JP2022093057A - Method for producing amlodipine besilate - Google Patents

Abstract

To provide a method for producing amlodipine besilate safely and at high yield.SOLUTION: A method for producing amlodipine besilate includes the step of causing phthaloyl amlodipine, having an amino group protected with a phthaloyl group, to react with ethylenediamine in a solvent containing water and an organic solvent immiscible with water, and then removing an aqueous layer in the solvent, to obtain an amlodipine base. The method further includes the step of causing the amlodipine base to react with benzenesulfonate, to obtain amlodipine besilate represented by the following formula (3).SELECTED DRAWING: None

Description

The present invention relates to a method for producing an amlodipine base and an amlodipine besylate.

Amlodipine (Chemical name: 2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl) and its thereof The salt is a drug useful for antihypertensive therapy having a calcium antagonistic action, and is used for the treatment of ischemic heart disease, hypertension and the like.

As the pharmaceutical component, an amlodipine base converted into a pharmaceutically acceptable salt such as besilate is used.

Regarding the method for producing an amlodipine base, conventionally, a method of reacting phthaloylamlodipine with hydrazine or methylamine as a deprotecting agent is known (Patent Documents 1, 3 to 5). As a method for producing amlodipine besilate, a method of reacting an amlodipine base with benzenesulfonic acid is known (Patent Document 2).

Special Publication No. 62-6703 Japanese Patent Application Laid-Open No. 62-240660 International Publication No. 2007/017538 International Publication No. 2005/023769 Japanese Unexamined Patent Publication No. 2007-15978

However, when phthaloylamlodipine is reacted with hydrazine as in the technique described in Patent Document 1, the desorbed phthalimide is precipitated as a solid, and it is necessary to remove it by filtration. This precipitated solid has poor filterability, and in actual production, it leads to filtration troubles such as delay in operation time and loss due to poor cleaning. In addition, since hydrazine and its derivatives are carcinogenic, it is necessary to strictly control the residual amount.

On the other hand, methylamine, which is also used as a deprotecting agent in the technique described in Patent Document 1, has a low boiling point of -6 ° C and is flammable and toxic, so its use in actual production should be avoided.

The present invention has been made in view of the above problems, and an object of the present invention is to provide a method for producing amlodipine besilate in a safe and high yield.

The method for producing amlodipine besilate according to one aspect of the present invention is described in the following formula (1).

で示されるフタロイルアムロジピンを、水に混和しない有機溶媒と水とを含む溶媒中にて、エチレンジアミンと反応させ、その後、溶媒中の水層を除去して、下記式（２）

Phthalloyl amlodipine represented by (2) is reacted with ethylenediamine in a solvent containing an organic solvent immiscible with water and water, and then the aqueous layer in the solvent is removed to obtain the following formula (2).

で示されるアムロジピン塩基を得る工程を含むことを特徴とする。

It is characterized by including a step of obtaining an amlodipine base represented by.

In the production method, it is preferable to further include a step of reacting the amlodipine base with benzenesulfonic acid (monohydrate or anhydride) to obtain amlodipine besilate.

Further, in the production method, it is preferable that the organic solvent is at least one selected from substituted benzene, acetic acid ester, ether, ketone, and hydrocarbon.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a method for producing amlodipine besilate in a safe and high yield.

Hereinafter, embodiments according to the present invention will be specifically described, but the present invention is not limited thereto.

The method for producing amlodipine besylate in the present embodiment is described in the following formula (1).

で示されるフタロイルアムロジピンを、水に混和しない有機溶媒と水とを含む溶媒中にて、エチレンジアミンと反応させ、その後、溶媒中の水層を除去して、下記式（２）

Phthalloyl amlodipine represented by (2) is reacted with ethylenediamine in a solvent containing an organic solvent immiscible with water and water, and then the aqueous layer in the solvent is removed to obtain the following formula (2).

で示されるアムロジピン塩基を得る工程を含むことを特徴とする。

It is characterized by including a step of obtaining an amlodipine base represented by.

