azepane-1-carbonitrile | 5321-89-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环庚烷
• 英文名称: azepane-1-carbonitrile
• CAS: 5321-89-1
• 化学式: C₇H₁₂N₂
• 分子量: 124.186
• InChiKey: CMIGYELBZZWTBE-UHFFFAOYSA-N

物化性质

• 沸点：
  110 °C(Press: 0.1 Torr)
• 密度：
  0.98±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  9
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  27
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  azepane-1-carbonitrile 在 三乙胺 作用下， 以 乙醇 为溶剂， 反应 2.0h， 生成 [2-Azepan-1-yl-4-(4-nitro-phenyl)-thiazol-5-yl]-(4-methoxy-phenyl)-methanone
  参考文献：
  名称：

  Funnell, Richard A.; Meakins, G. Denis; Peach, Josephine M., Journal of the Chemical Society. Perkin transactions I, 1987, p. 2311 - 2316

  摘要：

  DOI：
• 作为产物：
  描述：

  在 sodium tert-pentoxide 作用下， 以 乙二醇二甲醚 为溶剂， 反应 1.0h， 以74.1 mg的产率得到azepane-1-carbonitrile
  参考文献：
  名称：

  使用三氯乙腈对仲胺进行N氰化

  摘要：

  使用三氯乙腈作为廉价的氰源，已经开发出了一锅法的仲胺N-氰化反应。通过成功用于生物活性咯利普兰衍生的氨酰胺的最终合成步骤中的方法，可以轻松地以良好的分离收率将各种各样的环状和无环仲胺转化为相应的氰胺。与使用剧毒溴化氰相比，该方法表现出不同的选择性。

  DOI：

  10.1021/acs.orglett.6b02775

文献信息

• Process for preparing 3-(cyanimino)-3-amino-propionitriles
  申请人：The Upjohn Company

