(S)-3-hydroxy-2-methylamino-propionic acid methyl ester hydrochloride

• 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: (S)-3-hydroxy-2-methylamino-propionic acid methyl ester hydrochloride
• 英文别名: (S)-N-Methylserine methyl ester hydrochloride；N-methylserine methyl ester hydrochloride；methyl N-methyl-L-serinate hydrochloride；N-Me-Ser-OMe.HCl；methyl (2S)-3-hydroxy-2-(methylamino)propanoate;hydrochloride
• 化学式: C₅H₁₁NO₃*ClH
• 分子量: 169.608
• InChiKey: ZMOSKMOHEOBOGS-WCCKRBBISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.84
• 重原子数：
  10
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  58.6
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3'-(4-chloro-2,5-dimethyl-benzenesulfonylamino)-3,5-dimethyl-biphenyl-4-carboxylic acid chloride 、 (S)-3-hydroxy-2-methylamino-propionic acid methyl ester hydrochloride 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以6.05 g的产率得到(S)-2-{[3'-(4-chloro-2,5-dimethylphenylsulfonylamino)-3,5-dimethyl-biphenyl-4-carbonyl]-methylamino}-3-hydroxy-propionic acid methyl ester
  参考文献：
  名称：

  An Oral Sphingosine 1-Phosphate Receptor 1 (S1P₁) Antagonist Prodrug with Efficacy in Vivo: Discovery, Synthesis, and Evaluation

  摘要：

  A prodrug approach to optimize the oral exposure :of a series of sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists for chronic efficacy studies led to the discovery of dimethylphenylsulfonylamino)-3,5-dimethylbiphenyl-4-carbonyl]-methylamino}-4-dimethylaminobutyric acid methyl ester 14. Methyl ester prodrug 14 is hydrolyzed in vivo to the corresponding carboxylic, acid 15, a potent and selective S1P(1) antagonist.: Oral; administration of the prodrug 14 induces sustained peripheral blood lymphocyte reduction.. in rats. In a rat: cardiac transplantation model coadministration of a nonefficacious dose of prodrung 14 with a nonefficacious dose of sotrastaurin (19), a protein kinase C inhibitor, or everolimus mTOR inhibitor, effectively prolonged the survival time of rat cardiac allografts. This demonstrates that clinically useful immunomodulation mediated by the S1P(1) receptor can be achieved with an S1P(1) antagonist generated in vivo after oral administration of its prodrug.

  DOI：

  10.1021/jm3009508
• 作为产物：
  描述：

  甲醇 、 N-甲基-L-丝氨酸 在 氯化亚砜 作用下， 反应 4.0h， 生成 (S)-3-hydroxy-2-methylamino-propionic acid methyl ester hydrochloride
  参考文献：
  名称：

  α-或β-O-Ser/Thr糖苷和糖肽的一般方法。O-糖基环脑啡肽类似物的固相合成

  摘要：

  使用衍生自 L-丝氨酸 (3a-c)、L-苏氨酸 (4a,b) 和二肽酯 (5) 的高度亲核性 α-亚氨基酯（O'Donnell's Schiff 碱）已有效合成 O-连接糖肽. 已开发出通用方法，可以使用 Hanessian 修饰或 Helferich 修饰以优异的产率 (63-94%) 和优异的选择性 (>20:1) 提供 β-羟基-α-氨基酸衍生物 6-16 的 β-糖苷。 Koenigs-Knorr 反应。同样，使用 Lemieux 的原位异构化方法实现了选择性 α-糖基化。丝氨酸/苏氨酸羟基的亲核性增加已被证明是由于分子内氢键连接到 N=CPh 2 部分。中间席夫碱的脱保护已被证明，

  DOI：

  10.1021/ja00052a022

文献信息

• General methods for .alpha.- or .beta.-O-Ser/Thr glycosides and glycopeptides. Solid-phase synthesis of O-glycosyl cyclic enkephalin analogs
  作者：Robin Polt、Lajos Szabo、Jennifer Treiberg、Yushun Li、Victor J. Hruby

  DOI：10.1021/ja00052a022

  日期：1992.12

  O-Linked glycopeptides have been efficiently synthesis using the highly nucleophilic α-imino esters (O'Donnell's Schiff bases) derived from L-serine (3a-c), L-threonine (4a,b), and a dipeptide ester (5). General methodology has been developed which can provide β-glycosides of β-hydroxy-α-amino acid derivatives 6-16 in excellent yield (63-94%) and excellent selectivity (>20:1) using Hanessian's modification

  使用衍生自 L-丝氨酸 (3a-c)、L-苏氨酸 (4a,b) 和二肽酯 (5) 的高度亲核性 α-亚氨基酯（O'Donnell's Schiff 碱）已有效合成 O-连接糖肽. 已开发出通用方法，可以使用 Hanessian 修饰或 Helferich 修饰以优异的产率 (63-94%) 和优异的选择性 (>20:1) 提供 β-羟基-α-氨基酸衍生物 6-16 的 β-糖苷。 Koenigs-Knorr 反应。同样，使用 Lemieux 的原位异构化方法实现了选择性 α-糖基化。丝氨酸/苏氨酸羟基的亲核性增加已被证明是由于分子内氢键连接到 N=CPh 2 部分。中间席夫碱的脱保护已被证明，
• Total Synthesis of TAN-1057 A/B, a New Dipeptide Antibiotic fromFlexibacter sp. PK-74
  作者：Viktor V. Sokolov、Sergei I. Kozhushkov、Sofia Nikolskaya、Vladimir N. Belov、Mazen Es-Sayed、Armin de Meijere

  DOI：10.1002/(sici)1099-0690(199805)1998:5<777::aid-ejoc777>3.0.co;2-w

  日期：1998.5

  23 (30%). The latter was deprotected by hydrogenolysis to give the final compound as a mixture of two epimers − TAN-1057A, B − isolated previously from a strain of Flexibacter sp. PK-74. The intermediate 3 was prepared from 3-amino-2-(N-Z-N-methylamino)propionic acid methyl ester hydrochloride (16) and 2-methyl-2-thiopseudobiuret hydroiodide (18) in one step in 35% yield.

