氯胺酮

草awa留言 | 贡献2024年11月19日 (二) 22:58的版本

氯胺酮(Ketamine),是一种NMDA受体拮抗剂,与苯环己哌啶有关。

氯胺酮
化学数据
化学式C13H16ClNO
摩尔质量237.73 g·mol−1
识别信息
IUPAC名称(RS)-2-(2-氯苯基)-2-(甲基氨基)环己酮
CAS号
PubChem CID
药理数据
NMDAR(↓) [1][2]
DRD2(↑) [3][2][4][5]
  • 0.5Tooltip Ki(μM)
DAT(↓) [6]
  • 63Tooltip Ki(μM)
NET(↓) [6][7]
MOR1(↓) [8]
  • 42Tooltip Ki(μM)
MOR2(↓) [9]
  • 12.1Tooltip Ki(μM)
KOR1 [8][10]
氯胺酮
别名
  • K

  • K他命

  • k粉

合成[11]

1: 将邻溴氯苯(1 .20mL,10 .0mmol)溶解于溶剂中(THF20mL) ,然后于-90°C下逐滴加入正丁基锂(4.0mL,10.0mmol),在该温度下搅拌反应5h,然后依次逐滴加入环氧环己烷 (0 .5mL,5 .0mmol)和氯化镁乙醚溶液(0 .95mL,7 .5mmol)。

2: 反应完成后,将体系温度升至0°C,加入10ml饱和NH4Cl淬 灭 反 应 ,Et2O萃取( 3×30ml),合并有机相,有机相用无水Na4SO3干燥,抽干溶剂,柱层析(石油醚/乙酸乙酯=4:1),得到无色固体2-(2-氯苯)环己醇(1 .81g,产率86.0%)

3: 室温下,将2-(2-氯苯)环己醇(105mg,0 .5mmol)溶解于10mL重蒸DCM中,然后加入戴斯马丁氧化剂 ( DMP,254. 5mg,0.5mml ),室温搅拌。待原料消耗完之后 (TLC监测) ,加入5.0mLNa2S2O3及5.0mL饱和NaHCO3,然后用Et2O(3×10mL)萃取,合并有机相,有机相用无水Na2SO4干燥,抽干溶剂,柱层析(石油醚/乙酸乙酯=40:1) ,得到浅黄色固体2-(2-氯苯)环己酮(75.1mg,产率90%)

4: 在干燥的15ml封管中依次加入2-(2-氯苯)环己酮 (42mg,0.2mmol),硝酸铜(330mg,0.6mmol)及硫酸铜(16mg,0.1mmol),然后在氩气氛围下加入2ml1,2二氯乙烷(DCE),用盖子密封,由100°C油浴反应12h。当原料消耗完之后 ,将体系降温至室温,然后加入5ml石油醚稀释,直接进行柱层析(石油醚/乙酸乙酯=40:1 ),得到浅黄色固体2-2硝基2-(2-氯苯)环己酮(25.8,产率51%)

5: 室温下,将2-硝基-2-(2-氯苯)环己酮(50 .7mg,0.2mmol)溶解于2 .0mL醋酸/异丙醇中 ,然后加入锌粉 ,室温搅拌。反应完成后,加入2ml饱和NaHCO3溶液淬灭反应,然后用EtOAc萃取(3× 5ml),合并有机相,有机相用无水Na2SO4干燥,抽干溶剂,柱层析(石油醚/乙酸乙酯=1:1),得到浅黄色固体2-氨基-2-(2-氯苯)环己酮(39.8mg,产率89%)

6: 将2-氨基-2-(2-氯苯)环己酮(31 .3mg,0 .14mmol)溶解于1 .5mL甲醇中,然后依次加入甲醛(129μL,1 .7mmol,37%水溶液),醋酸(87μL,1 .4mmol)及氰基硼氢化钠(133mg,2 .1mmol) ,室温搅拌12h后,加入5 .0mL饱和碳酸钠溶液淬灭,乙醚(3×10mL)萃取,合并有机相,有机相用无水Na2SO4干燥,抽干溶剂,柱层析(石油醚/乙酸乙酯=1:1),最终得到白色固体氯胺酮(22 .3mg,产率65 .6%)

参考文献

  1. Morris PJ, Moaddel R, Zanos P, Moore CE, Gould TD, Zarate CA, Thomas CJ (September 2017). "Synthesis and N-Methyl-d-aspartate (NMDA) Receptor Activity of Ketamine Metabolites". Organic Letters. 19 (17): 4572–4575. doi:10.1021/acs.orglett.7b02177. PMC 5641405. PMID 28829612.
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  5. Jordan S, Chen R, Fernalld R, Johnson J, Regardie K, Kambayashi J, Tadori Y, Kitagawa H, Kikuchi T (July 2006). "In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D2 receptors". European Journal of Pharmacology. 540 (1–3): 53–6. doi:10.1016/j.ejphar.2006.04.026. PMID 16730695.
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  11. "CN106478367B - 一种合成氯胺酮的中间体化合物以及氯胺酮的合成方法" (in Chinese). 2016-09-30.{{cite web}}: CS1 maint: unrecognized language (link)