Sodium Carbonate → tert-Butyl 2-(5-(4-(benzyloxy)-2,3-difluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

HRID 579356Notes

Reaction equation

HRID 579356 reaction equation
[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[C:11]([F:18])[C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[S:25][C:24]([N:26]2[CH2:29][C:28]3([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:27]2)=[N:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:21]2[S:25][C:24]([N:26]3[CH2:29][C:28]4([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)[CH2:27]3)=[N:23][N:22]=2)=[C:11]([F:18])[C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 152187534-Benzyloxy-2,3-difluorobenzeneboronic acidHCID 86727178tert-Butyl 2-(5-bromo-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Product 1

HCID 86727179tert-Butyl 2-(5-(4-(benzyloxy)-2,3-difluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylateYield 36.3%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Nitrogen was bubbled through a stirred solution of (4-(benzyloxy)-2,3-difluorophenyl)boronic acid (356 mg, 1.349 mmol) and tert-butyl 2-(5-bromo-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (343 mg, 0.881 mmol) in dioxane (8 mL). To this solution was added Pd(PPh3)4 (52 mg, 0.045 mmol) followed by a solution of Na2CO3 (286 mg, 2.7 mmol) in water (2 mL). The reaction mixture was sealed and heated at 100° C. for 1 hour under microwave irradiation. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (75 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the crude product as a light orange/brown solid. The crude material was pre-absorbed onto silica gel and purified by flash chromatography using a 40 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a white solid (169 mg, 35% yield). LC-MS: Rt 1.62 min; MS m/z 529.4 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.82 (m, 1H), 7.46-7.51 (m, 2H), 7.36-7.45 (m, 3H), 7.24-7.32 (m, 1H), 5.30 (s, 2H), 3.89 (s, 4H), 3.24-3.31 (m, 4H), 1.66-1.78 (m, 4H), 1.40 (s, 9H).

Workup

  1. customThe reaction mixture was sealed
  2. washwashed with water (75 mL)
  3. customThe organic phase was separated
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated in vacuo
  7. customto afford the crude product as a light orange/brown solid
  8. customThe crude material was pre-absorbed onto silica gel
  9. custompurified by flash chromatography

Sources & evidence

ORD record
ord-24dabc6b1f344be3a436b96daf0f84d5
Source dataset
uspto-grants-2015_05
Patent number
US09040712B2

Reaction notes

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