2-(7-氯-1,8-萘啶-2-基)-3-羟基异吲哚啉-1-酮 | 55112-38-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡嗪类
• 中文名称: 2-(7-氯-1,8-萘啶-2-基)-3-羟基异吲哚啉-1-酮
• 英文名称: (±)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone
• 英文别名: 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one；3-Hydroxy-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone；2-(7-chloro-[1,8]naphthyridin-2-yl)-3-hydroxy-2,3-dihydro-isoindol-1-one；2-(7-Chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one；2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-3H-isoindol-1-one
• CAS: 55112-38-4
• 化学式: C₁₆H₁₀ClN₃O₂
• 分子量: 311.727
• InChiKey: UWERZJBLURGYFF-UHFFFAOYSA-N

物化性质

• 沸点：
  558.4±50.0 °C(Predicted)
• 密度：
  1.560±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  66.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(7-氯-1,8-萘啶-2-基)-3-羟基异吲哚啉-1-酮 在 水 、 potassium hydroxide 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 5,5-dimethyl-1,3-cyclohexadiene 为溶剂， 反应 54.0h， 生成 (±)-2-[1-(7-chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxoheptyl]benzoic acid
  参考文献：
  名称：

  An Efficient and Cost-Effective Synthesis of Pagoclone

  摘要：

  The compound (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5-methyl-2-oxohexyl)-1-isoindolinone (pagoclone) shows anxiolytic activity due to partial agonism of the benzodiazepine site of the GABA(A) receptor. We describe the development of an economical and practical process for a 100+ kg pilot plant production used to supply development needs. For the key reaction, a beta-keto phosphonium salt was prepared by selectively reacting a primary alpha-bromo ketone with triphenylphosphine in the presence of a secondary alpha-bromo ketone. A novel Wittig reaction with a 1-isoindolinone was used to produce racemic pagoclone. The enantiomerically pure drug substance was prepared by hydrolyzing a gamma-lactam and resolving the resulting enantiomeric carboxylic acids with (+)-ephedrine hemihydrate. An alternate resolution, involving chiral multicolumn chromatography (MCC) was also developed. The synthesis was completed by a racemization-free lactam formation to afford pagoclone.

  DOI：

  10.1021/op034060b
• 作为产物：
  描述：

  2-(7-氧代-1,7-二氢-1,8-萘啶-2-基)-1H-异吲哚-1,3(2H)-二酮 在 N,N-二甲基甲酰胺 、 sodium chloride 、 三氯氧磷 、 钾硼氢 作用下， 以 乙腈 、 水 为溶剂， 反应 4.0h， 以85%的产率得到2-(7-氯-1,8-萘啶-2-基)-3-羟基异吲哚啉-1-酮
  参考文献：
  名称：

  An Efficient and Cost-Effective Synthesis of Pagoclone

  摘要：

  The compound (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3S-(5-methyl-2-oxohexyl)-1-isoindolinone (pagoclone) shows anxiolytic activity due to partial agonism of the benzodiazepine site of the GABA(A) receptor. We describe the development of an economical and practical process for a 100+ kg pilot plant production used to supply development needs. For the key reaction, a beta-keto phosphonium salt was prepared by selectively reacting a primary alpha-bromo ketone with triphenylphosphine in the presence of a secondary alpha-bromo ketone. A novel Wittig reaction with a 1-isoindolinone was used to produce racemic pagoclone. The enantiomerically pure drug substance was prepared by hydrolyzing a gamma-lactam and resolving the resulting enantiomeric carboxylic acids with (+)-ephedrine hemihydrate. An alternate resolution, involving chiral multicolumn chromatography (MCC) was also developed. The synthesis was completed by a racemization-free lactam formation to afford pagoclone.

  DOI：

  10.1021/op034060b

文献信息

• Naphthyridine derivatives
  申请人：Rhone-Poulenc Industries

  公开号：US04086348A1

  公开（公告）日：1978-04-25

  Heterocyclic compounds of the formula: ##STR1## wherein the pyrroline ring and the symbols X.sub.1 and X.sub.2 together form an unsubstituted or substituted isoindoline nucleus, or a 6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine or 2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole nucleus, the 1,8-naphthyridin-2-yl nucleus is unsubstituted or substituted, and the grouping --NR.sub.1 R.sub.2 is an amino or substituted amino group, are new compounds which are active as tranquillizers, hypnotics, anti-convulsant agents and anti-spasmodics.

