Cesium carbonate → (3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-3-chlorophenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanone

HRID 1639500Notes

Reaction equation

HRID 1639500 reaction equation
[CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=3[Cl:16])[CH2:5]2)[CH2:3][O:2]1.CS(O[CH:22]1[CH2:25][N:24]([C:26]([C:28]2[O:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:31][N:32]=2)=[O:27])[CH2:23]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:3]1[C:4]2([CH2:5][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:22]4[CH2:23][N:24]([C:26]([C:28]5[O:29][C:30]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)=[N:31][N:32]=5)=[O:27])[CH2:25]4)=[CH:11][C:10]=3[Cl:16])[CH2:7]2)[CH2:1][O:2]1

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 580430991-(5-Phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yl methanesulfonateHCID 595635044-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-3-chlorophenol

Product 1

HCID 49801539(3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-3-chlorophenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanoneYield 44.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

1A (0.30 g, 1.25 mmol) was dissolved in dry DMF (10 mL) and 1C (0.61 g, 1.88 mmol) was added followed by Cs2CO3 (0.82 g, 2.50 mmol). The reaction mixture was stirred at 90° C. for 24 h. The mixture was filtered and approximately half the volume of solvent was evaporated. The product was purified by preparative RP HPLC (gradient: 15-55% acetonitrile over 30 min, 0.2% ammonia buffer). The pure fractions were combined and concentrated. Dichloromethane was added and the solution was dried (phase separator) and concentrated in vacuo. There was obtained 0.26 g (44.5%) of 1 as a solid. 1H NMR (500 MHz, CDCl3): δ 3.57 (s, 4H), 3.73 (s, 2H), 4.33 (d, 1H), 4.65 (dd, 1H), 4.73 (m, 1H), 4.77 (s, 4H), 5.06 (m, 1H), 5.14 (dd, 1H), 6.70 (d, 1H), 6.80 (s, 1H), 7.37 (m, 1H), 7.54 (m, 2H), 7.59 (m, 1H), 8.16 (d, 2H), MS (APCI+) m/z 467 [M+H]+. LC purity: 96%. A slurry experiment was performed by weighing 2.5 mg of Example 1 into a vial and adding ethanol (100 μL). The slurry was shaken for 7 days at ambient temperature and then crystals were collected using a small spatula. The crystals were dried in a hood for one hour and then analyzed using DSC (differential scanning calorimetry). A sample was weighed into an aluminium pan with a pierced lid and heated from 0° C. to 300° C. with a ramp of 5° C./min and modulated with the amplitude of ±0.6° C. every 45 seconds. The instrument was purged with nitrogen at 50 mL/minute; melting point 119±5° C.

Workup

  1. filtrationThe mixture was filtered
  2. customapproximately half the volume of solvent was evaporated
  3. customThe product was purified by preparative RP HPLC (gradient: 15-55% acetonitrile over 30 min, 0.2% ammonia buffer)
  4. concentrationconcentrated
  5. additionDichloromethane was added
  6. customthe solution was dried (phase separator)
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-07ea3f4e3f3c412fa2257c0e0339145a
Source dataset
uspto-grants-2012_02
Patent number
US08110566B2

Reaction notes

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