JP2002105049A - Method for producing racemic nitrogen-containing heterocyclic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To racemize an optically active nitrogen-containing heterocyclic derivative by using a general-purpose facility and an operable method. SOLUTION: This method for producing a racemic nitrogen-containing heterocyclic derivative comprises carrying out dehydration reaction of an optically active nitrogen-containing heterocyclic derivative with ketones, heating the reaction product in the presence of a strong alkali and hydrolyzing the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for racemizing an optically active nitrogen-containing heterocyclic derivative useful as an intermediate for agricultural chemicals and pharmaceuticals.

[0002]

2. Description of the Related Art As an industrial method for producing an optically active nitrogen-containing heterocyclic derivative, there is known a method for producing a chemically synthesized racemate by optical resolution. For example, optically active N-
A method for optically resolving a racemic 3-aminopyrrolidine derivative using an optical resolving agent such as an acyl amino acid derivative, an optically active N-sulfonyl amino acid derivative, or an optically active tartaric acid anilide (Japanese Patent Application Laid-Open No. 9-124595).
Methods for producing optically active 3-aminopyrrolidine derivatives are known. Here, when the optical resolution method is adopted, the industrially advantageous optically active substance is obtained by separating the useful optically active substance, and then employing a recycling method in which unnecessary optical isomers are racemized and optically resolved again. Production method. Therefore, racemization is a very important technique in a method for producing an optically active substance by optical resolution.

In general, as a method of racemizing optically active amines, a method of heating in the presence of an alkali is known, but a racemization reaction of an optically active nitrogen-containing heterocyclic derivative is difficult. Slightly, a racemization method of an optically active 3-aminopyrrolidine derivative is carried out in an organic solvent such as toluene or ether in the presence of a Raney cobalt catalyst under a hydrogen pressure of 1 to 10.
Only a method requiring a high temperature and a high pressure such as a method of performing racemization at 100 to 170 ° C. under a pressure of MPa (Japanese Patent No. 3021109, Japanese Patent Application Laid-Open No. 7-233146) is known.

[0004]

However, the above method has the drawbacks that it requires high pressure and high temperature and requires special equipment.

[0005] Therefore, if the production can be carried out with general-purpose equipment, the racemization reaction can be carried out with good operability and safely, which is industrially advantageous.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for producing a racemic nitrogen-containing heterocyclic derivative which can be handled by general-purpose equipment, and have reached the present invention.

That is, the present invention provides a compound represented by the general formula (1)

[0008]

Embedded image

(Where Q is-(CH ₂ ) n-or-(C
H ₂₎ means n-1-CO-, n represents 1-3. Also,
R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, a phenyl group or an aralkyl group, and * means an asymmetric center of the carbon atom. An optically active nitrogen-containing heterocyclic derivative represented by general formula (2):

[0010]

Embedded image

(Where R ⁵ and R ⁶ represent a hydrogen atom and a carbon atom of 1)
Represents a lower alkyl group, a phenyl group, and an aralkyl group. This is a method for producing a racemic nitrogen-containing heterocyclic derivative, which comprises reacting a ketone represented by the formula (1), heating in the presence of a strong alkali, and then hydrolyzing.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the term "optically active substance" means a substance containing at least 60% of either R-form or S-form optical isomer, and has an optical purity higher than that of the racemic form and the optically active form. Means that one of the optical isomers is contained in an amount of 40% or more and less than 60%, for example. The nitrogen-containing heterocyclic derivative used is represented by the above general formula (1), and includes a 3-aminopyrrolidine derivative, a 3-aminopyrrolidone derivative, a 3-aminopiperidine derivative, a 3-aminopiperidone derivative, An amino homopiperidine derivative and a 3-amino homo piperidone derivative. For example, 3-aminopyrrolidine, 3-amino-1-benzylpyrrolidine, 3-benzylamino-
Aminopyrrolidine derivatives such as 1-benzylpyrrolidine,
3-aminopyrrolidones such as 3-amino-1-benzylpyrrolidone, 3-aminopiperidine, 3-amino-1-
3-aminopiperidines such as benzylpiperidine;
3-aminopiperidones such as aminopiperidone; 3-aminohomopiperidines such as 3-aminohomopiperidine; 3-ethylamino-1-benzylhomopiperidine;
Amino homopiperidone and the like.

