JP2008120689A - Method for producing n-substituted formyl polymethylene imine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially advantageous method for producing an N-substututed formyl polyethylene imine. <P>SOLUTION: This method for producing the N-substituted formyl polyethylene imine represented by formula (2) [R is an aryl or an aralkyl; (m) is an integer of 0 to 3] by oxidizing an N-substituted hydroxymethyl polyethylene imine represented by formula (1) with an alkali metal hypohalite in the presence of a compound having a nitroxide-releasing group, is characterized by treating the compound having the nitroxide-releasing group with an oxidizing agent and then reusing the compound, when reusing the compound having the nitroxide-releasing group. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention is a compound useful as a synthetic intermediate for pharmaceuticals and the like (2):

（式中、Ｒはアリール基又はアラルキル基を表し、ｍは０〜３の整数である。）で示されるＮ−置換−ホルミルポリメチレンイミン（以下、Ｎ−置換−ホルミルポリメチレンイミン（２）という。）の製造方法に関する。

(In the formula, R represents an aryl group or an aralkyl group, and m is an integer of 0 to 3.) N-substituted-formylpolymethyleneimine (hereinafter, N-substituted-formylpolymethyleneimine (2) Is related to the manufacturing method.

  Conventionally, as a method for producing N-substituted-formylpolymethyleneimine (2), formula (1):

（式中、Ｒ及びｍは前記に同じ。）で示されるＮ−置換−ヒドロキシメチルポリメチレンイミン（以下、Ｎ−置換−ヒドロキシメチルポリメチレンイミン（１）という。）を、ニトロキシド遊離基を有する化合物の存在下、次亜ハロゲン酸アルカリ金属塩で酸化反応せしめる方法が知られており（例えば、特許文献１参照）、反応終了後に回収したニトロキシド遊離基を有する化合物は、Ｎ−置換−ホルミルポリメチレンイミン（１）の製造に再使用できることが記載されている。
特開２０００−１４３６２７

(In the formula, R and m are the same as above.) N-substituted hydroxymethylpolymethyleneimine (hereinafter referred to as N-substituted hydroxymethylpolymethyleneimine (1)) has a nitroxide free radical. There is known a method of oxidizing with an alkali metal hypohalous acid salt in the presence of a compound (see, for example, Patent Document 1), and a compound having a nitroxide free radical recovered after the reaction is N-substituted-formylpoly It is described that it can be reused for the production of methyleneimine (1).
JP 2000-143627 A

The present inventor diligently investigated the reuse of the compound having a recovered nitroxide free group after completion of the reaction. As a result, the recovered compound having a nitroxide free group has an impurity represented by the formula (3):
R-CHO (3)
(Wherein R is the same as above) (hereinafter referred to as aldehyde compound (3)), and if reused as it is, aldehyde compound (3) and alkali metal hypohalite For example, when the reaction is carried out in an amount equivalent to the theoretical amount by reducing the amount of alkali metal hypohalite used because the salt reacts, the yield of the target N-substituted-formylpolymethyleneimine (2) is increased. I found it to drop considerably. Accordingly, an object of the present invention is to provide an industrially advantageous method for producing N-substituted-formylpolymethyleneimine (2) which can solve such problems.

  In the present invention, N-substituted-formylpolymethyleneimine (2) is obtained by oxidizing N-substituted-hydroxymethylpolymethyleneimine (1) with an alkali metal hypohalite in the presence of a compound having a nitroxide free group. In the process for producing N) -formylpolymethyleneimine, the compound having a nitroxide free radical is reused after being treated with an oxidizing agent. It relates to a manufacturing method.

  According to the production method of the present invention, the by-product aldehyde compound (3) can be removed by treating a compound having a nitroxide free radical with an oxidizing agent, and the thus obtained compound having a nitroxide free radical is recycled. By using the hypohalous acid alkali metal salt corresponding to the theoretical amount, it is possible to suppress the yield reduction of the N-substituted formylpolymethyleneimine (2), and industrially advantageous N-substituted. -Formyl polymethyleneimine (2) can be produced.

Hereinafter, the present invention will be described in detail.
In formula (1) and formula (2), R represents an aryl group or an aralkyl group, preferably an aryl group. Examples of the aryl group include a phenyl group and naphthyl group which may have an alkyl group such as a methyl group or an ethyl group. Examples of the aralkyl group include a benzyl group, a 1-phenethyl group, and a 2-phenethyl group, which may have an alkyl group such as a methyl group or an ethyl group in an aromatic ring. m is an integer of 0 to 3, and preferably m is 1 or 2.

