2-Benzyliden-cyclohexanon-oxim | 41338-70-9

• 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-Benzyliden-cyclohexanon-oxim
• 英文别名: 2-Benzalcyclohexanone oxime；N-(2-benzylidenecyclohexylidene)hydroxylamine
• CAS: 41338-70-9
• 化学式: C₁₃H₁₅NO
• 分子量: 201.268
• InChiKey: RWOLAHHEUZXIJZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  32.6
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-Benzyliden-cyclohexanon-oxim 在 碘 、 碳酸氢钠 作用下， 以 四氢呋喃 、 水 为溶剂， 以76%的产率得到5-phenyltetrahydrobenzo[c]isoxazole
  参考文献：
  名称：

  Hansen, John F.; Kim, Yong In; McCrotty, Stephen E., Journal of Heterocyclic Chemistry, 1980, vol. 17, p. 475 - 479

  摘要：

  DOI：
• 作为产物：
  描述：

  2-苄烯基环己酮 在 盐酸羟胺 、 sodium acetate 作用下， 以 乙醇 、 水 为溶剂， 反应 1.0h， 生成 2-Benzyliden-cyclohexanon-oxim
  参考文献：
  名称：

  某些环状亚芳基酮及相关肟，肟酯和类似物的合成和细胞毒性评估。

  摘要：

  制备了许多脂环族酮的亚芳基衍生物和一些相应的肟，肟酯和相关化合物作为候选细胞毒剂。所有化合物均针对鼠L1210淋巴样白血病细胞进行了评估。通常，α，β-不饱和酮的细胞毒性最大，而肟则减少，而肟酯在该筛选中几乎没有或没有活性。在体外L1210和P388白血病筛查中检查相同的化合物时，在大多数情况下，L1210细胞对这些衍生物更敏感。所制备的化合物的一半以上在体外针对约55种人类肿瘤进行了评估，并显示出对一组或多组肿瘤疾病（尤其是白血病）的选择性毒性。可以看出结构和生物活性之间的一些相关性。代表性化合物的细胞毒性筛选和稳定性研究表明，酮，肟和肟酯在生物评价条件下是稳定的。四种代表性化合物的X射线晶体学分析揭示了与细胞毒性相关的结构特征，可在设计未来候选细胞毒素时考虑这些特征。

  DOI：

  10.1002/jps.2600830619

文献信息

• Easy Access to Isoquinolines and Tetrahydroquinolines from Ketoximes and Alkynes via Rhodium-Catalyzed C−H Bond Activation
  作者：Kanniyappan Parthasarathy、Chien-Hong Cheng

  DOI：10.1021/jo902084j

  日期：2009.12.18

  herein is a convenient and highly regioselective synthesis of substituted isoquinoline derivatives from various aromatic ketoximes and alkynes via a one-pot, rhodium-catalyzed C−H bond activation. In addition, tetrahydroquinoline derivatives are formed in good yields from 2-arylidene-1-cyclohexanone oximes possessing an exocyclic double bond and from tetrahydroxanthone oximes. A possible mechanism is

  本文描述的是通过一锅铑催化的CH键活化，从各种芳族酮肟和炔烃中方便，高度区域选择性地合成取代的异喹啉衍生物。另外，由具有环外双键的2-亚芳基-1-环己酮肟和由四氢蒽酮肟以高收率形成四氢喹啉衍生物。提出了一种可能的机制，该机制涉及通过将Rh（I）氧化加成至邻-CH键，螯合炔烃，还原消除，分子内电环化和芳构化来进行螯合辅助的CH活化。通过分离邻链烯基化产物7p和7q来支持该机理。。本文还描述了sp 3 CH键的铱催化活化的实例。
• Pd(II)-Catalyzed Synthesis of Alicyclic[<i>b</i>]-Fused Pyridines via C(sp²)–H Activation of <i>α,β</i>-Unsaturated <i>N</i>-Acetyl Hydrazones with Vinyl Azides
  作者：Biao Nie、Wanqing Wu、Chuanfei Jin、Qingyun Ren、Ji Zhang、Yingjun Zhang、Huanfeng Jiang

  DOI：10.1021/acs.joc.1c02086

  日期：2022.1.7

  A new synthetic protocol for alicyclic[b]-fused pyridines with complete regioselectivity from α,β-unsaturated N-acetyl hydrazones and vinyl azides via Pd(II)-catalyzed C–H activation/cyclization/aromatization strategy has been described. A series of five- to eight-membered alicyclic[b]-fused pyridines were prepared in a one-step manner with wide substrate scope and good functional group tolerance.

