JP4608922B2 - Method for producing nitrogen-containing heterocyclic compound - Google Patents

Description

  The present invention relates to a nitrogen-containing heterocyclic compound in which a side chain amino group is protected, which is an important compound as a synthetic raw material for pharmaceuticals and agricultural chemicals, and further, a nitrogen-containing heterocyclic compound in which an optically active side chain amino group is protected. It relates to a method of manufacturing.

Conventionally, as a method for producing a 3-substituted aminopyrrolidine derivative represented by the general formula (4),
(A) 3-amino-1-benzylpyrrolidine in a two-phase system of toluene and an aqueous sodium hydroxide solution, ditertiary butyl dicarbonate (hereinafter, ditertiary butyl dicarbonate is abbreviated as DiBoc) is added dropwise to 1-benzyl A method for synthesizing -3- (tertiary butoxycarbonylamino) pyrrolidine (hereinafter, “tertiary” is abbreviated as “t”) is known (for example, see Patent Document 1).

As a method for producing a 3 -substituted aminopyrrolidine derivative,
(B) A methanol solution of 1-benzyl-3- (t-butoxycarbonylamino) pyrrolidine was reacted in the presence of a 5% Pd—C catalyst at a temperature of 60 to 70 ° C. and a hydrogen pressure of 10 kg / cm ² for 7 hours. The manufacturing method is known. (For example, see Patent Document 1)

(C) 3-amino-1-formylpyrrolidine is added to methanol, ditertiary butyl dicarbonate is added dropwise to synthesize 3-t-butoxycarbonylamino-1-formylpyrrolidine, and then the formyl group at position 1 is converted to an inorganic base. For example, a method of synthesizing 3-t-butoxycarbonylaminopyrrolidine by hydrolysis in the presence of sodium hydroxide is also known. (For example, see Patent Document 2)

Japanese Patent No. 2995704 JP-A-8-259531

  Although the method (A) is an excellent reaction method with high selectivity, an organic solvent such as toluene is required. Further, in order to produce the general formula (5), as in the method (B), the toluene layer 1-Benzyl-3- (t-butoxycarbonylamino) pyrrolidine is stirred under ice-cooling, and the precipitated crystals are isolated by filtration and then hydrocracked under hydrogen pressure in a methanol solvent. However, it is not an environmentally friendly manufacturing method such as using various organic solvents. The method (C) is also an excellent synthesis method. However, 3-t-butoxycarbonylamino-1-formylpyrrolidine synthesized in methanol is removed by concentration operation and hydrolyzed again with an aqueous sodium hydroxide solution. In any case, complicated operations are necessary, and it is difficult to say that the manufacturing method is environmentally friendly. Therefore, an industrially advantageous method for producing a nitrogen-containing heterocyclic compound, and an optically active nitrogen-containing heterocyclic compound, which uses a general-purpose production apparatus and is friendly to the global environment, from readily available raw materials is desired. It was rare.

  As a result of intensive studies on a method for solving the above problems, the present inventors have reached the present invention. That is, the general formula (1)

(Wherein R ¹ represents a substituted or unsubstituted benzyl group, R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and m represents 0 or an integer of 1 ). The 1-substituted nitrogen-containing heterocyclic compound represented by the general formula (2) in the presence of a surfactant while controlling the pH to 9 to 13 in an aqueous solvent.
R ³ COX (2)
Here, R ³ represents an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, a phenyl group, a phenyloxyl group, an aralkyl group, or an aralkyloxyl group. X represents a chlorine atom or a bromine atom. Acid halides or general formula (3)
(R ³ CO) ₂ O (3)
(Wherein R ³ is the same as described above) and is reacted with an acid anhydride represented by the general formula (4)

(Wherein R ¹ , R ² , R ³ , and m are the same as described above) .

The formula to be used in here (1)

Is an optically active substance, the general formula (4) to be obtained,

Is a method for producing a nitrogen-containing heterocyclic compound which is an optically active substance.

