tetra-tert-butyl N--L-γ-glutamyl>-L-glutamate | 32719-57-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: tetra-tert-butyl N--L-γ-glutamyl>-L-glutamate
• 英文别名: Cbz-gGlu(OtBu)-gGlu(OtBu)-Glu(OtBu)-OtBu；ditert-butyl (2S)-2-[[(4S)-5-[(2-methylpropan-2-yl)oxy]-4-[[(4S)-5-[(2-methylpropan-2-yl)oxy]-5-oxo-4-(phenylmethoxycarbonylamino)pentanoyl]amino]-5-oxopentanoyl]amino]pentanedioate
• CAS: 32719-57-6
• 化学式: C₃₉H₆₁N₃O₁₂
• 分子量: 763.926
• InChiKey: LIZWJWFWHSVURK-KCHLEUMXSA-N

物化性质

• 熔点：
  76-78 °C
• 沸点：
  844.9±65.0 °C(Predicted)
• 密度：
  1.134±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  54
• 可旋转键数：
  26
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  202
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  tetra-tert-butyl N--L-γ-glutamyl>-L-glutamate 在 palladium on activated charcoal diethyl cyanophosphoridate 、 氢气 、 三乙胺 作用下， 以 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 5.5h， 生成 N--N-methylamino>-2-thenoyl>-L-γ-glutamyl>-L-γ-glutamyl>-L-glutamic acid trifluoroacetate
  参考文献：
  名称：

  Syntheses and thymidylate synthase inhibitory activity of the poly-.gamma.-glutamyl conjugates of N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid (ICI D1694) and other quinazoline antifolates

  摘要：

  Thirteen poly-gamma-glutamates derived from several novel antifolates have been synthesized by a convergent route. The syntheses of poly-gamma-glutamyl conjugates of N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid (8) (ICI D1694), 2-desamino-N10-propargyl-5,8-dideazafolic acid (6), 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (7), 2-desamino-2-methyl-N10-propargyl-2'-fluoro-5,8-dideazafolic acid (9), and 2-desamino-2-methyl-4-chloro-N10-propargyl-2'-fluoro-3,5,8-trideazafolic acid (11) are described. A key step in the route involves coupling of an alpha-tert-butyl-protected poly-gamma-glutamate of the required chain length to the appropriate 5,8-dideazapteroic acid, obtained by carboxypeptidase G2 cleavage of the parent monoglutamate, if available, or by chemical synthesis. Deprotection with trifluoroacetic acid in the final step gave the desired poly-gamma-glutamyl antifolates as their trifluoroacetate salts. As inhibitors of thymidylate synthase, these polyglutamates were more potent in every case than the corresponding non-polyglutamylated drug.

  DOI：

  10.1021/jm00083a008
• 作为产物：
  描述：

  Z-谷安酸叔丁基酯 在 palladium on activated charcoal N-甲基吗啉 、 氢气 、 氯甲酸异丁酯 作用下， 以 甲醇 为溶剂， 反应 0.67h， 生成 tetra-tert-butyl N--L-γ-glutamyl>-L-glutamate
  参考文献：
  名称：

  喹唑啉类抗叶酸抑制胸苷酸合酶：N10-炔丙基-5,8-二氮杂壬酸的四种低聚（L-γ-谷氨酰基）缀合物的合成及其酶抑制作用。

  摘要：

  描述了N10-炔丙基-5,8-二氮杂三酸的总共四个，三个，四个和五个L-谷氨酸残基的四个寡（γ-谷氨酰基）缀合物的合成。选择叔丁基作为羧基保护基是为了避免使用碱，从而避免了γ-α转肽的可能性。通过与氯甲酸异丁酯的混合酸酐将起始原料谷氨酸二叔丁基酯与N-（苄氧羰基）-L-谷氨酸α-叔丁酯偶联。产物中的苄氧羰基进行氢解得到羧基保护的二谷氨酸盐，将其用4-[（（苄氧羰基）氨基]苯甲酰氯酰化得到保护的氨基苯甲酰胺，或通过使用上述混合的酸酐/氢解顺序进一步循环成三-，四-和五谷氨酸。如上所述，每个姓氏也被酰化，得到苯甲酰胺。通过氢解除去苯甲酰胺中的苄氧羰基，并用炔丙基溴将由此暴露的氨基N-烷基化。用2-氨基-6-（溴甲基）-4-羟基喹唑啉氢溴酸盐进一步烷基化所得炔丙基胺，得到抗叶酸的聚（t-Bu）酯。在最后步骤中，用三氟乙酸脱保护，得到所需的抗叶酸剂，为其三氟乙酸盐。五至谷氨酸二戊酸酯对WI-L2人

