反应 #1726682

反应方程式

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

收率 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

收率 44.5%

溶剂

DMF

反应条件

后处理

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

实验过程

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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