  已经描述了一种通过 Pd(II) 催化的 C-H 活化/环化/芳构化策略从α,β-不饱和N-乙酰腙和乙烯基叠氮化物具有完全区域选择性的脂环族[ b ]-稠合吡啶的新合成方案。一步法制备了一系列具有广泛底物范围和良好官能团耐受性的五至八元脂环[ b ]-稠合吡啶。
• N-substituted azaheterocyclic carboxylic acids and esters thereof
  申请人：Novo Nordisk A/S

  公开号：US05639766A1

  公开（公告）日：1997-06-17

  The present invention relates to therapeutically active azaheterocyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful in treating a central nervous system ailment related to the GABA uptake.

  本发明涉及治疗活性的氮杂环化合物，其制备方法以及包含该化合物的制药组合物。这些新型化合物在治疗与GABA摄取有关的中枢神经系统疾病方面非常有用。
• Oxime ethers
  申请人：Egyt Gyogyszervegyeszeti Gyar

  公开号：US04083978A1

  公开（公告）日：1978-04-11

  Oxime ethers of the formula ##STR1## wherein R stands for a phenyl group which may be substituted by a halogen chlorine atom or by one to three methoxy groups; R.sup.1 and R.sup.2 denote each a hydrogen atom or together a valence bond; A denotes a C.sub.2 -C.sub.4 straight or branched-chain alkylene group; B is piperazino having a benzyl or C.sub.1-3 alkyl substituent on the nitrogen atom; and n denotes an integer from 3 to 6, have nicotine-lethality inhibiting, tetrabenazine-antagonistic and antiepileptic effects. This invention relates to novel oxime ethers possessing valuable therapeutic effects and their optical isomers and salts. The noval compounds have the general formula I ##STR2## wherein R stands for a phenyl group which may be substituted by a chlorine atom or by one to three methoxy groups; R.sup.1 and R.sup.2 denote each a hydrogen atom or together a valence bond; A denotes a C.sub.2 -C.sub.4 straight or branched-chain alkylene group; is piperazino having a benzyl or C.sub.1-3 alkyl substituent on the nitrogen atom; n denotes an integer from 3 to 6. The scope of the novel oxime ethers of the general formula I comprises obviously also all their possible stereoisomers and the mixtures thereof. The novel compounds of the general formula I can be produced according to the invention in the following ways: A. A ketone of the general formula II ##STR3## wherein R, R.sup.1, R.sup.2 and n have the same meaning as above, whereas Y denotes an oxygen or sulphur atom, is allowed to react with a hydroxylamine derivative of the general formula III h.sub.2 n -- o -- a -- b (iii) wherein A and B have the above-specified meaning. Ketones of the general formula II can be produced, e.g., in the way described in J. Am. Chem. Soc. 77, 624 /1955/ or in J. Chem. Soc. 1955, 1126, whereas hydroxylamine derivatives of the general formula III can be prepared, e.g., in the way described in J. Pharm. Sci. 58, 138 /1969/. B. A chlorine compound of the general formula IV ##STR4## wherein R, R.sup.1, R.sup.2 and n have the same meaning as above, is allowed to react with a hydroxylamine derivative of the general formula III, wherein A and B have the above-specified meaning. The compounds of general formula IV can be prepared by reacting 2-(p-chlorobenzal)-cyclohexanone with phosphorus oxychloride. c. An oxime of the general formula V ##STR5## wherein R, R.sup.1, R.sup.2 and n have the same meaning as above, is reacted with a halogen alkylamine derivative of the general formula VI hal -- A -- B (VI) wherein Hal denotes a halogen atom, preferably