1,4-Dioxane → 1-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-4-triisopropylsilanyloxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

HRID 60651Notes

Reaction equation

[C:1]([C:5]1[CH:6]=[C:7]([NH2:38])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[C:12]([O:28][CH2:29][CH2:30][O:31]C3CCCCO3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@H:40]1[CH2:45][CH2:44][CH2:43][C@@H:42]([CH3:46])[N:41]1[C:47]1[N:51]2[CH:52]=[C:53]([O:56][C@H:57]3[C:66]4[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=4)[C@@H:60]([NH2:67])[CH2:59][CH2:58]3)[CH:54]=[CH:55][C:50]2=[N:49][N:48]=1.CCN(C(C)C)C(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:94]1CCOC[CH2:95]1>CO>[C:1]([C:5]1[CH:6]=[C:7]([NH:38][C:95]([NH:67][C@@H:60]2[C:61]3[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:57]([O:56][C:53]3[CH:54]=[CH:55][C:50]4[N:51]([C:47]([N:41]5[C@H:40]([CH3:39])[CH2:45][CH2:44][CH2:43][C@@H:42]5[CH3:46])=[N:48][N:49]=4)[CH:52]=3)[CH2:58][CH2:59]2)=[O:94])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:20])[CH3:21])[CH:25]([CH3:27])[CH3:26])=[C:12]([O:28][CH2:29][CH2:30][OH:31])[CH:11]=2)[N:9]=1)([CH3:2])([CH3:4])[CH3:3]

Participants

Conditions

Temperature: 45 °C

Procedure

A solution of Intermediate 55e (710 mg, 2.17 mmol), Intermediate C (385 mg, 2.17 mmol) and DIPEA (250 μL, 3.25 mmol) in 1,4-dioxane (10 mL) was stirred at 60° C. overnight. After cooling, the mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give a gum (1.25 g, quantitative) that was used without further purification in the next step. TLC [DCM/MeOH (9:1) Rf=0.4]. A solution of the above product (1.25 g, 1.30 mmol) in MeOH (30 mL) was treated with pyridinium p-toluenesulfonate (978 mg, 3.90 mmol) and the resulting mixture was heated at 45° C. overnight. The volatiles were removed under reduced pressure and the residue was taken up in DCM (80 mL) and washed with water (20 mL). The organic phase was separated using a phase separating cartridge and the organic layer was evaporated in vacuo. The product was purified by FCC, eluting with 0-10% MeOH in DCM, to give the title compound (430 mg, 40%). LCMS (Method 3): Rt 5.41 min, m/z 879,880 [MH+].

Workup

temperatureAfter cooling
customthe mixture was partitioned between EtOAc and water
extractionThe aqueous layer was then extracted with EtOAc (3×10 mL)
washThe combined organic layers were washed with brine
dry with materialdried (Na2SO4)
filtrationfiltered
customevaporated in vacuo
customto give a gum (1.25 g, quantitative) that
customwas used without further purification in the next step
customThe volatiles were removed under reduced pressure
washwashed with water (20 mL)
customThe organic phase was separated
customseparating cartridge
customthe organic layer was evaporated in vacuo
customThe product was purified by FCC
washeluting with 0-10% MeOH in DCM

Sources & evidence

ORD record: ord-6fd2235ea9fb467bbe723e046296f69f
Source dataset: uspto-grants-2016_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09440974B2

Reaction notes

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