JPS595576B2 - Synthiclopropylmethylamine - Google Patents
SynthiclopropylmethylamineInfo
- Publication number
- JPS595576B2 JPS595576B2 JP5892975A JP5892975A JPS595576B2 JP S595576 B2 JPS595576 B2 JP S595576B2 JP 5892975 A JP5892975 A JP 5892975A JP 5892975 A JP5892975 A JP 5892975A JP S595576 B2 JPS595576 B2 JP S595576B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- acid
- general formula
- phenyl group
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】 本発明は一般式〔Ｉ〕 、、、泣゜゛”−゛（一。[Detailed description of the invention] The present invention is based on the general formula [I] ,,, Cry゜゛”−゛(1.
−、’””（式中、Ａｒｌはハロゲン基、低級アルキル
基および低級アルコキシル基よりなる置換基群より選ば
れた置換基を少なくとも１個、オルソまたはメタ位に、
有する置換フェニル基を表わし、Ａｒ２はフェニル基ま
たはハロゲン置換フェニル基を表わし、Ｒは水素原子、
低級アルキル基または低級ヒドロキシアルキル基を、Ａ
は低級アルキレン基を表わす。-, ''''' (wherein Arl has at least one substituent selected from the substituent group consisting of a halogen group, a lower alkyl group, and a lower alkoxyl group, at the ortho or meta position,
Ar2 represents a phenyl group or a halogen-substituted phenyl group, R is a hydrogen atom,
A lower alkyl group or lower hydroxyalkyl group, A
represents a lower alkylene group.
）で表わされる新規シクロプロピルメチルアミン誘導体
およびその酸附加塩の製造法に関する。) and a method for producing the novel cyclopropylmethylamine derivative and its acid addition salt.
さらに詳しくは一般式〔■〕Ａｒ４Ｒ 。For more details, please refer to the general formula [■] Ar4R .
、、□゜゜一゛＜０一。−、’゛”（式中、Ａｒｌ、Ａ
ｒ２、ＲおよびＡは先と同じ意味を有する。,,□゜゜1゛＜01. −, '゛'' (in the formula, Arl, A
r2, R and A have the same meaning as before.
）で表わされる新規アミド誘導体の酸アミド部分を還元
し、必要に応じてその酸附加塩とすることを特徴とする
一般式〔〕で表わされる新規シクロプロピルメチルアミ
ン誘導体およびその酸附加塩の製造法である。) Production of a novel cyclopropylmethylamine derivative represented by the general formula [ ] and its acid addition salt, which is characterized by reducing the acid amide moiety of the novel amide derivative represented by the formula [ ] and, if necessary, producing the acid addition salt thereof. It is the law.
本発明の目的化合物である一般式〔１〕で表わされるフ
エニル基のオルソまたはメタ位に置換基を有することを
特徴とするジフエニルシクロプロピルメチルアミン誘導
体は本発明者等により初めて合成された新規化合物であ
り、かつまた本発明者等の研究により、これらの本発明
化合物が強い抗テトラベナジン作用、抗トレモリン作用
を有することが見出されたものである。The diphenylcyclopropylmethylamine derivative, which is the object compound of the present invention and is characterized by having a substituent at the ortho or meta position of the phenyl group represented by the general formula [1], is a novel product synthesized for the first time by the present inventors. Through research conducted by the present inventors, it has been discovered that these compounds of the present invention have strong anti-tetrabenazine and anti-tremolin effects.
従つて、これらの本発明化合物はたとえば抗うつ剤等の
向精神薬として有用である。従つて、本発明の趣旨とす
るものは新規にして医薬的価値の高い当該化合物の有利
な製造法を提供せんとするものである。Therefore, these compounds of the present invention are useful as psychotropic drugs such as antidepressants. Therefore, the object of the present invention is to provide a novel and advantageous method for producing the compound of high pharmaceutical value.
本発明方法は＝般式〔〕で表わされる酸アミド誘導体の
酸アミド部分を還元してメチレン鎖とすることにより達
成されるが、その還元法としては＝般に酸アミド（〉Ｃ
ＯＮく）を還元してアミン（〉ＣＨ２Ｎく）にする際に
用いられる各種還元剤および各種の態項が可能である。The method of the present invention is achieved by reducing the acid amide moiety of the acid amide derivative represented by the general formula [] to a methylene chain.
Various reducing agents and various modes of use in reducing ON) to amines (〉CH2N) are possible.
