4′-methyl-d4T | 151989-82-1

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 英文名称: 4′-methyl-d4T
• 英文别名: 4'-methyl D4T；1-[(2R,5S)-5-(hydroxymethyl)-5-methyl-2H-furan-2-yl]-5-methyl-pyrimidine-2,4-dione；1-[(2R,5S)-5-(hydroxymethyl)-5-methyl-2H-furan-2-yl]-5-methylpyrimidine-2,4-dione
• CAS: 151989-82-1
• 化学式: C₁₁H₁₄N₂O₄
• 分子量: 238.243
• InChiKey: ARVZUQISYCBJRH-KCJUWKMLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4′-methyl-d4T 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 12.0h， 以74%的产率得到1-(2,3-dideoxy-4-C-methyl-β-D-glycero-pentofuranosyl)thymine
  参考文献：
  名称：

  Synthesis of 1-(2,3-Dideoxy-4-C-methyl-β-D-glycero-pent-2-enofuranosyl)thymine, 1-(2,3-Dideoxy-4-C-methyl-β-D-glycero-pentofuranosyl)thymine and 1-(4-C-Azidomethyl-2-deoxy-β-D-threo-pentofuranosyl)thymine

  摘要：

  异丙基亚甲基衍生物I与氯化硫酰在六甲基膦酰胺中反应，生成氯代衍生物II。用阳离子交换树脂（H+形式）处理II中的异丙基亚甲基基团，得到游离氯代核苷III。用三丁基锡还原氯代衍生物II，并随后去除异丙基亚甲基基团，得到脱氧衍生物V。这个化合物被叔丁基二苯基硅基保护，并转化为甲磺酸盐VII。去除甲磺基，随后去除硅基，得到1-(2,3-二去氧-4-C-甲基-β-D-glycero-pent-2-enofuranosyl)胸腺嘧啶（IX），通过氢化反应得到1-(2,3-二去氧-4-C-甲基-β-D-glycero-pentofuranosyl)胸腺嘧啶（X）。通过异丙基亚甲基衍生物I的甲磺化，甲磺基的亲核取代反应以及去除异丙基亚甲基基团，制备出1-(1-C-Azidomethyl-2-deoxy-β-D-threo-pentofuranosyl)胸腺嘧啶（XIII）。

  DOI：

  10.1135/cccc19931668
• 作为产物：
  描述：

  Acetic acid (2R,3R,4R,5R)-2-acetoxymethyl-4-bromo-2-methyl-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-3-yl ester 在 氨 、 铜 、 锌 作用下， 以 甲醇 为溶剂， 反应 0.5h， 生成 4′-methyl-d4T
  参考文献：
  名称：

  Synthesis and Biological Evaluation of 4′-C-Methyl Nucleosides

  摘要：

  A series of 2'-deoxy, 2',3'-unsaturated and 2',3'-dideoxynucleoside analogues, which have an additional methyl group at the 4'-position, have been synthesized. When evaluated for their inhibitory activity against HIV in MT-4 cell, 2'-deoxy-4'-C-methyl nucleosides exhibited potent activity.

  DOI：

  10.1080/07328319608002385

文献信息

• [EN] PHOSPHORAMIDATE NUCLEOSIDE PRODRUG FOR TREATING VIRAL DISEASES AND CANCER, PROCESSES FOR THEIR PREPARATION AND THEIR USE<br/>[FR] PROMÉDICAMENT NUCLÉOSIDE PHOSPHORAMIDATE DESTINÉ AU TRAITEMENT DES MALADIES VIRALES ET DU CANCER, LEURS PROCÉDÉS DE PRÉPARATION ET LEUR UTILISATION
  申请人：IVACHTCHENKO ALEXANDRE VASILIEVICH

  公开号：WO2018022221A1

  公开（公告）日：2018-02-01

  The present invention pertains to chemotherapeutic agents and their use for treating viral and cancerous diseases. These compounds are inhibitors of HCV NS5B polymerase, HBV DNA polymerase and, HIV-1 reverse transcriptase (RT) inhibitor, and for treatment of hepatitis B and C infection in mammals. These compounds are also of interest for the treatment of cancer. The phosphoramidate nucleoside prodrug of the general formula (1), a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, formula (1) wherein: Ar is aryl or hetaryl; R1 is H or CH3, R2 is the substituent selected from OCH2CH=CH2, OCH2CH≡CH, OCH2CH2CH2OCH3, formula (2), formula (3) or formula (4), R3 is H or CH3; R4 is OH, OR5, NR6R7; R5 is C1-C4-alkyl; R6 and R7 are not necessarily the same substituents selected from H or CH3, Z = O, or NH; an arrow (→) indicates the place of substituent connection; Nuc is formula (5) or (6); R8 and R9 are not necessarily the same substituents selected from H, F, Cl, CH3 or OH provided when continuous line and its accompanying dotted line ( ) together are the single carbon-carbon (C-C) bond or R8 and R9 are hydrogen provided when continuous line and its accompanying dotted line ( ) together are the double carbon-carbon bond (C=C); R10 is the substituent selected from R10.1- R10.5; R10.1 R10.2 R10.4 R10.5 ; R11 is the substituent selected from H, F, CI, CH3, or CF3; R12 is hydrogen, C1-C4-alkyl or C3-C6-cycloalkyl; X is oxygen or ethanediyl-1,1 (C=CH2); Y is O, S, CH2, or HO-CH group provided when continuous line and its accompanying dotted line (formula 7) together are the single carbon-carbon (C-C) bond or Y is CH group provided when continuous line and its accompanying dotted line (formula 7) together are the double carbon-carbon bond (C=C), and compound of the general formula (1), stereoisomers, isotope-enriched analogues, pharmaceutically acceptable salts, hydrates, solvates, or crystalline or polymorphic forms thereof, wherein: Ar is aryl or hetaryl; R1 is H or CH3; R2 is isopropyl; Nuc is formula (8), (9) or (10).

