JPS6326102B2 - - Google Patents
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- Publication number
- JPS6326102B2 JPS6326102B2 JP54058123A JP5812379A JPS6326102B2 JP S6326102 B2 JPS6326102 B2 JP S6326102B2 JP 54058123 A JP54058123 A JP 54058123A JP 5812379 A JP5812379 A JP 5812379A JP S6326102 B2 JPS6326102 B2 JP S6326102B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- carboxylic acid
- aminomethyl
- hydroxycyclohexane
- compound
- 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
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- 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（）
で示される新規物質４−アミノメチル−３−ヒド
ロオキシシクロヘキサン−１−カルボン酸および
その製造法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula () The present invention relates to a novel substance 4-aminomethyl-3-hydroxycyclohexane-1-carboxylic acid shown in the following, and a method for producing the same.
本発明化合物（）は医薬品の原料、例えば抗
プラスミン作用を有する薬剤４−アミノメチルシ
ロクヘキサンカルボン酸（以下AMCHAと称
す。）の製造中間体として有用な化合物である。 The compound () of the present invention is a compound useful as a raw material for pharmaceuticals, for example, as an intermediate in the production of 4-aminomethylsiloxanecarboxylic acid (hereinafter referred to as AMCHA), a drug having antiplasmin action.
本発明化合物（）は、シクロヘキセンカルボ
ン酸等の二重結合を有する化合物に緩和な条件で
直接アミノメチル基を導入するという新規な付加
反応により製造することが出来る。 The compound () of the present invention can be produced by a novel addition reaction in which an aminomethyl group is directly introduced into a compound having a double bond such as cyclohexenecarboxylic acid under mild conditions.
即ち、一般式（）
（式中Ｘは、シアノ基、カルボキシル基、低級ア
ルコキシカルボニル基又はカルバモイル基を示
す。）で示されるシクロヘキセン誘導体を酸性触
媒の存在下、一般式（）
Ｒ−CONHCH2OH （）
（式中Ｒは、フエニル基、ベンジル基又は低級ア
ルキル基を示す。）で示されるＮ−メチロール体
（）と反応させた後、加水分解することにより
本発明化合物（）は製される。 That is, the general formula () (In the formula, X represents a cyano group, a carboxyl group, a lower alkoxycarbonyl group, or a carbamoyl group.) A cyclohexene derivative represented by the general formula () R-CONHCH 2 OH () (in the formula R represents a phenyl group, a benzyl group, or a lower alkyl group.) The compound of the present invention () is produced by reacting with an N-methylol compound () represented by the formula () and then hydrolyzing it.
更に詳細に述べると、原料化合物のシクロヘキ
セン誘導体（）は、例えばブタジエンとアクリ
ル酸誘導体の環化付加反応により容易に収率良く
得ることが出来る、またＮ−メチロール体（）
は酸アミドとホルマリンまたはシアノ化合物（Ｒ
−CN）とホルマリンから容易に安価に製造され
る。 More specifically, the raw material compound cyclohexene derivative () can be easily obtained in good yield by, for example, a cycloaddition reaction of butadiene and an acrylic acid derivative, and the N-methylol derivative ()
is acid amide and formalin or cyano compound (R
-CN) and formalin.
Ｎ−メチロール体（）の使用量は、シクロヘ
キセン誘導体（）に対して当モル以上使用すれ
ば良いが、１〜２倍モルを使用するが望ましい。 The amount of the N-methylol derivative () to be used may be equal to or more than the equivalent mole of the cyclohexene derivative (), but it is preferable to use 1 to 2 times the mole.