  公开号：US04098791A1

  公开（公告）日：1978-07-04

  An improved multistep process for the production of intermediates for hypotensive compounds, which intermediates are of the formula V: ##STR1## wherein R.sub.1 and R.sub.2 are lower alkyl of 1 to 4 carbon atoms, inclusive, alkenyl of 3 or 4 carbon atoms, cycloalkyl from 3 to 7 carbon atoms, phenylalkyl in which the alkyl group is defined as above, or the group ##STR2## is a heterocyclic moiety of 4 to 8 ring members, e.g., azetidinyl, piperidino, pyrrolidinyl, hexahydroazepinyl, or heptamethyleneimino, each of which can be substituted by one or two methyl groups, N-alkylpiperazino, wherein alkyl is defined as above, morpholino, or thiomorpholino, and wherein R.sub.3 is hydrogen or alkyl of 1 to 4 carbon atoms, inclusive, starts with the corresponding secondary amine I ##STR3## wherein R.sub.1 and R.sub.2 have the significance of above. SU BRIEF SUMMARY OF THE INVENTION This invention is concerned with a new, improved process for the production of 2,N-dicyanoacetamidines which are the primary intermediates for anti-hypertensive 2,4-diamino-6-aminopyrimidine-3-oxides. This process can be illustratively represented as follows: ##STR4## wherein R.sub.1 and R.sub.2 are alkyl of 1 to 4 carbon atoms, inclusive, alkenyl of 3 to 4 carbon atoms inclusive, cycloalkyl from 3 to 7 carbon atoms, inclusive, phenylalkyl in which the alkyl group is defined as above, or the group ##STR5## is a heterocyclic moiety of 4 to 8 ring members, e.g., azetidinyl, pyrrolidinyl, piperidino, hexahydroazepinyl, or heptamethyleneimino, each of which can be substituted by 1 to 2 methyl groups, or 4-morpholino, 4-thiomorpholino, or N-alkylpiperazino, in which alkyl is defined as above; wherein R.sub.3 is hydrogen or alkyl defined as above, wherein X is chlorine, bromine or iodine. M is a metal ion selected from the group consisting of lithium, sodium, potassium, magnesium, calcium or aluminum, and Alk is alkyl of 1 to 4 carbon atoms, inclusive. From compounds of formula V, the final desired compounds VI are prepared by the single step: ##STR6## See U.S. Pat. No. 3,910,928. FIELD OF THE INVENTION The principal compound in this field is the compound in which ##STR7## is piperidino; thus the intermediate has the formula Va (below), and the final product has the formula VIa (below), produced by the process ##STR8## Prior to the present invention, compound Va has been produced by the following process: ##STR9## In the present new process the intermediate Va is produced by the following specific synthesis: ##STR10## The advantages in this process are: (1) the cost of the new process is less, since the price of cyanoacetic acid is only about one-third of that of malononitrile; (2) the new process provides 20-25% relative yield increase with a lower cost. In the new four-step synthesis of this invention, the step IV to V is similar to the reaction described in J. Chem. Soc. Chemical Communication, page 350, 1974, by Kristinsson. However, Kristinsson used cyanoacetic acid ethyl ester rather than the free acid, and as a result the carbethoxy group was incorporated into a new ring (a uracil ring). Thus, the process of Kristinsson cannot be used in this synthesis to give compounds of structure V, and therefore the last step is novel. DETAILED DESCRIPTION The preferred process of this invention is that in which the starting compounds are heterocyclic secondary amines, such as pyrrolidine, piperidine, morpholine, thiomorpholine, hexahydroazepine, heptamethyleneimine or N-alkylpiperazine in which alkyl is of 1 to 4 carbon atoms, inclusive. Most preferred of these starting compounds is piperidine, of which the process (with starting compound Ia) has been described above. The process with starting compound Ia provides the compound Va. Compound Va is the last intermediate used to make compound VIa: ##STR11## Compound VIa, under the generic name, minoxidil, is one of the more effective drugs in the treatment of hypertension, and works particularly well in the treatment of patients having toxic hypertension, often intractable by other drugs, and the patients are therefore in acute danger of life. Minoxidil is still a clinical experimental drug. Other compounds of formula VI also have been found to be anti-hypertensives and are useful for the treatment of hypertensive patients. U.S. Pat. No. 3,461,461 provides the details of how to use the compounds of formula VI in oral and parenteral formulations and the dosages and modes of administration. The new process for the final intermediates of formula