According to the present invention, an amino halide or acid anhydride is reacted with an amino-substituted-1-benzyl-containing heterocyclic compound in an aqueous solvent while adjusting the pH to 9 to 13 in the presence of a surfactant. Thus, an acylamino-1-benzyl nitrogen-containing heterocyclic compound can be produced from a readily available raw material in a high yield . Since the production method of the present invention can be carried out with an aqueous solvent, it can be said to be an environment-friendly production method. In addition, if an optically active amino-1-benzyl nitrogen-containing heterocyclic compound is used, the product acylamino-1-benzyl nitrogen-containing heterocyclic compound, and further acylamino nitrogen-containing heterocyclic compound can obtain an optically active substance. .

  The 1-substituted nitrogen-containing heterocyclic compound represented by the general formula (1) in the present invention is the general formula (6).

(Wherein R ¹ represents a substituted or unsubstituted benzyl group, and R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), and the 1-substituted-3-aminopyrrolidine derivative represented by Specifically, 1-benzyl-3-aminopyrrolidine, 1- (4-methylbenzyl) -3-aminopyrrolidine, 1-benzyl-3-methylaminopyrrolidine, 1- (4-methylbenzyl) -3 - ethyl aminopyrrolidine, but 2-aminomethyl-1-benzyl-pyrrolidinone emissions, and the like, in particular 1-benzyl-3-aminopyrrolidine, 1-benzyl-3-methylamino-pyrrolidinone down preferred. These optically active substances can also be used. Specifically, 3-position (R) the body structure or (S) optically active 1-substituted optically active substance of the body structure 3 aminopyrrolidine derivatives, optically active 1-substituted-3-amino-piperidin-induced body it is equal, preferably optically active 1-benzyl-3-aminopyrrolidine, optically active 1-benzyl-2-methylamino-pyrrolidinone down. Here, the optically active substance means a compound having an optical isomer ratio of 90% or more of either the (S) isomer or the (R) isomer.

  The acid halide represented by the general formula (2) includes alkyl carboxylic acid chlorides such as acetyl chloride and butyroyl chloride, alkyl carboxylic acid bromides such as acetyl bromide and butyroyl bromide, ethyl chlorocarbonate, butyl chlorocarbonate. Alkyl chlorocarbonates such as benzoyl chloride and toluoyl chloride, aromatic carboxylic acid bromides such as benzoyl bromide and toluoyl bromide, aryl chlorocarbonates such as phenyl chlorocarbonate and toluoyl chlorocarbonate Aralkylcarboxylic acid chlorides such as phenylacetyl chloride and phenylethyl chloride, aralkyl chlorocarbonates such as benzyl chlorocarbonate and phenylethyl chlorocarbonate, preferably ethyl chlorocarbonate, butyl chlorocarbonate, benzoyl chloride, toluoyl chloride, chloro Carbonic acid Eniru, chlorocarbonate toluyl, phenylacetyl chloride, phenylethyl chloride, chlorocarbonate benzyl, phenyl chlorocarbonate ethyl. The usage-amount is 0.8-1.5 equivalent with respect to the 1-substituted nitrogen-containing heterocyclic compound represented by General formula (1), Preferably it is 1.0-1.2 equivalent.

  The acid anhydride represented by the general formula (3) is an alkyl carboxylic acid anhydride such as acetic anhydride or butyric anhydride, a dialkyl dicarbonate such as dimethyl dicarbonate, diethyl dicarbonate or ditertiary butyl dicarbonate, Aromatic carboxylic anhydrides such as benzoic anhydride and toluic anhydride, aralkyl carboxylic anhydrides such as phenylacetic anhydride and phenylpropionic anhydride, and diaralkyl dicarbonates such as dibenzyldicarbonate, preferably acetic anhydride , Diethyl dicarbonate, ditertiary butyl dicarbonate, dibenzyl dicarbonate. The amount used is 0.8 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, with respect to the 1-substituted nitrogen-containing heterocyclic compound represented by the general formula (1).