触媒としては有機、無機酸、例えばギ酸、パラ
トルエンスルホン酸、硫酸、塩酸およびリン酸等
が使用出来、更にはルイス酸、例えば塩化アルミ
ニウム、塩化第二鉄、弗化ホウ素、二塩化テル
ル、四塩化チタン等も使用出来る。又、反応温度
は通常０〜150℃、特に０〜50℃が適用される。
反応後、酸またはアルカリ水溶液で加水分解し、
強酸性陽イオン交換樹脂で処理し、アンモニア溶
離液を濃縮乾固し、残留物にメタノールを加え濾
取すると４−アミノメチル−３−ヒドロキシシク
ロヘキサン−１−カルボン酸の白色晶が得られ
る。 As catalysts, organic and inorganic acids such as formic acid, para-toluenesulfonic acid, sulfuric acid, hydrochloric acid and phosphoric acid can be used, as well as Lewis acids such as aluminum chloride, ferric chloride, boron fluoride, tellurium dichloride, tetrachloride, etc. Titanium chloride etc. can also be used. Further, the reaction temperature is usually 0 to 150°C, particularly 0 to 50°C.
After the reaction, hydrolyze with acid or alkaline aqueous solution,
After treatment with a strongly acidic cation exchange resin, the ammonia eluent is concentrated to dryness, methanol is added to the residue, and the residue is collected by filtration to obtain white crystals of 4-aminomethyl-3-hydroxycyclohexane-1-carboxylic acid.
本発明による付加反応では、３−アミノメチル
−４−ヒドロオキシシクロヘキサン−１−カルボ
ン酸も多少副生するが、メタノール等の溶媒によ
る溶解度差またはパラトルエンスルホン酸等の塩
にすることによつて容易に除くことが出来る。 In the addition reaction according to the present invention, 3-aminomethyl-4-hydroxycyclohexane-1-carboxylic acid is also produced to some extent as a by-product, but this may be due to differences in solubility due to solvents such as methanol or by making it into a salt such as para-toluenesulfonic acid. It can be easily removed.
この様にして製される本発明化合物（）を、
例えばハロゲン化剤にて処理し、次いで還元すれ
ば容易に好収率でAMCHAが製される。 The compound of the present invention () produced in this way,
For example, AMCHA can be easily produced in good yield by treatment with a halogenating agent and then reduction.
従つて、本発明は医薬品として有用な
AMCHAの製造中間体として有用な新規化合物
４−アミノメチル−３−ヒドロオキシシクロヘキ
サン−１−カルボン酸およびその製造方法を、ひ
いてはかかる製造中間体を用いることにより、従
来とは方法を全く異にするAMCHAの新規かつ
工業的に有利な製造方法を提供するものである。 Therefore, the present invention is useful as a pharmaceutical.
By using a new compound 4-aminomethyl-3-hydroxycyclohexane-1-carboxylic acid useful as an intermediate for producing AMCHA and a method for producing the same, and by using such a production intermediate, the method is completely different from conventional methods. This provides a new and industrially advantageous manufacturing method for AMCHA.
以下、本発明を実施例および参考例によつて詳
細に説明する。 Hereinafter, the present invention will be explained in detail using Examples and Reference Examples.
実施例 １
３−シクロヘキセン−１−カルボン酸12.6ｇ
（0.1モル）を100mlのギ酸に溶解し、温度25℃で
１時間かけてＮ−メチロ−ルベンズアミド22.6ｇ
（0.15モル）を加え、その後同温で３時間撹拌す
る。反応後ギ酸を回収し、残留物に10％塩酸水
100mlを加え、３時間加熱還流して加水分解を行
なう。冷後不溶物を濾別し、濾液を強酸性陽イオ
ン交換樹脂ダイヤイオンSK−IBで処理し、流出
液の酸性がなくなつた後、５％アンモニア水を流
し、流出液を濃縮する。残留物にメタノールを加
え、析出する結晶を濾取し、この結晶を水−アセ
トンから再結晶すると、融点300℃（分解）の４
−アミノメチル−３−ヒドロオキシシクロヘキサ
ン−１−カルボン酸が得られる。Example 1 12.6 g of 3-cyclohexene-1-carboxylic acid
(0.1 mole) was dissolved in 100 ml of formic acid, and 22.6 g of N-methylolbenzamide was dissolved at a temperature of 25°C for 1 hour.
(0.15 mol) and then stirred at the same temperature for 3 hours. After the reaction, collect the formic acid and add 10% hydrochloric acid to the residue.