  DOI：

  10.1021/jm00121a029

文献信息

• Synthesis of the penta-glutamyl derivative of<i>N</i>-[4-[<i>N</i>-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)-propyl]amino]benzoyl]-L-glutamic acid (5-DACTHF). An acyclic analogue of tetrahydrofolic acid
  作者：Virgil L. Styles、James L. Kelley

  DOI：10.1002/jhet.5570270654

  日期：1990.9

  N-[4-[N-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propyl]amino]-benzoyl)-L-glutamic acid (1, 5-DACTHF, 543U76) was synthesized by a convergent route. L-γ-Glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid heptakis t-butyl ester (20) was prepared in ten steps from L-glutamic acid di-t-butyl ester and N-(benzyloxycarbonyl)-L-glutamic acid α-t-butyl ester. 4-[N-[3-(2,4-Diamino-1

  N- [4- [ N- [3-（2,4-二氨基-1,6-二氢-6-氧代-5-嘧啶基）丙基]氨基]-苯甲酰基）-L-谷氨酸的五谷氨酰基衍生物（1，5-DACTHF，543U76）通过会聚路线合成。L-γ-谷氨酰基-L-γ-谷氨酰基-L-γ-谷氨酰基-L-γ-谷氨酰基-L-γ-谷氨酰基-L-谷氨酸庚基叔丁基酯（20）由L-经十个步骤制备谷氨酸二吨丁基酯和ñ - （苄氧羰基）-L-谷氨酸α -叔丁基酯。由嘧啶基丙醛3合成的4- [ N- [3-（2,4-二氨基-1,6-二氢-6-氧代-5-嘧啶基）丙基]三氟乙酰胺基]苯甲酸（6）分三步，与20缩合，然后脱保护得到N- [4- [ N- [3-（2,4-二氨基-1,6-二氢-6-氧代-5-嘧啶基）丙基]氨基]苯甲酰基]-L-γ-谷氨酰基-L-γ-谷氨酰基-L-γ-谷氨酰基-L-γ-谷氨酰基-L-γ-谷氨酰基-L-谷氨酸（2）。六谷氨酸盐2是有效的甘氨酰胺核糖核苷酸转化酶抑制剂。
• [EN] PROCESSES OF PREPARING POLYGLUTAMATED ANTIFOLATES AND USES OF THEIR COMPOSITIONS<br/>[FR] PROCÉDÉS DE PRÉPARATION D'ANTIFOLATES POLYGLUTAMIQUES ET LEURS UTILISATIONS
  申请人：L E A F HOLDINGS GROUP LLC

  公开号：WO2021026310A1

  公开（公告）日：2021-02-11

  Provided herein are methods of preparing polyglutamated compounds, such as polyglutamated antifolates, and/or pharmaceutical compositions such as liposomal compositions comprising the same, Also provided herein are substantially pure polyglutamated compounds, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition such as liposomal composition comprising the same. The present disclosure further provides methods of using the polyglutamated compounds and compositions to treat diseases including hyperproliferative diseases such as cancer, disorders of the immune system such as rheumatoid arthritis, and infectious diseases such as HIV, malaria, and schistomiasis.

