JP2010100562A - Method for purifying intermediate for producing amlodipine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrial simple method for efficiently purifying and producing a compound which is an intermediate for producing amlodipine. <P>SOLUTION: The method for producing the purified compound (I) includes: suspending crude 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-phthalimidoethoxy)methyl-1, 4-dihydropyridine (I), which is the intermediate for producing amlodipine, in an acetate solvent and dissolving the same under heating; subsequently cooling the solution so as to induce precipitation of a crystal of an acetate solvate of the compound (I) from the solvent system; drying the obtained crystal of the solvate; and carrying out desolvation. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for purifying an intermediate for the production of amlodipine and pharmaceutically acceptable salts thereof.

  Formula (I):

4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine (hereinafter referred to as 1,4-dihydropyridine derivative) Is a compound known as an important synthetic intermediate of amlodipine besylate, which is an effective therapeutic agent for hypertension and angina pectoris.

  A method for producing the 1,4-dihydropyridine derivative of the above formula (I) is described in, for example, Patent Document 1, and as its production method, ethyl 4-chloroacetoacetate and N- (2-hydroxyethyl) phthalimide are used. Reaction with sodium hydride (NaH) as a base in tetrahydrofuran to produce ethyl 4- [2- (phthalimido) ethoxy] acetoacetate, then the resulting 4- [2- (phthalimido) ethoxy] acetoacetic acid A method is described in which ethyl is reacted in 2-propanol by adding 2-chlorobenzaldehyde and methyl 3-aminocrotonate, and acetic acid is added to obtain crude crystals of formula (I).

  The 1,4-dihydropyridine derivative of formula (I) thus prepared is treated with an ethanol solution of methylamine or the like and converted to the target amlodipine, but the compound of formula (I) obtained by the above reaction Contains various impurities, it is necessary to purify the obtained compound of formula (I) in order to obtain high-quality amlodipine, but this patent document does not describe this purification method.

Patent Literature 2 exists as a literature regarding a method for purifying a 1,4-dihydropyridine derivative of the formula (I). The method is only isolated by forming an acetate salt of the formula (I) and isolating it, and purifying the isolated acetate salt of (I) with an alcohol. is there.
Moreover, this method requires complicated steps such as a salt formation step, a purification step, and a desalting step, and is not preferable as an industrial method.

Thus, the 1,4-dihydropyridine derivative of the above formula (I), which is a production intermediate of amlodipine produced by a known method, contains various impurities. However, at present, there is a demand for a method for efficiently purifying the compound of formula (I) with a more industrial and simple method.
Japanese Examined Patent Publication No. 62-6703 Japanese Patent Laid-Open No. 2001-2676

  In view of the above-mentioned present situation, the present invention efficiently purifies the 1,4-dihydropyridine derivative represented by the formula (I) by an industrial and simple method for the compound of the formula (I) which is a production intermediate of amlodipine. It is an object of the present invention to provide a manufacturing method.

  In order to solve the problem, the present inventors have made various studies, and isolated a crude 1,4-dihydropyridine derivative of the formula (I) produced by a known method as crystals of an acetate solvate, It was found that a purified compound of formula (I) that can be derived into amlodipine can be efficiently obtained by desolvating by drying the crystals of the resulting acetate solvate. .

  The obtained 1,4-dihydropyridine derivative of the formula (I) is a compound having a high melting point (hereinafter sometimes referred to as a high melting point body) or a low melting point in differential scanning calorimetry (DSC analysis). Obtained as a compound (hereinafter sometimes referred to as a low melting point substance) or as a mixture of a high melting point substance and a low melting point substance in an arbitrary ratio, and these compounds all lead to high grade amlodipine. As a result, the present invention has been completed.

  Therefore, the present invention provides, as a basic aspect, from the solvent system by suspending the crude 1,4-dihydropyridine derivative represented by the formula (I) in an acetic ester solvent, dissolving it under heating, and then allowing the solution to cool. A purified formula (1), characterized in that crystals of the acetate solvate of the compound of formula (I) are precipitated and the resulting solvate crystals are isolated, dried and desolvated. It is a manufacturing method of the compound of I).

