Phosphorus oxychloride → 6-Chloro-8-[5-(3-cyclobutyl-3-aza bicyclo[3.1.0]hex-6-yl)-[1,3,4]oxadiazol-2-yl]chroman-5-ylamine

HRID 1523735Notes

Reaction equation

HRID 1523735 reaction equation
[CH:1]1([N:5]2[CH2:10][CH:9]3[CH:7]([CH:8]3[C:11]([OH:13])=O)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:19][C:20]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([NH:33][NH2:34])=O)=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][O:25]2>>[Cl:30][C:29]1[C:20]([NH2:19])=[C:21]2[C:26](=[C:27]([C:31]3[O:13][C:11]([CH:8]4[CH:7]5[CH:9]4[CH2:10][N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:6]5)=[N:34][N:33]=3)[CH:28]=1)[O:25][CH2:24][CH2:23][CH2:22]2

Participants

4

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 867249123-Cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylic acidHCID 867249165-Amino-6-chloro-chroman-8-carboxylic acid hydrazide

Product 1

HCID 715347776-Chloro-8-[5-(3-cyclobutyl-3-aza bicyclo[3.1.0]hex-6-yl)-[1,3,4]oxadiazol-2-yl]chroman-5-ylamineYield 14.1%

Procedure

To 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylic acid (74 mg, 0.40 mmol, obtained in preparation 8) was added phosphoryl chloride (1 mL). The mixture was stirred for 15 minutes and 5-amino-6-chloro chroman-8-carboxylic acid hydrazide (80 mg, 0.33 mmol) was added. The reaction mixture was gradually heated to reflux for 1 hour. 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 and was purified by silica gel column to obtain 6-chloro-8-[5-(3-cyclobutyl-3-aza bicyclo[3.1.0]hex-6-yl)-[1,3,4]oxadiazol-2-yl]chroman-5-yl amine (18 mg).

Workup

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

Sources & evidence

ORD record
ord-1aed4c554da44c39906336c9b94dc936
Source dataset
uspto-grants-2015_07
Patent number
US09079894B2

Reaction notes

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