JPH06256330A - Production of propiophenone derivative - Google Patents
Production of propiophenone derivativeInfo
- Publication number
- JPH06256330A JPH06256330A JP5041503A JP4150393A JPH06256330A JP H06256330 A JPH06256330 A JP H06256330A JP 5041503 A JP5041503 A JP 5041503A JP 4150393 A JP4150393 A JP 4150393A JP H06256330 A JPH06256330 A JP H06256330A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- propiophenone
- trioxane
- salt
- formula iii
- 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.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】この発明は、プロピオフェノン誘
導体の新規な製造法に関する。FIELD OF THE INVENTION The present invention relates to a novel method for producing a propiophenone derivative.
【０００２】[0002]
【従来の技術及び発明が解決しようとする課題】４−置
換−２−メチル−３−ピペリジノプロピオフェノン誘導
体は、中枢性筋弛緩作用及び鎮痛作用を有し、筋弛緩薬
として有用であり、従来から種々の方法で製造されてい
る。すなわち、４−置換プロピオフェノンに、 ａ）ホルマリンまたはパラホルムアルデヒドとピペリジ
ンとをイソプロパノール中で反応させてプロピオフェノ
ン誘導体を製造する（特公昭５５−２７９１４，特開昭
５２−８５１７５）、 ｂ）モノクロロジメチルエーテルとピペリジンとを反応
させて製造する（特開平３−２４０６７）、及び ｃ）１，３−ジオキソランとピペリジンとを酸存在下、
反応させて上記誘導体を製造する方法等がある（特開平
３−２７３７２）。BACKGROUND OF THE INVENTION 4-Substituted 2-methyl-3-piperidinopropiophenone derivatives have central muscle relaxant action and analgesic action and are useful as muscle relaxants. , And has been conventionally manufactured by various methods. That is, a 4-substituted propiophenone is reacted with a) formalin or paraformaldehyde and piperidine in isopropanol to produce a propiophenone derivative (JP-B-55-27914, JP-A-52-85175), b). It is produced by reacting monochlorodimethyl ether and piperidine (JP-A-3-24067), and c) 1,3-dioxolane and piperidine in the presence of an acid,
There is a method of reacting to produce the above derivative (JP-A-3-27372).
【０００３】ａ）の方法では原料のホルマリンが刺激性
で、かつ発ガンの危険性があり、取扱いに注意が必要で
あり、またパラホルムアルデヒドを用いる時は、反応時
の溶解性に問題がある。いずれも収率が６０〜８２％と
余りよくない。 ｂ）の方法では、モノクロロジメチルエーテルを用いる
が、これは非常に不安定で分解し易く、また発ガンの危
険性もある。 ｃ）の方法では、原料の１，３−ジオキソランが工業生
産されておらず、経済的に高価である。In the method (a), the raw material formalin is irritating and there is a risk of carcinogenesis, and it must be handled with care. When paraformaldehyde is used, there is a problem in solubility during the reaction. . In all cases, the yield is not so good as 60 to 82%. In the method b), monochlorodimethyl ether is used, but it is very unstable and easily decomposed, and there is a risk of carcinogenesis. In the method c), the raw material 1,3-dioxolane is not industrially produced and is economically expensive.
【０００４】以上のような問題点を克服するために、安
価で刺激臭のない、かつ発ガンの危険性のない原料を用
いて製造を試みた所、極めて簡便に、しかも殆んど定量
的といえる高収率で目的化合物を製造することができ
た。In order to overcome the above-mentioned problems, an attempt was made to manufacture the raw material which is inexpensive, has no irritating odor, and has no risk of carcinogenesis, and is extremely simple and almost quantitative. Thus, the target compound could be produced in a high yield.