  Specifically, the crude 1,4-dihydropyridine derivative represented by the formula (I) is reacted with ethyl 4-chloroacetoacetate and N- (2-hydroxyethyl) phthalimide in the presence of a base to give 4- [2- ( Obtained by producing ethyl phthalimido) ethoxy] acetoacetate and then reacting the resulting ethyl 4- [2- (phthalimido) ethoxy] acetoacetate with the addition of 2-chlorobenzaldehyde and methyl 3-aminocrotonate Is a process for preparing the purified compound of formula (I) as described above.

  More specifically, the present invention relates to a crude 1,4-dihydropyridine derivative in which the acetate solvent used is methyl acetate, ethyl acetate or isopropyl acetate, and the amount of the acetate solvent is represented by formula (I). In contrast, it is a process for producing a purified compound of formula (I) that is 3 to 5 times the weight.

  Most specifically, it is a method for producing a purified compound of formula (I) having a cooling rate of 1 to 2 hours and a cooling temperature of 0 to 5 ° C.

  The present invention also provides an acetate solvate of the 1,4-dihydropyridine derivative represented by the formula (I) as another embodiment, specifically, the acetate solvate is methyl acetate or ethyl acetate. It is an acetate solvate of a 1,4-dihydropyridine derivative represented by the formula (I) which is a solvate. That is, a methyl acetate solvate or an ethyl acetate solvate of a 1,4-dihydropyridine derivative represented by the formula (I).

  Furthermore, the present invention is, as another aspect, a purified 1,4-dihydropyridine derivative represented by the formula (I), which is a low-melting point substance that shows heat absorption at around 138 ° C. in DSC analysis.

  In yet another embodiment, the present invention is a purified 1,4-dihydropyridine derivative represented by the formula (I), which is a high-melting-point substance that shows heat absorption around 153 ° C. in DSC analysis.

  In still another embodiment, the present invention is a 1,4-dihydropyridine derivative represented by the formula (I) purified as a high melting point product and an arbitrary mixture of low melting point materials.

According to the present invention, a 1,4-dihydropyridine derivative represented by the formula (I), which is an amlodipine production intermediate, can be produced in a high yield as a pure product by a simple operation.
The crude 1,4-dihydropyridine derivative represented by the formula (I) produced by a conventional method contains various impurities. For purification, for example, the recrystallization operation is repeated three times or more. However, the compound of formula (I) purified to the desired high purity cannot be obtained, and repeated recrystallization is not suitable as an industrial production method in terms of production cost and recovery rate. It is.
On the other hand, the method of the present invention can effectively remove impurities other than the compound represented by formula (I).
Therefore, there is an advantage that a high-purity compound of the formula (I) that can be used in a process for obtaining a sufficiently high-grade amlodipine by a single purification operation can be obtained in a high yield.

Further, the production method of the present invention is capable of obtaining a high purification effect by causing a solvate of the formula (I) having a high purification effect to occur in the reaction system and crystallizing it. This crystal solvent can be easily removed by a normal drying operation, and as a result, a compound of formula (I) that can be directly used in the production process of amlodipine in the next step can be obtained without combining complicated steps. This is a very efficient method, and is unique in that the solvate of formula (I) is obtained by cooling crystallization.
Further, the cooling rate and cooling temperature in the method of the present invention are within a range where general industrial implementation is possible, and their applicability is extremely high.

  Further, according to the present invention, the 1,4-dihydropyridine derivative represented by the formula (I) includes two types of high-melting body and low-melting body, and further, the high-melting body and the low-melting body are purified as a mixture in an arbitrary ratio. It was revealed that 1,4-dihydropyridine derivatives represented by the formula (I) existed, and none of them were affected by the crystal polymorphism, and they were induced to high-grade amlodipine. It is very specific.

  As described above, the present invention is based on the solvent system by suspending the crude 1,4-dihydropyridine derivative represented by the formula (I) in an acetic ester solvent, dissolving it under heating, and then cooling the solution. Crystals of the acetate solvate of the compound of formula (I) are precipitated from, and the purified solvate crystals are isolated, dried and desolvated. It is a manufacturing method of the compound of I).

The crude 1,4-dihydropyridine derivative represented by the formula (I) used here can be produced by a known method (for example, Patent Document 1).
Specifically, ethyl 4-chloroacetoacetate and N- (2-hydroxyethyl) phthalimide were reacted in the presence of a base to produce ethyl 4- [2- (phthalimido) ethoxy] acetoacetate, and the resulting 4- This is a method obtained by reacting ethyl [2- (phthalimido) ethoxy] acetoacetate with the addition of 2-chlorobenzaldehyde and methyl 3-aminocrotonate. In the present invention, the method is represented by the formula (I). A crude 1,4-dihydropyridine derivative is produced.