As the ketones, general formula (2) can be used, and specific examples thereof include benzaldehyde, acetophenone, salicylaldehyde, and methyl isobutyl ketone. Preferred are benzaldehyde and acetophenone, and particularly preferred is benzaldehyde. .

The strong alkali is preferably represented by the general formula (3). Specific examples of the alkali metal alkoxide include potassium ethoxide, sodium isopropoxide and potassium sulphate.
c-butoxide, potassium tert-butoxide, potassium sec-pentoxide, potassium tert-pentoxide, and particularly preferably potassium tert-pentoxide.
-Butoxide.

The reaction method will be described. First, an optically active nitrogen-containing heterocyclic derivative and a ketone are reacted while continuously dehydrating with a Dean-Stark azeotropic dehydrator to produce a Schiff base or enamine. An organic solvent can be used in the reaction, but the ketone used in the reaction can also serve as the solvent. As the organic solvent, any compound which does not react with the nitrogen-containing heterocyclic derivative or ketone and which azeotropes with water can be used. Specifically, aromatic hydrocarbons such as benzene and toluene, and cyclohexane And aliphatic ethers such as dioxane. If the dehydration reaction is slow,
A catalyst may be added. The catalyst to be added is iron chloride,
Zinc chloride, aluminum chloride, boron trifluoride and the like may be used.

The amount of the ketone is preferably 0.9 to 10.0 mol, more preferably 1.0 to 1.5 mol, per 1 mol of the optically active nitrogen-containing heterocyclic derivative. Excessive use of ketones can also serve as a diluting solvent. The reaction temperature is preferably from 50 to 160C, more preferably from 70 to 150C. The reaction time varies depending on the substrate, but is usually 1 to 20 hours. Here, when the racemization reaction in the next step is continuously performed, the dehydration reaction is preferably completed. If the unreacted nitrogen-containing heterocyclic derivative and ketone remain, the dehydration reaction proceeds during the racemization reaction, water may be produced as a byproduct, and the racemization catalyst may be deactivated.

The Schiff base or enamine thus obtained is racemized by reacting it with a strong alkali. The racemization reaction in the method of the present invention can be carried out without a solvent or in the presence of a solvent, but the higher the Schiff base or enamine concentration, the faster the racemization rate. When a solvent is used, any optically active nitrogen-containing heterocyclic derivative, Schiff base, or any substance that does not alter the enamine and does not interfere with the racemization reaction may be used.
Aromatic solvents such as toluene, ether solvents such as dioxane and diethylene glycol dimethyl ether, alcohol solvents such as 2-propanol and tert-butanol, and solvents such as dimethyl sulfoxide can be used. The amount of the strong alkali to be used is preferably 0.01 to 1 mol, more preferably 0.1 to 1 mol, per 1 mol of the optically active nitrogen-containing heterocyclic derivative.
02 to 0.5 mol. If unreacted nitrogen-containing heterocyclic derivatives and ketones remain in the raw material of the racemization reaction, dehydration proceeds during the racemization reaction and water is by-produced, deactivating the racemization catalyst. there's a possibility that. In that case, if a large amount of the racemization catalyst is used, the racemization reaction proceeds without any problem, but the cost of the racemization catalyst increases. The racemization reaction is heated in the presence of a strong alkali such as a metal alkoxide. The heating temperature varies depending on the type of the substrate and the type and amount of the strong alkali catalyst, but is preferably 50 to 220 ° C, more preferably 100 to 200 ° C. Within this range, the rate of racemization is not too slow, and the purification of the nitrogen-containing heterocyclic compound is suppressed. The reaction time varies depending on the reaction conditions, but is usually 1 to 20 hours. The reaction can be carried out under normal pressure, slightly reduced pressure, or slightly increased pressure. After completion of the racemization reaction, water is added to hydrolyze. The hydrolysis temperature is preferably from 0 to 100 ° C, more preferably from 30 to 70 ° C.
° C. The amount of water to be added is 1.0 to 3.0 mol per 1 mol of the nitrogen-containing heterocyclic derivative. The reaction time depends on the reaction conditions, but is usually 0.5 to 2.0 hours. if,
If the hydrolysis reaction is slow, it is accelerated by adding an aqueous acid solution such as dilute sulfuric acid. After the completion of the hydrolysis reaction, the racemic nitrogen-containing heterocyclic derivative is isolated. An ordinary method can be used for the isolation method. For example, the basic aqueous solution after the hydrolysis may be directly extracted with an organic solvent to simultaneously separate the nitrogen-containing heterocyclic derivative and the ketone from the aqueous layer, and the solvent may be concentrated and then purified by distillation. Alternatively, an acid such as sulfuric acid is added to the basic aqueous solution after hydrolysis to make it acidic, and the mixture is extracted with an organic solvent.After separating and removing ketones, the aqueous layer is again made alkaline and extracted with an organic solvent. A nitrogen-containing heterocyclic derivative can be isolated.