  Although this invention is implemented in a water solvent, even if some organic solvent mixes in a raw material, it can implement without a problem. The substrate concentration of the reaction solution can be carried out as long as it can be stirred, but it is usually 1 to 50 wt%, preferably 5 to 40 wt%, particularly preferably 10 to 30 wt%. Within this range, workability is good and production efficiency is high.

  As the reaction method, a method of dropping the compound represented by the general formula (2) or the general formula (3) while stirring the mixture of the compound represented by the general formula (1) and water can be employed. Here, the reaction solution is adjusted to pH 9 to 13, preferably 10 to 12, and particularly preferably 10 to 11. When the compound represented by the general formula (2) or the general formula (3) is dropped, the compound represented by the general formula (4) is generated by reacting with the compound represented by the general formula (1). Halogen acids such as hydrochloric acid and bromic acid, acetic acid, carbonic acid and the like are generated as by-products, and the pH of the reaction solution decreases with the progress of the reaction. React. The base to be added may be a tertiary amine such as trimethylamine, an organic base such as pyridine, or an alkaline aqueous solution such as an alkali metal hydroxide, bicarbonate or carbonate, preferably sodium hydroxide or potassium hydroxide. An aqueous solution of an alkali metal hydroxide such as The alkaline aqueous solution can be used at any concentration, but when the substrate concentration of the reaction solution is lowered, the production efficiency is lowered. Therefore, it is usually 5 to 50%, preferably 30 to 48%. The reaction temperature is -3 to 60 ° C, preferably 0 to 40 ° C. If it is this temperature range, the compound represented by General formula (2) or General formula (3) will react effectively with the compound represented by General formula (1).

Reacting with coexistence interfacial active agent proceeds smoothly. Examples of the coexisting surfactant include tetrabutylammonium chloride, tri-long chain alkylmethylammonium chloride (C8 to C20 alicut 336, etc.), dilong chain alkyldimethylammonium chloride (C10 to C20 cation DS, etc.), benzalkonium, etc. Commercially available quaternary ammonium salts can be used, preferably tri-long-chain alkylmethylammonium chloride (C8 to C20 Aricut 336 and the like), di-long chain alkyldimethylammonium chloride (C16 to C20 cation DS and the like), and benzalkonium. Particularly preferred is an inexpensive dilong chain alkyldimethylammonium chloride (C16 to C20 cation DS, etc.). The amount added cannot be unconditionally defined by the type of surfactant, the general formula (1), or the type of the compound represented by the general formula (4), but is usually a 1-substitution represented by the general formula (1). It is 0.001-0.1 weight times with respect to a nitrogen-containing heterocyclic compound, Preferably it is 0.005-0.05 weight times, More preferably, it is 0.007-0.03 weight times. If the compound represented by the general formula (1) or the compound represented by the general formula (4) is low in water solubility, it scales to the vessel wall of the reaction vessel if no surfactant is present. or, become a massive, smoothly reaction is not such progress.

  The reaction time varies depending on the type of substrate, the amount used, the reaction temperature, etc., but is usually 0.5 to 10 hours.

  Thus, the nitrogen-containing heterocyclic compound represented by the general formula (4) is obtained. For isolation, a method of filtering crystals precipitated from an aqueous solution, a method of extracting with an organic solvent, or the like can be adopted, but when crystals are precipitated, a method of filtering to minimize environmental pollution Is preferred.

The thus obtained compound represented by the general formula (4) nitrogen-containing heterocyclic compound represented by is reacted with hydrogen, it is possible to make the hydrogenolysis reaction.

  A catalyst is allowed to coexist when reacting with hydrogen. As the catalyst, a catalyst in which Pd is supported on activated carbon, alumina or the like can be preferably used. Although any amount of Pd can be used, a commercially available catalyst of 1 to 30% by weight is preferred, and a catalyst of 2 to 10% by weight is particularly preferred. Moreover, any of dried products and water-containing products can be used. Although the amount of the catalyst used is not particularly limited, the Pd weight is preferably 0.0001 times by weight or more, particularly preferably 0.001 to 0.005 weight with respect to the nitrogen-containing heterocyclic compound represented by the general formula (4). Is double. If it is this range, reaction time will not become so long and it can implement highly economically. The Pd catalyst used here can be recovered by solid-liquid separation after the reaction is completed and reused.