a chlorine atom, whereas A and B have the above-specified meanings. The oxime of the general formula V can be produced, e.g., in the way described in Org. Synth. Coll. Vol. II, p. 70. d. A compound of the general formula V, wherein R, R.sup.1, R.sup.2 and n have the same meaning as above, is reacted with a dihaloalkane of the general formula VIII hal -- CH.sub.2 -- A' -- Hal' (VIII) wherein Hal and Hal' denote the same or different halogen atoms, whereas A' denotes a C.sub.1 -C.sub.3 straight or branched-chain alkylene group, and the obtained halogen alkyl ether is aminated. The reaction of the compounds of the general formula II and III (method a/) is carried out preferably in a solvent or a solvent mixture inert for the reaction. Solvents being inert for the reaction are, e.g., alcohols, preferably ethanol, or pyridine, triethyl amine etc. the temperature of the reaction can be varied within very wide limits. Though the reaction takes place according to our experience also at room temperature, the optimum reaction rate can be attained at the boiling point of the reaction mixture. In the reaction of the compounds of the general formula IV and III (method b/) the components can be allowed to react in an inert solent, in the presence of a base. Suitable inert solvents are, e.g., diethyl ether, dibutyl ether, tetrahydrofurane, dioxane, etc., or aromatic or aliphatic hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane, etc., whereas pyridine, triethyl amine, N-methyl morpholine, etc., can be applied as bases. The reaction can be carried out also without any inert solvent, using only the base as a solvent. The temperature of the reaction can be varied within wide limits. The upper limit is determined by the boiling point of the reaction mixture. When the end products are to be produced by a reaction of the compounds specified by the general formulas V and VI (method c/), the reaction is to be carried out in an inert solvent, in the presence of a basic condensing agent. Benzene and its homologues, e.g., toluene, xylene, cumol, etc., can be mentioned as inert solvents. In this case preferably sodium amide or sodium hydride are applied as condensing agents. Obviously the same result can be atained also by other alkali metal amides or hydrides. In that case the use of alcohols, such as ethyl, propyl, butyl alcohols, proved to be the most suitable. When an alkali hydroxide is applied as condensing agent, also water can be used as solvent. When the compounds of the general formula I are produced by reacting compounds of the general formula V with those of the general formula VIII (method d/), the reaction can be carried out in a solvent or a solvent mixture inert for the reaction. Benzene and its homologues, such as toluene, xylene, cumol, etc., can be mentioned as inert solvents. In this case sodium amide or sodium hydride can be used as condensing agents. The same result can be attained on applying an alkali metal as condensing agent but in that case expediently ethanol is used as solvent. The amination of the obtained halogen alkyl ether is carried out under pressure in an autoclave, in the presence of the corresponding amine. The compounds of the