Sodium hydride → (1S,4R)-4-(3-Cyclohexyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamine

HRID 75623Notes

Reaction equation

[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[CH:15]1([C:21]2[N:25]3[CH:26]=[C:27](F)[CH:28]=[CH:29][C:24]3=[N:23][N:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C=O)C>[CH:15]1([C:21]2[N:25]3[CH:26]=[C:27]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:28]=[CH:29][C:24]3=[N:23][N:22]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1

Participants

Conditions

Temperature: 60 °C

Procedure

An opaque brown solution of Intermediate 1d (171 mg, 1.05 mmol) and sodium hydride (60% dispersion in oil, 120 mg, 3.00 mmol) in dry DMF (2 mL) was stirred at RT under Argon for 30 min. Intermediate 34b (219 mg, 1.00 mmol) was added, and the resulting dark solution stirred at 60° C. for 2 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (2 mL), applied to an SCX-2 cartridge, and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo left a brown oil. Flash chromatography (silica 25 g, 2-10% [2M NH3 in MeOH] in DCM) gave a yellow oil. Freeze-drying from MeCN-water (1:2, 3 mL) left the title compound as a pale yellow solid (203 mg, 56%). LCMS (Method 3): Rt 2.29 min, m/z 363 [MH+].

Workup

concentrationThe cooled solution was concentrated in vacuo
dissolutionredissolved in MeOH (2 mL)
washwashed with MeOH
washThe product was eluted with 2M NH3 in MeOH
concentrationconcentration in vacuo
waitleft a brown oil
customFlash chromatography (silica 25 g, 2-10% [2M NH3 in MeOH] in DCM) gave a yellow oil
dry with materialFreeze-drying from MeCN-water (1:2, 3 mL)
waitleft the title compound as a pale yellow solid (203 mg, 56%)

Sources & evidence

ORD record: ord-9b498db0f0c145b7ad085211e2cc8d8d
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08835431B2

Reaction notes

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