N-Methyl-N-n-propyl-β-(3.4-dimethoxyphenyl)ethylamin | 73676-22-9

• 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: N-Methyl-N-n-propyl-β-(3.4-dimethoxyphenyl)ethylamin
• 英文别名: 2-(3,4-Dimethoxyphenyl)aethyl n-propyl methylamin；3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane；N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylpropan-1-amine
• CAS: 73676-22-9
• 化学式: C₁₄H₂₃NO₂
• 分子量: 237.342
• InChiKey: YDDJPKKXAIRXDK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  17
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  21.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  N-(3,4-二甲氧基苯乙基)甲酰胺 、 丙酸乙酯 生成 N-Methyl-N-n-propyl-β-(3.4-dimethoxyphenyl)ethylamin
  参考文献：
  名称：

  由胺，内酰胺和氨基甲酸酯一锅合成叔胺

  摘要：

  已经开发了由酰胺，内酰胺和氨基甲酸酯一锅法合成不对称叔胺的方法。对于所检查的所有情况，该反应都是通用的，但含N-芳基的实例除外，该实例无法通过该方法进行操作。

  DOI：

  10.1016/s0040-4039(01)95418-8

文献信息

• Phenylalkylamino-alkyl derivatives of quinazolinone and phthalazinone
  申请人：Boehringer Ingelheim GmbH

