KR100467707B1 - Preparation of crystal form ⅱ of clarithromycin - Google Patents

Abstract

The present invention relates to a method for preparing a second crystalline form for clarithromycin, in particular, through a simple process that does not require a separate crystalline conversion or separation process, thermodynamically stable compared to other crystalline forms used in industrial drug preparation A method for preparing a second crystalline form of clarithromycin in high yield and high purity.

Description

The manufacturing method of the 2nd crystalline form of clarithromycin {PREPARATION OF CRYSTAL FORM II OF CLARITHROMYCIN}

The present invention relates to a method for preparing a second crystalline form for clarithromycin, in particular, through a simple process that does not require a separate crystalline conversion or separation process, thermodynamically stable compared to other crystalline forms, industrial drug preparation A method for preparing a second crystalline form of clarithromycin for use in high yield and high purity.

6-O-methylerythromycin A (Clarithromycin) shows excellent antibacterial activity against Gram-positive bacteria, some Gram-negative bacteria, anaerobic bacteria, Mycoplasma, Chlamydia, etc. Macrolides are antibiotics. The compound is stable under acidic conditions and is effective upon oral administration. In addition, the clarithromycin is effectively used in the treatment of upper respiratory tract infections in children and adults.

[Formula 1]

Depending on the pharmaceutical utility of such clarithromycin, a number of methods for preparing clarithromycin have been proposed in the past. In more detail about the method for producing clarithromycin according to the prior art, the method for producing clarithromycin known so far is, as a patent document, Korean Patent Application No. 91-5898 (Taisho), 91- 7572 (Taisho), 91-2142 (Taisho), 95-9367 (Taisho), 96-434 (Taisho), Republic of Korea Patent Publication No. 90-18132 (Taisho), Republic of Korea Patent Publication 91 J. Antibiotics (V.46, No. 4, 647 (1993)), J. Antibiotics (V.46, No. 7, 1163 (1993)), J. Antibiotics (V.37, No. 2, 187 (1984)), Heterocycles (V. 36, No. 2, 243 (1993)), J. Antibiotics (286 (1990)) and the like.

These conventional methods for producing clarithromycin can be broadly classified into the following three types of production methods.

First, the first method is a relatively early production method introduced in the Republic of Korea Patent Application Nos. 91-5898, 91-7572, etc., as shown in the following Scheme 1, first, carbobenzyloxy group (Cbz group) After protecting the 2'-OH and 3'-dimethylamino group of the erythromycin 9-oxime derivative in which the oxime group was substituted at 9-0, the erythromycin derivative having the carbobenzyloxy protecting group introduced therein Is reacted with a methylating agent such as methyl iodide to selectively methylate the 6-OH group of the erythromycin derivative, and then undergoes deprotection through a hydrogenation reaction, while removing the oxime group, thereby producing the final result, clarithromycin. That's how.

Scheme 1

However, since the final deprotection reaction proceeds through a hydrogenation reaction, the production method according to the related art has a problem that the reaction is not completed by a catalytic poison, and moreover, an oxime group is introduced into erythromycin. Reaction steps such as a step, a protecting group introduction step, a methylation step, a deprotection step and an oxime group removal step are complicated, and a yield is also low. In particular, the process of regenerating the methyl group of the 3'-dimethylamino group becomes difficult. It is true that the selectivity was low at the introduction of methyl group to the 6-OH group, so that a large number of by-products in which the methyl group was substituted by other hydroxy groups were generated.

Next, the second type of manufacturing method has been proposed to solve the problem of the first manufacturing method, in particular, to lower the yield caused by the generation of various by-products, such a manufacturing method is Korean Patent Application No. 91-2142 And the like. On the other hand, in the above production method, as can be seen in the following Reaction Scheme 2, first, an oxime group is introduced into 9-O of erythromycin to prepare an erythromycin 9-oxime derivative, and then 3 After protecting the '-dimethylamino group with the quaternary salt of the same group, the methyl group is selectively introduced into the 6-OH group and proceeded to deprotection and oxime elimination reaction as in the first preparation method, thereby resulting in the final clarithromycin. Will be manufactured.