  As the reaction solvent, an organic solvent, water, or a mixed solvent thereof can be used, but water is preferred. When water is used as the reaction solvent, since the dispersibility of the nitrogen-containing heterocyclic compound represented by the general formula (4) may be poor, it is preferable to coexist with a surfactant for the purpose of improving dispersibility, The aforementioned surfactants can be used.

  Reaction temperature is 0-100 degreeC, Preferably it is 20-80 degreeC, Most preferably, it is 30-60 degreeC. When the nitrogen-containing heterocyclic compound represented by the general formula (4) melts and separates into two layers from water, the progress of the reaction is suppressed because the melt adheres to the catalyst and inhibits the activity. It is preferable to make it react with hydrogen below melting | fusing point of General formula (4).

One general formula (4) nitrogen-containing heterocyclic compound represented by the reaction solvent, Pd catalyst, and optionally charged surfactant, a method of stirring under a hydrogen presence at a predetermined temperature can be employed. Here, as a method of stirring in the presence of hydrogen, (i) a method of supplying hydrogen under pressure, (ii) a method of supplying hydrogen under normal pressure while venting at atmospheric pressure, and (iii) normal pressure Any method such as a method of contacting with hydrogen sealed in the above can be adopted, but the method (ii) or (iii) which does not require special pressure-resistant equipment is preferable. Here, in the method of contacting with hydrogen sealed at normal pressure, hydrogen may be consumed and the pressure may be lower than atmospheric pressure. However, if the pressure is slightly reduced, the process proceeds without problems. The reaction time varies depending on the type of substrate, reaction solvent, Pd catalyst addition amount, hydrogen supply method, etc., but is usually 1 to 30 hours.

A particularly effective method is a method in which a Pd catalyst is added to an aqueous solution of a nitrogen-containing heterocyclic compound represented by the general formula (4) obtained by the reaction and hydrogen is supplied at normal pressure. By employing this method, the reaction solvent is only water, the general formula (1) nitrogen-containing heterocyclic compound represented by either et nitrogenous heterocyclic compound can be prepared in one pot, it can be said that the production method in consideration of the environment .

  In order to isolate the nitrogen-containing heterocyclic compound represented by the general formula (5) thus produced, a usual method can be adopted. For example, after filtering and recovering the Pd catalyst from the reaction solution, (iv) a method of concentrating the mother liquor and filtering the precipitated crystals, (v) a method of recrystallizing and filtering the concentrate with an appropriate solvent, (vi) There is a method of distilling the concentrate, and a suitable method may be adopted depending on the type of the nitrogen-containing heterocyclic compound represented by the general formula (5).

  Here, if the optically active form of the nitrogen-containing heterocyclic compound represented by the general formula (1) is used, the optically active form of the nitrogen-containing heterocyclic compound represented by the general formula (4) is hardly racemized. Can be manufactured. Furthermore, the optically active substance of the nitrogen-containing heterocyclic compound represented by General formula (5) can be manufactured by making it react with hydrogen.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.

In the examples, the composition analysis of the reaction solution and the purity analysis of the distillate were calculated by GC and HPLC area%. For example, in the case of 3-t-butoxycarbonylaminopyrrolidine (3-BocAP) and 1-benzyl-3-t-butoxycarbonylaminopyrrolidine (3-BocBAP), GC analysis was performed under the following conditions.
GC analysis conditions Column: SHIMAZU HiCap-CBP1-M50-0.25 <manufactured by SHIMAZU>
ID 0.2mmφ × 50 m, 0.25μm
Column temperature: 130 ℃ (15min) → 10 ℃ / min → 260 ℃ (12min)
RT: 3-BocAP 12.7min
3-BocBAP 27.1min

