Phosphorus oxychloride → 5-Chloro-7-{5-[1-(tetrahydro pyran-4-yl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-2,3-dihydro benzofuran-4-yl amine

HRID 1523736Notes

Reaction equation

HRID 1523736 reaction equation
[O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:21][C:22]1[C:27]2[CH2:28][CH2:29][O:30][C:26]=2[C:25]([C:31]([NH:33][NH2:34])=O)=[CH:24][C:23]=1[Cl:35]>>[Cl:35][C:23]1[CH:24]=[C:25]([C:31]2[O:15][C:13]([CH:10]3[CH2:9][CH2:8][N:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:12][CH2:11]3)=[N:34][N:33]=2)[C:26]2[O:30][CH2:29][CH2:28][C:27]=2[C:22]=1[NH2:21]

Participants

4

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 252204681-Tetrahydro-2H-pyran-4-ylpiperidine-4-carboxylic acidHCID 867249204-Amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid hydrazide

Product 1

HCID 715347815-Chloro-7-{5-[1-(tetrahydro pyran-4-yl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-2,3-dihydro benzofuran-4-yl amineYield 13.1%

Procedure

To 1-(tetrahydro pyran-4-yl) piperidine-4-carboxylic acid (168.2 mg, 0.58 mmol) was added phosphoryl chloride (1.76 mL). The mixture was stirred for 15 minutes and 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid hydrazide (101.2 mg, 0.0.44 mmol, obtained in preparation 3) was added. The reaction mixture was gradually heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, triturated with hexanes (2×20 mL) and the crude mass was basified with aqueous sodium bicarbonate solution. The basified mixture was extracted with 10% methanol in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The residual mass was purified by silica gel column to obtain 5-chloro-7-{5-[1-(tetrahydro pyran-4-yl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-2,3-dihydro benzofuran-4-yl amine (23.5 mg).

Workup

  1. temperatureThe reaction mixture was gradually heated
  2. temperatureto reflux for 2 hours
  3. customtriturated with hexanes (2×20 mL)
  4. extractionThe basified mixture was extracted with 10% methanol in dichloromethane
  5. dry with materialThe organic layer was dried over anhydrous sodium sulphate
  6. customthe solvent was removed under reduced pressure
  7. customThe residual mass was purified by silica gel column

Sources & evidence

ORD record
ord-f4353d00a6104b0b82ea430db0cf99d7
Source dataset
uspto-grants-2015_07
Patent number
US09079894B2

Reaction notes

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