  公开号：US04134980A1

  公开（公告）日：1979-01-16

  Compounds of the formula ##STR1## wherein A is ##STR2## where R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms; R.sub.2 is alkoxy of 1 to 3 carbon atoms; R.sub.3 is alkoxy of 1 to 3 carbon atoms or, together with R.sub.2, methylenedioxy or ethylenedioxy; R.sub.4 is hydrogen, alkyl of 1 to 3 carbon atoms or benzyl; R.sub.5 is hydrogen or alkyl of 1 to 3 carbon atoms; R.sub.6 is hydrogen or alkoxy of 1 to 3 carbon atoms; R.sub.7 is alkoxy of 1 to 3 carbon atoms or, together with R.sub.6, methylenedioxy or ethylenedioxy; and N is 2 or 3; And non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as heart rate reducers and mild antihypertensives. This invention relates to novel N-(phenylalkylaminoalkyl)-substituted quinazolinones and phthalazinones and nontoxic acid addition salts thereof, as well as to various methods of preparing these compounds. More particularly, the present invention relates to a novel class of N-substituted quinazolinones and phthalazinones represented by the formula ##STR3## wherein A is ##STR4## where R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms; R.sub.2 is alkoxy of 1 to 3 carbon atoms; R.sub.3 is alkoxy of 1 to 3 carbon atoms or, together with R.sub.2, methylenedioxy or ethylenedioxy; R.sub.4 is hydrogen, alkyl of 1 to 3 carbon atoms or benzyl; R.sub.5 is hydrogen or alkyl of 1 to 3 carbon atoms; R.sub.6 is hydrogen or alkoxy of 1 to 3 carbon atoms; R.sub.7 is alkoxy of 1 to 3 carbon atoms or, together with R.sub.6, methylenedioxy or ethylenedioxy; and N is 2 or 3; Or a non-toxic, pharmacologically acceptable acid addition salt thereof. A preferred sub-genus thereunder is constituted by compounds of the formula I where R.sub.1 and R.sub.5 are each hydrogen, methyl, ethyl, n-propyl or isopropyl; R.sub.4 is hydrogen, methyl, ethyl, n-propyl, isopropyl or benzyl; R.sub.2, r.sub.3 and R.sub.7 are each methoxy, ethoxy, n-propoxy or isopropoxy; R.sub.6 is hydrogen, methoxy, ethoxy, n-propoxy or isopropoxy; R.sub.2 and R.sub.3, together with each other, are methylenedioxy or ethylenedioxy; R.sub.6 and R.sub.7, together with each other, are methylenedioxy or ethylenedioxy; and n is 2 or 3; and non-toxic, pharmacologically acceptable acid addition salts thereof. A further, especially preferred sub-genus thereunder is constituted by compounds of the formula I where R.sub.2 and R.sub.3 are methoxy in the 6- and 7-position, respectively, or, together with each other, methylenedioxy or ethylenedioxy; R.sub.4 is hydrogen or methyl; R.sub.5 is hydrogen; R.sub.6 is hydrogen or methoxy in the 3-position; R.sub.7 is methoxy in the 4-position or, together with R.sub.6, methylenedioxy or ethylenedioxy; and n is 2 or 3; and non-toxic, pharmacologically acceptable acid addition salts thereof. The compounds embraced by formula I may be prepared by the following methods: Method A By reacting a compound of the formula ##STR5## wherein R.sub.2, R.sub.3, A and n have the same meanings as in formula I, and Z is a leaving-group, such as chlorine, bromine, iodine, alkylsulfonyloxy or arylsulfonyloxy, with a phenylalkylamine of the formula ##STR6## wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 have the same meanings as in formula I. The reaction is carried out in an inert solvent, such as ether, tetrahydrofuran, methylformamide, dimethylformamide, dimethylsulfoxide, chlorobenzene or benzene, and depending upon the reactivity of substituent Z, at a temperature between -50 and +250.degree. C, but preferably at the boiling point of the particular solvent which is used. The presence of an acid-binding agent, such as an alkali metal alcoholate, an alkali metal hydroxide, an alkali metal carbonate, especially potassium carbonate, or a tertiary organic base, particularly triethylamine or pyridine, or of a reaction accelerator, such as potassium iodide, is of advantage. Method B By reacting a compound of the formula ##STR7## wherein A, R.sub.2 and R.sub.3 have the same meanings as in formula I, with a phenylalkylamine of the formula ##STR8## wherein R.sub.4, R.sub.5, R.sub.6 and n have the same meanings as in formula I, and Z has the same meanings as in formula II. The reaction is carried out in an inert solvent, such as acetone, dimethylformamide, dimethylsulfoxide or chlorobenzene, and, depending