【０００５】[0005]
【課題を解決するための手段】この発明によれば、式
（Ｉ）：According to the present invention, the formula (I):
【０００６】[0006]
【化４】 （式中、Ｒは低級アルキル基を表わす）で示される４−
置換プロピオフェノンと、式（II）：[Chemical 4] (In the formula, R represents a lower alkyl group)
A substituted propiophenone and formula (II):
【０００７】[0007]
【化５】 〔式中、Ｚは式（ＣＨ2）ｎ、（ｎ＝０，１）〕で示さ
れる環状アミンまたはその塩と、１，３，５−トリオキ
サンとを反応させることを特徴とする、一般式（III)[Chemical 5] [Wherein Z is a cyclic amine represented by the formula (CH 2 ) n, (n = 0, 1)] or a salt thereof, and 1,3,5-trioxane are reacted. (III)
【０００８】[0008]
【化６】 （式中、Ｒ，Ｚは前記と同意義）で示されるプロピオフ
ェノン誘導体およびその薬理学的に受容な塩の製造方法
が提供される。[Chemical 6] A method for producing a propiophenone derivative represented by the formula (wherein R and Z are as defined above) and a pharmacologically acceptable salt thereof is provided.
【０００９】上記式（Ｉ）におけるＲで示される低級ア
ルキル基としては、炭素数１〜３の飽和アルキル基を意
味し、例えば、メチル、エチル、ｎ−プロピルまたはイ
ソプロピル基が用いられ、特にエチル基が好ましい。The lower alkyl group represented by R in the above formula (I) means a saturated alkyl group having 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl or isopropyl group is used, particularly ethyl group. Groups are preferred.
【００１０】この発明に用いられる環状アミンとして
は、ピロリジンまたはピペリジンが用いられ、特にピペ
リジンが好ましい。またその塩としては塩酸塩、臭化水
素酸塩、弗化水素酸塩等のハロゲン化水素酸塩が用いら
れ、特に塩酸塩が好ましい。この発明に用いられる１，
３，５−トリオキサンは、ホルマリンに硫酸を作用させ
て製造され、工業的にも大規模に生産されており、市販
品が比較的安価に得られる。As the cyclic amine used in the present invention, pyrrolidine or piperidine is used, and piperidine is particularly preferable. As the salt, hydrohalide such as hydrochloride, hydrobromide and hydrofluoride is used, and the hydrochloride is particularly preferable. Used in this invention 1,
3,5-Trioxane is produced by reacting formalin with sulfuric acid, is industrially produced on a large scale, and is commercially available at a relatively low cost.
【００１１】この１，３，５−トリオキサンは、構造上
３個の活性メチレン基を有し、その全てをメチレン源と
して利用できる。従って４−置換プロピオフェノン
（Ｉ）１モルに対し、理論上は１／３モルの少量で十分
である。また、１，３，５−トリオキサンは、水、アル
コール等に可溶な結晶であり、厳密に計量できる利点を
有する。This 1,3,5-trioxane has three active methylene groups structurally, and all of them can be used as a methylene source. Therefore, a small amount of 1/3 mol is theoretically sufficient with respect to 1 mol of 4-substituted propiophenone (I). Further, 1,3,5-trioxane is a crystal soluble in water, alcohol and the like, and has an advantage that it can be strictly measured.
【００１２】反応は、通常反応を阻害しない溶媒中で行
われる。反応を阻害しない溶媒としては、低級アルコー
ル類が用いられ、炭素数１から４の飽和アルコール、例
えばメタノール、エタノール、ｎ−プロパノール、イソ
プロパノール、ｎ−ブタノール、イソブタノール、ｔ−
ブタノール等が用いられる。The reaction is usually carried out in a solvent that does not interfere with the reaction. As the solvent that does not inhibit the reaction, lower alcohols are used, and saturated alcohols having 1 to 4 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Butanol or the like is used.
【００１３】反応は、通常触媒量の酸の存在下に行われ
る。用いられる酸としては、塩酸、硝酸または硫酸が挙
げられ、その使用量は４−置換プロピオフェノン（Ｉ）
の１モルに対し０．０１〜０．２モル、特に０．０５〜
０．１モルが好ましい。反応は、４−置換プロピオフェ
ノン（Ｉ）１モルに対し、環状アミン（II）・塩酸塩
１．０〜２．５モル、好ましくは１．１〜１．５モル、
１，３，５−トリオキサン０．３〜２．０モル、好まし
くは０．８〜１．５モルを用いて行われる。The reaction is usually carried out in the presence of a catalytic amount of acid. Examples of the acid used include hydrochloric acid, nitric acid and sulfuric acid, and the amount thereof used is 4-substituted propiophenone (I).