  N-substituted-hydroxymethyl polymethyleneimines (1) include N-substituted-hydroxymethyl azetidines, N-substituted-hydroxymethyl pyrrolidines, N-substituted-hydroxymethyl piperidines and N-substituted-hydroxymethyl hexaxines. Methyleneimines, preferably N-substituted-hydroxymethylpyrrolidines and N-substituted-hydroxymethylpiperidines. Specifically, N-benzyl-2- (hydroxymethyl) pyrrolidine, N-benzyl-3- (hydroxymethyl) pyrrolidine, N-benzyl-2- (hydroxymethyl) piperidine, N-benzyl-3- (hydroxymethyl) ) Piperidine, N-benzyl-4- (hydroxymethyl) piperidine and the like.

  Then, by the production method of the present invention, the hydroxymethyl group of the N-substituted-hydroxymethylpolymethyleneimine (1) is oxidized to a formyl group to produce the corresponding N-substituted-formylpolymethyleneimine (2). For example, N-substituted-formylazetidine, N-substituted-hydroxymethylpyrrolidines, N-substituted-hydroxymethylpiperidines and N-substituted-hydroxymethylhexamethyleneimines, respectively. , N-substituted-formylpyrrolidines, N-substituted-formylpiperidines and N-substituted-formylhexamethyleneimines are prepared. Specific examples of N-substituted-formylpolymethyleneimine (2) include N-benzyl-2-formylpyrrolidine, N-benzyl-3-formylpyrrolidine, N-benzyl-2-formylpiperidine, N-benzyl-3- Examples include formylpiperidine and N-benzyl-4-formylpiperidine.

  The compound having a nitroxide free radical used in the present invention is preferably a compound having a bulky substituent in the vicinity of the free radical. Med. Chem. 41, 3477 (1998) and the like, 2,2,6,6-tetramethylpiperidine-1-oxyl and derivatives thereof, 2,2,5,5-tetramethylpyrrolidine-1-oxyl and derivatives thereof 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl and derivatives thereof, specifically, 2,2,6,6-tetramethylpiperidine-1-oxyl, Acyloxy group (eg, acetoxy group, propionyloxy group, benzoyloxy group, etc.), alkoxy group (eg, methoxy group, ethoxy group, propoxy group, etc.) at the 4-position of 2,6,6-tetramethylpiperidine-1-oxyl Or a 2,2,6,6-tetramethylpiperidine-1-oxyl derivative having a substituent such as an aralkyloxy group (eg, benzyloxy group) 2,2,5,5-tetramethylpyrrolidine-1-oxyl, an acyloxy group (for example, acetoxy group, propionyloxy group, 3-position of 2,2,5,5-tetramethylpyrrolidine-1-oxyl, 2,2,5,5-tetramethylpyrrolidine having a substituent such as benzoyloxy group, alkoxy group (for example, methoxy group, ethoxy group, propoxy group, etc.) or aralkyloxy group (for example, benzyloxy group, etc.) -1, -oxyl derivative, 2,2,5,5-tetramethyl-3-pyrrolin-1-oxyl, acyloxy at the 3-position of 2,2,5,5-tetramethyl-3-pyrrolin-1-oxyl Groups (for example, acetoxy group, propionyloxy group, benzoyloxy group, etc.), alkoxy groups (for example, methoxy group, ethoxy group, propoxy group) Group) or an aralkyl group (e.g., such as 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl derivatives having a substituent such as a benzyloxy group). The amount used is 0.0005 to 10 mol, preferably 0.1 to 1.0 mol, per 1 mol of N-substituted-hydroxymethylpolymethyleneimine (1).