More specifically, ethyl 4-chloroacetoacetate and N- (2-hydroxyethyl) phthalimide are reacted in tetrahydrofuran using sodium hydride (NaH) as a base to give 4- [2- (phthalimido) ethoxy] acetoacetic acid. Then, ethyl 4- [2- (phthalimido) ethoxy] acetoacetate was reacted in 2-propanol by adding 2-chlorobenzaldehyde and methyl 3-aminocrotonate, and acetic acid was added. This is a method for obtaining a crude crystal of the formula (I).
Therefore, the specific method for producing the crude 1,4-dihydropyridine derivative represented by the formula (I) described in Patent Document 1 constitutes a part of this specification.

The method for purifying a crude 1,4-dihydropyridine derivative represented by the formula (I) provided by the present invention is specifically performed as follows.
That is, the crude 1,4-dihydropyridine derivative represented by the formula (I) produced above is suspended in an acetic acid ester solvent and heated to be dissolved in the acetic acid ester solvent. Examples of the acetate solvent used include methyl acetate, ethyl acetate, and isopropyl acetate. Among them, methyl acetate is preferably used.

The amount of the acetate solvent used cannot be generally limited, but is 3 to 5 times the weight of the crude 1,4-dihydropyridine derivative represented by the formula (I), preferably about 4 times the weight.
If the amount of the solvent is too large, the yield of the crystal of the target acetate solvate of the formula (I) is lowered, and if it is too small, the target purification becomes difficult.

After the dissolution of the crude compound of formula (I) is confirmed, cooling is then carried out. When this cooling is immediately cooled to about 0 to 5 ° C. by water cooling and refrigerant cooling, crystals are deposited in the system during the cooling.
In a normal recrystallization operation, a method of increasing the purification effect by maintaining the internal temperature at a temperature at which crystallization is recognized and lowering the cooling gradient is adopted. However, in the case of the present invention, means for efficiently precipitating and generating crystals was adopted by cooling to 0 to 5 ° C. within a short time that can be industrially implemented within 1 to 2 hours. Next, the precipitated crystals are collected by filtration.
The obtained wet crystal is an acetate solvate of the 1,4-dihydropyridine derivative represented by the formula (I).

The wet crystal of the acetate solvate of the 1,4-dihydropyridine derivative represented by the formula (I) thus prepared was desolvated by ordinary drying, and as a result, the target purified A 1,4-dihydropyridine derivative represented by the formula (I) can be obtained.
In addition, drying may be performed under reduced pressure or further under heating.

  The purified 1,4-dihydropyridine derivative represented by the formula (I) prepared according to the present invention is treated, for example, by the method described in Patent Document 1 and derived into high-grade amlodipine.

The 1,4-dihydropyridine derivative of the formula (I) purified by the above-described method of the present invention can be obtained individually as a high melting point body having a high melting point or a low melting point body having a low melting point in DSC analysis. In addition, it was obtained as a mixture in an arbitrary ratio of the high melting point body and the low melting point body.
These compounds were all capable of being induced into high-grade amlodipine.

  The present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to the examples.

Example 1:
545 L of methyl acetate was put into a 1500 L glass lining reaction can, and 140 kg of crude crystals of the compound of the formula (I) obtained by the method described in Patent Document 1 were added. Heating was performed in this state, the crude crystals were dissolved at around 60 ° C., and then cooled. Slow cooling was performed to around 40 ° C. at which the start of crystal precipitation was observed, and the mixture was cooled to around 30 ° C. where most of the crystals were precipitated, and further cooled to 0 to 5 ° C. by cooling.
After aging for 1 hour, the precipitated solid and liquid were separated, and the crystals were washed with cold methyl acetate to obtain 125 kg of a methyl acetate hydrate of 1,4-dihydropyridine derivative represented by the formula (I).
The powder X-ray diffraction data of the methyl acetate solvate of the compound of formula (I) obtained here [namely, methyl acetate solvate of the compound of formula (I)] is shown in FIG.
Subsequently, the obtained methyl acetate hydrate (wet body) of the compound of the formula (I) was dried under reduced pressure, and 113 kg of the purified 1,4-dihydropyridine derivative of the formula (I) without the solvent of the solvate Was obtained in a yield of 80.7%.