Add 100 ml and heat under reflux for 3 hours to perform hydrolysis. After cooling, insoluble matter is filtered off, and the filtrate is treated with a strongly acidic cation exchange resin Diaion SK-IB. After the acidity of the effluent disappears, 5% aqueous ammonia is poured in and the effluent is concentrated. Methanol is added to the residue, the precipitated crystals are collected by filtration, and the crystals are recrystallized from water-acetone to give 4.
-Aminomethyl-3-hydroxycyclohexane-1-carboxylic acid is obtained.
元素分析値（％） C8H15NO3に対して
計算値 Ｃ 55.64、Ｈ 8.73、Ｎ 8.12
実測値 Ｃ 55.47、Ｈ 8.73、Ｎ 8.09
実施例 ２
３−シクロヘキセン−１−カルボン酸メチルエ
ステル14ｇ（0.1モル）をリン酸100mlに溶解し、
温度15℃で１時間かけてＮ−メチロールアセトア
ミド9.3ｇ（0.15モル）を加え、その後同温で３
時間撹拌する。反応後、反応液に10％塩酸水150
mlを加え、３時間加熱還流して加水分解を行な
う。この加水分解液をそのまま実施例１と同様の
方法で処理すると４−アミノメチル−３−ヒドロ
オキシシクロヘキサン−１−カルボン酸が得られ
る。Elemental analysis value (%) C 8 H 15 Based on NO 3 Calculated value C 55.64, H 8.73, N 8.12 Actual value C 55.47, H 8.73, N 8.09 Example 2 14 g of 3-cyclohexene-1-carboxylic acid methyl ester ( 0.1 mol) in 100 ml of phosphoric acid,
9.3 g (0.15 mol) of N-methylolacetamide was added over 1 hour at a temperature of 15°C, and then 3
Stir for an hour. After the reaction, add 150% 10% hydrochloric acid to the reaction solution.
ml and heated under reflux for 3 hours to perform hydrolysis. When this hydrolyzed solution is directly treated in the same manner as in Example 1, 4-aminomethyl-3-hydroxycyclohexane-1-carboxylic acid is obtained.
実施例 ３
３−シクロヘキセン−１−カルボン酸ニトリル
10.7ｇ（0.1モル）を100mlの酢酸と9.8ｇの硫酸の
混合液に溶解し、温度30℃で１時間かけてＮ−メ
チロールアセトアミド12.4ｇ（0.2モル）を加え、
その後同温で３時間撹拌する。反応後酢酸を回収
し、10％硫酸水100mlを加え、３時間加熱還流し
て加水分解する。その後、実施例１と同様の方法
で処理すると、４−アミノメチル−３−ヒドロオ
キシシクロヘキサン−１−カルボン酸が得られ
る。Example 3 3-cyclohexene-1-carboxylic acid nitrile
10.7 g (0.1 mol) was dissolved in a mixture of 100 ml of acetic acid and 9.8 g of sulfuric acid, and 12.4 g (0.2 mol) of N-methylolacetamide was added over 1 hour at a temperature of 30°C.
Thereafter, the mixture was stirred at the same temperature for 3 hours. After the reaction, acetic acid is collected, 100 ml of 10% sulfuric acid water is added, and the mixture is heated under reflux for 3 hours for hydrolysis. Thereafter, treatment is performed in the same manner as in Example 1 to obtain 4-aminomethyl-3-hydroxycyclohexane-1-carboxylic acid.