The optical purity analysis method varies depending on the object. For example, in the case of 3-t-butoxycarbonylaminopyrrolidine, optically active tartaric acid derivative anhydride is obtained by converting 3-aminopyrrolidine (AP) obtained by acid hydrolysis. It was made to react with (made by Toray Industries, Inc.), and induced | guided | derived to the optically active tartaric acid derivative, Then, it measured by HPLC equipped with the ODS column.
HPLC analysis conditions

Column: CAPCELL PAC C18 SG120 <made by SISEIDO>
4.6mmφ × 150mm
Developing solution: 0.03% ammonia water adjusted to pH 4.0 with acetic acid / methanol = 50/50
Flow rate: 1.0ml / min
Column temperature: 40 ° C
RT: R-AP derivative 24.8min
S-AP derivative 29.1min

Reference Example (S) 3-Amino-1-benzylpyrrolidine Production Method A 200 ml four-necked flask equipped with a stirrer, dropping funnel, Dimroth and thermometer was charged with 80 g of diglyme and 8.8 g of sodium borohydride (0.23). And a mixture of L-asparagine benzylamide methyl ester hydrochloride (referred to as ABN hydrochloride) and L-isoasparagine benzylamide methyl ester hydrochloride (referred to as IABN hydrochloride) with stirring under ice cooling. 0.0 g (optical purity of 98% ee or more, about 0.05 mol) was added. Next, a solution obtained by diluting 5.7 g (0.06 mol) of concentrated sulfuric acid in 20 ml of diglyme was added dropwise over about 30 minutes, followed by stirring for 2 hours. The temperature of the reaction solution was raised to 65 ° C., and the mixture was further stirred for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. After 70 g of water was added and dissolved, 25 g of concentrated hydrochloric acid was added and stirred at 65 ° C. for 4 hours. The reaction solution was cooled to room temperature and neutralized by adding 32 g of 46% sodium hydroxide while stirring. Extraction was performed 3 times with 100 ml of toluene, and all toluene layers were combined and concentrated under reduced pressure. The concentrate was subjected to vacuum distillation to obtain 7.3 g of (S) -3-amino-1-benzylpyrrolidine as a fraction at 130 to 133 ° C./1.3 kPa. As a result of analyzing the distillate, the chemical purity was 99%, and the optical purity was 96.7% ee. In order to improve the optical purity, a salt is formed with L-tartaric acid, recrystallized with water, dehydrated with sodium hydroxide and extracted with toluene, and then distilled to obtain an optical purity of 99.5% ee or more ( S) -3-Amino-1-benzylpyrrolidine was obtained.

Example 1
In a 500 ml four-necked flask equipped with a stirrer, thermometer, Dimroth condenser and dropping funnel, 17.6 g (0.1 mol optical purity 99.5% ee) of (S) -3-amino-1-benzylpyrrolidine, water 158.7 g and Cation DS (manufactured by Sanyo Chemical) 0.2 g were charged, and the pH was adjusted to 11 ± 0.5 with a 48% aqueous sodium hydroxide solution. While stirring at 50 to 60 ° C., 26.2 g (0.12 mol) of ditertiary butyl dicarbonate (hereinafter abbreviated as DiBoc) was added dropwise over about 2 hours. During this time, the reaction solution was adjusted to pH 11 ± 0.5 with 48% aqueous sodium hydroxide solution. After further stirring for 1 hour, the mixture was cooled to room temperature and the precipitated crystals were filtered. The crystals were vacuum dried at 50 ° C. to obtain 26.0 g of (S) -1-benzyl-3-t-butoxycarbonylaminopyrrolidine. Yield 94.1%, chemical purity 99.1%, optical purity 99.5% ee.

Comparative Example 1
When DiBoc was added dropwise in the same manner as in Example 1 without adjusting the pH, the final pH was 6 or less, and the conversion was stagnant at about 90%. Even when 4.4 g (0.02 mol) of DiBoc was added, the reaction did not proceed. Although isolated in the same manner as in Example 1, the yield was as low as 86.9%.