upon the reactivity of substituent Z, at a temperature between 0 and 150.degree. C, but preferably at the boiling point of the particular solvent which is used. The presence of an acid-binding agent, such as an alkali metal alcoholate, an alkali metal hydroxide, an alkali metal carbonate, especially potassium carbonate, an alkali metal amide or a tertiary organic base, particularly triethylamine or pyridine, or of a reaction accelerator, such as potassium iodide, is of advantage. Method C By reacting an aldehyde of the formula ##STR9## wherein R.sub.2, R.sub.3, A and n have the same meanings as in formula I, or an acetal thereof, with an amine of the formula III in the presence of catalytically activated hydrogen. The reductive amination is carried out with hydrogen in the presence of a hydrogenation catalyst, such as palladized charcoal, at a hydrogen pressure of 5 atmospheres, in a solvent, such as methanol, ethanol or dioxane, and at a temperature between 0 and 100.degree. C, but preferably between 20 and 80.degree. C. Method D By reacting an amine of the formula ##STR10## wherein R.sub.2, R.sub.3, R.sub.4, A and n have the same meanings as in formula I, with a phenylalkyl compound of the formula ##STR11## wherein R.sub.5, R.sub.6 and R.sub.7 have the same meanings as in formula I, and Z has the same meanings as in formula II. The reaction is carried out in an inert solvent, such as acetone, methylene chloride, dimethylformamide, dimethylsulfoxide or chlorobenzene, and, depending upon the reactivity of substituent Z, at a temperature between 0 and 150.degree. C, but preferably at the boiling point of the particular solvent which is used. The presence of an acid-binding agent, such as an alkali metal alcoholate, an alkali metal hydroxide, an alkali metal carbonate, especially potassium carbonate, or a tertiary organic base, particularly triethylamine or pyridine, or of a reaction accelerator, such as potassium iodide, is of advantage. Method E For the preparation of a quinazolinone derivative of the formula I, by reacting a benzoxazin-4-one of the formula ##STR12## wherein R.sub.1, R.sub.2 and R.sub.3 have the same meanings as in formula I, with an alkylenediamine of the formula wherein R.sub.4, R.sub.5, R.sub.6 and R.sub.7 have the same meanings as in formula I. The reaction is advantageously carried out in a solvent, such as benzene, dioxane, a lower alkanoic acid such as glacial acetic acid, or dimethylformamide, and optionally in the presence of an acid catalyst at a temperature between 50 and 150.degree. C, but preferably at the boiling point of the particular solvent which is used. The preferred solvent is glacial acetic acid. The reaction may, however, also be performed without a solvent. If the end product of methods A through E is a compound of the formula I wherein R.sub.4 is benzyl, the same may be de-benzylated to yield the corresponding compound wherein R.sub.4 is hydrogen. The de-benzylation is preferably effected by means of catalytic hydrogenation, for example with hydrogen in the presence of a catalyst such as palladized charcoal, in a solvent such as ethanol or ethylacetate, at a temperature between 25 and 75.degree. C and at a hydrogen pressure of 1 to 7 atmospheres. On the other hand, if the end product of methods A through E is a compound of the formula I wherein R.sub.4 is hydrogen; the same may be alkylated at the bridge nitrogen atom to form the corresponding compound where R.sub.4 is alkyl. The alkylation is carried out with a conventional alkylating agent, for example with an alkyl halide such as methyl iodide, ethyl iodide or isopropyl bromide, or with a dialkylsulfate such a dimethylsulfate, in a solvent such as acetone, dimethylformamide or dioxane, optionally in the presence of an inorganic or tertiary organic base, at a temperature between 0 and 50.degree. C. A methylation may also be effected by reaction with a mixture of formaldehyde and formic acid, preferably at the boiling point of said mixture. The compounds embraced by formula I are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid, maleic acid, 8-chlorotheophylline or the like. The starting compounds of the formulas II through X are either described in the literature or may be prepared by known methods, as described in the examples below.