general formula I can be converted in a known way into acid addition or quaternary ammonium salts. For the preparation of the acid addition salts physiologically tolerable acids, such as hydrogen halides, sulphuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, maleic acid, acetic acid, propionic acid, methane-sulphonic acid, succinic acid, etc., can be preferably applied. In order to prepare quaternary ammonium compounds the compounds of the general formula I are allowed to react with compounds suitable for quaternerization, e.g., with an alkyl halide or methanesulphonic acid ester. The biological activity of the novel compounds according to the invention has been proved by a number of various tests. Of the observed effects the local analgesic, nicotine-lethanlity inhibiting, tetrabenazineantagonistic and antiepileptic effects were the most significant ones. The inhibition of nicotine-lethality was determined on mice by the method of Stone (Stone, C.A. et al.: Arch. Intern. Pharmacodynamie 117, 419 /1958/) in groups of 10 mice each, at oral administration. The results are given in Table I. Table I ______________________________________ Compound LD.sub.50 ED.sub.50 Therapeutic (in Example) mg/kg mg/kg index ______________________________________ 2 1450 43 33.7 10 600 56 10.7 6 650 43 15.1 7 400 11 36.4 15 1900 100 19.0 17 1200 40 30.0 18 1000 70 14.3 Trihexyphenidyl (Artane) 365 40 9.13 ______________________________________ +rb Therapeutic index = LD.sub.50ED.sub.50 The antiepileptic effect was investigated on mice, at oral administration. Maximum electroshock (MES) was provoked by means of corneal electrodes, applying the known method of Swinyard (Swinyard et al.: J. Pharmacol. Exp. Ther. 106, 319-330 /1952/). The effect on tetracor-spasm was examined by the modified method of Banziger and Hane (Banziger, R. and Hane, L.D.: Arch. Int. Pharmacodyn. 167, 245-249 /1967/). The results are given in Table II. Table II ______________________________________ Tetracor- spasm in- MES Thera- hibition Thera- Compound LD.sub.50 ED.sub.50 peutic ED.sub.50 peutic (in Example) mg/kg mg/kg index mg/kg index ______________________________________ 2 1450 150 9.7 50 29.0 1 620 105 5.9 74 8.4 Trimethadion (Ptimal) 2100 490 4.3 400 5.3 ______________________________________ The tetrabenazine-reserpine antagonistic effect was investigated on mice in groups of 10 aminals each, at oral administration. The inhibition or suspension of the effect of the observed maximum dose was recorded, and the ED.sub.50 values were calculated on the basis of the dose vs. effect curves. The results are shown in Table III. Table III ______________________________________ Tetra- benazine Reserpine antago- Thera- antagonism Thera- Compound LD.sub.50 nism,ED.sub.50 peutic ED.sub.50, peutic (in Example) mg/kg mg/kg index mg/kg index ______________________________________ 1 620 7 88.6 over 130 4.8 18 1000 28 36.0 about 250 4 Amitriptylin 225 13 17.3 65 3.5 ______________________________________ The new compounds of formula I and their methods of preparation are further illustrated by the aid of the following non-limiting Examples. EXAMPLE 1 2-Benzal-1-(N-benzylpiperazinylpropoxyimino)-cyclohexane