Synthesis Of A Novel Antitumor Reagent PRIMA-1 And Its Derivatives

PRIMA-1seriescompoundsarenovelantitumorreagents,whichcanreactivate human mutant p53, induce apoptosis in human tumor cells andinhibit tumor xenograft growth in vivo, so have remarkable antitumoractivityandagoodapplicationprospect.The synthesis of 2,2-bis(hydroxymethyl)-1-azabicyclo[2.2.2]octan-3-one (PRIMA-1), 2,2-bis(hydroxymethyl)-1-azabicyclo[2.2.2]octan-3-one dicarboxylate derivatives, 2-hydroxymethyl-2-methoxymethyl-1-aza-bicyclo[2.2.2]octan-3-one (PRIMA-1MET) and 2-hydroxymethyl-2-ethoxymethyl-1-azabicyclo[2.2.2]octan-3-one were studied. The structureoftheproductswasconfirmedbyIR,1H-NMRandMS.The synthesis of 3-quinuclidinone hydrochloride, the keyintermediate of PRIMA-1 was studied. 3-Quinuclidinone hydrochloridewas synthesized from 4-piperidinecarboxylic acid by esterification,nucleophilic substitution, Dieckmann condensation and hydrolysis reaction. The total yield of 3-quinuclidinone hydrochloride was 43.8%.Theoptimumprocessparameterswerediscussedanddetermined.PRIMA-1 was synthesized from 3-quinuclidinone hydrochloride byAldol condensation. Then 2,2-bis(hydroxymethyl)-1-azabicyclo[2.2.2]-octan-3-onedicarboxylatederivativeswassynthesizedbyesterificationofPRIMA-1 with acyl chloride. The optimum reaction conditions of Aldolreaction were determined as follow: 30 ml formalin, 50℃, 70 min andK2CO3/3-quinuclidinone hydrochloride=1.1. The yield of PRIMA-1 was43.5%. The optimum reaction conditions of esterification weredetermined as follow: PRIMA-1/acyl chloride/triethylamine = 1/3/6,reaction temperature 40℃, reaction time 22 hours, 30 ml CH2Cl2, 30 mgDMAP.Theyieldof2,2-bis(hydroxylmethyl)-1-azabicyclo[2.2.2]octan-3-one dibenzoatewas 53.7%,28%higher than that reportedbyreferences.The yield of 2,2-bis(hydroxymethyl)-1-azabicyclo[2.2.2]octan-3-onediacrylatewas47.4%,thiscompoundhasnotbeenreportedinliterature.The synthesis of PRIMA-1MET and its analogues by using a newroute was also studied. PRIMA-1METand its analogues was synthesizedfrom 3-quinuclidinone by Mannich reaction, Michael reaction and Aldolcondensation. The yield of 2-methylene-3-quinuclidinone was 85.6%.The optimumreaction conditions of Michael reaction were determined asfollow: a solution of 2-methylene-3-quinuclidinone and methanol (80equiv) was heated under reflux in the presence of molecular sieve type 4A for 24 hours, the yield of 2-methoxymethyl-1-azabicyclo[2.2.2]octan-3-one was 63.5%. The reaction time was shorten in the new processcompared with the old one. The total yield of PRIMA-1METwas 37.1%,22% higher than that reported by references. The total yield of2-hydroxymethyl-2-ethoxymethyl-1-azabicyclo[2.2.2]octan-3-one was13.5%,thiscompoundhasnotbeenreportedinliterature.ItprovidedthetheoreticalbasisandthefeasibleprocessparametersfortheindustrializationofPRIMA-1andPRIMA-1MET.