  本发明涉及一种新型的N-(苯基烷基氨基烷基)-取代的喹唑啉酮和邻苯二甲酰亚胺酮以及其无毒、药理学上可接受的酸加成盐，以及制备这些化合物的各种方法。这些化合物及其盐可用作心率降低剂和轻度降压剂。其中，A为##STR2##，其中R.sub.1为1至3个碳原子的氢或烷基；R.sub.2为1至3个碳原子的烷氧基；R.sub.3为1至3个碳原子的烷氧基或与R.sub.2一起，为亚甲二氧基或乙二氧基；R.sub.4为氢、1至3个碳原子的烷基或苄基；R.sub.5为氢或1至3个碳原子的烷基；R.sub.6为氢或1至3个碳原子的烷氧基；R.sub.7为1至3个碳原子的烷氧基或与R.sub.6一起，为亚甲二氧基或乙二氧基；N为2或3。其中，优选的亚属包括式I的化合物，其中R.sub.1和R.sub.5分别为氢、甲基、乙基、正丙基或异丙基；R.sub.4为氢、甲基、乙基、正丙基、异丙基或苄基；R.sub.2、R.sub.3和R.sub.7分别为甲氧基、乙氧基、正丙氧基或异丙氧基；R.sub.6为氢、甲氧基、乙氧基、正丙氧基或异丙氧基；R.sub.2和R.sub.3一起为亚甲二氧基或乙二氧基；R.sub.6和R.sub.7一起为亚甲二氧基或乙二氧基；N为2或3；以及其无毒、药理学上可接受的酸加成盐。其中，特别优选的亚属包括式I的化合物，其中R.sub.2和R.sub.3分别为6-和7-位甲氧基，或一起为亚甲二氧基或乙二氧基；R.sub.4为氢或甲基；R.sub.5为氢；R.sub.6为3-位氢或甲氧基；R.sub.7为4-位甲氧基或与R.sub.6一起，为亚甲二氧基或乙二氧基；N为2或3；以及其无毒、药理学上可接受的酸加成盐。式I所包含的化合物可通过以下方法制备：方法A通过将式II的化合物（其中R.sub.2、R.sub.3、A和n的含义与式I中相同，Z为离去基团，例如氯、溴、碘、烷基磺酰氧基或芳基磺酰氧基）与式III的苯基烷胺反应（其中R.sub.4、R.sub.5、R.sub.6和R.sub.7的含义与式I中相同），在惰性溶剂（例如醚、四氢呋喃、甲基甲酰胺、二甲基甲酰胺、二甲基亚砜、氯苯或苯）中进行，根据取代基Z的反应性，在-50至+250℃的温度下进行，但最好在所使用的特定溶剂的沸点下进行。碱金属醇盐、碱金属氢氧化物、碱金属碳酸盐（特别是碳酸钾）或三级有机碱（尤其是三乙胺或吡啶）的存在，或反应加速剂（例如碘化钾）是有优势的。方法B通过将式IV的化合物（其中A、R.sub.2和R.sub.3的含义与式I中相同）与式II的苯基烷胺反应（其中R.sub.4、R.sub.5、R.sub.6和n的含义与式I中相同，Z的含义与式II中相同），在惰性溶剂（例如丙酮、二甲基甲酰胺、二甲基亚砜或氯苯）中进行，在0至150℃的温度下进行，但最好在所使用的特定溶剂的沸点下进行，根据取代基Z的反应性。碱金属醇盐、碱金属氢氧化物、碱金属碳酸盐（特别是碳酸钾）、碱金属酰胺或三级有机碱（尤其是三乙胺或吡啶）的存在，或反应加速剂（例如碘化钾）是有优势的。方法C通过将式V的醛（其中R.sub.2、R.sub.3、A和n的含义与式I中相同）或其缩醛与式III的胺在催化氢的存在下进行还原胺化反应。还原胺化反应在催化氢存在下，用氢气在催化剂（例如钯化木炭）存在下进行，压力为5个大气压，在溶剂（例如甲醇、乙醇或二噁烷）中进行，在0至100℃的温度下进行，但最好在20至80℃之间。方法D通过将式VI的胺（其中R.sub.2、R.sub.3、R.sub.4、A和n的含义与式I中相同）与式II的苯基化合物反应（其中R.sub.5、R.sub.6和R.sub.7的含义与式I中相同，Z的含义与式II中相同），在惰性溶剂（例如丙酮、甲基氯化物、二甲基甲酰胺、二甲基亚砜或氯苯）中进行，在0至150℃的温度下进行，但最好在所使用的特定溶剂的沸点下进行，根据取代基Z的反应性。碱金属醇盐、碱金属氢氧化物、碱金属碳酸盐（特别是碳酸钾）或三级有机碱（尤其是三乙胺或吡啶）的存在，或反应加速剂（例如碘化钾）是有优势的。方法E用于制备式I的喹唑啉酮衍生物，通过将式VII的苯并噁唑酮（其中R.sub.1、R.sub.2和R.sub.3的含义与式I中相同）与式VIII的烷基二胺反应，其中R.sub.4、R.sub.5、R.sub.6和R.sub.7的含义与式I中相同。反应优选在溶剂（例如苯、二噁烷、较低的脂肪酸，例如冰醋酸或二甲基甲酰胺）中进行，可选地在酸催化剂的存在下，在50至150℃的温度下进行，但最好在所使用的特定溶剂的沸点下进行。优选的溶剂是冰醋酸。然而，该反应也可以在无溶剂的情况下进行。如果方法A到E的最终产物是式I的化合物，其中R.sub.4为苄基，则可以去苄基以得到相应的R.sub.4为氢的化合物。去苄基最好是通过催化氢化反应实现的，例如在乙醇或乙酸乙酯中使用催化剂（例如钯化木炭）和氢气，在25至75℃的温度下，在1至7个大气压的氢气压力下进行。另一方面，如果方法A到E的最终产物是式I的化合物，其中R.sub.4为氢，则可以在桥氮原子上烷基化以形成相应的R.sub.4为烷基的化合物。烷基化可以使用常规的烷基化试剂进行，例如使用烷基卤化物（例如碘甲烷、碘乙烷或溴异丙烷）或二烷基硫酸酯（例如二甲基硫酸酯），在溶剂（例如丙酮、二甲基甲酰胺或二噁烷）中进行，可选地在无机或三级有机碱的存在下，在0至50℃的温度下进行。也可以通过与甲醛和甲酸的混合物反应来进行甲基化，最好在该混合物的沸点下进行。式I所包含的化合物是有机碱，因此可与无机或有机酸形成酸加成盐。无毒、药理学上可接受的酸加成盐的例子包括与盐酸、磷酸、氢溴酸、硫酸、乳酸、酒石酸、马来酸、8-氯茶碱或类似物形成的盐。式II到X的起始化合物或已在文献中描述，或可以通过已知的方法制备，如下面的例子所述。
• Neue Benzofuranderivate und diese enthaltende therapeutische Mittel
  申请人：BASF Aktiengesellschaft