A solution of 20.1 g (0.1 moles) of 2-benzalcyclohexanone-oxime in 200 ml anhydrous toluene is dropwise added at 85.degree. C under stirring, to a suspension of 2.4 g (0.1 moles) of sodium hydride in 50 ml of anhydrous toluene. The mixture is kept for two hours at 130.degree. C, then a solution of 27.8 g (0.11 moles) of N-benzylpiperazinylpropyl chloride in 50 ml of anhydrous toluene is added. The mixture is kept for 12 hours at 130.degree. C, then cooled and shaken with a solution of 35 g of tartaric acid in 150 ml water. The aqueous phase is cooled to 0.degree.-5.degree. C and made alkaline to pH 10 with ammonium hydroxide. After extraction with dichloroethane, the solvent is distilled off and the residual crude phase processed to fumarate without any distillation. Yield: 35 g (84.3%). Difumarate: m.p. 196.degree. C. Citrate: m.p. 125.degree.-126.degree. C. Maleinate: m.p. 190.degree. C. (under decomposition). Tartrate: m.p. 198.degree.-200.degree. C. Iodomethylate: m.p. 134.degree.-135.degree. C. (under decomposition). Hydrochloride: m.p. 211.degree.-212.degree. C. Analysis: C.sub.35 H.sub.43 N.sub.3 O.sub.9 Calculated: C, 64.70%; H, 6.67%; N, 6.46%. Found: C, 64.35%; H, 6.70%; N, 6.38%. EXAMPLE 2 2-Benzal-1-(N-methylpiperazinylpropoxyimino)-cyclohexane One proceeds in the way as specified in Example 1, with the difference that, instead of N-benzylpiperazinylpropyl chloride, 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride are applied. Yield: 27.4 g (80.5%). Difumarate: m.p. 192.degree. C. Anaylsis: C.sub.29 H.sub.39 N.sub.3 O.sub.9 Calculated: C, 60.71%; H, 6.85%; N, 7.32%. Found: C, 60.58%; H, 7.28%; N, 7.36%. EXAMPLE 3 1-(N-Methylpiperazinylpropoxyimino)-2-(o-methoxybenzal)-cyclohexane On starting from 2.4 g (0.1 moles) of sodium hydride, 23.1 g (0.1 moles) of 2-(o-methoxybenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, on proceeds in the way as specified in Example 1. Yield: 35.2 g (95%). Fumarate: m.p. 189.degree.-191.degree. C. Analysis: C.sub.30 H.sub.41 N.sub.3 O.sub.10. Calculated: C, 59.69%; H, 6.85%; N, 6.96%. Found: C, 59.43%; H, 7.00%; N, 6.92%. EXAMPLE 4 1-(N-Methylpiperazinylpropoxyimino)-2-(m-methoxybenzal)-cyclohexane On starting from 2.4 g (0.1 moles) of sodium hydride, 23.1 g (0.1 moles) of 2-(m-methoxybenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 31.2 g (84.2%). Fumarate: m.p. 187.degree.-189.degree. C. Analysis: C.sub.30 H.sub.41 N.sub.3 O.sub.10. Calculated: C, 59.69%; H, 6.85%; N, 6.96%. Found: C, 59.45%; H, 7.00%; N, 6.81%. EXAMPLE 5 1-(N-Methylpiperazinylpropoxyimino)-2-(p-methoxybenzal)-cyclohexane On starting from 2.4 g (0.1 moles) of sodium hydride, 23.1 g (0.1 moles) of 2-(p-methoxybenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpipeazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 30.5 g (82.5%). Fumarate: m.p. 190.degree. C. Analysis: C.sub.30 H.sub.41 N.sub.3 O.sub.10. Calculated: C, 59.69%; H, 6.85%; N, 6.96%. Found: C, 59.54%; H, 6.65%; N, 6.92%. EXAMPLE 6 1-(N-benzylpiperazinylpropoxyimino)-2-(m-methoxybenzal)-cyclohexane On starting from 2.4 g (0.1 moles) of sodium hydride, 23.1 g (0.1 moles) of 2-(m-methoxybenzal)-cyclohexanone oxime and 27.8 g (0.11 moles) of N-benzylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 21.3 g (95.5%). Difumarate: m.p. 195.degree.