0.01-0.2 mol, especially 0.05-
0.1 mol is preferred. The reaction is cyclic amine (II) / hydrochloride 1.0 to 2.5 mol, preferably 1.1 to 1.5 mol, per 1 mol of 4-substituted propiophenone (I).
It is carried out using 0.3 to 2.0 mol of 1,3,5-trioxane, preferably 0.8 to 1.5 mol.
【００１４】反応温度は特に限定されないが、７０〜１
５０℃、特に９０〜１００℃が好ましい。反応時間は、
特に限定されないが、１〜１５時間、好ましくは３〜６
時間である。反応は収率が殆んど定量的に、かつワン・
ポット（one-pot)式で行われる。次に実施例を挙げて説
明する。The reaction temperature is not particularly limited, but 70 to 1
50 ° C, particularly 90 to 100 ° C is preferable. The reaction time is
Although not particularly limited, 1 to 15 hours, preferably 3 to 6
It's time. The reaction yields almost quantitatively and
It is done in a one-pot manner. Next, examples will be described.
【００１５】[0015]
実施例１ ４’−エチル−２−メチル−３−ピペリジノプロピオフ
ェノンの製造 ４−エチルプロピオフェノン３０ｇ（０．１９モル）、
１，３，５−トリオキサン１６．７ｇ（０．１９モ
ル）、ピペリジン塩酸塩２７．１ｇ（０．２２モル）お
よびイソプロパノール１５mlの混合物に濃塩酸０．９ml
（０．０１モル）を加え、９５℃で４時間加熱攪拌後、
溶媒を減圧留去し、残留物に水を加えて溶解させた。水
溶液を酢酸エチルで洗浄し、水層を水酸化ナトリウムで
アルカリ性（ｐＨ８）にしてエーテルで抽出した。有機
層を水洗、硫酸マグネシウムで乾燥後、乾燥塩酸ガスを
通じて目的物・塩酸塩５３．１ｇ（収率９７％）を得
た。Example 1 Preparation of 4'-ethyl-2-methyl-3-piperidinopropiophenone 30 g (0.19 mol) of 4-ethylpropiophenone,
A mixture of 16.7 g (0.19 mol) of 1,3,5-trioxane, 27.1 g (0.22 mol) of piperidine hydrochloride and 15 ml of isopropanol was added to 0.9 ml of concentrated hydrochloric acid.
(0.01 mol) was added, and the mixture was heated with stirring at 95 ° C. for 4 hours,
The solvent was distilled off under reduced pressure, and water was added to the residue to dissolve it. The aqueous solution was washed with ethyl acetate, the aqueous layer was made alkaline (pH 8) with sodium hydroxide and extracted with ether. The organic layer was washed with water, dried over magnesium sulfate, and then passed through dry hydrochloric acid gas to obtain 53.1 g (yield 97%) of the target product / hydrochloride.
Claims (1)
置換プロピオフェノンと、式（II）： 【化２】 〔式中、Ｚは式（ＣＨ2）ｎ、（ｎ＝０．１）〕で示さ
れる環状アミンまたはその塩と、 １，３，５−トリオキサンとを反応させることを特徴と
する、 一般式（III) 【化３】 （式中、Ｒ，Ｚは前記と同意義）で示されるプロピオフ
ェノン誘導体およびその薬理学的に受容な塩の製造方
法。1. Formula (I): (In the formula, R represents a lower alkyl group)
Substituted propiophenone and a compound of formula (II): [Wherein Z is a cyclic amine represented by the formula (CH 2 ) n, (n = 0.1)] or a salt thereof, and 1,3,5-trioxane is reacted. (III) [Chemical Formula 3] A method for producing a propiophenone derivative represented by the formula (wherein R and Z are as defined above) and a pharmacologically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5041503A JPH06256330A (en) | 1993-03-02 | 1993-03-02 | Production of propiophenone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5041503A JPH06256330A (en) | 1993-03-02 | 1993-03-02 | Production of propiophenone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06256330A true JPH06256330A (en) | 1994-09-13 |
Family
ID=12610169
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5041503A Pending JPH06256330A (en) | 1993-03-02 | 1993-03-02 | Production of propiophenone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06256330A (en) |
-
1993
- 1993-03-02 JP JP5041503A patent/JPH06256330A/en active Pending
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