先ず好適の還元剤としては水素化アルミニウムリチウム
、ナトリウム水素化ビス（メトキシエトキシ）アルミニ
ウム等の金属水素化合物が挙げられる。First, suitable reducing agents include metal hydride compounds such as lithium aluminum hydride and sodium bis(methoxyethoxy)aluminum hydride.
これらの金属水素化合物は不活性溶媒中、酸アミド誘導
体と反応させることによつて達成されるが、不活性溶媒
としてはジエチルエーテル、ジイソプロピルエーテル、
テトラヒドロフラン、ジオキサン、エチレングライコー
ルジメチルエーテル等が特に好適な溶媒として挙げられ
るがヘプタン、ヘキサン、シクロヘキサン、ベンゼン、
トルエン等もあわせ用いることもできる。These metal hydride compounds are produced by reacting with acid amide derivatives in an inert solvent, and examples of the inert solvent include diethyl ether, diisopropyl ether,
Particularly suitable solvents include tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, etc., but heptane, hexane, cyclohexane, benzene,
Toluene etc. can also be used together.
還元剤は反応が充分に進行するだけの量を用いることが
望ましく、また反応温度としては、適宜冷却または加熱
することにより反応を抑制または促進することが可能で
ある。It is desirable to use the reducing agent in an amount sufficient to allow the reaction to proceed sufficiently, and the reaction can be suppressed or accelerated by appropriately cooling or heating the reaction temperature.
その他該酸アミドの還元法としては、実用性のあるもの
として、水素化硼素金属、ジボラン等を用いる方法が挙
げられる。Other practical methods for reducing the acid amide include methods using boron metal hydride, diborane, and the like.
水素化硼素ナトリウムは入手の容易さ、あるいはアルコ
ール性溶媒を用いることが可能な点で使用し易い還元剤
であるが、酸アミド基に対する還元能力は弱いので、本
発明方法の目的には塩化アルミニウム等の塩類との共存
下で用いる方法、あるいは酸アミド部分をトリエチルオ
キソニウム・フルオロボレート〔（Ｃ２Ｈ５）３＋０・
ＢＦ４−〕等で活性化したる後に水素化硼素ナトリウム
で還元するという方法を用いることができる。Sodium borohydride is a reducing agent that is easy to use because it is easily available or an alcoholic solvent can be used, but its ability to reduce acid amide groups is weak, so aluminum chloride is not suitable for the purpose of the method of the present invention. A method in which the acid amide moiety is used in the coexistence with salts such as triethyloxonium fluoroborate [(C2H5)3+0.
A method can be used in which activation is performed with BF4-] or the like, followed by reduction with sodium borohydride.
また、ジボランも当該酸アミド基の還元剤として用いる
ことができる。Diborane can also be used as a reducing agent for the acid amide group.
反応終了後は通常の有機化学的手法により成績体をとり
だすことができる。After the reaction is completed, the resultant can be taken out using conventional organic chemistry techniques.
本発明方法によつて得られる前記一般式〔１〕の化合物
は、アミン誘導体であるので、所望に応じて生理的に許
容される各種の無機酸および有機？酸たとえば塩酸、硫
酸、臭化水素酸、酢酸、蓚酸、クエン酸、リンゴ酸、酒
石酸、フマール酸、コハク酸などと酸附加塩を形成する
ことができる。Since the compound of general formula [1] obtained by the method of the present invention is an amine derivative, it may be optionally selected from various physiologically acceptable inorganic acids and organic acids. Acid salts can be formed with acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid, succinic acid, and the like.
本発明方法の一般式において、Ａｒｌで表わされる部分
はオルソまたはメタ位に置換基を有する置換フエニル基
を表わすものであるが、置換基ととしてはフルオール、
クロール、ブロム等のハロゲン基、メトキシ、エトキシ
等の低級アルコキシル基およびメチル、エチル、プロピ
ル等の低級アルキル基よりなる置換基群より選ばれた置
換基を示すものである。なおＡｒ，は少なくともオルソ
またはメタ位に前記の置換基を１個有することを必須条
件として、残された位置に前記置換基を一個ないし二個
有することもできる。In the general formula of the method of the present invention, the moiety represented by Arl represents a substituted phenyl group having a substituent at the ortho or meta position, and examples of the substituent include fluor,
It represents a substituent selected from the substituent group consisting of halogen groups such as chlorine and bromine, lower alkoxyl groups such as methoxy and ethoxy, and lower alkyl groups such as methyl, ethyl and propyl. Note that Ar must have at least one of the above-mentioned substituents at the ortho or meta position, and can also have one or two of the above-mentioned substituents at the remaining positions.
