method of claim 23 , wherein R is tert-butoxycarbonyl.
25 . The method of claim 1 , wherein Z is Br.
26 . The method of claim 13 , wherein the first starting material of formula (II) is reacted with the Grignard reagent in a mixture comprising an aromatic solvent selected from the group consisting of benzene, toluene, and xylene.
27 . A method of preparing a compound represented by formula (I):
wherein R is Boc (tert-butoxycarbonyl);
comprising:
i) converting a first starting material represented by formula (II):
wherein Y is Br;
into an organozinc intermediate of formula (II-B) by reacting the first starting material of formula (II) with iPrMgCl in anisole and tetrahydrofuran, to form an organometallic intermediate represented by formula (II-A):
wherein X 2 is Cl;
followed by reacting the organometallic intermediate of formula (II-A) with ZnCl 2 in methyl tetrahydrofuran to form the organozinc intermediate represented by formula (II-B):
wherein X is Cl; and
ii) reacting the organozinc intermediate of formula (II-B) with a second starting material represented by formula (III):
wherein R is Boc (tert-butoxycarbonyl) and Z is Br;
in the presence of the palladium catalyst to form the compound of formula (I); wherein the palladium catalyst is Pd 2 (dba) 3 , wherein the reaction further comprises tBu 3 P—HBF 4 , KotBu, and N-methyl-2-pyrollidinone.