(3-fluorobenzyl) 2,2,2-trichloroacetimidate | 214139-75-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (3-fluorobenzyl) 2,2,2-trichloroacetimidate
• 英文别名: 3-fluorobenzyl trichloroacetimidate；(3-Fluorophenyl)methyl 2,2,2-trichloroethanimidate
• CAS: 214139-75-0
• 化学式: C₉H₇Cl₃FNO
• 分子量: 270.518
• InChiKey: BOZHBHLJNUNVIM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  33.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3-fluorobenzyl) 2,2,2-trichloroacetimidate 在 2-羟基吡啶 、 三氟甲磺酸 作用下， 以 1,4-二氧六环 、 1,2-二氯乙烷 为溶剂， 反应 6.0h， 生成 (2R,3R,4R,5R)-2,5-bis[(3-fluorophenyl)methoxy]-3,4-dihydroxy-N,N'-bis[(1S)-2-methyl-1-(methylcarbamoyl)propyl]hexanediamide
  参考文献：
  名称：

  Design and Synthesis of Potent C₂-Symmetric Diol-Based HIV-1 Protease Inhibitors:  Effects of Fluoro Substitution

  摘要：

  Implementation of derivatized carbohydrates as C-2-symmetric HIV-1 protease inhibitors has previously been reported. With the objective of improving the anti-HIV activity of such compounds, we synthesized a series of fluoro substituted P1/P1 ' analogues. These compounds were evaluated for antiviral activity toward both wild type and mutant virus. The potency of the analogues in blocking HIV-1 protease was moderate, with K-i values ranging from 1 to 7 nM. Nonetheless, compared to the parent nonfluorous inhibitors, a majority of the compounds exhibited improved antiviral activity, for example the 3-fluorobenzyl derivative 9b, which had a K-i value of 7.13 nM and displayed one of the most powerful antiviral activities in the cellular assay of the series. Our results strongly suggest that fluoro substitution can substantially improve antiviral activity. The X-ray crystal structures of two of the fluoro substituted inhibitors (9a and 9f) cocrystallized with HIV-1 protease are discussed.

  DOI：

  10.1021/jm001134q
• 作为产物：
  描述：

  3-氟苄醇 、 三氯乙腈 在 四丁基硫酸氢铵 作用下， 以 二氯甲烷 为溶剂， 反应 2.58h， 以95%的产率得到(3-fluorobenzyl) 2,2,2-trichloroacetimidate
  参考文献：
  名称：

  Design and Synthesis of Potent C₂-Symmetric Diol-Based HIV-1 Protease Inhibitors:  Effects of Fluoro Substitution

  摘要：

  Implementation of derivatized carbohydrates as C-2-symmetric HIV-1 protease inhibitors has previously been reported. With the objective of improving the anti-HIV activity of such compounds, we synthesized a series of fluoro substituted P1/P1 ' analogues. These compounds were evaluated for antiviral activity toward both wild type and mutant virus. The potency of the analogues in blocking HIV-1 protease was moderate, with K-i values ranging from 1 to 7 nM. Nonetheless, compared to the parent nonfluorous inhibitors, a majority of the compounds exhibited improved antiviral activity, for example the 3-fluorobenzyl derivative 9b, which had a K-i value of 7.13 nM and displayed one of the most powerful antiviral activities in the cellular assay of the series. Our results strongly suggest that fluoro substitution can substantially improve antiviral activity. The X-ray crystal structures of two of the fluoro substituted inhibitors (9a and 9f) cocrystallized with HIV-1 protease are discussed.

  DOI：

  10.1021/jm001134q

文献信息

• Antiviral protease inhibitors
  申请人：Medivir AB

  公开号：US20010044547A1

  公开（公告）日：2001-11-22

  Compounds of formula (I), wherein A and A are independently the same or different group of formula (II) wherein: R′ is H, CH 3 , C(CH 3 ) 2 ,—OR a , —N(R a ) 2 , —N(R a )OR a or -DP; R is H or CH 3 ; R a is H, C 1 -C 3 alkyl; D is a bond, alkylene, —C(═O)—, —S(O)— or S(O) 2 —; P is an optionally substituted, mono or bicyclic carbo- or hetereocycle; R″ is H, any of the sidechains found in the natural amino acids, carboxacetamide, or a group (CH 2 ) n DP; M is a bond or —C(═O)N(R′″)-; Q is absent, a bond, —CH(OH)— or CH 2 —; or R″ together with Q, M and R define an optionally substituted 5 or 6 membered carbo- or heterocyclic ring which is optionally fused with a further 5 or 6 membered carbo- or heterocyclic ring; with the proviso that R is —OR a , -, N(R a ) 2 , —N(R a )OR a or -DP, if M is a bond and Q is absent; X is H, OH, OCH 3 , Y is H, OH, OCH 3 , but X and Y are not both H; Z′ and Z″ are independently —(CH 2 ) m P where P is as defined above; n and m are independently 0, 1 or 2; and pharmaceutically acceptable salts and prodrugs thereof have utility as aspartyl protease inhibitors of HIV. They can be prepared in a facile two step synthesis from novel 2,5-di-O-benzyl-L-mannaro-1,4:6,3-dilactone intermediates.