  本文提供了制备多聚谷氨酸化合物的方法，例如多聚谷氨酸化抗叶酸类化合物，以及包含这些化合物的药物组合物，还提供了基本纯净的多聚谷氨酸化合物，或其药用可接受盐，或包含这些化合物的药物组合物。本公开还提供了使用多聚谷氨酸化合物和组合物治疗疾病的方法，包括高增殖性疾病如癌症，免疫系统紊乱如类风湿性关节炎，以及传染病如艾滋病、疟疾和血吸虫病。
• First use of the Taylor pteridine synthesis as a route to polyglutamate derivatives of antifolates
  作者：Henry Bader、Andre Rosowsky

  DOI：10.1021/jo00010a038

  日期：1991.5

  The di- through penta-gamma-L-glutamates of 2-desamino-2-methylaminopterin, a new antifolate with a novel mechanism of action requiring gamma-polyglutamylation for biological activity, were prepared. alpha-tert-Butyl gamma-methyl L-glutamate was condensed with 4-nitrobenzoyl chloride, the methyl ester selectively hydrolyzed with base, and the product condensed with di-tert-butyl L-glutamate to obtain tri-tert-butyl N-(4-nitrobenzoyl)-gamma-L-glutamyl-L-glutamate. Reduction of the nitro group followed by reaction with 2-amino-5-(chloromethyl)-pyrazine-3-carbonitrile yielded tri-tert-butyl [4-[[(2-amino-3-cyanopyrazin-5-yl)methyl]amino]benzoyl]-L-gamma-glutamyl-L-glutamate, which was heated with acetamidine acetate to form tri-tert-butyl N-[4-[[(4-amino-2-methylpteridine-6-yl)methyl]amino]benzoyl]-gamma-L-glutamyl-L-glutamate. Removal of the ester groups with trifluoroacetic acid then gave 2-desamino-2-methylaminopterin diglutamate. A similar sequence was employed to convert esterified oligomers with three, four, and five glutamyl residues to 2-desamino-2-methylaminopterin tri-, tetra-, and pentaglutamate. This is the first example of the preparation of the polyglutamates of an antifolate via the Taylor pteridine synthesis.
• STYLES, VIRGIL L.;KELLEY, JAMES L., J. HETEROCYCL. CHEM., 27,(1990) N, C. 1809-1813
  作者：STYLES, VIRGIL L.、KELLEY, JAMES L.

  DOI：——

  日期：——
• Quinazoline antifolates inhibiting thymidylate synthase: synthesis of four oligo(L-.gamma.-glutamyl) conjugates of N10-propargyl-5,8-dideazafolic acid and their enzyme inhibition
  作者：Krzysztof Pawelczak、Terence R. Jones、Michal Kempny、Ann L. Jackman、David R. Newell、Leszek Krzyzanowski、Barbara Rzeszotarska

  DOI：10.1021/jm00121a029

  日期：1989.1

  benzyloxycarbonyl group in the product gave a carboxyl-protected diglutamate, which either was acylated with 4-[(benzyloxycarbonyl)amino] benzoyl chloride to give a protected aminobenzamide or was cycled further by using the above mixed anhydride/hydrogenolysis sequence into tri-, tetra-, and pentaglutamates. Each of the last named was also acylated, as above, to give a benzamide. The benzyloxycarbonyl group in the

  描述了N10-炔丙基-5,8-二氮杂三酸的总共四个，三个，四个和五个L-谷氨酸残基的四个寡（γ-谷氨酰基）缀合物的合成。选择叔丁基作为羧基保护基是为了避免使用碱，从而避免了γ-α转肽的可能性。通过与氯甲酸异丁酯的混合酸酐将起始原料谷氨酸二叔丁基酯与N-（苄氧羰基）-L-谷氨酸α-叔丁酯偶联。产物中的苄氧羰基进行氢解得到羧基保护的二谷氨酸盐，将其用4-[（（苄氧羰基）氨基]苯甲酰氯酰化得到保护的氨基苯甲酰胺，或通过使用上述混合的酸酐/氢解顺序进一步循环成三-，四-和五谷氨酸。如上所述，每个姓氏也被酰化，得到苯甲酰胺。通过氢解除去苯甲酰胺中的苄氧羰基，并用炔丙基溴将由此暴露的氨基N-烷基化。用2-氨基-6-（溴甲基）-4-羟基喹唑啉氢溴酸盐进一步烷基化所得炔丙基胺，得到抗叶酸的聚（t-Bu）酯。在最后步骤中，用三氟乙酸脱保护，得到所需的抗叶酸剂，为其三氟乙酸盐。五至谷氨酸二戊酸酯对WI-L2人