Scheme 2

However, even with this method, since the hydrogenation reaction is applied in the deprotection step, there is still a problem that the reaction is not completed by the catalyst poison, and moreover, an oxime group introduction step for protecting erythromycin, a protecting group introduction step, and methylation. Problems such as complicated reaction steps such as step, deprotection step and oxime group removal step and low yield cannot be solved, resulting in lower yield of the final production of clarithromycin and complicated reaction step. Done.

Finally, when looking at the third type of manufacturing method for clarithromycin, the manufacturing method is a manufacturing method disclosed in Korean Patent Application Nos. 95-9367, 96-434, etc., As can be seen in Scheme 3, first, in the same manner as the preparation method described above, a 9-oxime derivative of erythromycin is prepared, and then the oxime group is protected using a benzyl derivative and a ketal derivative, while 2'- OH and 4'-OH groups were protected using a substituted silyl group, and then the 6-OH group of the erythromycin derivative having the protecting group introduced was optionally methylated, and the 9-oxime group, 2'-OH and 4'-OH groups By simultaneously removing the protecting groups introduced, the final object is to produce clarithromycin.

Scheme 3

In the case of this manufacturing method, the selectivity of the methylation process is relatively high, so that the generation of by-products is relatively low, the yield is relatively high, and the oxime removal process and the deprotection process can be performed in a single step reaction. The reaction process is simpler, but the oxime group introduction step, the protecting group introduction step, the methylation step and the deprotection step (simultaneous with the oxime group removal step) for erythromycin are required. There is a problem that the complexity, in particular, because the ketal derivative used as a protecting group for oxime should be used after synthesis through a separate manufacturing process, there was a problem that the actual reaction process is more complicated.

Accordingly, there is an urgent need for a method for producing clarithromycin in high yield through a simpler process.

On the other hand, it has been found that the above clarithromycin may have two or more crystalline forms defined as the first type, the second type, and the like (see Korean Patent Publication No. 2000-29591). This crystalline form is identified by infrared spectrum, differential scanning calorimetry magnetic temperature diagram and powder X-ray diffraction pattern.

However, in the method for preparing clarithromycin according to the prior art as described above, the crystal of the first type in the process of recrystallizing the final prepared clarithromycin using an organic solvent such as ethanol, tetrahydrofuran, isopropyl acetate and isopropanol, etc. It was found that mainly forms. However, all drugs currently manufactured and marketed using clarithromycin are formulated from the thermodynamically more stable type 2, which is why when producing clarithromycin according to the prior art as described above, The process of converting the first crystalline form into the second crystalline form, such as by applying heat to ritamycin, was required separately, resulting in a more complicated manufacturing process of clarithromycin and a lower yield.

Of course, in order to solve this problem, Korean Patent Laid-Open Publication No. 2001-29591 discloses clarithromycin (mainly made of type 1 or a mixture of type 1 and type 2 prepared according to a conventional method). .) Is recrystallized with a specific solvent such as alkanols having 1 to 5 carbon atoms, ketones having 3 to 12 carbon atoms, etc., except for ethanol or isopropanol, to separate and purify the second form of clarithromycin without a separate conversion process. Although disclosed, this method also, according to the preparation method according to the prior art, once produced clarithromycin in the form of type 1 or a mixture of type 1 and type 2, and then this type of clarithromycin As a method of converting and preparing the second crystalline form from the second step, the final yield of clarithromycin for the second crystalline form is lowered. Point who will still exist.

According to this problem of the prior art, through the simple manufacturing process without a separate conversion or separation process, the clarithromycin can be prepared directly in the form of the second crystalline form, and also the second crystalline form of the clarithromycin There is an urgent need for a process for the preparation of the second crystalline form of clarithromycin that allows for production in yield, high purity.

In order to solve this problem of the prior art, the present invention can be prepared in the form of a second thermodynamically stable crystalline form of clarithromycin through a simple step consisting only of the protecting group introduction step, methylation step and deprotection process, There is no need for a separate process for the conversion or separation, and moreover, the second crystalline form for clarithromycin can be prepared in high yield and high purity through a simple process step as compared with the conventional method for producing clarithromycin. Its main purpose is to provide a process for the preparation of the second crystalline form of clarithromycin.

1 is a diagram showing an X-ray diffraction spectrum of clarithromycin prepared according to an embodiment of the present invention.