  公开号：EP0303920A1

  公开（公告）日：1989-02-22

  Benzofuranderivate der Formel worin R¹ und R² unabhängig voneinander Wasserstoff, Alkyl oder Phenylalkyl mit jeweils 1 bis 4 C-Atomen im Alkylrest bedeuten, R³, R3′ und R3˝ Wasserstoff, Benzoxy, Fluor, Chlor, Brom, Hydroxy,C₁-₆-Alkoxy, Amin, das ein- oder zweifach C₁-₄-alkyliert oder C₁-₄-acyliert sein kann, Nitro, Hydroxymethyl oder C₁-₄-Alkyl darstellen, und zwei benachbarte Reste R³ und R³′ zusammen den Rest -CH=CH-NH bedeuten können; R⁴ und R⁵ unabhängig voneinander Wasserstoff, C₁-₄-Alkyl, Phenylalkyl mit 1-4 C-Atomen im Alkylrest, wobei der Phenylkern durch Fluor, Chlor oder Brom, C₁-₄-Alkoxy, gegebenenfalls ein- oder zweifach C₁-₄-alkyliertes Amin oder Nitro mono- oder disubstituiert sein kann, bedeuten, oder R⁴ und R⁵ zusammen eine 3- bis 6-gliedrige Kette bilden, die ein Sauerstoff- oder Stickstoffatom enthalten und mit einem Benzolring verbunden sein kann, der seinerseits durch Fluor, Chlor oder Brom C₁-₄-Alkoxy, gegebenenfalls ein-oder zweifach C₁-₄-alkyliertes Amin oder Nitro substituiert sein kann, X eine der Gruppen -CO-CH=CH-, -CO-CH₂-CH₂- oder -CHOH-CH₂-CH₂- darstellt, n die Zahl 2 oder 3 ist und eine Einfach- oder Doppelbindung darstellt, mit der Maßgabe, daß, wenn R¹ und R² gleichzeitig Methyl darstellen, R⁴ nur Wasserstoff oder Alkyl und R⁵ nur einen gegebenenfalls substituierten Phenylalkylrest bedeuten kann, oder R⁴ und R⁵ zusammen eine 3- bis 6-gliedrige, gegebenenfalls ein Sauerstoff- oder Stickstoffatom enthaltende Kette bilden, die mit einem gegebenenfalls substituierten Benzolring verbunden ist, und diese enthaltende therapeutische Mittel.

  式中的苯并呋喃衍生物 其中 R¹ 和 R² 相互独立地为氢、烷基或苯基烷基，每个烷基中含有 1 至 4 个碳原子、 R³、R3′和 R3˝是氢、苯氧基、氟、氯、溴、羟基、C₁-₆-烷氧基、胺，可进行一次或两次 C₁-₄-烷基化或 C₁-₄-酰基化、硝基、羟甲基或 C₁-₄-烷基，两个相邻的基 R³ 和 R³′ 可共同代表基 -CH=CH-NH； R⁴ 和 R⁵ 相互独立地代表氢、C₁-₄-烷基、烷基中含有 1-4 个 C 原子的苯基烷基，其中苯基核可以被氟、氯或溴单取代或二取代，C₁-₄-烷氧基，可选择被 C₁-₄-烷基化胺或硝基单取代或二取代、或 R⁴ 和 R⁵ 共同形成一条 3-6 元链，该链可包含一个氧原子或氮原子，并与一个苯环相连，该苯环又可被氟、氯或溴 C₁-₄-₄-烷氧基取代，可选择被 C₁-₄-₄-烷基化胺或硝基单取代或二取代、 X 代表基团-CO-CH=CH-、-CO-CH₂-CH₂-或-CHOH-CH₂-CH₂-中的一个、 n 是数字 2 或 3，以及 代表单键或双键，但当 R¹ 和 R² 同时代表甲基时，R⁴ 可仅代表氢或烷基，R⁵ 可仅代表任选取代的苯基烷基，或 R⁴ 和 R⁵ 共同形成一条 3 至 6 元链，其中任选含有一个氧原子或氮原子，该链与任选取代的苯环相连，以及含有相同内容的治疗剂。
• A convenient One-Pot Synthesis of an Unsymmetrical Propane-1,3-diamine BRL 61010A
  作者：Robin P Attrill、Thomas W Ramsay、Graham R Slater、Paul Smith

  DOI：10.1080/00397919908086040

  日期：1999.3

  The one-pot condensation of N-methylhomoveratrylamine with acrolein followed by in situ reductive amination with 3,4-dimethoxyaniline to give an unsymmetrical propane 1,3-diamine in excellent yield is described.
• HOLLAND H. L.; JOHNSON G. B., TETRAHEDRON LETT., 1979, NO 36, 3395-3396
  作者：HOLLAND H. L.、 JOHNSON G. B.

  DOI：——

  日期：——