Example 2
In a 200 ml four-necked flask equipped with a stirrer, thermometer, Dimroth condenser, and dropping funnel, 3.5 g (0.02 mol) of 3-amino-1-benzylpyrrolidine, 100 g of water, and cation DS (manufactured by Sanyo Chemical) 0. 1 g was charged and the pH was adjusted to 11 ± 0.5 with a 48% aqueous sodium hydroxide solution. While stirring at 30 to 40 ° C., 4.1 g (0.024 mol) of benzyl chlorocarbonate was added dropwise over about 1 hour. During this time, the reaction solution was adjusted to pH 11 ± 0.5 with 48% aqueous sodium hydroxide solution. After further reacting for 1 hour, the mixture was cooled to room temperature and the precipitated crystals were filtered. The crystals were vacuum dried at 50 ° C. to obtain 5.7 g of 1-benzyl-3-benzyloxycarbonylaminopyrrolidine. Yield 91.0%, chemical purity 98.6%.

Reference example 2
The (S) -1-benzyl-3-t-butoxy obtained in Example 1 was placed in a 500 ml four-necked flask equipped with a stirrer, thermometer, Dimroth condenser, and gas inlet tube with a 5 l hydrogen balloon at the tip. Carbonylaminopyrrolidine 24.0 g (chemical purity 97.6%, optical purity 99.5% ee), water 150 g, cation DS 0.1 g, and 5% Pd / C 1.4 g (PE type manufactured by N.E. Chemcat) 55. 27% water content) and stirred at 40 ° C. overnight. The hydrogen balloon was much smaller. The mixture was then cooled to room temperature with stirring, and the catalyst was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to about 30 g with an evaporator and then distilled under reduced pressure to obtain 13.4 g of (S) -3-t-butoxycarbonylaminopyrrolidine as a fraction of 120 to 125 ° C./0.7 kPa. Yield 83.1%, chemical purity 99.1%, optical purity 99.3% ee.

Example 3
In the same manner as in Example 1, instead of cation DS, 0.2 g of Sandet ET (manufactured by Sanyo Kasei) was added and reacted, and the precipitated crystals were filtered. The crystals were vacuum dried at 50 ° C. to obtain 21.5 g of (S) -1-benzyl-3-t-butoxycarbonylaminopyrrolidine. Yield 77.8%, chemical purity 99.0%, optical purity 99.5% ee.

Example 4
In the same manner as in Example 1, (S) -3-amino-1-benzylpyrrolidine was replaced with 1-benzyl-3-ethylaminopyrrolidine 20.4 g (0.1 mol), and DiBoc was replaced with 16.8 g of benzoyl chloride. Were reacted in the same manner, and the precipitated crystals were filtered. The crystals were vacuum-dried at 50 ° C. to obtain 26.5 g of 1-benzyl-3- (ethylbenzoylamino) pyrrolidine. Yield 86.0%, chemical purity 98.5%.

Reference example 3
In the same manner as in Example 1, 26.2 g of DiBoc was added dropwise over about 2 hours while stirring at 30 to 40 ° C., and further stirred overnight. Next, the dropping funnel attached to the reaction flask was removed and replaced with a gas introduction tube equipped with a 10 l hydrogen balloon at the tip. Next, 2.8 g of 5% Pd / C (PE type 55.27% water content manufactured by N.E. Chemcat) was charged, and the system was replaced with hydrogen, followed by stirring at 30 to 40 ° C. in the presence of hydrogen. Reacted overnight. After cooling to room temperature, the catalyst was filtered under reduced pressure and distilled under reduced pressure in the same manner as in Example 3 to obtain 13.6 g of (S) -3-tert-butoxycarbonylaminopyrrolidine as a fraction of 118 to 120 ° C./0.6 kPa. It was. The yield based on (S) -3-amino-1-benzylpyrrolidine was 73.0%, chemical purity 99.2%, and optical purity 99.3% ee.