-197.degree. C. Analysis: C.sub.36 H.sub.45 N.sub.3 O.sub.10 Calculated: C, 63.61%; H, 6.67%; N, 6.18%. Found: C, 63.90%; H, 6.78%; N, 6.12%. EXAMPLE 7 1-[2'-Methyl-3'-(4"-methylpiperazinylpropoxyimino)]-2-(p-methoxybenzal)-cyc lohexane On starting from 2.4 g (0.1 moles) of sodium hydride, 23.1 g (0.1 moles) of 2-(p-methoxybenzal)-cyclohexanone oxime and 21.0 g (0.11 moles) of N-methylpiperazinylisobutyl chloride, one proceeds in the way as specified in Example 1. Yield: 32.5 g (84.4%). Difumarate: m.p. 186.degree.-190.degree. C. Analysis: C.sub.31 H.sub.43 N.sub.3 O.sub.10 Calculated: C, 60.28%; H, 7.01%; N, 6.81%. Found: C, 59.92%; H, 7.25%; N, 6.74%. EXAMPLE 8 1-(N-Methyliperazinylpropoxyimino)-2-(3',4'-dimethoxybenzal)-cyclohexane On starting from 2.4 g (0.1 moles) of sodium hydride, 26.1 g (0.1 moles) of 2-(3',4'-dimethoxybenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 34.1 g (85%). Difumarate: m.p. 186.degree.-188.degree. C. Analysis: C.sub.31 H.sub.43 N.sub.3 O.sub.11 Calculated: C, 58.76%; H, 6.84%; N, 6.63%. Found: C, 58.58%; H, 6.64%, N, 6.61%. EXAMPLE 9 1-(N-Methylpiperazinylpropoxyimino)-2-(3',4',5'-trimethoxybenzal)-cyclohexa ne On starting from 2.4 g (0.1 moles) of sodium hydride, 29.1 g (0.1 moles) of 2-(3',4',5'-trimethoxybenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 39.0 g (90.5%). Difumarate: m.p. 185.degree.-186.degree. C. Cyclamate: m.p. 166.degree.-167.degree. C. Analysis: C.sub.32 H.sub.45 N.sub.3 O.sub.12 Calculated: C, 57.92%; H, 6.83%; N, 6.33%. Found: C, 58.24%; H, 7.00%; N, 6.30%. EXAMPLE 10 1-N-Benzylpiperazinylpropoxyimino)-2-(3',4',5'-trimethoxybenzal)-cyclohexan On starting from 2.4 g (0.1 moles) of sodium hydride, 29.1 g (0.1 moles) of 2-(3',4',5'-trimethoxybenzal)-cyclohexanone oxime and 27.8 g (0.11 moles) of N-benzylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 46.5 g (92%). Difumarate: m.p. 188.degree.-189.degree. C. Analysis: C.sub.38 H.sub.49 N.sub.3 O.sub.12 Calculated: C, 61.6%; H, 6.7%; N, 5.7%. Found: C, 61.5%; H, 6.9%; N, 5.63%. EXAMPLE 11 2-Benzal-1-[2'-methyl-3'-(4"-methylpiperazinyl)-propoxyimino]-cyclohexane On starting from 2.4 g (0.1 moles) of sodium hydride, 20.1 g (0.1 moles) of 2-benzalcyclohexanone oxime and 20.76 g (0.11 moles) of 2-methyl-3-(4'-methylpiperazinyl)-propyl chloride, one proceeds in the way specified in Example 1. Yield: 29.5 g (83%) of a pale yellow oil. Difumarate: m.p. 190.degree.-191.degree. C. Analysis: C.sub.30 H.sub.41 N.sub.3 O.sub.9 Calculated: C, 61.31%; H, 7.03%; N, 7.15%. Found: C, 61.15%; H, 7.19%; N, 7.28%. EXAMPLE 12 2-(m-Chlorobenzal)-1-[3'-(4"-methylpiperazinyl)-propoxyimino]-cyclohexane On starting from 2.4 g (0.1 moles) of sodium hydride, 23.5 g (0.1 moles) of 2-(m-chlorobenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 26.8 g (71.4%). Difumarate: m.p. 194.degree.-196.degree. C. Analysis: C.sub.29 H.sub.38 ClN.sub.3 O.sub.9 Calculated: C, 57.25%; H, 6.3%; Cl, 5.84 %; N, 6.4%. Found: C, 57.10%; H, 6.2%; Cl, 5.73%; N, 6.29%. EXAMPLE 13 2-(p-Chlorobenzyl)-1-[3'-(4"-methylpiperazinyl)-propoxyimino]-cyclohexane On starting from 2.4 g (0.1 moles) of sodium hydride, 23.74 g (0.1 moles) of 2-(p-chlorobenzyl)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methyl-piperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 33.8 g (89.5%). Difumarate: m.p. 194.degree.