Reaktion #1726682

Reaktionsgleichung

1A

4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-3-chlorophenol

1C

1-(5-Phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yl methanesulfonate

Cs2CO3

→

1

Ausbeute 44.5%

(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

Ausbeute 44.5%

Lösungsmittel

DMF

Reaktionsbedingungen

Aufarbeitung

1. 1
   FiltrationThe mixture was filtered
2. 2
   Sonstigeapproximately half the volume of solvent was evaporated
3. 3
   SonstigeThe product was purified by preparative RP HPLC (gradient: 15-55% acetonitrile over 30 min, 0.2% ammonia buffer)
4. 4
   Einengenconcentrated
5. 5
   workup.ADDITIONDichloromethane was added
6. 6
   Sonstigethe solution was dried (phase separator)
7. 7
   Einengenconcentrated in vacuo

Vorschrift

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.

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