一方、Ａｒ２で示される部分はフエニル基または前記ハ
ロゲン置換フエニル基を示すものである。Ｒは、水素原
子またはメチル、エチル、プロピル、ブチル等の低級ア
ルキル基およびヒドロキシメチル、ヒドロキシエチル、
ヒドロキシプロピル等の低級ヒドロキシアルキル基を表
わし、Ａはエチレン、プロピレン、トリメチレン等の低
級アルキレン基を表わす。On the other hand, the moiety represented by Ar2 represents a phenyl group or the halogen-substituted phenyl group. R is a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl,
It represents a lower hydroxyalkyl group such as hydroxypropyl, and A represents a lower alkylene group such as ethylene, propylene, trimethylene, etc.
なお、本発明の原料化合物は本発明者等により初めて合
成された新規化合物であるが、たとえば下記合成経路に
より合成することができる。The raw material compound of the present invention is a novel compound synthesized for the first time by the present inventors, and can be synthesized, for example, by the following synthetic route.
（式中、Ａｒｌ、Ａｒ２、ＲおよびＡは先と同じ意味を
有する。）すなわち一般式〔〕で表わされる化合物をジ
アゾ酢酸エステルによるカルベン反応で＝般式 １〔
〕で表わされるシクロプロパンカルボン酸誘導体を得る
。(In the formula, Arl, Ar2, R and A have the same meanings as above.) That is, a compound represented by the general formula [] is subjected to a carbene reaction with a diazoacetate to form the formula 1 [
] to obtain a cyclopropanecarboxylic acid derivative.
ついでこの〔〕を通常の方法でそのジメチルアミドもし
くはメチルアミド誘導体〔〕に導くことができる。以下
に実施例により本発明方法をより詳細に説 １明するが
本発明方法はもとより、これに限定されない。This [ ] can then be converted into its dimethylamide or methylamide derivative [ ] by a conventional method. The method of the present invention will be explained in more detail with reference to Examples below, but the method of the present invention is not limited thereto.
実施例 １
リチウムアルミニウムハイドライド（０．３３７）を乾
燥エーテル（１０ｒ１Ｌ１）に加え、そこへ氷冷攪二拌
下、乾燥エーテル（１０ＴＩＩＩ）に溶かした、２−フ
エニル一２−（ｍ−クロロフエニル）シクロプロパンカ
ルボン酸、Ｎ−メチル−Ｎ−（３−ヒドロキシプロピル
）アミド（１．００７）を滴下し、その後室温で１時間
撹拌を続けた。Example 1 Lithium aluminum hydride (0.337) was added to dry ether (10r1L1), and 2-phenyl-2-(m-chlorophenyl)cyclo dissolved in dry ether (10TIII) was added thereto under ice-cooling and stirring. Propanecarboxylic acid, N-methyl-N-(3-hydroxypropyl)amide (1.007) was added dropwise, followed by continued stirring at room temperature for 1 hour.
★過剰の金属錯化合物を水により分解し
、その混合物のエーテル抽出液よりエーテルを留去する
ことにより目的のＮ−メチノレ一Ｎ−（３−ヒドロキシ
プロピル）−２−フエニル一２−（ｍ−クロロフエニル
）シクロプロピルメチルアミンが油状物として得られた
。赤外線吸収スペクトル（フイルム法） ３３５０（Ｂ
ｒ）、 ３０６０１３０２０、２９４０１１５９５、１
５６５、１４８０１１０７５、７００ｃ７ｎ−１実施例
１中の２−フエニル一２−（ｍ−クロロフエニル）シク
ロプロパンカルボン酸、Ｎ−メチル−Ｎ−（３−ヒドロ
キシプロピル）アミドを一般式〔Ｈ〕の適当な出発物質
の当モル量で置き換え、実施例１の方法に準じて本反応
を行い、次の化合物を得た。★Excess metal complex compound is decomposed with water, and the ether is distilled off from the ether extract of the mixture to obtain the desired N-methyl-N-(3-hydroxypropyl)-2-phenyl-2-(m- chlorophenyl)cyclopropylmethylamine was obtained as an oil. Infrared absorption spectrum (film method) 3350 (B
r), 306013020, 294011595, 1
565, 148011075, 700c7n-1 2-phenyl-2-(m-chlorophenyl)cyclopropanecarboxylic acid and N-methyl-N-(3-hydroxypropyl)amide in Example 1 are converted to an appropriate compound of the general formula [H]. This reaction was carried out according to the method of Example 1, substituting the equimolar amount of the starting material, to obtain the following compound.
