Purification method for 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one

Abstract

The objective is to provide a purification method for 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one, a raw material for 9-azabicyclo[3.3.1]nonane derivatives, that is easy to obtain and highly pure. [Solution] A reaction product containing 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one as the main component and a polymer of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one and glutaraldehyde as an impurity is brought into contact with activated carbon in a solvent. By removing the polymer of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one and glutaraldehyde, A method for purifying 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one having an impurity content of 0.20 wt or less.

Description

Technical Field

[0001] The present invention relates to a method for purifying 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one.

Background Art

[0002] 9-Azabicyclo[3.3.1]nonane derivatives are known to be useful as acaricides, pharmaceuticals, and the like. Patent Document 1 describes a 9-azabicyclo[3.3.1]nonane derivative as a therapeutic or prophylactic agent for diseases or disorders in which inhibition of the reuptake of monoamine neurotransmitters contributes to the therapeutic effect, for example, a therapeutic or prophylactic agent for depression or pain. However, this document describes a synthesis scheme of a 9-azabicyclo[3.3.1]nonane derivative from 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one. Further, it is described that 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one can be obtained in a yield of 54% by reacting gluteraldehyde, benzylamine hydrochloride, and 3-oxopentanedioic acid in water in the presence of sodium acetate, acidifying the reaction mixture with hydrochloric acid water, and then basifying it with sodium hydroxide. Patent Document 2 describes preparing 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one-2,4-dicarboxylic acid ethyl ester by reacting gluteraldehyde, benzylamine, and diethyl 3-oxopentanedioate in an alcohol solvent, crystallizing this as a hydrochloride, and then decarboxylating it under basic conditions to obtain 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one in a yield of 74%.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

[0004] The object of the present invention is to provide a purification method for easily and highly purely obtaining 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one, which is a raw material for the above-mentioned 9-azabicyclo[3.3.1]nonane derivative. [Means for solving the problem]

[0005] The inventors have completed the present invention as a result of diligent research. In other words, the present invention relates to the following invention. [1] A reaction product containing 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one or its hydrochloride as the main component, and a polymer of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one and glutaraldehyde as an impurity, is brought into contact with activated carbon in a solvent. By removing the polymer of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one and glutaraldehyde, A method for purifying 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one having an impurity content of 0.20 wt% or less. [2] 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one having an impurity content of 0.20 wt% or less derived from polymers of 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one and glutaraldehyde. [Effects of the Invention]

[0006] 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one, a raw material for 9-azabicyclo[3.3.1]nonane derivatives, can be easily obtained in high purity. [Brief explanation of the drawing]

[0007] [Figure 1]The CAD and TIC chromatograms of a sample mixed with an impurity standard and a quantitative IS are shown. In the figure, "OBB" stands for 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one. "Impurity" means impurity. [Figure 2] The characteristic mass spectrum observed between tR = 10.5 and 21 min is shown. The figure shows the mass spectrum at tR = 11.36. [Figure 3] The figure shows the mass spectrum at tR = 14.72. [Figure 4] The figure shows the mass spectrum at tR = 15.80. [Figure 5] The calibration curve for impurity standards is shown. The vertical axis represents the ratio of the area value of the impurity standard to the area value of the impurity standard. The horizontal axis represents the ratio of the weight of the impurity standard to the weight of the impurity standard. [Figure 6] The figure shows the CAD chromatogram of PEG960. [Figure 7] The figure shows the calibration curve for the derived substitute standard and the calibration curve for the impurity standard superimposed on each other for comparison. The vertical axis shows the ratio of the area value of the impurity standard or substitute standard to the area value of IS. The horizontal axis shows the ratio of the weight of the impurity standard or substitute standard to the weight of IS. [Modes for carrying out the invention]

[0008] The 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one to which the purification method of the present invention is applicable is 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one produced using glutaraldehyde as a starting material. Examples of such manufacturing methods include the manufacturing methods described in Patent Documents 1 and 2 mentioned above. The manufacturing scheme described in Patent Document 1 is as follows:

[0009] [ka]

[0010] The production scheme described in Patent Document 2 is as follows.