  As a result of quality evaluation by HPLC of the purified 1,4-dihydropyridine derivative represented by the formula (I), each impurity was 0.10% or less and the total impurity amount was 0.30% or less. The quality was sufficient to obtain amlodipine.

Comparative example:
400 mL of methyl acetate was placed in a 500 mL reaction vessel, and 100 g of crude crystals of the 1,4-dihydropyridine derivative represented by the formula (I) used in Example 1 were further added. The reaction vessel was heated, and dissolution of the crude crystals was confirmed at around 60 ° C., and then cooling was started. Slow cooling was performed to around 40 ° C. where crystals began to precipitate, and then gradually cooled to 30 ° C. over 3 hours.
Further cooling is carried out to 0 to 5 ° C., aging for 1 hour, followed by solid-liquid separation, washing of the crystals with cold methyl acetate, and a solvate of the 1,4-dihydropyridine derivative represented by the formula (I) Got. The obtained solvate was then dried under reduced pressure to obtain 76.6 g (yield: 76.6%) of a recrystallized product of the compound represented by the formula (I).

  As a result of quality evaluation by HPLC for the obtained recrystallized product, the most impurity was 0.32%, and the total impurity amount was 0.50%.

This recrystallized product was subjected to the same recrystallization operation, and as a result of trying to obtain the quality of the compound of the formula (I) obtained in Example 1, even if the recrystallization operation was repeated 3 times, The quality of the compound of formula (I) obtained was not met.
When the recrystallization operation of this comparative example was repeated three times, the recrystallization yield was 53.6%.

  The results of HPLC analysis of the compounds of formula (I) obtained in Example 1 and Comparative Example are collectively shown in Table 1 below.

Example 2:
In a 200 mL reaction vessel, 80 mL of ethyl acetate was added, and 20 g of a crude crystal of a 1,4-dihydropyridine derivative represented by the formula (I) was added. The reaction vessel was heated, and dissolution of crystals was confirmed at around 76 ° C., followed by cooling. Slow cooling was performed until the precipitation of crystals started at around 30 ° C, and after cooling to around 25 ° C where most of the crystals were precipitated, further cooling was performed to 0 to 5 ° C. After aging for 1 hour, solid-liquid separation was performed, and the crystals were washed with cold ethyl acetate to obtain 20.3 g of an ethyl acetate solvate of the compound of formula (I).
The powder X-ray diffraction data of the ethyl acetate solvate of the compound of formula (I) thus obtained [that is, the ethyl acetate solvate of the compound of formula (I)] is shown in FIG. 2, and the infrared absorption spectrum is shown in FIG. It was.
Subsequently, the obtained methyl acetate hydrate (wet) of the compound of formula (I) was dried under reduced pressure, and 16.1 g of the purified 1,4-dihydropyridine derivative of formula (I) was obtained in a yield of 80.5%. Got in.

<About DSC analysis>
The purified 1,4-dihydropyridine derivative represented by the formula (I) and the methyl acetate solvate of the formula (I) were subjected to thermal analysis by DSC.
The 1,4-dihydropyridine derivative represented by the formula (I) and the methyl acetate solvate of the formula (I) showed a clear difference in DSC analysis.
The methyl acetate solvate of the formula (I) showed broad heat absorption around 100 ° C.
On the other hand, the 1,4-dihydropyridine derivative represented by the formula (I) has a low melting point body in which heat absorption is observed at around 138 ° C. and a high melting point body in which heat absorption is observed at around 153 ° C., which are obtained as a single product. It has been confirmed that it can be obtained as a mixture in a certain ratio.

FIG. 4 shows a DSC analysis chart of methyl acetate solvate of the compound of formula (I), FIG. 5 shows a DSC analysis chart of the low melting point substance of formula (I), and FIG. 6 shows the high melting point of formula (I). FIG. 7 shows a DSC analysis chart of a mixture of the low melting point body and the high melting point body of the formula (I).
Further, FIG. 8 shows powder X-ray diffraction data of the low melting point substance of the formula (I), and FIG. 9 shows powder X-ray diffraction data of the high melting point body of the formula (I).