Reference example 4
A 500 ml four-necked flask equipped with a stirrer, thermometer, Dimroth condenser, and dropping funnel was charged with 17.6 g of 3-amino-1-benzylpyrrolidine (0.1 mol optical purity 99.5% ee) and 120 g of water. The pH was adjusted to 11-12 with 48% aqueous sodium hydroxide. While stirring at 40 to 50 ° C., 11.2 g (0.11 mol) of acetic anhydride was added dropwise over about 2 hours. During this time, the reaction solution was adjusted to pH 11 ± 0.5 with 48% aqueous sodium hydroxide solution. After further stirring for 1 hour and cooling to room temperature, the analysis revealed that the 3-amino-1-benzylpyrrolidine peak disappeared and the 3-acetylamino-1-benzylpyrrolidine peak was detected.

Comparative Example 2
In Example 1, (B) -1-benzyl-3-t-butoxycarbonylaminopyrrolidine formed on the wall of the flask when DiBoc was added dropwise without adjusting the pH and without adding cation DS. It was difficult to stir and the workability was very poor. Moreover, the raw material (S) -3-amino-1-benzylpyrrolidine was taken into the precipitated crystals, and the conversion rate was low.

According to the present invention, an amino halide or acid anhydride is reacted with an amino-substituted-1-benzyl-containing heterocyclic compound in an aqueous solvent while adjusting the pH to 9 to 13 in the presence of a surfactant. Thus, an acylamino-1-benzyl nitrogen-containing heterocyclic compound can be produced from a readily available raw material in a high yield. Furthermore, by hydrocracking the benzyl group at the 1-position, an acylamino nitrogen-containing heterocyclic compound with high yield and high purity can be produced. Since the production method of the present invention can be carried out with an aqueous solvent, it can be said to be an environment-friendly production method. In addition, if an optically active amino-1-benzyl nitrogen-containing heterocyclic compound is used, the product acylamino-1-benzyl nitrogen-containing heterocyclic compound, and further acylamino nitrogen-containing heterocyclic compound can obtain an optically active substance. .

Claims (5)

General formula (1)

(Wherein R ¹ represents a substituted or unsubstituted benzyl group, R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and m represents 0 or an integer of 1 ). The 1-substituted nitrogen-containing heterocyclic compound represented by the general formula (2) in the presence of a surfactant while controlling the pH to 9 to 13 in an aqueous solvent.
R ³ COX (2)
Here, R ³ represents an alkyl group having 1 to 4 carbon atoms, an alkoxyl group, a phenyl group, a phenyloxyl group, an aralkyl group, or an aralkyloxyl group. X represents a chlorine atom or a bromine atom. Acid halides or general formula (3)
(R ³ CO) ₂ O (3)
(Wherein R ³ is the same as described above) and is reacted with an acid anhydride represented by the general formula (4)

(Wherein R ¹ , R ² , R ³ and m are the same as described above). Production method of general formula (3) acid anhydride represented by is a di-tert-butyl dicarbonate according to claim 1 nitrogen-containing heterocyclic compound as claimed. The method for producing a nitrogen-containing heterocyclic compound according to claim 1 or 2, wherein the surfactant is an alkyl ether sulfonate or a quaternary ammonium salt. 1-substituted nitrogen-containing heterocyclic compound represented by the general formula (1) is an optically active substance, a nitrogen-containing heterocyclic compound represented by the general formula (4) is an optically active substance of claim 1-3 The manufacturing method of the nitrogen-containing heterocyclic compound of any one of Claims 1. The 1-substituted nitrogen-containing heterocyclic compound represented by the general formula (1) is represented by the general formula (6).

(Wherein R ¹ and R ² are the same as described above), a nitrogen-containing heterocyclic compound represented by the general formula (4) is represented by the general formula (7).

The nitrogen-containing complex according to any one of claims 1 to 4 , which is a 3-substituted-aminopyrrolidine derivative represented by the formula (wherein R ¹ , R ² and R ³ are the same as defined above). A method for producing a ring compound.