Page 157 - 《精细化工》2021年第3期

第 3 期 顾 娜，等: 千克级 DPP-4 抑制剂氢溴酸替格列汀工艺改进 ·577·

留时间与最大单杂基本一致，推测最大单杂为化合 metformin in Korean patients with type 2 diabetes mellitus: A
物Ⅲ），温度过低可能使杂质析出，导致杂质峰变大， 16-week, randomized, double-blind, placebo-controlled phase Ⅲ
trial[J]. Diabetes Obesity & Metabolism, 2015, 17(3): 309-312.
产物的溶解度与温度有关，溶解度随温度升高逐渐 [5] BORCH R F, DURST H D. Lithium cyanohydridoborate, a versatile
变大。因此，析晶温度可控制在 0~5 ℃。 new reagent[J]. Journal of the American Chemical Society, 1969,
91(14): 3996-3997.
2.5 验证实验
[6] LI J J. A collection of detailed mechanisms and synthetic applications[M].
在最佳条件下，经 3 次平行实验验证，终产物 RONG G B (荣国斌), Translation (译). 5th ed. Beijing: Science
的总收率分别为 88.33%、87.80%、87.50%，纯度分 Press (科学出版社), 2020: 66-68.
[7] HUANG Y (黄雨), LI M (李敏), YU X (俞雄), et al. Application of
别为 99.95%、99.93%、99.91%，最大单杂含量分别 sodium triacetoxyborohydride (STAB-H) in reductive amination[J].
为 0.03%、0.04%、0.06%，产品质量符合外售标准 Chinese Journal of Pharmaceuticals (中国医药工业杂志), 2008,
（外售质量标准为：原料残留含量小于 0.15%，最 39(9): 695-701.
[8] LI N (李楠), LIANG X M (梁晓梅), DONG Y H (董燕红), et al.
大未知单杂含量小于 0.50%，总杂含量小于 1.00%）。 Recent progress in reductive amination reaction[J]. Chinese Journal
of Organic Chemistry (有机化学), 2007, 27(1): 1-7.
3 结论 [9] ZHAO Y (赵艳), YAO J S (姚金水), DAI G (戴罡), et al. Research
on mechanisms and methods of deprotection of N-Boc[J]. Journal of
（1）以化合物Ⅱ和Ⅲ为原料，通过胺化还原、 Shangdong Insitute of Light Industry (山东轻工业学院学报), 2009,
23(2): 6-7.
脱保护成盐、异丙醇析晶确定了千克级氢溴酸替格 [10] GE L ( 格林 ), WU Z ( 伍兹 ). Protective groups in organic
列汀的合成路线，在乙酸催化下，胺化还原反应确 synthesis[M]. Shanghai: East China University of Science and
Technology Press (华东理工大学出版社), 2004.
定了还原剂Ⅴ最佳用量为 n(Ⅱ)∶n(Ⅲ)∶n(Ⅴ)=
[11] ZHANG J (张杰), WANG L X (王磊鑫), CHEN Y (陈勇). Tiglietine
1.0∶1.0∶1.5，反应时间 2~3 h，脱保护成盐工艺中 hydrobromide amorphous form and preparation method thereof:
HBr 的用量为 n(Ⅱ)∶n(Ⅲ)∶n(HBr)＝1.0∶1.0∶ CN108727364A[P]. 2018-04-16.
[12] ZHANG S L (张生烈), GE J H (葛建华), WANG Z Y (王朝阳),
3.5，反应时间为 4 h，异丙醇析晶温度为 0~5 ℃。
et al. Teneligliptin synthesis method: CN105294673[P]. 2014-06-18.
（2）胺化还原仅使用甲苯为反应溶剂，该体系 [13] YOSHIDA T, AKAHOSHI F, SAKASHITA H, et al. Fused bicyclic
的甲苯溶剂无需特殊处理。与现有工艺使用甲苯与 heteroarylpiperazine-substituted l-prolylthiazolidines as highly potent
DPP-4 inhibitors lacking the electrophilic nitrile group[J]. Bioorganic
四氢呋喃的混合溶剂相比，还原产物（Ⅳ）在反应 & Medicinal Chemistry, 2012, 20(16): 5033-5041.
液中纯度可达 98.40%，反应完毕无需蒸馏分离出产 [14] LI M (李明). The synthesis of teneligliptin[D]. Shijiazhuang: Hebei
物，直接在甲苯中脱保护成盐。甲苯不仅作为胺化 University of Science and Technology (河北科技大学), 2017.
[15] YOSHIDA T, SAKASHITA H, UEDA N, et al. Salt of
还原反应的溶剂，也是脱保护成盐的反应溶剂，提 prolinederivative, solvate thereof, and production method thereof:
高了反应溶剂的使用率，优化后的工艺避免了减压 JP2013032376A[P]. 2013-02-14.
[16] YOSHIDA T, AKAHOSHI F, SAKASHITA H, et al. Discovery and
蒸馏，使反应溶剂得到充分利用，降低了成本，操
preclinical profile of teneligliptin(3-[(2S, 4S)-4-[4-(3-methyl-1-
作简便，易于放大，适合工业化生产。 phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbon-yl]thia
zolidine): A highly potent, selective, long-lasting and orally active
参考文献： dipeptidyl peptidase Ⅳ inhibitor for the treatment of type 2
diabetes[J]. Bioorganic & Medicinal Chemistry, 2012, 20(19): 5705-
[1] XU W (许雯), WENG J P (翁建平). The definition and standard of
5719.
remission in type 2 diabetes[J]. Chinese Journal of Diabetes Mellitus
[17] LITTLER B J, AIZENBERG M, AMBHAIKAR N B, et al.
(中华糖尿病杂志), 2019, 11(6): 374-378.
Development of a manufacturing process for an HCV protease
[2] LI C J (李翠娟), ZHANG B B (张冰宾), LE Z P (乐治平), et al.
inhibitor candidate molecule[J]. Organic Process Research &
Design, synthesis and inhibitory activities of multi-substituted
Development, 2015, 19(2): 386-387.
pyridine derivatives on DPP-Ⅳ protease[J]. Fine Chemicals (精细化
[18] CUI Z K (崔哲凯), ZHUO G L (卓广澜). Synthesis of the key
工), 2014, 31(10): 1235-1244.
[3] LIU Q (刘琼), HE C Y (何翠英), WEI J F (卫家芬). Research intermediate (2S)-4-oxo-2-(3-thiazolidinylcarbonyl)-1-pyrrolidinecarboxylic
progress of DPP-4 inhibitors in the treatment of type 2 diabetes acid tert-butyl ester of teneligliptin[J]. Fine Chemical Intermediates
mellitus and its clinical application[J]. Practical Pharmacy and (精细化工中间体), 2018, 48(6): 41-44.
Clinical Remedies (实用药物与临床), 2015, 18(7): 856-859. [19] HE X (何旭), WANG J Y (王加燕), ZHANG C (张池), et al.
[4] KIM M K, RHEE E J, HAN K A, et al. Efficacy and safety of Synthesis method of teneligliptin-related impurity: CN110028496A[P].
teneligliptin, a dipeptidyl peptidase-4 inhibitor, combined with 2019-04-26.