[0011]

Chemical formula

[0012] When these production methods are carried out, it can be seen that colored tar components are by-produced. Regarding the colored tar components, in the production method of PSEUDOPELLETIERINE described in "Organic Syntheses, Coll. Vol. 4, p.816 (1963); Vol. 37, p.73 (1957).", which is the prototype of these production methods, it is also listed as "the dark-brown resin". The mixing of by-products will reduce the purity of the target product. Although the purity will increase with repeated purification, there is a problem that the yield of the target product will decrease this time. On the other hand, if the purification method of the present invention is applied, the target 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one can be obtained easily and with high purity.

[0013] The identification of the impurities to be removed was carried out by considering the reaction mechanism and analyzing the results of instrumental analysis. It was found that the polymer of 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one, which is the target product, and glutaraldehyde, which is the starting material, is an impurity.

[0014] From the reaction mechanism, it is considered to be due to aldol condensation as shown in the following scheme. It is considered that multiple condensations occur because there are multiple carbon atoms in the polymer that are susceptible to nucleophilic addition.

[0015]

Chemical formula

[0016] Analysis of the instrumental analysis results suggested the presence of the following compounds among the impurities. It was also found that compounds with even higher molecular weights than these compounds were present among the impurities.

[0017] [ka]

[0018] Based on the above, it was concluded that the polymer of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one and glutaraldehyde was an impurity.

[0019] As a result of investigating methods for removing the aforementioned impurities from the reaction product, it was found that the aforementioned impurities can be efficiently removed by contacting a reaction product containing 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one or its hydrochloride as the main component, and a polymer of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one and glutaraldehyde as an impurity, with activated carbon in a solvent.

[0020] The reaction product to be purified is the reaction product obtained as a result of carrying out the manufacturing scheme described above. The reaction product to be purified may be the reaction product isolated according to standard methods, or, if liquid-liquid separation was performed in the intermediate stage, the acidic aqueous layer in which the reaction product is dissolved may be the target. The solvent is not particularly limited as long as it is a solvent in which the reaction product to be purified dissolves, but alcoholic solvents such as methanol, ethanol, and n-propanol; aromatic hydrocarbon solvents such as benzene, toluene, and xylene are preferred. Acidic aqueous solutions are also preferred. The amount of solvent used is not particularly limited, but is preferably 0.1 to 10 parts by weight per 1 part by weight of the reaction product.

[0021] The activated carbon used is either made by activating plant-based raw materials such as wood, bamboo, coconut shells, and walnut shells using a "high-temperature carbonization method" that carbonizes them in a gaseous state such as water vapor or air, or by making them porous using chemicals such as zinc chloride. Specifically, these include Shirasagi (registered trademark) M, Shirasagi A, Shirasagi P, refined Shirasagi, special Shirasagi, granular Shirasagi KL, and granular Shirasagi LH. 2c Examples include (manufactured by Osaka Gas Chemical Co., Ltd.), and Taiko® S-type, Taiko K-type, and Taiko SG-type (all manufactured by Futamura Chemical Co., Ltd.), but are not limited to these commercially available products. The activated carbon used is preferably 5 to 400 mesh, and more preferably 10 to 200 mesh. The activated carbon may be in the form of crushed, granular, or granular material. The amount of activated carbon used is not particularly limited, but is preferably 0.1 to 50 parts by weight per 1 part by weight of the reaction product.

[0022] The method for contacting the reaction product with activated carbon in a solvent is not particularly limited and can be carried out using known contact methods. Examples include adding activated carbon to a solvent containing the reaction product and stirring as necessary, or flowing the solvent containing the reaction product down a column containing activated carbon. While the reaction product is in contact with activated carbon in a solvent, the temperature inside the reactor can be set to, for example, preferably 0°C to 60°C. The pressure inside the reactor may be atmospheric pressure. The contact time is not particularly limited, for example, 0.5 hours to 24 hours. Contact is preferably carried out under an inert gas atmosphere. After contact, the activated carbon is separated by filtration. As a result, by carrying out the purification method of the present invention, 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one with an impurity content of 0.20 wt% or less can be obtained.