  Moreover, in the manufacturing method of this invention, the reaction in presence of a phase transfer catalyst is preferable from the point of improving a yield. Examples of the phase transfer catalyst include known phase transfer catalysts that are generally used in organic synthesis reactions, and are preferably ionic types such as quaternary ammonium salts, pyridinium salts, and quaternary phosphonium salts. Specifically, examples of the quaternary ammonium salt include tetramethylammonium chloride, tetrabutylammonium chloride, trioctylmethylammonium chloride, benzyltrimethylammonium chloride, and benzyltributylammonium chloride, and chloride ions of these salts. Examples of the pyridinium salt include N-butylpyridinium chloride, N-hexylpyridinium chloride, N-octylpyridinium chloride, and the like, which include other anions (for example, bromide ion, iodide ion and hydrogen sulfate ion). N-alkylpyridinium chloride such as N-laurylpyridinium chloride, N-cetylpyridinium chloride, N-lauryl-2-picolium chloride, N-cetyl-2-pico N-alkylpicolinium chlorides such as um chloride, N-lauryl-3-picolium chloride, N-cetyl-3-picolium chloride, N-lauryl-4-picolium chloride, N-cetyl-4-picolium chloride, N-alkyl-4 such as N-butyl-4-phenylpropylpyridinium chloride, N-hexyl-4-phenylpropylpyridinium chloride, N-octyl-4-phenylpropylpyridinium chloride, N-lauryl-4-phenylpropylpyridinium chloride -Phenylpropylpyridinium chloride, and those in which chloride ions of these salts are replaced with other anions (for example, bromide ion, iodide ion, hydrogen sulfate ion, etc.), and quaternary phosphonium salts include Tetrabutylphos Nitrogen chloride, tetraphenylphosphonium chloride, tributyldecylphosphonium chloride, triethylhexadecylphosphonium chloride, and the chloride ions of these salts replaced with other anions (eg, bromide ion, iodide ion, hydrogen sulfate ion, etc.) Is mentioned. The amount used is 0.0005 to 1 part by weight, preferably 0.05 to 0.2 part by weight per 1 part by weight of N-substituted-hydroxymethylpolymethyleneimine (1).

  Moreover, as an alkali metal hypohalous acid salt in this invention, the sodium salt and potassium salt of hypochlorous acid and hypobromite can be used, Preferably it is sodium hypochlorite. The amount used is sufficient if it corresponds to the theoretical amount, and is usually 0.5 to 1.5 mol, preferably 0.8 to 1 mol per mol of N-substituted-hydroxymethylpolymethyleneimine (1). .2 moles.

  Further, an alkali metal such as sodium bromide, potassium bromide, or magnesium bromide, or a bromide salt such as an alkaline earth metal may be added. The addition amount is 0.01 to 5 mol, preferably 0.05 to 1.5 mol per mol of N-substituted-hydroxymethylpolymethyleneimine (1).

  A solvent is usually used for the reaction. As the solvent, a mixed solvent of water and at least one hydrophobic organic solvent selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, mesitylene, ethyl acetate, ethyl ether, isopropyl ether and the like is used. The Although there is no restriction | limiting in particular in the usage-amount of a solvent, 4-15 weight part of organic solvents and 0.1-4 weight part of water are suitable with respect to 1 weight part of N-substituted-hydroxymethyl polymethyleneimine (1). It is.

  The reaction temperature is usually in the range of −10 to 60 ° C., but preferably in the range of −5 to 30 ° C. About reaction time, it changes with reaction temperature, the kind of raw material compound, the usage-amount, etc., and can change suitably according to each condition.

  From the reaction mixture after completion of the reaction, for example, N-substituted-formylpolymethyleneimine (2) produced as follows can be isolated. That is, the obtained reaction mixture is separated into an aqueous layer and an organic layer, and an aqueous solution of an acid is added to the organic layer to form a salt of N-substituted formylpolymethyleneimine (2) and an acid. To do. By performing such acid treatment, the aqueous layer contains an acid salt of N-substituted-formylpolymethyleneimine (2), and the organic layer has a nitroxide free radical compound and an aldehyde compound (3) used in the reaction. However, since each distributes, the N-substituted formylpolymethyleneimine (2) can be separated from the compound having a nitroxide free group and the aldehyde compound (3). Next, alkali is added to the aqueous layer to form free N-substituted-formylpolymethyleneimine (2) from the acid salt of N-substituted-formylpolymethyleneimine (2), and then a hydrophobic organic solvent is added. If extracted and the organic layer is distilled, N-substituted-formylpolymethyleneimine (2) can be isolated.