By using ethylenediamine instead of conventional hydrazine as the deprotecting agent as in the present embodiment, the desorbed phthalimide becomes water-soluble. This eliminates the need to filter phthalimide, which was conventionally precipitated as a solid, shortens the operation time, and suppresses the occurrence of filtration troubles such as poor cleaning.

The solvent used for the above reaction in the present embodiment includes an organic solvent immiscible with water and water. By adopting such a two-layer system, the desorbed water-soluble phthalimide is transferred to the aqueous layer, so that the equilibrium between the amlogipin base and the reaction intermediate can be biased toward the amlogipin base, and the reaction intermediate can be displaced. We thought that the residual amount could be reduced.

The organic solvent immiscible with water is not particularly limited, and examples thereof include substituted benzene, acetic acid ester, ether, ketone, and hydrocarbon. More specifically, for example, toluene, xylene, benzene, 2-methyltetratetraester, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, heptane, methyl isobutyl ketone and the like can be mentioned. These may be used alone or in combination of two or more.

In the present embodiment, the amount of ethylenediamine used in the above reaction is preferably 0.8 to 2.0 times the volume of phthaloylamlodipine as a raw material.

In addition, the total amount of the solvent used in the above reaction in the present embodiment is preferably about 2.0 to 5.0 times the volume of the raw material phthaloylamlodipine.

Further, the ratio of the organic solvent immiscible to water and water in the solvent is preferably about 2: 0.4 to 1: 1 in volume. If the ratio of water in the solvent is in this range, it is considered that the above-mentioned effects can be more easily obtained.

The reaction may be carried out by adding ethylenediamine and a solvent to phthaloylamlodipine and reacting in one step, or by adding ethylenediamine to phthaloylamlodipine and reacting, and then using an organic solvent and water that are immiscible with water. A solvent containing the above may be added and reacted (two-step reaction). From the viewpoint of efficiency and further reduction of by-product impurities, the former one-step reaction is preferable.

In the case of a one-step reaction, for example, the reaction temperature is preferably about 35 to 85 ° C., and the reaction time is preferably about 30 minutes to 25 hours.

When the above reaction is carried out in two steps, for example, the reaction time of the first step (reacting by adding ethylenediamine to phthaloylamlogipine) is about 40 to 60 ° C., and the reaction time is about 2 to 4 hours. The reaction time of the second step (the reaction is carried out by adding a solvent) can be about 50 to 70 ° C., and the reaction time can be about 2 to 20 hours.

In either case, by removing the aqueous layer in the solvent after the reaction, the water-soluble phthalimide transferred to the aqueous layer can be removed, and the amlodipine base can be obtained in high yield. The removal of the aqueous layer can be performed by adding water to the reaction solution containing the amlodipine base. As described above, since the desorbed water-soluble phthalimide exists in the aqueous layer, the desorbed phthalimide can be removed by removing the aqueous layer.

The production method of the present embodiment is not particularly limited as long as it includes the reaction step, and the amlodipine besylate represented by the following formula (3) can be obtained by a known means. Can be done.

For example, the amlodipine base obtained in the above step can be directly reacted with benzenesulfonic acid to obtain amlodipine besylate. Alternatively, the amlodipine base obtained in the above step may be isolated once, and then the amlodipine base may be reacted with benzenesulfonic acid to obtain amlodipine besylate.

From the viewpoint of productivity, it is preferable to directly react the amlodipine base with benzenesulfonic acid to obtain amlodipine besilate. In that case, benzenesulfonic acid is added to the reaction solution obtained from the above reaction step to react.

In the present embodiment, for convenience, the step of obtaining the amlodipine base as described above is referred to as a first step, and the step of reacting the obtained amlodipine base with benzenesulfonic acid to obtain an amlodipine besylate is referred to as a second step.

The second step will be described more specifically. First, as described above, since the aqueous layer has been removed from the reaction solution containing the amlodipine base obtained in the first step, the organic layer remaining in the reaction solution is further washed with water. After washing, azeotropic dehydration may be performed to reduce the water content in the organic layer. Then, after adding methanol to the organic layer, benzenesulfonic acid is added. At that time, benzenesulfonic acid monohydrate dissolved in an organic solvent (for example, methanol, ethanol, isopropyl alcohol, etc.) is added. You may.