V, herein claimed, is useful to lower the price of the final medicament of formula VI. In carrying out the process of the invention, a selected secondary amine of formula I is reacted in solution with cyanogen halide and a base. Solvents used in this reaction include water, ether and non-polar organic solvents, such as diethyl or dipropyl ether, methylethyl ether, tetrahydrofuran, ethyl acetate, acetone and hydrocarbons, e.g., pentane, hexane, toluene and the like. The reaction temperature is preferably kept low, between about 0.degree. and 15.degree. C. when water is solvent, and can be lower for the organic solvents. A two-phase system, water-organic solvent, is preferred. As bases, sodium or potassium hydroxide or carbonate are preferred, usually in aqueous solution. In the preferred embodiment of this invention a solution of the secondary amine is cooled to 0.degree. to 10.degree. C. and cyanogen halide is slowly added, in small portions, using an excess of 10% to 25%. Larger excess of this reagent is operative, but is not necessary or desirable. The base, aqueous sodium or potassium hydroxide is preferred, is added slowly and the temperature is kept at the low level of 0.degree. to 10.degree. C. After stirring for 1/2 to 2 hours, the product II, the carbonitrile of the amine, is isolated and purified by conventional procedures, such as extraction, washing, chromatography, crystallization, distillation and the like. Cyanogen halide used in this process is available commercially or can be made by standard methods, e.g., using sodium cyanide and a halogen source. Compound II is treated with a metal alkoxide of which the alkyl group of the alkoxide is of 1 to 4 carbon atoms, inclusive, and the metal is lithium, sodium, potassium, magnesium or aluminum, in a lower alkanol solution of 1 to 4 carbon atoms, inclusive, to give compound III. Sodium or potassium methoxide or ethoxide is preferred. In the preferred embodiment of the invention the N-carbonitrile of the amine (II) in methanol is reacted at 10.degree. to 50.degree. C. preferably at room temperature (20.degree. to 30.degree. C.) with the methoxide. Higher or lower temperatures can be selected and are operative in this reaction. The reaction time is from 2 to 48 hours. At the termination of the reaction the resultant compound, a methyl 1-aminocarboximidate (III), is isolated and purified by conventional means, e.g., extraction, evaporation, crystallization, distillation or the like. Compound III in solution is treated with a cyanogen halide and thereto is added a base to produce compound IV. As solvent, ethers, e.g., methylethyl, diethyl, ethylpropyl ether or tetrahydrofuran, or hydrocarbons, e.g., hexane or toluene, or mixtures thereof, or the like may be used. As base sodium or potassium carbonate or bicarbonate is utilized. In the preferred embodiment of this invention to a solution of compound III in an ether is added cyanogen bromide followed by anhydrous sodium or potassium carbonate. The reaction is carried out between 0.degree. C. and the boiling temperature of the solvent, with room temperature preferred. The reaction time is between 2 to 48 hours. After the reaction is terminated, the product IV, a methyl N'-cyano-1-carboximidate, is isolated and purified by conventional means, e.g., filtration, evaporation, extraction, chromatography, crystallization or the like. Compound IV is converted to compound V, a 2,N-dicyanoacetamidine, by treating a solution of IV with a solution of a cyanoacetic acid of formula X, and a base. Preferred bases are sodium or potassium alkoxides. As solvents alcohols, e.g., methanol, ethanol and the like, ethers, e.g., tetrahydrofuran, diethylether, hydrocarbons, e.g., benzene, toluene and the like, dimethylformamide, or mixtures thereof, or the like can be used. The solution of the cyanoacetic acid VII and base is mixed with a solution of compound IV in one of the before-mentioned solvents. The mixture is stirred from 1 to 48 hours at temperatures between 0.degree. and 50.degree. C. with room temperature (20.degree. to 30.degree. C.) preferred. After the reaction is terminated, the solution is acidified, preferably with acetic acid, evaporated and extracted. The product is isolated from the extracts and purified in conventional manners, e.g., by extraction, crystallization, chromatography, distillation or the like. Starting cyanoacetic acids if not commercially available can be synthesized by the method cited by R. B. Wagner et al. in "Synthetic Organic Chemistry", John Wiley (1965) p. 593.

