抗2型糖尿病药西他列汀杂质A的合成研究
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摘要
目的合成西他列汀杂质A。方法将2,4,5-三氟苯乙酸、米氏酸和3-三氟甲基-5,6,7,8-四氢-1,2,4-三唑[4,3-α]吡嗪盐酸盐以"一锅法"反应得到中间体1-{3-三氟甲基-5,6-二氢-1,2,4-三唑并[4,3-a]吡嗪-7(8H)-基}-4-(2,4,5-三氟苯基)-1,3-丁二酮,再经硼氢化钠还原得到西他列汀杂质A。结果目标化合物的结构经IR、MS和1H-NMR确证。结论该方法未见文献报道,具有成本低、操作简单、反应温和、收率高等优点。
OBJECTIVE To synthesize the impurity A of sitagliptin which is a highly selective DPP-4 inhibitor used for treatment of type 2 diabetes. METHODS 1-{ 3-Trifluoromethyl-5,6-dihydro-1,2,4-triazo[4,3-a]piperazin-7( 8H)-yl}-4-( 2,4,5-trifluorophenyl) butane-1,3-dione was prepared from 2,4,5-triflurophenylacetic acid,meldrum' s acid and 3-trifluromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride with one-pot reaction,followed by reduction with sodium borohydride to yield the impurity A of sitagliptin. RESULTS The structure of the impurity A of sitagliptin was characterized by IR,MS,and1H-NMR. CONCLUSION The established synthetic route of the impurity A in this study has not been reported in the literature,and has the advantages of lowcost,easy operation,mild reaction,and high overall yield.
OBJECTIVE To synthesize the impurity A of sitagliptin which is a highly selective DPP-4 inhibitor used for treatment of type 2 diabetes. METHODS 1-{ 3-Trifluoromethyl-5,6-dihydro-1,2,4-triazo[4,3-a]piperazin-7( 8H)-yl}-4-( 2,4,5-trifluorophenyl) butane-1,3-dione was prepared from 2,4,5-triflurophenylacetic acid,meldrum' s acid and 3-trifluromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride with one-pot reaction,followed by reduction with sodium borohydride to yield the impurity A of sitagliptin. RESULTS The structure of the impurity A of sitagliptin was characterized by IR,MS,and1H-NMR. CONCLUSION The established synthetic route of the impurity A in this study has not been reported in the literature,and has the advantages of lowcost,easy operation,mild reaction,and high overall yield.
引文
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[6]BALSELLA J,DIMICHELE L,LIU J,et al.Synthesis of[1,2,4]Triazolo[4,3-a]piperazine via highly rreactive chloromethyloxadiazoles[J].Org Lett,2005,36(32):1039-1042.
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[8]SAKAKI J I,KOBAYASHI S,SATO M,et al.Synthesis of 1,3-dioxin-4-ones and their use in syhthesis.ⅩⅧ.Synthesis of aazetidin-2-ones from 1,3-dioxin-4-ones via 3-hydroxycarboxamides[J].Chem Pharm Bull,1989,37(11):2952-2960.
[9]LIU X,ZHANG N,YANG J M,et al.Hydrogen bond-assisted6π-azaelectrocyclization of penta-2,4-dienamides:synthesis of dihydropyridin-2(3H)-ones[J].J Org Chem,2013,78(7):3323-3328.
[10]HANSEN K B,BALSELLS J,DREHER S,et al.First generation process for the preparation of the DPP-4 inhibitor sitagliptin[J].Org Process Res Dev,2005,9(5):634-639.
[11]BIFLU T,FENG D Q,LIANG G B.3-Amino-4-phenylbuttanoic Acid Dderivative as Dipeptidyl Peptide Inhibitor for the Treatment or Prevention of Diabetes:EP,1624874B[P].20041202.
[12]JAUME B,LIU J C.Process to Tetrahydriazolopyrazines and Intermediates:WO,2004080958[P].20040923.
[2]HERMAN G A,BERGMAN A,STERVENS C,et al.Effect of single oral doses of sitagliptin,a dipeptidylpetidase-4 inhibitor,on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes[J].J Clin Endocrinol Metab,2006,91(11):4612-4619.
[3]KIM D,WANG L P,BECNOI M,et al.(2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-rifluorophenyl)butan-2-amine:a potent,orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes[J].J Med Chem,2005,48(1):141-151.
[4]KOTHARI H M,DAVE M G,PANDEY B,et al.Improved process for preparation of(2r)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]-triazolo[4,3-a]pyrazin-7(8h)-yl]-1-(2,4,4-trifluorophenyl)butan-2-amine and new impuretes in preparation:WO,2010032264[P].20100325.
[5]HANSEN K B,HSIAO Y,XU F,et al.Highly efficient asymmetric synthesis of sitagliptin[J].J Am Chem Soc,2009,131(25):8798-8804.
[6]BALSELLA J,DIMICHELE L,LIU J,et al.Synthesis of[1,2,4]Triazolo[4,3-a]piperazine via highly rreactive chloromethyloxadiazoles[J].Org Lett,2005,36(32):1039-1042.
[7]BETTE V,MORTREUX A,SAVOIA D,et al.Zinc-diamine]-catalyzed hydrosilylation of ketones in methanol.New developments and mechanistic insights[J].Adv Synth Catal,2005,347(347):289-302.
[8]SAKAKI J I,KOBAYASHI S,SATO M,et al.Synthesis of 1,3-dioxin-4-ones and their use in syhthesis.ⅩⅧ.Synthesis of aazetidin-2-ones from 1,3-dioxin-4-ones via 3-hydroxycarboxamides[J].Chem Pharm Bull,1989,37(11):2952-2960.
[9]LIU X,ZHANG N,YANG J M,et al.Hydrogen bond-assisted6π-azaelectrocyclization of penta-2,4-dienamides:synthesis of dihydropyridin-2(3H)-ones[J].J Org Chem,2013,78(7):3323-3328.
[10]HANSEN K B,BALSELLS J,DREHER S,et al.First generation process for the preparation of the DPP-4 inhibitor sitagliptin[J].Org Process Res Dev,2005,9(5):634-639.
[11]BIFLU T,FENG D Q,LIANG G B.3-Amino-4-phenylbuttanoic Acid Dderivative as Dipeptidyl Peptide Inhibitor for the Treatment or Prevention of Diabetes:EP,1624874B[P].20041202.
[12]JAUME B,LIU J C.Process to Tetrahydriazolopyrazines and Intermediates:WO,2004080958[P].20040923.