The amount of benzenesulfonic acid used in the second step of the present embodiment is preferably about 1.0 to 1.4 equivalents with respect to the amlodipine base.

Further, as the benzenesulfonic acid used in the second step of the present embodiment, a monohydrate may be used or an anhydride may be used.

The dropping temperature of the benzenesulfonic acid solution in the second step is preferably 10 to 40 ° C, more preferably about 25 ° C, and the dropping time is preferably about 1 to 16 hours.

The reaction solution obtained in the second step is cooled, the precipitated amlodipine besylate is collected by filtration, washed and dried, whereby a highly pure amlodipine besylate can be obtained in high yield. The cooling temperature is about −5 to 25 ° C., and the precipitate can be washed with isopropyl alcohol. Further, the drying is preferably performed at 40 to 60 ° C., more preferably at a temperature of about 50 ° C. for 2 hours or more.

Next, a case where the amlodipine base is once isolated between the first step and the second step will be described.

The isolation of the amlodipine base can be performed by cooling the reaction solution obtained in the first step, precipitating the amlodipine base, collecting the precipitate, washing and drying, and the like.

Specifically, for example, after the reaction of the first step is completed, seed crystals are added to the organic layer remaining after the aqueous layer is removed at 30 to 40 ° C., and then an organic solvent such as heptane is added at 25 to 40 ° C. It is preferably added at 30-35 ° C. Then, the amlodipine base can be isolated by cooling to −10 to 0 ° C., collecting the precipitated crystals, washing with a mixed solvent of toluene and heptane, and drying. The drying is preferably carried out, for example, at 40 to 60 ° C., more preferably at 50 ° C. for 2 hours or more under reduced pressure.

By dissolving the isolated amlodipine base in methanol and then adding a solution of benzenesulfonic acid in isopropyl alcohol, amlodipine besilate can be obtained in the same manner as in the second step.

The amlodipine besylate obtained by the production method of the present embodiment can be used as it is for pharmaceutical purposes, but if necessary, it is dissolved in alcohols such as methanol and isopropyl alcohol, and then recrystallized before use. You can also do it.

The amlodipine besylate produced in the present embodiment can be formulated by a known method and used as a single agent or a combination drug in various dosage forms.

Hereinafter, the present invention will be described in more detail by way of examples, but the scope of the present invention is not limited thereto.

(Example 1: Production of amlodipine base)
Phtaloyl amlodipine (300 g), toluene (600 mL), ethylenediamine (300 mL) and water (150 mL) were added and reacted at 70 ° C. for 4 hours. Water (450 mL) was added and the aqueous layer was removed, then seed crystals (1.5 g) were added to the resulting organic layer at 40 ° C., followed by heptane (1200 mL) at 35 ° C. and cooled to −10 ° C. The precipitated crystals were collected by filtration and washed twice with a mixed solution of toluene (100 mL) and heptane (200 mL). The product was dried under reduced pressure at 50 ° C. to obtain 207 g of the title compound (yield 91%; peak area in HPLC: 98.66%).

(Example 2: Production of amlodipine besylate)
Phtaloylamlodipine (30 g), toluene (60 mL), water (15 mL) and ethylenediamine (30 mL) were added and reacted at 70 ° C. for 5 hours. After adding water (45 mL) and removing the aqueous layer, the organic layer was washed with water (60 mL). Toluene (60 mL) was added and azeotropic dehydration was performed twice. MeOH (4 mL) followed by an isopropyl alcohol (IPA) solution (131 mL) of benzenesulfonic acid monohydrate (11 g) and seed crystals (3 mg) were added at 25 ° C and cooled to -5 ° C. The precipitated crystals were collected by filtration and washed twice with IPA (30 mL). The product was dried under reduced pressure at 50 ° C. to obtain 26 g of the title compound (yield 87%; peak area in HPLC: 99.97%).

