2-trifluoromethyl-6-hydroxybenzoic acid | 144433-66-9

• 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: 2-trifluoromethyl-6-hydroxybenzoic acid
• 英文别名: 2-hydroxy-6-(trifluoromethyl)benzoic acid
• CAS: 144433-66-9
• 化学式: C₈H₅F₃O₃
• 分子量: 206.121
• InChiKey: WFRWCWJAKXBJCK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  57.5
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  甲醇 、 2-trifluoromethyl-6-hydroxybenzoic acid 在 三甲基硅烷化重氮甲烷 作用下， 以 正己烷 、 乙酸乙酯 为溶剂， 以93%的产率得到2-羟基-6-三氟甲基苯甲酸甲酯
  参考文献：
  名称：

  Novel spiropiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine]

  摘要：

  Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6 J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6 J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3 mg/kg) in our preliminary analysis. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.11.043
• 作为产物：
  描述：

  间三氟甲基苯酚 在 正丁基锂 、 三氟化硼乙醚 、 potassium tert-butylate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 19.0h， 生成 2-trifluoromethyl-6-hydroxybenzoic acid
  参考文献：
  名称：

  氟酚和（三氟甲基）酚作为位点选择性金属化反应的底物：保护或不保护

  摘要：

  O-甲氧基甲基 (MOM) 保护的氟酚类可以完全金属化，然后进行位点选择性亲电取代。2-和4-异构体表现出矛盾的反应性：当使用丁基锂时，在与 O 相邻的位置发生去质子化，而与 F 相邻的位置受到超碱性混合物的攻击。丁基锂和叔丁醇钾 (LIC-KOR)。MOM 保护的（三氟甲基）苯酚仅在 O 邻位发生反应。间位异构体提供了另一个可选位点选择性的例子，在 2-位与 LIC-KOR 试剂进行 H/金属交换，在 6-位与仲丁基锂进行交换。未保护的（三氟甲基）苯酚也可以在 O-去质子化后进行邻位金属化，尽管生成的产物产率适中。[在 SciFinder (R) 上]

  DOI：

  10.1002/1099-0690(200108)2001:15<2911::aid-ejoc2911>3.0.co;2-w

文献信息

• Some reactions of 3,4-bis(trifluoromethyl)furan and its precursor, 2,3-bis(trifluoromethyl)-7-oxabicyclo[2,2,1]hepta-2,5-diene: novel isocoumarin formation from thermal reaction of the furan with ethyl propynoate
  作者：Aliyu B. Abubakar、Brian L. Booth、Nadia N.E. Suliman、Anthony E. Tipping

  DOI：10.1016/s0022-1139(00)81185-9

  日期：1992.3

  2,2,1]hepta-2,5-diene (2) gives 3,4-bis(trifluoromethyl)furan (1). Treatment of oxanorbornadiene (2) with triflic acid (in CH2Cl2 under reflux) and then with water affords a mixture of 2,3-bis(trifluoromethyl)phenol (4) (6%), tris-(6-trifluoromethylsalicylide) (5) (45%) and 2-trifluoromethyl-6-hydroxybenzoic acid (6) (16%); analogous reaction with conc. sulphuric acid gives only the phenol 4 (44%)

  2,3-双（三氟甲基）-7-氧杂双环[2,2,1]庚-2,5-二烯（2）在450℃下的热解得到3,4-双（三氟甲基）呋喃（1）。用三氟甲磺酸（在CH 2 Cl 2中，在回流条件下）然后用水处理草并降冰片二烯（2），得到2,3-双（三氟甲基）苯酚（4）（6％），三-（6-三氟甲基水杨酸内酯）的混合物（5）（45％）和2-三氟甲基-6-羟基苯甲酸（6）（16％）；与类似的反应。硫酸仅产生苯酚4（44％）。
• Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] analogs
  作者：Yoshikazu Uto、Yuko Ueno、Yohei Kiyotsuka、Yuriko Miyazawa、Hitoshi Kurata、Tsuneaki Ogata、Makiko Yamada、Tsuneo Deguchi、Masahiro Konishi、Toshiyuki Takagi、Satoko Wakimoto、Jun Ohsumi

  DOI：10.1016/j.ejmech.2010.07.044

  日期：2010.11

  In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1'-6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID(50) = 0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC(50) (mouse)= 2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg). (C) 2010 Elsevier Masson SAS. All rights reserved.
• Novel spiropiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine]
  作者：Yoshikazu Uto、Yohei Kiyotsuka、Yuko Ueno、Yuriko Miyazawa、Hitoshi Kurata、Tsuneaki Ogata、Tsuneo Deguchi、Makiko Yamada、Nobuaki Watanabe、Masahiro Konishi、Nobuya Kurikawa、Toshiyuki Takagi、Satoko Wakimoto、Keita Kono、Jun Ohsumi

  DOI：10.1016/j.bmcl.2009.11.043

  日期：2010.1

  Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1'-6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6 J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6 J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3 mg/kg) in our preliminary analysis. (C) 2009 Elsevier Ltd. All rights reserved.
• Fluorophenols and (Trifluoromethyl)phenols as Substrates of Site-Selective Metalation Reactions: To Protect or not To Protect
  作者：Elena Marzi、Florence Mongin、Andrea Spitaleri、Manfred Schlosser

  DOI：10.1002/1099-0690(200108)2001:15<2911::aid-ejoc2911>3.0.co;2-w

  日期：2001.8

  deprotonation occurs at the position adjacent to the O when butyllithium is employed whereas the position adjacent to the F is attacked by the superbasic mixt. of butyllithium and K tert-butoxide (LIC-KOR). The MOM-protected (trifluoromethyl)phenols react exclusively at O-neighboring positions. The meta isomer provides another example of optional site selectivity, undergoing H/metal exchange at the 2-position

  O-甲氧基甲基 (MOM) 保护的氟酚类可以完全金属化，然后进行位点选择性亲电取代。2-和4-异构体表现出矛盾的反应性：当使用丁基锂时，在与 O 相邻的位置发生去质子化，而与 F 相邻的位置受到超碱性混合物的攻击。丁基锂和叔丁醇钾 (LIC-KOR)。MOM 保护的（三氟甲基）苯酚仅在 O 邻位发生反应。间位异构体提供了另一个可选位点选择性的例子，在 2-位与 LIC-KOR 试剂进行 H/金属交换，在 6-位与仲丁基锂进行交换。未保护的（三氟甲基）苯酚也可以在 O-去质子化后进行邻位金属化，尽管生成的产物产率适中。[在 SciFinder (R) 上]