In order to achieve the above object, the present invention comprises the steps of preparing an 2'-acetoxy erythromycin A derivative of the formula (3) by reacting erythromycin A of formula (2) with acetic anhydride in the presence of triethylamine; Preparing a 6-O-methyl-2'-acetoxy-erythromycin derivative of Chemical Formula 4 by methylating the 2'-acetoxy erythromycin A derivative of Chemical Formula 3; And reacting the 6-O-methyl-2'-acetoxy-erythromycin derivative of Chemical Formula 4 under methanol to prepare clarithromycin of Chemical Formula 1 in the form of a second crystalline form. It provides a process for the second crystalline form of clarithromycin represented by Scheme 4 below.

Scheme 4

According to the production method according to the present invention, the clarithromycin can be produced in a high yield by a simple process step consisting of introducing a protecting group into a 2'-OH group, a selective methylation step to a 6-OH group, and a deprotection step. As described above, all of the problems of the prior art as described above can be solved, and in particular, as clearly demonstrated through the examples described later, according to the results of the present inventors, the acetyl protecting group was introduced into the 2'-OH group. After the methylation process, the methylation of the 6-OH group can be carried out without the generation of by-products in which the methyl is substituted with other OH groups. Therefore, according to the present invention, a high yield is obtained through a very simple process. Low clarithromycin and its second crystalline form can be prepared.

Furthermore, in the above-described manufacturing method of the present invention, as clearly supported by the following examples and the accompanying drawings, the final product, clarithromycin, is directly produced in the form of a second crystalline form, and thus, a separate It is possible to produce a second crystalline form of pharmaceutically useful clarithromycin with high yield and high purity through an extremely simple process, even though it does not go through a crystalline conversion process or a separation process.

In the preparation method for the second crystalline form of clarithromycin according to the present invention, in the step of methylating the 2'-acetoxy erythromycin A derivative of the formula (3), erythromycin in the method for producing clarithromycin according to the prior art Any methylating agent used to methylate derivatives of A can be used.

Among these, the methylation step in the present invention is preferably carried out by reacting the 2'-acetoxy erythromycin A derivative of Formula 3 with methyl iodine in the presence of potassium hydroxide. By proceeding with methylation in this way, it is possible to further increase the selectivity and yield of the methylation step described above, thereby further increasing the final yield for clarithromycin.

Hereinafter, an example of the manufacturing method for the second crystalline form of clarithromycin according to the present invention will be described in more detail.

According to the preparation method of the present invention, in the preparation of the clarithromycin second crystalline form, as shown in Scheme 4, first, erythromycin having a structure of formula (2) is reacted with acetic anhydride in the presence of triethylamine. By reacting, 2'-acetoxy erythromycin A derivative of Chemical Formula 3 is prepared. In this case, erythromycin used as a reactant is prepared by fermenting Streptomyces erythreus according to a known method, and reacting it with acetic anhydride in an organic solvent to protect the 2'-OH group of erythromycin. By introducing an acetyl group, to prepare the erythromycin derivative of the formula (3).

In this process, as the organic solvent, all of the conventional solvents used in the conventional acylation reaction for alcohol can be used. In particular, it is preferable to use acetone, and the pH is preferably maintained at about 9-9.5 during the protective group introduction reaction as described above.

Thereafter, 6-O-methyl-2'-acetoxy-erythromycin derivative represented by Chemical Formula 4 is prepared by reacting the 2'-acetoxy erythromycin A derivative of Chemical Formula 3 with a methylating agent. When the methylation process is performed for Formula 3, selective methylation of the 6-OH group may proceed, and according to this method, a second crystalline form of final clarithromycin may be prepared without generation of by-products.

As the methylating agent used in the methylation process, all of the methylating agents used in the conventional method for preparing clarifymycin, etc. may be generally used. In particular, methyl iodine is used as a methylating agent under potassium hydroxide, so that It is preferred to prepare the '-acetoxy erythromycin A derivative. By using such a methylating agent, the yield of the overall reaction and by-products can be further reduced, thereby increasing the yield of final clarithromycin.

In addition, in the methylation process, all of the organic solvents that have already been used in the conventional method for preparing clarithromycin can be used. However, when methyl iodine is used as the methylating agent under potassium hydroxide, butylene oxide and dimethyl sulfoxide may be used. Preference is given to using mixed solvents.