(Example 3: Production of amlodipine base (reaction in two steps))
Phtaloylamlodipine (30 g) and ethylenediamine (30 mL) were added and reacted at 55 ° C. for 2 hours. Subsequently, toluene (60 mL) and water (60 mL) were added and reacted at 60 ° C. for 2 hours. After removing the aqueous layer, toluene (60 mL), water (60 mL) and hydrochloric acid were added to adjust the pH to 4. After removing the organic layer, isopropyl acetate (60 mL) and an aqueous NaOH solution were added to adjust the pH to 11. After removing the aqueous layer, seed crystals (0.2 g) and heptane (131 mL) were added to the obtained organic layer at 35 ° C. and cooled to −5 ° C. The precipitated crystals were collected by filtration and washed twice with a mixed solution of isopropyl acetate and heptane (mixing ratio of 2: 5 by volume, 30 mL). Drying under reduced pressure was carried out at 50 ° C. to obtain 19 g (yield 84%; peak area in HPLC: 98.85%).

(Example 4: Production of amlodipine besylate (reaction in two steps))
Phtaloylamlodipine (5.4 g), isopropyl acetate (27 mL) and ethylenediamine (3.7 mL) were added and reacted at 75 ° C. for 4 hours. Water (27 mL) was added and reacted at 75 ° C. for 2 hours. After removing the aqueous layer, it was washed with water (27 mL). An IPA solution (5.4 mL) of besilic acid monohydrate (1.76 g) was added to the obtained organic layer at room temperature, and the mixture was cooled to 0 ° C. The precipitated crystals were collected by filtration and washed twice with IPA (5.4 mL). The product was dried under reduced pressure at 50 ° C. to obtain 3.9 g of the title compound (yield 69%; peak area in HPLC: 99.95%).

As described above, from the results of Examples 1 to 4, it was confirmed that the amlodipine base and amlodipine besilate with less impurities can be obtained in high yield by the production method of the present invention.

[Comparative test 1]
The filterability of the desorbed phthalimide when conventional hydrazine was used for deprotection was evaluated.

(Comparative example)
Methanol solution (5.4 mL) of phthaloyl amlodipine (10.8 g), ethyl acetate (54 mL) and hydrazine monohydrate (4.0 g) was added and reacted at 30 ° C. to release the amlodipine base and phthalimide (solid). The included suspension was obtained. When the filterability was evaluated by a compression filtration tester using the suspension, the average filtration resistivity was 1.1 × 10 ¹¹ .

Regarding this result, referring to page 26 of "Technical Journal Sumitomo Chemical 2007-II" (published on November 30, 2007), the average filtration resistivity is 2 × 10 ¹⁰ to 10 ¹¹ which is “not good”, 10 ¹¹ Since it is evaluated as "bad" in the super, the filterability of Comparative Example 1 (hydrazine method) can be evaluated as "bad".

[Comparative test 2]
When conventional hydrazine is used for deprotection (comparative example) and when ethylenediamine is used for deprotection as in this example, the time required for filtration of phthalimide desorbed from the raw material phthaloylamlodipine and When the loss of the amlodipine base, which is the target product, was compared, it was found that in the comparative example, filtration took 20 hours or more, and the loss of the target product due to poor cleaning was as high as 12%. On the other hand, according to the method of this example, phthalimide was removed by liquid separation, and the time required for the liquid separation was very good at 5 minutes on a laboratory scale. In addition, the loss of the target substance to the water layer was 1% or less.

From the above, according to the production method of the present invention, as compared with the conventional method (method using hydrazine), phthalimide can be removed only by liquid separation without the need for a filtration operation, and further, the target product (amlodipine) can be removed. It was found that the loss of base) was also small.

Claims (3)

The following formula (1)

Phthalloyl amlodipine represented by (2) is reacted with ethylenediamine in a solvent containing an organic solvent immiscible with water and water, and then the aqueous layer in the solvent is removed to obtain the following formula (2).

A method for producing amlodipine besilate, which comprises the step of obtaining the amlodipine base shown in. The method for producing amlodipine besilate according to claim 1, further comprising a step of reacting the amlodipine base with benzenesulfonic acid to obtain amlodipine besilate. The method for producing amlogipin besilate according to claim 1 or 2, wherein the organic solvent is at least one selected from substituted benzene, acetic acid ester, ether, ketone, and hydrocarbon.