[0023] The reaction product to be purified can be prepared by the following manufacturing method. 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one-2,4-dicarboxylate ethyl ester, a precursor of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one, is produced, for example, by reacting diethyl 3-oxopentanedioate, glutaraldehyde, and benzylamine in a solvent by stirring and mixing at 0°C to 40°C. Examples of solvents include alcohol-based solvents such as methanol, ethanol, and n-propanol, and water-soluble solvents such as water, or mixtures thereof. After the reaction is complete, the target product can be isolated by performing the usual post-treatment procedures in organic synthesis chemistry, and, if necessary, by conventionally known separation and purification methods. Alternatively, this precursor may be treated in an acidic solution to precipitate it in order to isolate it as a hydrochloride salt. Furthermore, this precursor can be used in the production of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one without isolation.

[0024] 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one can be prepared by heating and stirring its precursor and an alkali metal hydroxide in a solvent at 80°C to 120°C. Examples of solvents include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; polar aprotic solvents such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, sulfolane, dimethylacetamide, and N-methylpyrrolidone; protic solvents such as acetic acid; and one or a mixture thereof of water. Examples of alkali metal hydroxides include sodium hydroxide, potassium hydroxide, and lithium hydroxide. After the reaction is complete, the reaction product can be isolated by conventional post-treatment procedures in organic synthesis chemistry, and, if necessary, by conventionally known separation and purification methods. Furthermore, to isolate the reaction product as a hydrochloride salt, it may be treated in an acidic solution to precipitate it. The content of the aforementioned impurities in the reaction product can be confirmed by purifying the reaction product using silica gel column chromatography (using hexane / ethyl acetate as the developing solvent), washing the silica gel with methanol, and then concentrating the solution of the eluted impurities.

[0025] The reaction product to be purified can also be prepared by the following manufacturing method. 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one can be produced, for example, by mixing 3-oxopentanedioic acid, glutaraldehyde, and benzylamine in a solvent at 0°C to 10°C, and then reacting them with stirring at 50°C to 70°C. Examples of solvents include mixed solvents of water with alcohol-based solvents such as methanol, ethanol, and n-propanol, and mixed solvents of water with aromatic hydrocarbon-based solvents such as benzene, toluene, and xylene. After the reaction is complete, the reaction product can be isolated by conventional post-treatment procedures in organic synthesis chemistry, and, if necessary, by conventionally known separation and purification methods. The content of the aforementioned impurities in the reaction product can be confirmed by purifying the reaction product using silica gel column chromatography (using hexane / ethyl acetate as the developing solvent), washing the silica gel with methanol, and then concentrating the solution of the eluted impurities. [Examples]

[0026] Examples are shown below, but the technical scope of the present invention is not limited to these. [Reference Example 1] Example of preparation of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one-2,4-dicarboxylate ethyl hydrochloride Ethanol (17.5 mL) was added to a 100 mL four-necked flask and cooled to 0°C to 5°C. Diethyl 3-oxopentanedioate (25.13 g, 124.3 mmol) and 50% glutaraldehyde (25.95 g, 129.6 mmol) were added, and the mixture was stirred for 10 minutes while maintaining the temperature at 0°C to 5°C (this is called Solution A). Ethanol (12.0 mL) was added to a 300 mL four-necked flask and cooled to 0°C to 5°C. Benzylamine (20.17 g, 188.2 mmol) was added and stirred for 20 minutes. Solution A, prepared earlier, was then added dropwise over 4 hours using an ice-cooled dropping funnel. After the dropwise addition was complete, the temperature was gradually increased and the mixture was aged at 25-28°C for 1 hour. 36% hydrochloric acid (21.37 g) was then added, followed by water (25.0 mL), and then seed crystals (2 mg) were added. After the crystals precipitated, the mixture was cooled to 0-5°C and stirred for 20 minutes. After that, stirring was stopped and the mixture was aged in a refrigerator (0-5°C) for 17 hours. Cold ethanol (12.5 mL) was added to the flask, and the crystals in the flask were transferred to a Kiriyama funnel. The obtained crystals were washed twice with cold ethanol (12.5 mL) and once with cold water (12.5 mL). The crystals on the Kiriyama funnel were transferred to a 200 mL round-bottom flask and dried using a vacuum pump to obtain 44.01 g of the title compound in a yield of 86.4%.