  式为：##STR1##其中吡咯烯环和符号X.sub.1和X.sub.2共同形成未取代或取代的异吲哚啉核，或6,7-二氢-5H-吡咯并[3,4-b]吡嗪，6,7-二氢-5H-吡咯并[3,4-b]吡啶或2,3,6,7-四氢-5H-1,4-噁硫杂吡咯核，1,8-萘啶-2-基核未取代或取代，以及基团--NR.sub.1 R.sub.2为氨基或取代氨基基团的杂环化合物是一种新的具有镇静、催眠、抗惊厥作用和抗痉挛作用的化合物。
• Isoindolinone derivatives, production and use thereof
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US04695572A1

  公开（公告）日：1987-09-22

  A compound of the formula ##STR1## wherein X is hydrogen, halogen or nitro; Ar is phenyl or naphthyridinyl which may optionally be substituted; and either one of Z.sup.1 and Z.sup.2 is hydrogen and the other is lower alkanoyloxy or hydroxy, each of Z.sup.1 and Z.sup.2 is lower alkoxy, or Z.sup.1 and Z.sup.2 combinedly represent hydroxyimino, oxo or a group of the formula: ##STR2## in which Y is oxygen or sulfur and A is a branched or unbranched lower alkylene chain; and a salt thereof, act on the central nervous system but are weak in adverse effects such as hypnotic and muscle relaxant effects.

  化合物的式子为##STR1## 其中X为氢、卤素或硝基；Ar为苯基或萘啶基，可选择性地被取代；Z.sup.1和Z.sup.2中的任意一个为氢，另一个为低碳酰氧基或羟基，Z.sup.1和Z.sup.2各自为低烷氧基，或Z.sup.1和Z.sup.2联合表示羟亚胺基、氧代或式子的一组：##STR2## 其中Y为氧或硫，A为支链或直链低碳烷基链；以及其盐，对中枢神经系统有作用，但其不良反应较弱，如催眠和肌肉松弛作用。
• [EN] 2-AMINO-NAPHTHYRIDINE DERIVATIVES<br/>[FR] DÉRIVÉS 2-AMINO-NAPHTYRIDINES
  申请人：CONCERT PHARMACEUTICALS INC

  公开号：WO2012116288A1

  公开（公告）日：2012-08-30

  The invention in one embodiment is directed to a compound of Formula A: as defined herein, or a pharmaceutically acceptable salt thereof.

  在一个实施例中，该发明涉及公式A的化合物：如此处所定义，或其药学上可接受的盐。
• Pyrrole derivatives, and pharmaceutical compositions which contain them
  申请人：Rhone-Poulenc Sante

  公开号：US04960779A1

  公开（公告）日：1990-10-02

  Pyrrole derivatives of formula (I): ##STR1## in which A forms with the pyrrole ring an isoindoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, 2,3,6,7-tetrahydro-5H-[1,4]oxathiino[2,3-c]pyrrole or 2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrole ring-system, Het.dbd.naphthyridinyl, pyridyl or quinolyl which are unsubstituted or substituted with halogen, (1 to 4 C) alkyl, (1 to 4 C) alkyloxy, (1 to 4 C) alkylthio or CF.sub.3, Y.dbd.CO, C.dbd.NOH or CHOH and R.dbd.(3 to 10 C) alkenyl, alkyl which is unsubstituted or substituted with OH, alkyloxy, alkylthio, (3 to 6 C) cycloalkyl, NH.sub.2, alkylamino, dialkylamino, alkylcarbonylamino, piperazinyl, piperidyl, 1-azetidinyl, morpholino, pyrrolidinyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, (1-piperazinyl)carbonyl, piperidinocarbonyl, pyrrolidinocarbonyl, phenyl, pyridyl, 1-imidazolyl or alternatively R.dbd.2- or 3-pyrrolididnyl, 2-, 3- or 4-piperidyl, (3 to 6 C) cycloalkyl or phenyl which is unsubstituted or substituted with halogen, (1 to 4 C) alkyl, (1 to 4 C) alkyloxy, (1 to 4 C) alkylthio, the said alkyl radicals and portions containing, except where specifically stated, 1 to 10 C, and the piperazinyl, piperidino, piperidyl, pyrrolidinyl, azetidinyl radicals being unsubstituted or substituted at any position by alkyl, alkylcarbonyl, benzyl or hydroxyalkyl, or can alternatively form a lactam group with the nitrogen atom of the ring, and their salts and optical isomers are useful as anxiolytics.