And as an oxidizing agent process of the compound which has a nitroxide free group in the manufacturing method of this invention, the organic layer obtained in the said acid treatment containing the compound and aldehyde compound (3) which have a nitroxide free group normally is an oxidizing agent. (Hereinafter referred to as oxidant treatment). In this way, the aldehyde compound (3) is represented by the formula (4):
R-COOH (4)
(Wherein R is the same as above) and is oxidized to a carboxylic acid (hereinafter referred to as carboxylic acid (4)). Then, if it extracts by adding aqueous alkali solution, the organic layer containing the compound which has the nitroxide free radical which can be reused for reaction from which the aldehyde compound (3) was removed will be obtained. The organic layer can be reused as it is or as a compound having a nitroxide free radical for the preparation of N-substituted-formylpolymethyleneimine, with the organic solvent removed.

  The oxidizing agent is not particularly limited as long as it oxidizes the aldehyde compound (3) to produce the carboxylic acid (4). For example, hydrogen peroxide, perborate, permanganate, perchromic acid Examples thereof include salts, perorganic acids, alkali metal halides and the like, preferably alkali metal halides. Examples of the alkali metal phosphite include sodium chlorite, potassium chlorite, sodium bromite, potassium bromite and the like, preferably sodium chlorite. The amount of the oxidizing agent used is 0.5 to 10 mol, preferably 1 to 3 mol based on 1 mol of the aldehyde compound contained in the recovered compound having a nitroxide free group. The oxidizing agent can also be used as an aqueous solution, and the concentration at that time is 1 to 45%, preferably 10 to 35%.

  In order to carry out the oxidizing agent treatment, water is preferably present in the organic layer obtained in the acid treatment containing the compound having a nitroxide free group and the aldehyde compound (3), and more preferably a buffering agent is allowed to coexist. Examples of the organic solvent that forms the organic layer include at least one hydrophobic organic solvent selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, mesitylene, ethyl acetate, ethyl ether, isopropyl ether, and the like. It is done. The amount of the solvent used is not particularly limited, but 4 to 15 parts by weight of the organic solvent and 2 to 10 parts by weight of water are suitable for 1 part by weight of the N-substituted-hydroxymethylpolymethyleneimine (1).

  Examples of the buffer include alkali metal phosphates such as sodium phosphate and potassium phosphate, and alkali metal acetates such as sodium acetate and potassium acetate. The amount of the buffer used is not particularly limited as long as the buffer used functions effectively. Further, a hypohalous acid scavenger such as 2-methyl-2-butene, hydrogen peroxide, sulfamic acid, resorcinol may be used. The usage-amount of this hypohalous acid scavenger is 0.1-20 mol with respect to 1 mol of alkali metal halous acid salts to be used, Preferably it is 0.5-10 mol.

  The reaction temperature is usually in the range of −10 to 50 ° C., but preferably in the range of 0 to 30 ° C. About reaction time, it changes with reaction temperature, the kind of raw material compound, the usage-amount, etc., and can change suitably according to each condition.

  Since the mixture after the oxidant treatment is separated into an aqueous layer and an organic layer, the organic layer is separated, and an alkaline aqueous solution is added to the organic layer. In this way, an alkali metal salt of carboxylic acid (4) is generated, and the alkali metal salt can be distributed in the aqueous layer, and the compound having a nitroxide free radical can be distributed in the organic layer. Although the alkali used in this case is not particularly limited, for example, metal hydroxides such as sodium hydroxide and potassium hydroxide, and metal carbonates such as sodium hydrogen carbonate and potassium carbonate are used. The amount of the alkali used is 0.5 to 20 mol, preferably 1 to 5 mol, relative to 1 mol of the aldehyde compound contained in the recovered compound having a nitroxide free group. Next, by separating the organic layer, an organic layer containing a compound having a nitroxide free radical used in the reaction from which the aldehyde compound (3) has been removed is obtained. The organic layer can be reused as it is or after removal of the organic solvent as a compound having a nitroxide free radical for the preparation of N-substituted-formylpolymethyleneimine.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. The HPLC and GC analysis conditions in the following examples are as follows.

