Process for the preparation of (9S)-N-[3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine and its solid form
The present invention relates to a process for the preparation of a compound (I), and its solid form, which is a modulator of γ-secretase and may be useful for prophylaxis and treatment of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
1 . A process for the preparation of a compound (I),
comprising the following steps:
step a) formation of compound (III),
via the reaction of compound (II),
and 4-chloro-6-methyl-pyrimidine;
step b) formation of compound (IV),
via de-protection reaction of compound (III) and formation of HCl salt;
step c) cross coupling forming of compound (I),
via Buchwald cross coupling reaction from compound (IV) and compound (V)
2 . The process according to claim 1 , characterized in that the formation of compound (III) in step a) is performed in the presence of a solvent, wherein the solvent is selected from the group consisting of MeOH, IPA, tBuOH, and water with 5% wt TPGS-750-M.
3 . The process according to claim 1 , characterized in that the formation of compound (III) in step a) is performed in the presence of a base, wherein base is selected from the group consisting of KOAc, NaOAc, NaOH, KOH, K 2 CO 3 , Na 2 CO 3 , DIPEA and TEA.
4 . The process according to claim 1 , characterized in that the formation of compound (III) in step a) is performed at 0~120° C.
5 . The process according to claim 1 , characterized in that the formation of compound (IV) in step b) is performed in the presence of a solvent, wherein the solvent is selected from the group consisting of DCM, THE, ACN and Acetone.
6 . The process according to claim 5 , characterized in that the volume of solvent is from 5 to 15 V.
7 . The process according to claim 1 , characterized in that the formation of compound (IV) in step b) is performed in the presence of an acid, wherein the acid is HCl.
8 . The process according to claim 7 , characterized in that the equivalent of acid is from 5 to 15 eq.
9 . The process according to claim 1 , characterized in that the formation of compound (IV) in step b) is performed at −20~70° C.
10 . The process according to claim 1 , characterized in that the formation of compound (I) in step c) is performed in the presence of a base, wherein the base is selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , KHCO 3 , NaOH, and KOH.
11 . The process according to claim 1 , characterized in that the formation of compound (I) in step c) is performed in the presence of an additive, wherein the additive is selected from the group consisting of H 2 O, TEA, t-BuOH, IPA, PEG-400, TPGS-750-M, DMF, Glycerol and DMAc.
12 . The process according to claim 1 , characterized in that the formation of compound (I) in step c) is performed in the presence of a solvent, wherein the solvent is selected from the group consisting of IPAc, EtOAc, MTBE, Tol, THE, 2-MeTHF and TAAz.
13 . The process according to claim 1 , characterized in that the formation of compound (I) in step c) is performed in the presence of a catalyst, wherein the catalyst is selected from the group consisting of Pd(OAc) 2 and Pd 2 (dba) 3 .
14 . The process according to claim 1 , characterized in that the formation of compound (I) in step c) is performed in the presence of a ligand, wherein the ligand is selected from the group consisting of BrettPhos, AdCyBrettPhos, tBuBrettPhos, AdBrettPhos, RocPhos, tBuXphos, BippyPhos, MetBuXphos and Me 3 MeOtBuXphos.
15 . The process according to claim 1 , characterized in that the formation of compound (I) in step c) is performed at 20~102° C. for 1~16 hours.
16 . The process according to claim 1 , characterized in that the formation of compound (I) in step c) further comprising recrystallization in a solvent, wherein the solvent is selected from the group consisting of heptane, hexane and petroleum ether.
17 . The process according to claim 16 , characterized in that the recrystallization is performed at 20~80° C. for 1~48 hours.
18 . The process according to claim 1 , characterized in that the formation of compound (I) in step c) further comprising removing residual Pd after the cross coupling reaction using metal scavengers, wherein the metal scavengers are selected from the group consisting of one or more of SiliaMetS Thiol, SiliaMetS DMT, SiliaBond Amine, SiliaMetS AMPA, SiliaMetS Cysteine, SiliaMetS DEAM, SiliaMetS Diamine, SiliaMetS DOTA, SiliaMetS Imidazole, SiliaMetS TAAcOH, SiliaMetS TAACONa, SiliaMetS Thiourea, SiliaBond Tosic Acid, SiliaMetS Triamine and MP-TMT.