参考例
４−アミノメチル−３−ヒドロオキシシクロヘ
キサン−１−カルボン酸17.3ｇ（0.1モル）を塩
化チオニル50mlに溶解し、温度25℃で一夜放置し
た後、過剰の塩化チオニルを回収する。次いで残
留物に水150mlを加え、濃アンモニアでアルカリ
性として、ラネーニツケル３ｇを触媒として水素
圧30Kg／cm2、温度50℃で３時間水素添加する。そ
の後、触媒を濾別して濾液を濃縮乾固し、再び水
に溶解し、強酸性陽イオン交換樹脂ダイヤイオン
SK−LBで処理し、５％アンモニア流出液を濃縮
乾固する。残留物を水−メタノールから再結晶す
ると、４−アミノメチルシクロヘキサンカルボン
酸12.6ｇが得られる。Reference Example 17.3 g (0.1 mol) of 4-aminomethyl-3-hydroxycyclohexane-1-carboxylic acid was dissolved in 50 ml of thionyl chloride, and after standing overnight at a temperature of 25°C, excess thionyl chloride was recovered. Next, 150 ml of water was added to the residue, made alkaline with concentrated ammonia, and hydrogenated using 3 g of Raney nickel as a catalyst at a hydrogen pressure of 30 Kg/cm 2 and a temperature of 50° C. for 3 hours. After that, the catalyst is filtered out, the filtrate is concentrated to dryness, and then dissolved in water again to form a strongly acidic cation exchange resin called Diaion.
Treat with SK-LB and concentrate the 5% ammonia effluent to dryness. Recrystallization of the residue from water-methanol gives 12.6 g of 4-aminomethylcyclohexanecarboxylic acid.
実施例 ４
３−シクロヘキセン−１−カルボン酸アミド
12.5ｇ（0.1モル）を100mlの蟻酸に溶解し、温度
25℃で１時間かけてＮ−メチロールベンズアミド
22.6ｇ（0.15モル）を加え、その後同温度で３時
間撹拌する。反応後蟻酸を回収し、残留物に10％
塩酸100mlを加え、３時間加熱還流し、加水分解
を行なう。その後、実施例１と同様の方法で処理
し、４−アミノメチル−３−ヒドロオキシシクロ
ヘキサン−１−カルボン酸が得られる。Example 4 3-cyclohexene-1-carboxylic acid amide
Dissolve 12.5 g (0.1 mole) in 100 ml of formic acid, and
N-methylolbenzamide for 1 hour at 25°C.
Add 22.6 g (0.15 mol) and stir at the same temperature for 3 hours. After the reaction, formic acid is recovered and the residue contains 10%
Add 100 ml of hydrochloric acid and heat under reflux for 3 hours to perform hydrolysis. Thereafter, it is treated in the same manner as in Example 1 to obtain 4-aminomethyl-3-hydroxycyclohexane-1-carboxylic acid.
Claims (1)
シクロヘキサン−１−カルボン酸。 ２ 一般式 （式中Ｘは、シアノ基、カルボキシル基、低級ア
ルコキシカルボニル基又はカルバモイル基を示
す。）で示されるシクロヘキセン誘導体を酸性触
媒の存在下、一般式 Ｒ−CONHCH2OH （式中Ｒは、フエニル基、ベンジル基又は低級ア
ルキル基を示す。）で示されるＮ−メチロール体
と反応せしめ、次いで加水分解することを特徴と
する一般式 で示される４−アミノメチル−３−ヒドロオキシ
シクロヘキサン−１−カルボン酸の製造法。[Claims] 1. General formula 4-aminomethyl-3-hydroxycyclohexane-1-carboxylic acid represented by 2 General formula ( In the formula, , a benzyl group or a lower alkyl group), and then hydrolyzed. A method for producing 4-aminomethyl-3-hydroxycyclohexane-1-carboxylic acid represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5812379A JPS55151539A (en) | 1979-05-14 | 1979-05-14 | Novel cyclohexane derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5812379A JPS55151539A (en) | 1979-05-14 | 1979-05-14 | Novel cyclohexane derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55151539A JPS55151539A (en) | 1980-11-26 |
| JPS6326102B2 true JPS6326102B2 (en) | 1988-05-27 |
Family
ID=13075194
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5812379A Granted JPS55151539A (en) | 1979-05-14 | 1979-05-14 | Novel cyclohexane derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55151539A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104640843A (en) | 2012-07-19 | 2015-05-20 | 大日本住友制药株式会社 | 1-(cycloalkyl-carbonyl)proline derivative |
-
1979
- 1979-05-14 JP JP5812379A patent/JPS55151539A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55151539A (en) | 1980-11-26 |
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