  化合物的式子（I），其中A和A独立地是式子（II）的相同或不同的基团，其中：R'是H，CH3，C（CH3）2，—ORa，—N（Ra）2，—N（Ra）ORa或-DP; R是H或CH3; Ra是H，C1-C3烷基; D是键，烷基，—C(═O)—，—S（O）—或S（O）2—; P是一个可选的取代的，单环或双环的碳或杂环；R″是H，天然氨基酸中发现的任何侧链，羧乙酰胺或一个组（CH2）nDP; M是键或—C(═O)N（R'″）-; Q不存在，是键，—CH（OH）—或CH2—; 或R″与Q、M和R一起定义一个可选的取代的5或6元环或杂环，该环可以与另一个可选的取代的5或6元环或杂环融合；条件是，如果M是键且Q不存在，则R是—ORa，-，N（Ra）2，—N（Ra）ORa或-DP；X是H，OH，OCH3，Y是H，OH，OCH3，但X和Y不都是H；Z′和Z″独立地是—（CH2）mP，其中P如上定义；n和m独立地是0、1或2；以及其药学上可接受的盐和前药具有作为HIV天冬氨酸蛋白酶抑制剂的用途。它们可以从新的2,5-二-O-苄基-L-曼纳罗-1,4:6,3-二内酯中间体中方便地进行两步合成。
• ANTIVIRAL PROTEASE INHIBITORS
  申请人：MEDIVIR AB

  公开号：EP1005493A1

  公开（公告）日：2000-06-07
• US6291687B1
  申请人：——

  公开号：US6291687B1

  公开（公告）日：2001-09-18
• US6489364B2
  申请人：——

  公开号：US6489364B2

  公开（公告）日：2002-12-03
• [EN] ANTIVIRAL PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTEASES ANTIVIRAUX
  申请人：MEDIVIR AB

  公开号：WO1998045330A1

  公开（公告）日：1998-10-15

  (EN) Compounds of formula (I), wherein A' and A'' are independently the same or different group of formula (II) wherein: R' is H, CH3, C(CH3)2, -ORa, -N(Ra)2, -N(Ra)ORa or -DP; R''' is H or CH3; Ra is H, C1-C3 alkyl; D is a bond, alkylene, -C(=O)-, -S(O)- or -S(O)2-; P is an optionally substituted, mono or bicyclic carbo- or heterocycle; R'' is H, any of the sidechains found in the natural amino acids, carboxacetamide, or a group (CH2)nDP; M is a bond or -C(=O)N(R''')-; Q is absent, a bond, -CH(OH)- or -CH2-; or R'' together with Q, M and R' define an optionally substituted 5 or 6 membered carbo- or heterocyclic ring which is optionally fused with a further 5 or 6 membered carbo- or heterocyclic ring; with the proviso that R' is -ORa, -N(Ra)2, -N(Ra)ORa or -DP, if M is a bond and Q is absent; X is H, OH, OCH3; Y is H, OH, OCH3, but X and Y are not both H; Z' and Z'' are independently -(CH2)mP where P is as defined above; n and m are independently 0, 1 or 2; and pharmaceutically acceptable salts and prodrugs thereof have utility as aspartyl protease inhibitors of HIV. They can be prepared in a facile two step synthesis from novel 2,5-di-O-benzyl-L-mannaro-1,4:6,3-dilactone intermediates.(FR) Cette invention se rapporte à des composés représentés par la formule (I) dans laquelle A' et A' sont indépendamment un même groupe ou deux groupes différents représentés par la formule (II). Dans cette formule (II), R' est H, CH3, C(CH3)2, -ORa, -N(Ra)2, -N(Ra)ORa ou -DP; R''' est H ou CH3; Ra est H, alkyle C1-C3; D est une liaison, alkylène, -C(=O)-, -S(O)- ou -S(O)2-; P est mono- ou carbo-bicyclique ou hétérocyclique, éventuellement substitué; R' est H, toute chaîne latérale que l'on trouve dans les acides aminés naturels, carboxacétamide ou un groupe (CH2)nDP; M est une liaison ou -C(=O)N(R''')-; Q est absent, une liaison, -CH(OH)- ou -CH2-; ou R' et Q, M et R' définissent un noyau carbo- ou hétérocyclique, à 5 ou 6 éléments, éventuellement substitué, qui est éventuellement condensé avec un autre noyau carbo- ou hétérocyclique, à 5 ou 6 éléments; à condition que R' soit -ORa, -N(Ra)2, -N(Ra)ORa ou -DP, si M est une liaison et Q absent; X est H, OH, OCH3, Y est H, OH, OCH3, mais X et Y ne sont pas tous deux H; Z' et Z'' sont indépendamment -(CH2)mP où P est défini ci-dessus; n et m sont indépendamment 0, 1 ou 2. L'invention se rapporte également à des sels pharmaceutiquement acceptables et à des précurseurs de ces composés qui s'avèrent utiles en tant qu'inhibiteurs d'aspartyle protéase du VIH. Il est possible de préparer ces composés par une synthèse aisée en deux étapes à partir de nouveaux intermédiaires de 2,5-di-O-benzyl-L-mannaro-1,4:6,3-dilactone.