[0018]

The present invention will be described in more detail with reference to the following Examples and Comparative Examples, but the present invention is not limited by these ranges. The reagents used here are reagent grade products. The optical purity of 3-amino-1-benzylpyrrolidine (hereinafter, abbreviated as “BAP”) in Examples was measured by reacting with O, O′-ditoluoyl-L-tartaric anhydride to obtain two diastereomers. After induction by HP
Determined by LC analysis.

[0019]

Embedded image

<HPLC conditions> Column: CAPCELLPAK C18 SG120 (Shiseido) 46 mmφ × 150 mm Mobile phase: water / methanol = 61/39 (v / v) In addition, water was added to a 0.03% ammonia aqueous solution in advance by adding acetic acid to pH. = 4.7 was used.

[0021] The racemization ratio was calculated by the following equation.

[0022]

(Equation 1)

Example 1 A 500 ml flask equipped with a Dean-Stark dehydrator was charged with 1.8 g of S-BAP (0.0500 mol, 9
9.06% ee), 8.40 g of benzaldehyde (0.
0790 mol) and 150 ml of toluene, and the mixture was heated and refluxed at 108 to 115 ° C for 3 hours while continuously separating water. After confirming that no more water was generated, the reaction solution was cooled to room temperature while stirring. T-B
0.85 g (0.0076 mol) of uOK was added, and
The mixture was heated under reflux at 08 to 115 ° C for 6 hours. Then, the reaction solution was cooled to room temperature with stirring, 100 ml of 2N-HCl was added while keeping the temperature at 40 ° C. or lower, and the mixture was further stirred at room temperature for 1 hour. The separated aqueous layer was separated and adjusted to pH 9 or higher by adding an aqueous NaOH solution. When the prepared solution was analyzed by GC, 7.22 g (0.0410 mol) of BAP was obtained.
Was obtained (82% recovery). Further, after extracting this aqueous layer with toluene, it was concentrated and distilled under reduced pressure.
(0.5 kPa to 1.0 kPa) as BAP
5.78 g (0.0328 mol) were obtained. The isolation yield is
It was 65.6%. The chemical purity was 99.2%, the optical purity was 10.01% ee, and the racemization ratio was 89.9%.

Example 2 After heating for 1 hour while azeotropically dehydrating in the same manner as in Example 1,
About 120 ml of toluene as a solvent was distilled off, and DMSO was added.
Add 150 ml and t-BuOK 0.85 g and add 195 to
The mixture was heated and refluxed at 200 ° C. After 2 hours, the reaction solution was cooled to room temperature while stirring, and then treated in the same manner as in Example 1. When the separated aqueous layer was analyzed, the recovery of BAP was 65%, the optical purity was 11.20% ee, and the racemization rate was 88.7%.

Example 3 In place of t-BuOK in Example 1, NaOMe 2.7 was used.
The reaction was carried out in the same manner by using 5 g (0.050 mol) and heating for 16 hours. When the separated aqueous layer was analyzed,
The recovery rate of BAP is 68%, and the optical purity is 60.52% e.
e, racemization ratio was 38.9%.