  一种改进的多步法用于生产降压化合物的中间体，这些中间体的化学式为V:其中R₁和R₂为1至4个碳原子的低碳烷基，3或4个碳原子的烯基，3至7个碳原子的环烷基，苯基烷基，其中烷基如上所定义，或者基团是4到8个环成员的杂环基，例如，氮杂杂环基，哌啶基，吡咯啉基，六氢螺环庚啶基或七亚甲基亚胺基，每个基团可被一个或两个甲基基团取代，N-烷基哌嗪基，其中烷基如上所定义，吗啉基或硫吗啉基，其中R₃为氢或1至4个碳原子的烷基，起始物为相应的二级胺I，在本发明中，提供了一种用于制备抗高血压2,4-二氨基-6-氨基嘧啶-3-氧化物的主要中间体2,N-二氰基乙酰胺的新型、改进的生产方法。这个过程可以举例表示如下：其中R₁和R₂为1至4个碳原子的烷基，3至4个碳原子的烯基，3至7个碳原子的环烷基，苯基烷基，其中烷基如上所定义，或者基团是4到8个环成员的杂环基，例如，氮杂杂环基，吡咯啉基，哌啶基，六氢螺环庚啶基或七亚甲基亚胺基，每个基团可被1到2个甲基基团取代，或者4-吗啉基，4-硫吗啉基，或N-烷基哌嗪基，其中烷基如上所定义；其中R₃为氢或如上所定义的烷基，其中X为氯、溴或碘。M为锂、钠、钾、镁、钙或铝等金属离子，Alk为1至4个碳原子的烷基。从化合物V的化学式，最终所需的化合物VI通过单步制备：参见美国专利号3,910,928。发明领域本领域中的主要化合物是其中##STR7##为哌啶基；因此，中间体的化学式为Va（下文），最终产物的化学式为VIa（下文），由以下过程产生：##STR4##其中R₁和R₂为1至4个碳原子的烷基，3至4个碳原子的烯基，3至7个碳原子的环烷基，苯基烷基，其中烷基如上所定义，或者基团为##STR5##是4到8个环成员的杂环基，例如，氮杂杂环基，吡咯啉基，哌啶基，六氢螺环庚啶基或七亚甲基亚胺基，每个基团可被1到2个甲基基团取代，或者4-吗啉基，4-硫吗啉基，或N-烷基哌嗪基，其中烷基如上所定义；其中R₃为氢或如上所定义的烷基，其中X为氯、溴或碘。M为锂、钠、钾、镁或铝等金属离子，Alk为1至4个碳原子的烷基。从化合物V的化学式，最终所需的化合物VI通过单步制备：##STR6##参见美国专利号3,910,928。发明领域本领域中的主要化合物是其中##STR7##为哌啶基；因此，中间体的化学式为Va（下文），最终产物的化学式为VIa（下文），由以下过程产生：##STR8##在现有的新工艺中，化合物Va是通过以下工艺生产的：##STR9##在本发明的新工艺中，中间体Va是通过以下特定合成产生的：##STR10##这个工艺的优势在于：（1）新工艺的成本较低，因为氰乙酸的价格仅为马隆二腈的三分之一；（2）新工艺提供了20-25%的相对产率增加和更低的成本。在本发明的新四步合成中，步骤IV至V类似于1974年KriSTinsson在《J. Chem. Soc. Chemical Communication》第350页描述的反应。然而，KriSTinsson使用了氰乙酸乙酯而不是游离酸，结果羰酸乙酯基团被并入了一个新环（尿嘧啶环）。因此，KriSTinsson的工艺不能用于此合成以得到结构V的化合物，因此最后一步是新颖的。详细描述本发明的首选工艺是起始化合物为杂环二级胺，例如吡咯啉、哌啶、吗啉、硫吗啉、六氢螺环庚啶、七亚甲基哌嗪，其中烷基为1至4个碳原子。其中最理想的起始化合物是哌啶，其工艺（以起始物Ia）如上所述。使用起始物Ia的工艺提供了化合物Va。化合物Va是用于制备化合物VIa的最后中间体：##STR11##化合物VIa，以通用名称米诺地尔（minoxidil）而闻名，是治疗高血压中更有效的药物之一，特别适用于对其他药物无效的有毒高血压患者，这些患者常处于生命危险之中。米诺地尔仍然是一种临床实验药物。化合物VI的其他化合物也被发现具有降压作用，并且对于治疗高血压患者非常有用。美国专利号3,461,461提供了如何在口服和静脉制剂中使用化合物VI以及剂量和给药方式的详细信息。本领域中对化合物VI的最终中间体的新工艺，有助于降低化合物VI的最终药物的价格。在执行本发明的工艺中，化学式I的选择的二级胺在溶液中与氰卤化物和碱反应。在这个反应中使用的溶剂包括水，醚和非极性有机溶剂，如二乙基醚、二丙基醚、甲乙醚、四氢呋喃、乙酸乙酯、丙酮和烃，例如戊烷、己烷、甲苯等。反应温度最好保持较低，即在0°C至15°C之间，当溶剂为水时，可以更低。两相体系，即水-有机溶剂，是首选的。作为碱，最好使用氢氧化钠或碳酸钠，通常在水溶液中。在本发明的首选实施例中，将二级胺的溶液冷却至0°C至10°C，缓慢加入氰卤化物，使用超量的10%至25%。这种试剂的更大过量是有效的，但不是必要的或理想的。碱，最好是氢氧化钠或碳酸钠，缓慢加入，温度保持在0°C至10°C的低水平。搅拌1/2至2小时后，得到产物II，胺的氰基腈，通过传统方法如萃取、洗涤、色谱、结晶、蒸馏等得到并纯化。在这个过程中使用的氰卤化物可以在商业上获得，或者可以通过标准方法制备，例如使用氰化钠和卤素源。化合物II与1至4个碳原子的烷基的金属烷氧基反应，金属可以是锂、钠、钾、镁或铝，在1至4个碳原子的烷醇溶液中，以给出化合物III。最好使用甲醇或乙醇的钠或钾甲醇醚。在本发明的首选实施例中，甲醇中的胺的N-氰基腈（II）在10°C至50°C反应，最好在室温（20°C至30°C）与甲醇醚反应。在这个反应中可以选择更高或更低的温度，并且在这个反应中是有效的。反应时间为2至48小时。在反应结束时，得到的化合物，甲基1-氨基羰基胺（III），通过传统方法如萃取、蒸发、结晶、蒸馏等得到并纯化。溶液中的化合物III与氰卤化物反应，加入碱以产生化合物IV。可以使用醚，例如甲乙醚、二乙醚、乙丙醚或四氢呋喃，或者烃，例如己烷或甲苯，或者它们的混合物等作为溶剂。作为碱，可以使用碳酸钠或碳酸氢钠。在本发明的首选实施例中，在醚中的化合物III的溶液中先加入溴化氰，然后加入无水的碳酸钠或碳酸钾。反应在0°C至溶剂的沸腾温度之间进行，室温最佳。反应时间为2至48小时。反应结束后，产物IV，甲基N'-氰基-1-羰基胺，通过传统方法如过滤、蒸发、萃取、色谱、结晶等得到并纯化。化合物IV通过与化学式X的氰乙酸的溶液和碱的溶液反应，转化为化合物V，一种2,N-二氰基乙酰胺。最好使用钠或钾烷氧化物作为碱。可以使用醇，例如甲醇、乙醇等，醚，例如四氢呋喃、二乙醚，烃，例如苯、甲苯等，二甲基甲酰胺，或者它们的混合物等作为溶剂。将氰乙酸VII和碱的溶液与化合物IV的溶液混合在前述的溶剂中之一中。在0°C至50°C的温度范围内搅拌1至48小时，室温（20°C至30°C）最佳。在反应结束后，溶液酸化，最好使用乙酸酸化，蒸发和萃取。从提取物中分离和纯化产物，通过传统方法如萃取、结晶、色谱、蒸馏等。如果起始的氰乙酸不是商业可获得的，可以通过R. B. Wagner等人在《合成有机化学》，John Wiley（1965）第593页引用的方法进行合成。
• <i>N</i> ‐Cyanation of Primary and Secondary Amines with Cyanobenzio‐doxolone (CBX) Reagent
  作者：Zimin Chen、Weiming Yuan

