CAS: 945976-76-1; (S)-2-Amino-3-(4-(2-Amino-6-((R)-2,2,2-Trifluoro-1-(3'-Methoxy-[1,1'-Biphenyl]-4-yl)Ethoxy)Pyrimidin-4-yl)Phenyl)Propanoic Acid

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(S)-3-[4-(2-amino-6-chloropyrimidin-4-yl)phenyl]-2-{[(tert-butoxy)carbonyl]amino}propanoic acid (R)-2,2,2-trifluoro-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)-ethan-1-ol (S)-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)phenyl)-2-((tertbutoxycarbonyl)amino)propanoic acid (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)phenyl)-propanoic acid toluenesulfonate (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate tosylate monohydrate (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoate maleate

合成工艺路线路线简述

  • 1443306-54-4 = 945976-76-1
    反应条件:1.1 Catalysts: Di-μ-Chlorobis[(1,2,5,6-η)-1,5-Cyclooctadiene]Diiridium,Ferrocene,1-[bis[3,5-Bis(1,1-Dimethylethyl)Phenyl]Phosphino]-2-[(1R)-1-[[(1R,2S... Solvents: Isopropanol; 2 H,25 °C1.2 Reagents: Sodium Hydroxide,Hydrogen Solvents: Toluene; 16 H,40 Atm,Rt2.1 -
    标题:Asymmetric Hydrogenation Of Trifluoromethyl Ketones: Application In The Synthesis Of Odanacatib And Lx-1031
    作者:Zhu,Tiao-Zhen; Et Al
    参考文献:Organic Chemistry Frontiers 日期:2021 卷标:8(14) 页码:3705-3711]

    1116459-85-8 = 945976-76-1 [标题:Reaction Conditions
    标题:Asymmetric Hydrogenation Of Trifluoromethyl Ketones: Application In The Synthesis Of Odanacatib And Lx-1031
    作者:Zhu,Tiao-Zhen; Et Al
    参考文献:Organic Chemistry Frontiers 日期:2021 卷标:8(14) 页码:3705-3711]

    10365-98-7 + 80418-12-8 = 945976-76-1 [标题:Reaction Conditions
    标题:Asymmetric Hydrogenation Of Trifluoromethyl Ketones: Application In The Synthesis Of Odanacatib And Lx-1031
    作者:Zhu,Tiao-Zhen; Et Al
    参考文献:Organic Chemistry Frontiers 日期:2021 卷标:8(14) 页码:3705-3711]

    10365-98-7 + 16184-89-7 = 945976-76-1
    反应条件:1.1 Reagents: Potassium Carbonate Catalysts: Tetrakis(Triphenylphosphine)Palladium Solvents: Methanol,Toluene,Water; 6 H,Rt -> Reflux2.1 Catalysts: Di-μ-Chlorobis[(1,2,5,6-η)-1,5-Cyclooctadiene]Diiridium,Ferrocene,1-[bis[3,5-Bis(1,1-Dimethylethyl)Phenyl]Phosphino]-2-[(1R)-1-[[(1R,2S... Solvents: Isopropanol; 2 H,25 °C2.2 Reagents: Sodium Hydroxide,Hydrogen Solvents: Toluene; 16 H,40 Atm,Rt3.1 -
    标题:Asymmetric Hydrogenation Of Trifluoromethyl Ketones: Application In The Synthesis Of Odanacatib And Lx-1031
    作者:Zhu,Tiao-Zhen; Et Al
    参考文献:Organic Chemistry Frontiers 日期:2021 卷标:8(14) 页码:3705-3711]

    16184-89-7 = 945976-76-1
    反应条件:1.1 Catalysts: Di-μ-Chlorobis[(1,2,5,6-η)-1,5-Cyclooctadiene]Diiridium,Ferrocene,1-[bis[3,5-Bis(1,1-Dimethylethyl)Phenyl]Phosphino]-2-[(1R)-1-[[(1R,2S... Solvents: Isopropanol; 2 H,25 °C1.2 Reagents: Sodium Hydroxide,Hydrogen Solvents: Toluene; 16 H,40 Atm,Rt2.1 -3.1 -
    标题:Asymmetric Hydrogenation Of Trifluoromethyl Ketones: Application In The Synthesis Of Odanacatib And Lx-1031
    作者:Zhu,Tiao-Zhen; Et Al
    参考文献:Organic Chemistry Frontiers 日期:2021 卷标:8(14) 页码:3705-3711
📜(S)-2-Amino-3-(4-(2-Amino-6-((R)-2,2,2-Trifluoro-1-(3'-Methoxy-[1,1'-Biphenyl]-4-yl)Ethoxy)Pyrimidin-4-yl)Phenyl)-Propanoic Acid Toluenesulfonate置于sodium Hydroxide体系中,用 四氢呋喃,水 作为反应溶剂,以16.7%的收率获得产物lx-1031; 4-[2-氨基-6-[(1R)-2,2,2-三氟-1-(3'-甲氧基联苯-4-基)乙氧基]嘧啶-4-基]-L-苯丙氨酸
参考文献:色氨酸羟化酶抑制剂lx1031(用于治疗肠易激综合征的候选药物)的工艺开发
标题:色氨酸羟化酶抑制剂lx1031(用于治疗肠易激综合征的候选药物)的工艺开发
摘要:开发了色氨酸羟化酶抑制剂lx1031的两种工艺路线,用于治疗肠易激综合症.他们共享相同的左手和右手起始材料以及倒数第二个中间体.左手部分的手性中心是通过三氟甲基芳基酮的noyori不对称氢化而建立的.右手硼酸经由的钯催化的硼化制备升-酪氨酸衍生的三氟甲磺酸芳基酯.这两个片段从右侧或左侧结合到嘧啶核上,分别构成了第一代和第二代途径.从倒数第二个中间体中除去boc保护基,得到lx1031.还讨论了纯化和分离lx1031两性离子所克服的挑战.两种工艺路线均以千克为单位成功完成,以提供lx1031 Api用于临床前和临床研究.
DOI:10.1021/acs.Oprd.9B00520

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主要参考文献


1: Camilleri M. LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin. Neurogastroenterol Motil. 2011 Mar;23(3):193-200. doi: 10.1111/j.1365-2982.2010.01643.x. Epub 2010 Dec 15. Review.
2: Camilleri M. LX-1031, a tryptophan 5-hydroxylase inhibitor that reduces 5-HT levels for the potential treatment of irritable bowel syndrome. IDrugs. 2010 Dec;13(12):921-8. Review.

合成参考文献


参考文献:10.1124/mol.119.115964
摘要:Lee TD, Lee OW, Brimacombe KR, Chen L, Guha R, Lusvarghi S, Tebase BG, Klumpp-Thomas C, Robey RW, Ambudkar SV, Shen M, Gottesman MM, Hall MD. A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein. Molecular Pharmacology. 2019 Nov;96(5):629–40. doi: 10.1124/mol.119.115964.
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