  TAN-1057 (1a, b) - 一种对耐甲氧西林金黄色葡萄球菌具有活性的新型天然二肽抗生素 - 从 Nα、Nδ、Nω-tri-ZL-精氨酸 20b 开始，通过相应的重氮酮 21b 合成。这在光解后重排为烯酮，其被 (±)-2,4,5,6-四氢-5-甲氨基-2-脲基嘧啶-4-一 (3) 捕获，得到完全保护的二肽 23 (30%) . 后者通过氢解脱保护得到最终化合物，为两种差向异构体的混合物 - TAN-1057A，B - 先前从 Flexibacter sp. 菌株中分离。PK-74。中间体3由3-氨基-2-(NZN-甲基氨基)丙酸甲酯盐酸盐(16)和2-甲基-2-硫代伪缩二脲氢碘化物(18)一步制备，产率为35％。
• [EN] THIADIAZOLIDINEDIOXIDE P2X7 RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DU RÉCEPTEUR P2X7 À BASE DE THIADIOZOLIDINEDIOXYDE
  申请人：GLAXO GROUP LTD

  公开号：WO2011054947A1

  公开（公告）日：2011-05-12

  The invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein: R1 is C1-3alkyl or C1fluoroalkyl-CH2; R2 is hydrogen, C1-4alkyl, C1fluoroalkyl-CH2-, C3-6cycloalkyl, C3-6cycloalkyl-methyl-, optionally substituted benzyl, or optionally substituted heteroaryl-(CH2)n-, wherein n is 0 or 1, wherein in R2 the benzyl is optionally substituted on the ring with one or two substituents independently being methyl, methoxy, fluorine or chlorine, and wherein in R2 the heteroaryl-(CH2)n- optionally substituted on the heteroaryl ring with one or two substituents independently being C1-3alkyl, CF3, methoxy, a halogen atom, or cyano; and wherein: R3, R4, R5, R6 and R7 independently are hydrogen, a halogen atom, C1-4alkyl, trifluoromethyl, or cyano, such that one or both of R3 and R7 is or are a group other than hydrogen.

  本发明提供了式（I）的化合物或其药学上可接受的盐，其中：R1是C1-3烷基或C1氟代烷基-CH2；R2是氢、C1-4烷基、C1氟代烷基-CH2-、C3-6环烷基、C3-6环烷基-甲基、可选地取代的苄基或可选地取代的杂环烷基-(CH2)n-，其中n为0或1，在R2中，苄基在环上可选地被一个或两个取代基取代，这些取代基独立地是甲基、甲氧基、氟或氯，在R2中，杂环烷基-(CH2)n-在杂环烷基环上可选地被一个或两个取代基取代，这些取代基独立地是C1-3烷基、CF3、甲氧基、卤素原子或氰基；其中：R3、R4、R5、R6和R7独立地是氢、卤素原子、C1-4烷基、三氟甲基或氰基，使得R3和/或R7是除氢外的一个或多个基团。
• Fluorogenic Peptide Substrates for Serine and Threonine Phosphatases
  作者：Fengtian Xue、Christopher T. Seto

  DOI：10.1021/ol1003065

  日期：2010.5.7

  A new fluorescent assay for Ser/Thr protein phosphatases has been developed. Hydrolysis of a phosphoSer residue liberates the Ser hydroxyl group, which induces a cyclization reaction on the N-terminal carbamate and releases a fluorescent reporter. Sequence selectivity is observed using several peptide substrates against alkaline phosphatase (ALP), bacteriophage lambda protein phosphatase (lambda-PPase), and vaccinia H1 related phosphatase (VHR). These studies suggest that the assay could be a useful tool for profiling the substrate specificities of medicinally important phosphatases.
• An Oral Sphingosine 1-Phosphate Receptor 1 (S1P₁) Antagonist Prodrug with Efficacy in Vivo: Discovery, Synthesis, and Evaluation
  作者：Daniela Angst、Philipp Janser、Jean Quancard、Peter Buehlmayer、Frederic Berst、Lukas Oberer、Christian Beerli、Markus Streiff、Charles Pally、Rene Hersperger、Christian Bruns、Frederic Bassilana、Birgit Bollbuck

  DOI：10.1021/jm3009508

  日期：2012.11.26

  A prodrug approach to optimize the oral exposure :of a series of sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists for chronic efficacy studies led to the discovery of dimethylphenylsulfonylamino)-3,5-dimethylbiphenyl-4-carbonyl]-methylamino}-4-dimethylaminobutyric acid methyl ester 14. Methyl ester prodrug 14 is hydrolyzed in vivo to the corresponding carboxylic, acid 15, a potent and selective S1P(1) antagonist.: Oral; administration of the prodrug 14 induces sustained peripheral blood lymphocyte reduction.. in rats. In a rat: cardiac transplantation model coadministration of a nonefficacious dose of prodrung 14 with a nonefficacious dose of sotrastaurin (19), a protein kinase C inhibitor, or everolimus mTOR inhibitor, effectively prolonged the survival time of rat cardiac allografts. This demonstrates that clinically useful immunomodulation mediated by the S1P(1) receptor can be achieved with an S1P(1) antagonist generated in vivo after oral administration of its prodrug.