  As is clear from these figures, the 1,4-dihydropyridine derivative represented by the formula (I) and the methyl acetate solvate of the formula (I) showed a clear difference in the DSC analysis, and the formula (I ) The compounds were found to exist as low and high melting point singles as well as mixtures thereof.

In addition, even if it exists in any of the low melting point body of the obtained compound of a formula (I), a high melting point body, and its mixture, when induced | guided | derived to amlodipine, it did not affect the quality of the obtained amlodipine.
That is, in the present invention, only through the acetate solvate of the compound represented by the formula (I) affects the quality, and the low melting point of the compound of the formula (I) by the method of the present invention. Even if any of the body, the high melting point body, and the mixture were obtained, there was no difference in the purification effect.

  As described above, according to the method of the present invention, the 1,4-dihydropyridine derivative represented by the formula (I), which is an amlodipine production intermediate, can be produced with high quality. According to the method of the present invention, impurities other than the compound represented by the formula (I) can be effectively removed, and in addition, it is used in a step of obtaining sufficiently high-quality amlodipine by a single purification operation. Since the compound of formula (I) that can be obtained can be obtained in high yield, its utility value is tremendous as an industrial production method.

2 is a powder X-ray diffraction data of a methyl acetate solvate of the compound of formula (I). 2 is a powder X-ray diffraction data of an ethyl acetate solvate of the compound of formula (I). 2 is an infrared absorption spectrum of an ethyl acetate solvate of the compound of formula (I). 2 is a DSC analysis chart of methyl acetate solvate of the compound of formula (I). It is a DSC analysis chart of the low melting point body of a compound of formula (I). It is a DSC analysis chart of the high melting point body of a compound of formula (I). It is a DSC analysis chart of the mixture of the low melting point body and high melting point body of a compound of Formula (I). It is a powder X-ray-diffraction data of the low melting point body of a compound of Formula (I). It is a powder X-ray-diffraction data of the high melting point body of a compound of Formula (I).

Claims (10)

Formula (I):

The crystalline 1,4-dihydropyridine derivative represented by formula (1) is suspended in an acetic ester solvent, dissolved under heating, and then the solution is cooled to obtain crystals of the acetic ester solvate of the compound of formula (I) from the solvent system. A method for producing a purified compound of formula (I), characterized in that the solvate crystals obtained by precipitation are isolated, dried and desolvated.   The crude 1,4-dihydropyridine derivative represented by the formula (I) is obtained by reacting ethyl 4-chloroacetoacetate with N- (2-hydroxyethyl) phthalimide in the presence of a base to give 4- [2- (phthalimido) ethoxy] acetate. The ethyl acetate according to claim 1, which is obtained by producing ethyl acetate and then reacting the resulting ethyl 4- [2- (phthalimido) ethoxy] acetoacetate with addition of 2-chlorobenzaldehyde and methyl 3-aminocrotonate. Production method.   The production method according to claim 1 or 2, wherein the acetate solvent used is methyl acetate, ethyl acetate or isopropyl acetate.   The production method according to claim 1 or 2, wherein the amount of the acetate solvent used is 3 to 5 times the weight of the crude 1,4-dihydropyridine derivative represented by the formula (I).   The manufacturing method according to claim 1 or 2, wherein the cooling temperature is 0 to 5 ° C.   An acetate solvate of a 1,4-dihydropyridine derivative represented by the formula (I).   The acetate solvate of a 1,4-dihydropyridine derivative represented by the formula (I) according to claim 6, wherein the acetate solvate is a methyl acetate solvate or an ethyl acetate solvate.   A 1,4-dihydropyridine derivative represented by the formula (I) obtained by the production method according to any one of claims 1 to 5, which is a low-melting-point substance that absorbs heat at around 138 ° C in DSC analysis.   A 1,4-dihydropyridine derivative represented by the formula (I) obtained by the production method according to any one of claims 1 to 5, which is a high-melting-point substance that shows heat absorption at around 153 ° C in DSC analysis.   A formula (I) obtained by the production method according to any one of claims 1 to 5, which is a mixture of a low-melting-point body that absorbs heat at around 138 ° C and a high-melting body that recognizes heat absorption at around 153 ° C in DSC analysis. 1,4-dihydropyridine derivative shown.

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