-195.degree. C. Analysis: C.sub.29 H.sub.40 ClN.sub.3 O.sub.9 Calculated: C, 57.09%; H, 6.60%; Cl, 5.31%; N, 6.89%. Found: C, 57.13%; H, 6.82%; Cl, 5.77%; N, 6.84%. EXAMPLE 14 2-Benzal-1-[3'-(4"-methylpiperazinyl)-propoxyimino]-cycloheptane On starting from 2.4 g (0.1 moles) of sodium hydride, 21.5 g (0.1 moles) of 2benzalcycloheptanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 26.5 g (72.5%). Difumarate: m.p. 196.degree.-197.degree. C (under decomposition). Analysis: C.sub.30 H.sub.41 N.sub.3 O.sub.9 Calculated: C, 61.31%; H, 7.03%; N, 7.15. Found: C, 61.20%; H, 6.94%; N, 7.10%. EXAMPLE 15 2-Benzal-1-[3'-(4"-methylpiperazinyl)-propoxyimino]-cyclopentane On starting from 2.4 g (0.1 moles) of sodium hydride, 18.7 g (0.1 moles) of 2-benzalcyclopentanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 31.3 g (95.8%). Difumarate: m.p. 205.degree.-206.degree. C (under decomposition). Analysis: C.sub.28 H.sub.37 N.sub.3 O.sub.9 Calculated: C, 60.09%; H, 6.66%; N, 7.51%. Found: C, 59.83%; H, 6.50%, N, 7.53%. EXAMPLE 16 2-Benzal-1-[2'-methyl-3'-(4"-methylpiperazinyl)-propoxyimino]-cyclohexane The solution of 20.1 g (0.1 moles) of 2-benzalcyclohexanone oxime in 200 ml of anhydrous toluene is dropwise added at 85.degree. C, under continuous stirring, to the suspension of 2.4 g (0.1 moles) of sodium hydride in 50 ml of anhydrous toluene. After boiling the reaction mixture for 2 hours, 18.86 g (0.11 moles) of 1-bromo-3-chloro-2-methylpropane are added, and the reaction mixture is boiled for a few hours. After cooling the mixture to 80.degree. C, a solution of 11 g (0.11 moles) of N-methylpiperazine in 20 ml of anhydrous toluene is dropwise added and the reaction mixture is kept for further 6 hours at this temperature. After cooling and washing with water, a solution of 22 g of fumaric acid in 220 ml of anhydrous ethanol is poured to the toluene solution, the mixture is cooled, and the precipitated crystals are filtered off. Yield in difumarate: 48 g (81.7%); m.p. 190.degree.-191.degree. C. The produce is identical with that described in Example 11. EXAMPLE 17 1-(N-Methylpiperazinylpropoxyimino)-2-benzal-cyclooctane difumarate On starting from 2.4 g (0.1 moles) of sodium hydride, 22.9 g (0.1 moles) of 2-benzalcyclooctanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 33.8 g (95%). Fumarate: m.p. 206.degree.-207.degree. C. Analysis: C.sub.31 H.sub.43 N.sub.3 O.sub.9 Calculated: C, 61.88%; H, 7.20%; N, 6.98%. Found: C, 61.38%; H, 7.05%; N, 6.92%. EXAMPLE 18 2-Benzal-1-[3'-(4"-benzylpiperazinyl)propoxyimino]-cyclopentane difumarate On starting from 2.4 g (0.1 moles) of sodium hydride, 18.7 g (0.1 moles) of 2-benzalcyclopentanone oxime and 27.8 g (0.11 moles) of N-benzylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1. Yield: 37.4 g (94%). Difumarate: m.p. 210.degree.-211.degree. C. Analysis: C.sub.34 H.sub.41 N.sub.3 O.sub.9 Calculated: C, 64.22%; H, 6.50%; N, 6.61%. Found: C, 64.12%, H, 6.61%, N, 6.60%.