Claims (1)
低級アルコキシル基よりなる置換基群より選ばれた置換
基を少なくとも１個、オルソまたはメタ位に有する置換
フェニル基を表わし、Ａｒ＿２はフェニル基またはハロ
ゲン置換フェニル基は表わし、Ｒは水素原子、低級アル
キル基、または低級ヒドロキシアルキル基を、Ａは低級
アルキレン基を表わす。 ）で表わされる新規アミド誘導体のアミド部分を還元し
、必要に応じてその酸附加塩とすることを特徴とする一
般式▲数式、化学式、表等があります▼ （式中、Ａｒ＿１、Ａｒ＿２、ＲおよびＡは先と同じ意
味を有する。 ）で表わされる新規シクロプロピルメチルアミン誘導体
の製造法。[Claims] 1 General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ , represents a substituted phenyl group at the ortho or meta position, Ar_2 represents a phenyl group or a halogen-substituted phenyl group, R represents a hydrogen atom, a lower alkyl group, or a lower hydroxyalkyl group, and A represents a lower alkylene group.) The general formula is characterized by reducing the amide moiety of the new amide derivative represented by ▲ and making it into an acid salt if necessary ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Ar_1, Ar_2, R and A has the same meaning as above.) A method for producing a novel cyclopropylmethylamine derivative.
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5892975A JPS595576B2 (en) | 1975-05-16 | 1975-05-16 | Synthiclopropylmethylamine |
| US05/635,331 US4103030A (en) | 1974-12-11 | 1975-11-26 | Novel cyclopropylmethylamine derivatives |
| AT910775A AT339275B (en) | 1974-12-11 | 1975-12-01 | PROCESS FOR THE PRODUCTION OF NEW 2,2-DIPHENYLCYCLOPROPYLMETHYLAMINES AND THEIR ACID ADDITION SALTS |
| SE7513795A SE7513795L (en) | 1974-12-11 | 1975-12-08 | PROCEDURE FOR MAKING NEW CYCLOPROPYLMETHYLAMINE DERVAT |
| CA241,210A CA1060049A (en) | 1974-12-11 | 1975-12-08 | Cyclopropylmethylamine derivatives |
| DE19752555352 DE2555352A1 (en) | 1974-12-11 | 1975-12-09 | 2,2-DIPHENYLCYCLOPROPYLMETHYLAMINE DERIVATIVES |
| GB50471/75A GB1481504A (en) | 1974-12-11 | 1975-12-09 | Cyclopropylmethylamine derivatives |
| AU87373/75A AU494427B2 (en) | 1975-12-09 | Novel cyclopropylmethylamine derivatives | |
| FR7537833A FR2293922A1 (en) | 1974-12-11 | 1975-12-10 | PROCESS FOR PREPARING CYCLOPROPYLMETHYLAMINE DERIVATIVES, NEW PRODUCTS THUS OBTAINED AND THEIR USE AS ANTAGONIST AGENTS OF THE EFFECTS OF DEPRESSIVE PRODUCTS ON THE CENTRAL NERVOUS SYSTEM |
| NL7514481A NL7514481A (en) | 1974-12-11 | 1975-12-11 | NEW CYCLOPROPYL METHYLAMINE DERIVATIVES. |
| CH1612075A CH617177A5 (en) | 1974-12-11 | 1975-12-11 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5892975A JPS595576B2 (en) | 1975-05-16 | 1975-05-16 | Synthiclopropylmethylamine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS51136656A JPS51136656A (en) | 1976-11-26 |
| JPS595576B2 true JPS595576B2 (en) | 1984-02-06 |
Family
ID=13098512
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5892975A Expired JPS595576B2 (en) | 1974-12-11 | 1975-05-16 | Synthiclopropylmethylamine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS595576B2 (en) |
-
1975
- 1975-05-16 JP JP5892975A patent/JPS595576B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS51136656A (en) | 1976-11-26 |
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