[HPLC]
Column; L-column (4.6 mmΦ × 25 cm; manufactured by Chemical Substance Evaluation Research Organization)
Column temperature: 40 ° C
Detection: 220 nm
Eluent: 0.2% perchloric acid: acetonitrile = 9: 1 (10 minutes) -9: 1 → 3: 7 (40 minutes) -3: 7 (10 minutes) -3: 7 → 9: 1 (10 Min) -9: 1 (10 min)
Eluent flow rate: 1.0 mL / min [GC]
Column; DB-17 (1.0 μm) 0.53 mmφ × 30 m (manufactured by J & W Scientific)
Carrier gas: Helium 20 mL / min Column temperature: 50 ° C-(5 ° C / min)-100 ° C (20 ° C / min)-250 ° C (2.5 min)
Detector; FID
Detector temperature: 250 ° C
Inlet temperature: 300 ° C
Analysis time: 20 minutes

Reference example 1
80 g of 2,2,6,6-tetramethylpiperidine-1-oxyl (hereinafter referred to as TEMPO) and 21 g of tetrabutylammonium bromide were dissolved in 1250 g of toluene, and while maintaining the temperature at 11 to 13 ° C. with stirring, N-benzyl 680 g of a toluene solution containing 210 g of -4-hydroxymethylpiperidine and 680 g of a 12 wt% sodium hypochlorite aqueous solution were simultaneously added dropwise over 8 hours, and the mixture was further stirred for 2 hours. The reaction mixture after completion of the reaction was separated into an aqueous layer and an organic layer, and the obtained organic layer was analyzed by HPLC. As a result, the yield of N-benzyl-4-formylpiperidine was 58% (N-benzyl-4 -Based on hydroxymethylpiperidine). While maintaining this organic layer at 10 to 20 ° C., 675 g of 6 wt% hydrochloric acid was added. 30 minutes after the completion of the dropping, the aqueous layer and the organic layer were separated to obtain 1700 g of an organic layer. When analyzed by the organic layer GC, 78 g of TEMPO and 27 g of benzaldehyde were contained. The organic layer was washed with 300 g of a 0.5 wt% aqueous sodium bicarbonate solution, and the resulting organic layer was concentrated under reduced pressure, and then recovered 550 g of TEMPO solution (containing TEMPO: 76 g, benzaldehyde: 18 g) was obtained. It was.

Example 1
Water (200 g) and potassium dihydrogen phosphate (37 g) were added to 500 g of the TEMPO solution obtained in Reference Example 1 (69 g of TEMPO and 16 g of benzaldehyde), and the solution was stirred and suspended. A 25 wt% aqueous sodium chlorite solution (104 g) was added dropwise at 15 ° C. for 6 hours. After completion of dropping, the reaction solution is separated by allowing to stand for 2 hours, and the organic layer is washed with a 5% by weight aqueous sodium hydrogen carbonate solution (500 g) and then purified 457 g (containing 64 g of TEMPO and 0.8 g of benzaldehyde). )

  To 177 g of the TEMPO solution thus obtained (containing 25 g of TEMPO), 180 g of toluene and 6 g of tetrabutylammonium bromide were added, and 62 g of N-benzyl-4-hydroxymethylpiperidine was maintained while maintaining the temperature at 11 to 13 ° C. with stirring. Toluene solution 201 g containing 12 wt% sodium hypochlorite aqueous solution 200 g was added dropwise simultaneously over 8 hours, and the mixture was further stirred for 2 hours. The reaction mixture after completion of the reaction was separated into an aqueous layer and an organic layer, and the obtained organic layer was analyzed by HPLC. As a result, the yield of N-benzyl-4-formylpiperidine was 57%.

Comparative Example 1
The same operation as in Production Example 1 was performed using 181 g of the TEMPO solution obtained in Reference Example 1 (containing 25 g of TEMPO) instead of the TEMPO solution in Example 1, and the obtained organic layer was analyzed by HPLC. As a result, the yield of N-benzyl-4-formylpiperidine was 52%.

Claims (2)

Formula (1):

(Wherein R represents an aryl group or an aralkyl group, and m is an integer of 0 to 3). In the presence of a compound having a nitroxide free group, N-substituted hydroxymethylpolymethyleneimine Oxidation reaction with an alkali metal halohalide salt gives formula (2):

In the method for producing an N-substituted-formylpolymethyleneimine represented by the formula (wherein R and m are the same as above), the compound having a nitroxide free radical is oxidized when the compound having a nitroxide free radical is reused. A method for producing an N-substituted-formylpolymethyleneimine, which is treated with an agent and reused.   The production method according to claim 1, wherein the oxidizing agent is an alkali metal halite.