tert-butyl (3R)-3-aminopiperidine-1-carboxylate → (R)-tert-butyl 3-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-ylamino)piperidine-1-carboxylate

HRID 634180Notes

Reaction equation

HRID 634180 reaction equation
[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22](S(C)(=O)=O)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1>O1CCOCC1.CN1CCCC1=O.C(Cl)Cl>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22]([NH:39][C@@H:40]5[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]5)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:2])[CH3:3]

Participants

6

Reactant 2

HCID 1501974tert-butyl (3R)-3-aminopiperidine-1-carboxylateHCID 683282892-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole

Product 1

HCID 86725106(R)-tert-butyl 3-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-ylamino)piperidine-1-carboxylateYield 50%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 13387N-methyl-2-pyrrolidoneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A yellow solution of 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (177.5 mg, 0.284 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (Small Molecules, Inc., Hoboken, N.J.; 0.251 mL, 1.296 mmol) in dioxane (2.0 mL) was heated in an open microwave vial at 90° C. for 2 d. The resulting solid residue was taken up in N-methyl-2-pyrrolidinone (0.4 mL) and heated under argon at 120° C. for 2.5 days. The mixture was then diluted with DCM (10 mL), concentrated onto silica gel, and chromatographically purified (silica gel, 0-100% EtOAc/Hex) to provide (R)-tert-butyl 3-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-ylamino)piperidine-1-carboxylate (98.0 mg, 0.142 mmol, 50%) as a yellow oil: MS (ESI, pos. ion) m/z: 689.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (1H, s), 8.07 (1H, s), 8.06 (1H, d, J=8.2 Hz), 7.93 (1H, d, J=8.7 Hz), 7.82 (2H, d, J=8.4 Hz), 7.62 (1H, t, J=7.8 Hz), 7.28 (2H, d, J=8.0 Hz), 7.24 (2H, s), 6.63 (1H, d, J=8.2 Hz), 5.55 (1H, dt, J=12.0, 5.9 Hz), 4.40 (1H, d, J=6.1 Hz), 3.61-3.74 (2H, m), 3.47-3.57 (2H, m), 3.36-3.45 (2H, m), 3.30 (2H, m), 2.35 (3H, s), 1.47 (9H, s), 1.44 (6H, br. s.).

Workup

  1. concentrationconcentrated onto silica gel
  2. customchromatographically purified (silica gel, 0-100% EtOAc/Hex)

Sources & evidence

ORD record
ord-81582483bbef41789cb34684a170c06c
Source dataset
uspto-grants-2016_04
Patent number
US09321756B2

Reaction notes

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