Example 4 In the same manner as in Example 1, 3.52 g of S-BAP was placed in a 100 ml flask equipped with a Dean-Stark dehydrator.
(0.020 mol, 39.00% ee), 2.88 g (0.0240 mol) of acetophenone, zinc chloride 0.15
g (0.0011 mol) and 20 ml of toluene were added, and the mixture was heated to reflux at 108 to 115 ° C while azeotropically dehydrating. 12
After an hour, the reaction solution is cooled to room temperature while stirring, and then t
-BuOK (0.45 g, 0.0040 mol) was added, and the mixture was heated and refluxed again at 108 to 115 ° C. After about 3 hours, the reaction solution was cooled to room temperature while stirring, treated in the same manner as in Example 1, and the separated aqueous layer was analyzed.
Was 80%, the optical purity was 14.00% ee, and the racemization rate was 64.1%.

Comparative Example 1 A 100 ml flask equipped with a reflux tube was charged with S-BAP0.
76 g (0.0043 mol, 99.06% ee), DM
SO10 ml, t-BuOK 0.21 g (0.0018
Mol), and the mixture was heated under reflux at 195 to 200 ° C. for about 3 hours. When processed and analyzed in the same manner as in Example 1, the recovery of BAP was 86%, and the optical purity was 95.52%.
ee and the racemization ratio were 3.53%. Racemization did not proceed only by heating with a strong alkali.

Comparative Example 2 In a 100 ml flask equipped with a reflux tube, S-BAP1.
76 g (0.0100 mol, 67.00% ee), benzaldehyde 1.17 g (0.0110 mol), DMS
20 ml of O was added, and the mixture was stirred at room temperature without azeotropic dehydration. Then, t-BuOK 0.22 g (0.002
0 mol), and the mixture was heated under reflux at 195 to 200 ° C for 6 hours. When processing and analysis were performed in the same manner as in Example 1,
The recovery rate of BAP is 91%, and the optical purity is 65.70% e.
e, racemization ratio was 1.94%. Even when S-BAP is reacted with benzaldehyde, the equilibrium is not biased toward the Schiff base unless the produced water is removed out of the system. Therefore, the racemization did not progress even when heated with a strong alkali.

[0029]

According to the present invention, a racemic nitrogen-containing heterocyclic derivative can be easily produced by racemizing an optically active nitrogen-containing heterocyclic derivative by a method which can be carried out with general-purpose equipment. The obtained racemic nitrogen-containing heterocyclic derivative obtained can be used as a raw material for producing a useful optically active nitrogen-containing heterocyclic derivative by optical resolution.

Claims (3)

[Claims] 1. A compound of the general formula (I) (Wherein Q is - (CH ₂₎ n-or _{- (CH 2) n-1} -CO
Means-, and n represents 1-3. R ¹ , R ² , R
³ and R ⁴ each independently represent a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, a phenyl group, or an aralkyl group, and * means an asymmetric center of the carbon atom. ) And an optically active nitrogen-containing heterocyclic derivative represented by the general formula (2): (Where R ⁵ and R ^{6 each} represent a hydrogen atom, a lower alkyl group having 1 to 8 carbon atoms, a phenyl group, or an aralkyl group, but excluding a hydrogen atom).
A process for producing a racemic nitrogen-containing heterocyclic derivative, comprising heating in the presence of a strong alkali and subsequently hydrolyzing. The strong alkali is represented by the general formula (3) R ⁷ OM (3) (where R ⁷ represents a lower alkyl group having 1 to 5 carbon atoms;
M represents sodium, potassium or lithium. 2. The method for producing a racemic nitrogen-containing heterocyclic derivative according to claim 1, wherein the alkali metal alkoxide is represented by the formula: 3. The process for producing a racemic nitrogen-containing heterocyclic derivative according to claim 1, wherein the optically active nitrogen-containing heterocyclic derivative is a pyrrolidine derivative.