Ammonium Chloride → tert-butyl (3R)-3-[{4-[5-(2-{(1S)-1-[(ethoxycarbonyl)oxy]ethyl}-2H-tetrazol-5-yl)-1-methyl-1H-pyrazol-4-yl]benzoyl}(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate

HRID 588384Notes

Reaction equation

HRID 588384 reaction equation
[F-].[Cs+].[CH3:3][C:4]1[C:5]([N:10]([C:24](=[O:40])[C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[N:6][CH:7]=[CH:8][CH:9]=1.[C:41](=[O:60])([O:45][C@H:46]([N:48]1[N:52]=[N:51][C:50]([C:53]2[N:57]([CH3:58])[N:56]=[CH:55][C:54]=2I)=[N:49]1)[CH3:47])[O:42][CH2:43][CH3:44].[Cl-].[NH4+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.CCOC(C)=O.O1CCOCC1>[CH2:43]([O:42][C:41]([O:45][C@H:46]([N:48]1[N:52]=[N:51][C:50]([C:53]2[N:57]([CH3:58])[N:56]=[CH:55][C:54]=2[C:28]2[CH:29]=[CH:30][C:25]([C:24]([N:10]([C:5]3[C:4]([CH3:3])=[CH:9][CH:8]=[CH:7][N:6]=3)[C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)=[O:40])=[CH:26][CH:27]=2)=[N:49]1)[CH3:47])=[O:60])[CH3:44]

Participants

8

Reactant 4

HCID 25517Ammonium ChlorideHCID 25953Cesium fluorideHCID 117661195(S)-ethyl 1-[5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazol-2-yl]ethyl carbonate2×HCID 123439813Tert-butyl (R)-3-(N-(3-methylpyridin-2-YL)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-YL)benzamido)piperidine-1-carboxylate

Product 1

HCID 117661190tert-butyl (3R)-3-[{4-[5-(2-{(1S)-1-[(ethoxycarbonyl)oxy]ethyl}-2H-tetrazol-5-yl)-1-methyl-1H-pyrazol-4-yl]benzoyl}(3-methylpyridin-2-yl)amino]piperidine-1-carboxylateYield 77%

Reagents, catalysts & solvents 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A 3-neck round-bottom flask fitted with a reflux condenser was charged with dioxane (8.5 mL) and aqueous CsF (7.65 mL, 1M solution, 7.65 mmol). This was heated to 80° C. for 0.5 h under nitrogen atmosphere. After 30 min, Preparation 24, tert-butyl (3R)-3-{(3-methylpyridin-2-yl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]amino}piperidine-1-carboxylate (1.66 g, 3.19 mmol) was added followed by Preparation 23a, (S)-ethyl 1-[5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazol-2-yl]ethyl carbonate (1.00 g, 2.55 mmol), and Pd(amphos)Cl2 catalyst (90.6 mg, 0.128 mmol). The reaction was stirred at 80° C. for 5.5 h. Aqueous ammonium chloride solution (10 mL) was added followed by EtOAc (10 mL). The layers were separated, and the aqueous phase was further extracted with EtOAc (3×15 mL), dried with MgSO4, passed through a plug of silica, and concentrated. The crude material was purified via MPLC using a gradient of 20-70% EtOAc/heptane to afford tert-butyl (3R)-3-[{4-[5-(2-{(1S)-1-[(ethoxycarbonyl)oxy]ethyl}-2H-tetrazol-5-yl)-1-methyl-1H-pyrazol-4-yl]benzoyl}(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate as a colorless solid (1.05 g, 77%). 1H NMR (CDCl3) δ: 8.41 (d, 1H), 7.61 (s, 1H), 7.36-7.32 (m, 1H), 7.24-7.10 (m, 6H), 4.76-4.46 (m, 2H), 4.32 (q, 2H), 4.07 (s, 3H), 3.47-3.36 (m, 1H), 2.67-2.14 (m, 3H), 2.06-1.99 (m, 6H), 1.81-1.59 (m, 3H), 1.47 (s, 9H), 1.36 (t, 3H).

Workup

  1. customA 3-neck round-bottom flask fitted with a reflux condenser
  2. additionwas added
  3. customThe layers were separated
  4. extractionthe aqueous phase was further extracted with EtOAc (3×15 mL)
  5. dry with materialdried with MgSO4
  6. concentrationconcentrated
  7. customThe crude material was purified via MPLC

Sources & evidence

ORD record
ord-97973db55d1843beaee31ff9b8e1dbde
Source dataset
uspto-grants-2016_01
Patent number
US09227956B2

Reaction notes

Loading…