[0027] [Reference Example 2] Example of the production of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one-2,4-dicarboxylate ethyl hydrochloride (22.10 g, 53.91 mmol), water (17.0 mL), and DMSO (10.5 g) were added to a 200 mL flask. The mixture was heated to 100-105°C in an oil bath and distilled at atmospheric pressure for 1 hour. A 25% NaOH aqueous solution (6.91 g) was then added, and distillation at atmospheric pressure was performed again. Subsequently, 17.0 mL of water was added, and atmospheric distillation was performed. This process of adding 17.0 mL of water when the solution in the flask was depleted was repeated four times, and atmospheric distillation was carried out for a total of 19 hours. After cooling, toluene (43 mL), water (27.0 mL), and 25% NaOH aqueous solution (2.12 g) were added, and the mixture was separated. Quantitative analysis of 52.99 g of the separated organic layer was performed, yielding the compound described in the title with a yield of 93.4%. This organic layer was concentrated to obtain a reaction product containing the title compound. The impurity content in the reaction product, derived from the polymer of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one and glutaraldehyde, was 1.33 wt%.

[0028] The content of the aforementioned impurities was calculated using the following method. Hereafter, they will simply be referred to as "impurities." [Reference Example 3] Preparation of impurity standards, selection of internal standards, and creation of calibration curves After loading 10.00 g of the reaction product into a medium-pressure silica gel column, the reaction product was eluted with a hexane / ethyl acetate gradient and then fractionated into components that eluted with 100% ethyl acetate (referred to as component 1), components that eluted with 100% MeOH (referred to as component 2), and components that were adsorbed onto the column (referred to as component 3). The weights of each component were measured, and it was found that 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one was 9.925 g, component 1 was 35 mg (yellow), and component 2 was 30 mg (brown). Regarding component 3, the weight of the column could not be directly measured because the component eluted from the silica gel column when MeOH was passed through it, but it was calculated to be 10 mg as the weight difference of the reaction product. A mixture of component 1 and component 2 was used as the impurity standard. The analytical conditions were determined as shown in Table 1. The impurity standard was eluted broadly up to approximately tR = 10.5 to 25 min, while 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one was eluted at tR = 20.9 min. For quantitative analysis, p-terphenyl, which elutes after 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one, was selected as the internal standard (IS).

[0029] [Table 1]

[0030] Figure 1 shows the CAD chromatogram and TIC chromatogram of a sample prepared by mixing the impurity standard and the quantitative IS. Figures 2 to 4 show characteristic mass spectra observed at tR = 10.5–21 min. It was found that impurities with a molecular weight distribution were present.

[0031] Next, a calibration curve was created for the impurity standard. The IS solution was prepared by weighing approximately 1 g of p-terphenyl into a 1 L glass container and adding 1 L of acetone. For calibration curve confirmation, 20.6 mg of the impurity standard was accurately weighed into a vial, and 10 mL of IS solution was accurately added to prepare impurity standard 1. 5 mL was accurately dispensed from impurity standard 1, and 5 mL of IS solution was accurately added to prepare impurity standard 2. 5 mL was accurately dispensed from impurity standard 2, and 5 mL of IS solution was accurately added to prepare impurity standard 3. 1 mL was accurately dispensed from impurity standard 1, and 9 mL of IS solution was accurately added to prepare impurity standard 4. 1 mL was accurately dispensed from impurity standard 2, and 9 mL of IS solution was accurately added to prepare impurity standard 5. Each impurity standard was analyzed under the conditions shown in Table 1. The calibration curve was developed using the internal standard method. The analysis results are shown in Table 2. The calibration curve for the impurity standard is shown in Figure 5.