  公式（I）的吡咯衍生物：##STR1## 其中A与吡咯环形成异吲哚啉，6,7-二氢-5H-吡咯[3,4-b]吡嗪，2,3,6,7-四氢-5H-[1,4]噁嗪并[2,3-c]吡咯或2,3,6,7-四氢-5H-[1,4]二噻并[2,3-c]吡咯环系，Het.dbd.naphthyridinyl，吡啶基或喹啉基，它们未被取代或被卤素，（1至4C）烷基，（1至4C）烷氧基，（1至4C）烷硫基或CF.sub.3取代，Y.dbd.CO，C.dbd.NOH或CHOH，R.dbd.（3至10C）烯基，未被取代或被取代为OH，烷氧基，烷硫基，（3至6C）环烷基，NH.sub.2，烷基氨基，二烷基氨基，烷基羰基氨基，哌嗪基，哌啶基，1-氮杂丙烷基，吗啉基，吡咯啉基，氨基甲酰基，烷基氨甲酰基，二烷基氨甲酰基，（1-哌嗪基）羰基，哌啶基羰基，吡咯啉基羰基，苯基，吡啶基，1-咪唑基，或者R.dbd.2-或3-吡咯烷基，2-，3-或4-哌嗪基，（3至6C）环烷基或未被取代或被卤素，（1至4C）烷基，（1至4C）烷氧基，（1至4C）烷硫基取代的苯基，所述烷基基团和部分含有，除非特别说明，1至10C，哌嗪基，哌啶基，哌嗪基，吡咯啉基，氮杂丙烷基未被取代或被取代为烷基，烷基羰基，苄基或羟基烷基，或者可以与环的氮原子形成内酰胺基团，它们的盐和光学异构体可用作抗焦虑剂。
• Heterocyclic compounds
  申请人：Rhone-Poulenc Industries

  公开号：US04220646A1

  公开（公告）日：1980-09-02

  Heterocyclic compounds of the formula: ##STR1## wherein the pyrroline ring and the symbols R.sub.1 and R.sub.2 together form an isoindoline, 6,7-dihydro-5H-pyrrolo-[3,4-b]pyrazine, 2,3,6,7-tetrahydro-5H-1,4-oxathiino-[2,3-c]pyrrole or 2,3,6,7-tetrahydro-5H-1,4-dithiino-[2,3-c]pyrrole nucleus, Het represents an optionally substituted pyrid-2-yl, quinol-2-yl or 1,8-naphthyridin-2-yl radical, Z represents oxygen or sulphur and R represents hydrogen, alkyl or halo-substituted alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, optionally substituted phenyl, phenylalkyl, the phenyl ring of which may optionally be substituted, phenylalkenyl, the phenyl ring of which may optionally be substituted, or R represents a 5- or 6-membered heterocyclic radical containing one or two hetero-atoms selected from nitrogen, oxygen and sulphur, and, when the pyrroline ring and the symbols R.sub.1 and R.sub.2 together form an isoindoline nucleus, the residue of the isoindoline nucleus represented by R.sub.1 and R.sub.2 may optionally be substituted, possess pharmacological properties, and are especially useful as tranquillizers, anti-convulsant agents, decontracturants and agents to produce hypnosis.

  式子为：##STR1## 其中吡咯烃环和符号R.sub.1和R.sub.2共同形成异吲哚啉、6,7-二氢-5H-吡咯并[3,4-b]吡嗪、2,3,6,7-四氢-5H-1,4-噁嗪并[2,3-c]吡咯或2,3,6,7-四氢-5H-1,4-二噻吩并[2,3-c]吡咯核，Het代表可选取代的吡啶-2-基、喹啉-2-基或1,8-萘啉-2-基基团，Z代表氧或硫，R代表氢、烷基或卤代烷基、烯基、炔基、环烷基、烷氧基、可选取代的苯基、苯基烷基，其中苯环可选取代，苯基烯基，其中苯环可选取代，或R代表含有一或两个氮、氧和硫杂原子的5-或6-成员杂环基团，当吡咯烃环和符号R.sub.1和R.sub.2共同形成异吲哚啉核时，由R.sub.1和R.sub.2表示的异吲哚啉核残基可选取代，具有药理学特性，特别适用于镇静剂、抗惊厥剂、解痉剂和产生催眠作用的剂。