  本发明涉及具有有价值的治疗作用的新型肟醚化合物及其光学异构体和盐，其通式为##STR1##其中R代表苯基，可以被卤素氯原子或1至3个甲氧基取代；R.sup.1和R.sup.2分别表示氢原子或共价键；A表示C.sub.2-C.sub.4直链或支链烷基；B是带有苄基或C.sub.1-3烷基取代的哌嗪基；n表示3至6的整数。这些化合物具有抑制尼古丁致死、四苯乙酸酯拮抗和抗癫痫的作用。这些新型肟醚具有通式I##STR2##其中R代表苯基，可以被氯原子或1至3个甲氧基取代；R.sup.1和R.sup.2分别表示氢原子或共价键；A表示C.sub.2-C.sub.4直链或支链烷基；B是带有苄基或C.sub.1-3烷基取代的哌嗪基；n表示3至6的整数。新型肟醚化合物的范围显然包括所有可能的立体异构体及其混合物。可以按照以下方式制备通式I的新型化合物：A.将通式II的酮##STR3##其中R，R.sup.1，R.sup.2和n具有上述相同的含义，而Y表示氧或硫原子，与通式III的羟胺衍生物反应，其中h.sub.2 n--o--a--b(iii)其中A和B具有上述规定的含义。通式II的酮可以通过J. Am. Chem. Soc. 77, 624 /1955/或J. Chem. Soc. 1955, 1126中所述的方法制备，而通式III的羟胺衍生物可以通过J. Pharm. Sci. 58, 138 /1969/中所述的方法制备。B.将通式IV的氯化合物##STR4##其中R，R.sup.1，R.sup.2和n具有上述相同的含义，与通式III的羟胺衍生物反应，其中A和B具有上述规定的含义。通式IV的化合物可以通过将2-(对氯苯甲醛)-环己酮与氧化亚磷酸三氯酯反应制备。c.将通式V的肟##STR5##其中R，R.sup.1，R.sup.2和n具有上述相同的含义，与通式VI的卤代烷基胺衍生物反应，其中hal--A--B(vi)其中Hal表示卤素原子，优选为氯原子，而A和B具有上述规定的含义。通式V的肟可以通过Org. Synth. Coll. Vol. II, p. 70中所述的方法制备。d.将通式V的化合物，其中R，R.sup.1，R.sup.2和n具有上述相同的含义，与通式VIII的二卤代烷烃反应，其中hal--CH.sub.2--A'--Hal'(viii)其中Hal和Hal'表示相同或不同的卤素原子，而A'表示C.sub.1-C.sub.3直链或支链烷基，所得到的卤代烷醚被胺化。通式II和III化合物（方法a/）的反应通常在反应惰性溶剂或溶剂混合物中进行。对于反应惰性的溶剂，例如乙醇或吡啶，三乙胺等。反应温度可以在非常广泛的范围内变化。虽然据我们的经验，反应也可以在室温下进行，但最佳反应速率可以在反应混合物的沸点下达到。在通式IV和III化合物（方法b/）的反应中，可以在惰性溶剂中，在碱的存在下，让组分反应。适用于反应惰性溶剂是例如二乙醚，二丁基醚，四氢呋喃，二噁烷等，或苯和烷烃，例如苯，甲苯，二甲苯，己烷，环己烷等，而吡啶，三乙胺，N-甲基吗啉等则可作为碱。反应也可以在没有惰性溶剂的情况下进行，仅使用碱作为溶剂。反应温度可以在广泛的范围内变化。上限由反应混合物的沸点确定。当通式V和VI化合物（方法c/）反应时，反应应在惰性溶剂中，在存在基础缩合剂的情况下进行。作为惰性溶剂可以提到苯及其同系物，例如甲苯，二甲苯，甲苯，等。在这种情况下，优选使用氨基钠或氢化钠作为缩合剂。显然，也可以通过其他碱金属胺或氢化物获得相同的结果。在这种情况下，使用乙醇，丙醇或丁醇等醇是最合适的。当碱金属羟化物作为缩合剂时，也可以使用水作为溶剂。当通式I的化合物是通过反应通式V和VIII的化合物（方法d/）获得时，反应可以在惰性溶剂或溶剂
• Rh(III)-Catalyzed Synthesis of Multisubstituted Isoquinoline and Pyridine <i>N</i>-Oxides from Oximes and Diazo Compounds
  作者：Zhuangzhi Shi、Dennis C. Koester、Mélissa Boultadakis-Arapinis、Frank Glorius

  DOI：10.1021/ja406338r

  日期：2013.8.21

  Multisubstituted isoquinoline and pyridine N-oxides have been prepared by Rh(III)-catalyzed cyclization of oximes and diazo compounds via aryl and vinylic C-H activation. This intermolecular annulation involving tandem C-H activation, cyclization, and condensation steps proceeds under mild conditions, obviates the need for oxidants, releases N-2 and H2O as the byproducts, and displays a broad substituent scope.