[0032] [Table 2]

[0033] [Reference Example 4] Selection of substitutes for impurity standards, and creation and validity assessment of calibration curves. To explore alternative standards, four samples of PEG (Mw=440, 960) and PS (polystyrene) (Mw=780, 1200) were tested. Each analysis was performed under the conditions described in Table 1. The peak shape of PEG960 was the best. The chromatogram of PEG960 is shown in Figure 6. Using PEG960 as a substitute standard, 19.89 mg of PEG960 was accurately weighed into a vial, and 10 mL of IS solution was accurately added to create substitute standard 1. 5 mL was accurately dispensed from substitute standard 1, and 5 mL of IS solution was accurately added to create substitute standard 2. 5 mL was accurately dispensed from substitute standard 2, and 5 mL of IS solution was accurately added to create substitute standard 3. 1 mL was accurately dispensed from substitute standard 1, and 9 mL of IS solution was accurately added to create substitute standard 4. 1 mL was accurately dispensed from substitute standard 2, and 9 mL of IS solution was accurately added to create substitute standard 5. Each substitute standard was analyzed under the conditions shown in Table 1, and the results were compared with the calibration curve of the impurity standard. The internal standard method was used for the calibration curve of the substitute standards. The analysis results are shown in Table 3.

[0034] [Table 3]

[0035] To compare the calibration curve derived for the substitute standard with the calibration curve for the impurity standard, they are overlaid on each other in Figure 7. The approximate straight line (dashed line) for impurity standards was extended to include impurity standards 2 through 5 in the calculation range. It can be seen that substitute standard 1, which has the highest concentration, deviates downward from the approximate straight line of the impurity standard. It is known that the area value of CAD is curved, and this is thought to be the reason. The approximate straight lines of the calibration curves for substitute standards 2 to 5, excluding substitute standard 1, yielded results that were almost the same as the approximate straight line of the impurity standard, and it was considered that PEG960 can be used as a substitute standard if the area ratio is in the range of 2.7 or less.

[0036] [Reference Example 5] Determination of Impurities Alternative standards were used as calibration curves for the quantitative determination of impurities. 80 mg of the reaction product was weighed into a vial, and 0.5 mL of IS solution was added. For samples with an area ratio exceeding 2.7, the sample was re-prepared so that the area ratio did not exceed 2.7. Impurities were detected as peaks using the vertical splitting method for all tR values ​​from 10.0 to 19.5 min. IS was detected as a peak using the baseline method. The weight percentage of impurities was calculated by dividing the determined impurity weight by the weighed value. Similarly, 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one was also quantified after activated carbon treatment.

[0037] [Example 1] Removal of impurities from reaction products To 15.74 g of the obtained organic layer (containing 3.43 g, 14.96 mmol, of 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one), toluene (3 mL), water (30 mL), and 36% hydrochloric acid (3.03 g) were added and the mixture was separated. Activated carbon (0.34g) was added to the separated aqueous layer and allowed to stand for 47 hours. After Celite filtration, 4.85 g of 25% NaOH aqueous solution was added to the filtrate, followed by 50 mL of toluene. The separated organic layer was washed twice with 10 mL of water. The resulting organic layer was concentrated using an evaporator and dried with a vacuum pump to obtain 3.35 g of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one crystals in a yield of 97.6%. The impurity content in the crystals was 0.16 wt%.

Claims

1. A reaction product containing 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one or its hydrochloride as the main component, and a polymer of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one and glutaraldehyde as an impurity, is brought into contact with activated carbon in a solvent. By removing the polymer of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one and glutaraldehyde, A method for purifying 9-benzyl-9-azabicyclo[3.3.1]nonan-3-one having an impurity content of 0.20 wt% or less.

2. 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one having an impurity content of 0.20 wt% or less derived from a polymer of 9-benzyl-9-azabicyclo[3.3.1]nonane-3-one and glutaraldehyde.

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