  DOI：10.1002/chem.202102354

  日期：2021.10.25

  An efficient electrophilic N-cyanation of amines with a stable and less-toxic cyanobenziodoxole reagent towards the synthesis of cyanamides is disclosed. This synthetically practicable strategy allows the construction of a wide variety of cyanamides under very mild and simple conditions with a broad functional group compatibility, and showcases a huge potential in late-stage modification of complex

  公开了胺的有效亲电N-氰化与稳定且毒性较低的氰基苯并氧杂环戊烷试剂以合成氰胺。这种综合可行的策略允许在非常温和和简单的条件下构建具有广泛官能团兼容性的各种氰胺，并在复杂分子的后期改性中展现出巨大的潜力。
• Rybin, A. G.; Zil'berman, E. N.; Trachenko, V. I., Journal of general chemistry of the USSR, 1982, vol. 52, # 8, p. 1606 - 1607
  作者：Rybin, A. G.、Zil'berman, E. N.、Trachenko, V. I.、Sotnik, A. N.

  DOI：——

  日期：——
• Synthesis and anti-arrhythmic activity of aminoguanidine derivatives
  作者：I Érczi、G Rablóczky、A Varró、G Somogy I、M Kürthy、I Bódy

  DOI：10.1016/0223-5234(93)90133-y

  日期：1993.1

  A series of new aminoguanidine derivatives were synthesized and tested for anti-arrhythmic activity. The compounds selected were investigated on other test models. Finally, compound 13 1-(2,6-dimethylphenyl)-4,4-dimethyl-aminoguanidine-hydrochloride (B-GYKI-38 233) was chosen for detailed study.
• Bock, H.; Dieck, H. tom, Chemische Berichte, 1966, vol. 99, p. 213 - 226
  作者：Bock, H.、Dieck, H. tom

  DOI：——

  日期：——