  本发明涉及化疗药物及其用于治疗病毒性和癌症疾病的用途。这些化合物是HCV NS5B聚合酶、HBV DNA聚合酶和HIV-1逆转录酶（RT）抑制剂，用于治疗哺乳动物中的乙型和丙型肝炎感染。这些化合物也对癌症治疗具有兴趣。通用式（1）的磷酰胺核苷前药的立体异构体、同位素富集类似物、药学上可接受的盐、水合物、溶剂合物或晶体或多形式，式（1）其中：Ar为芳基或杂芳基；R1为H或CH3，R2为从O CH=CH2、O CH≡CH、O O 、式（2）、式（3）或式（4）中选择的取代基，R3为H或 ；R4为OH、OR5、NR6R7；R5为C1-C4-烷基；R6和R7不一定相同，选择自H或 的取代基，Z=O或NH；箭头（→）表示取代基连接的位置；Nuc为式（5）或（6）；R8和R9不一定相同，选择自H、F、Cl、 或OH，提供当连续线及其相应的虚线（）一起为单碳-碳（C-C）键时，或R8和R9为氢，提供当连续线及其相应的虚线（）一起为双碳-碳键（C=C）时；R10为从R10.1-R10.5中选择的取代基；R10.1 R10.2 R10.4 R10.5；R11为从H、F、Cl、 或CF3中选择的取代基；R12为氢、C1-C4-烷基或C3-C6-环烷基；X为氧或乙烯二基-1,1（C= ）；Y为O、S、 或HO-CH基，提供当连续线及其相应的虚线（式7）一起为单碳-碳（C-C）键时，或Y为CH基，提供当连续线及其相应的虚线（式7）一起为双碳-碳键（C=C）时，以及通用式（1）的化合物、立体异构体、同位素富集类似物、药学上可接受的盐、水合物、溶剂合物或晶体或多形式，其中：Ar为芳基或杂芳基；R1为H或 ；R2为异丙基；Nuc为式（8）、（9）或（10）。
• [EN] TERT-BUTYL-SULPHOXIDE METHOD FOR PRODUCING FESTINAVIR<br/>[FR] PROCÉDÉ À BASE DE TERT-BUTYL-SULPHOXYDE POUR LA PRODUCTION DE FESTINAVIR
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2014201122A1

  公开（公告）日：2014-12-18

  Tert-butyl sulphoxide method for producing festinavir is set forth.

  叔丁基亚砜法生产费司他韦。
• [EN] METHOD FOR PRODUCING FESTINAVIR USING 5-METHYLURIDINE AS STARTING MATERIAL<br/>[FR] PROCÉDÉ DE PRODUCTION DE FESTINAVIR AVEC DE LA 5-MÉTHYLURIDINE EN TANT QUE MATIÈRE DE DÉPART
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2014172264A1

  公开（公告）日：2014-10-23

  The NRTI compound festinavir is made using 5-methyluridine as a starting material, followed by Claisen rearrangement.

  NRTI化合物festinavir是使用5-甲基尿嘧啶作为起始物质制成的，然后进行克莱森重排反应。
• A NEW APPROACH TO THE SYNTHESIS OF 4′-CARBON-SUBSTITUTED NUCLEOSIDES: DEVELOPMENT OF A HIGHLY ACTIVE ANTI-HIV AGENT 2′, 3′-DIDEHYDRO-3′-DEOXY-4′-ETHYNYLTHYMIDINE
  作者：Kazuhiro Haraguchi、Shingo Takeda、Masanori Sumino、Hiromichi Tanaka、Ginger E. Dutschman、Yung-Chi Cheng、Takao Nitanda、Masanori Baba

  DOI：10.1081/ncn-200059774

  日期：2005.4.1

  Oxidation of 3'-O-TBDMS-4',5'-unsaturated thymidine 3 with dimethyldioxirane (DMDO) allowed the isolation of the epoxide 4. Upon reacting with organosilicon reagents in the Presence of SnCl4, 4 underwent stereoselective ring opening to give 4'-alpha-allyl (6), 4'-alpha-(2-bromoallyl) (7), 4'-alpha(cyclopenten-3-yl) (8), and 4'-alpha-cyano (9) derivatives of thymidine. Reactions of the 3'-epimer 12 with organoaluminum reagents gave 4-alpha-methyl (13), 4'-alpha-vinyl (14), and 4'-alpha-ethynyl (15) analogues. Compounds 13-15 were transformed into corresponding 2',3'-didehydro-3'-deoxy derivatives. Evaluation of their ability to inhibit the replication of HIV in cell culture showed that 4'-ethynyl-d4T (19) is more potent and less toxic than the parent compound d4T.
• Synthesis of a highly active new anti-HIV agent 2′,3′-Didehydro-3′-deoxy-4′-ethynylthymidine
  作者：Kazuhiro Haraguchi、Shingo Takeda、Hiromichi Tanaka、Takao Nitanda、Masanori Baba、G.E. Dutschman、Yung-Chi Cheng

  DOI：10.1016/j.bmcl.2003.07.009

  日期：2003.11

  Compounds having methyl, vinyl, and ethynyl groups at the 4'-position of stavudine (d4T: 2',3'-didehydro-3'-deoxythymidine) were synthesized. The compounds were assayed for their ability to inhibit the replication of HIV in cell culture. The 4'-ethynyl analogue (15) was found to be more potent and less toxic than the parent compound stavudine. (C) 2003 Elsevier Ltd. All rights reserved.