Meanwhile, after the selective methylation process as described above, the 6-O-methyl-2'-acetoxy-erythromycin derivative of Chemical Formula 4 is reacted under methanol to deprotect the clathrate of Chemical Formula 1 as a final product. Ritromycin is produced. As can be seen from the following examples and the accompanying drawings, the clarithromycin prepared through this process was found to have the form of a second crystalline form that is thermodynamically stable and pharmaceutically useful. In the production method of the present invention, no separate crystalline conversion step or separation step is required.

In addition, by performing a separate purification process for the prepared clarithromycin, it is possible to further increase the purity, this purification process is in accordance with the conventional purification method of organic compounds.

Hereinafter, the preparation method for the second crystalline form of clarithromycin according to the present invention will be described in more detail with reference to preferred examples. However, this is presented as an example and thus should not be construed as determining the scope of the present invention.

Example 1 : Preparation of 2'-acetoxy erythromycin A derivative (Formula 3)

After dissolving 20 g of erythromycin of Formula 2 in 100 ml of acetone, 5.3 ml of acetic anhydride and 7.5 ml of triethylamine were added to the solution for reaction for 6 hours. Then, 7.5 ml of triethylamine and 8.5 ml of water were added to the reaction product, followed by reaction for 30 minutes. At this time, the pH of the reaction solution is 9-9.5. Thereafter, 100 ml of water is dropped into the reaction product, and the layers are separated over 4 hours while stirring. The resultant is then filtered and dried to yield 20.3 g of 2'-acetoxy erythromycin A derivative.

Yield: 101.5% (by weight)

96% in mall

Melting Point: 123-135 ℃

Example 2 Preparation of 6-O-Methyl-2'-acetoxy-erythromycin Derivative (Formula 4)

20 g of the 2'-acetoxy erythromycin A derivative obtained in Example 1 was dissolved in a mixed solvent of 200 ml of butylene oxide and 60 ml of dimethyl sulfoxide, followed by stirring and cooling the temperature of the reaction solution to -15 ° C. do. Then, 2.6 g of potassium hydroxide was added to the reaction solution, 3.2 ml of methyl iodine was slowly added over 15 minutes, and then reacted for about 45 minutes. 2 ml of an aqueous 33% dimethylamine solution was added to the reaction product, followed by reaction for 30 minutes. Thereafter, 200 ml of dichloromethane is added, then stirred, and layer separation is performed on the resultant. Then, the aqueous layer was extracted once again using dichloromethane, then mixed again with the organic layer, washed with water, and the pH was adjusted to 9. Drying the resultant with 20 g of anhydrous sodium sulfate can prepare 19.6 g of 6-O-methyl-2'-acetoxy-erythromycin derivative.

Yield: 96% (based on molar)

Melting Point: 249-225 ℃

Example 3 Preparation of Clarythromycin (Formula 1) in Second Crystalline Form

19.6 g of 6-O-methyl-2'-acetoxy-erythromycin derivative prepared in Example 2 is dissolved in methanol, stirred, and heated under reflux for 6 hours. 40 ml of acetic ether was added to the resultant, stirred, and the layers separated for 2 hours. The resultant is then filtered and dried to yield 6.5 g of chlorthromycin. In order to investigate the crystalline form of this clarithromycin, X-ray diffraction spectrum of clarithromycin prepared through the above example was measured, and the results are shown in FIG. 1.

Yield: 33% by weight

Melting Point: 221-225 ℃

That is, as shown in the X-ray diffraction spectrum of Figure 1, according to the production method according to the present invention, even without undergoing a separate crystalline conversion process or separation process, in the form of the second crystalline form clarithromycin of the formula (1) Is manufactured.

Example 4 Purification of Clarythromycin

6.5 g of clarithromycin prepared in Example 3 is dissolved in 98 ml of alcohol and heated for 30 minutes under reflux. Immediately thereafter, the resultant is filtered to remove insoluble residues, and the layers are separated to precipitate crystals. Drying these crystals yields 3.8 g of purified clarithromycin.

Yield: 3.8 g

Melting Point: 223-225 ℃

As described above, according to the present invention, even without a separate crystalline conversion process or separation process, a pharmacologically useful class is provided through a simple process consisting of three steps of introducing a protecting group, selective methylation, and removing a protecting group. The second crystalline form of ritamycin can be prepared in high yield, high purity.

Therefore, according to the present invention, the second crystalline form of clarithromycin can be produced in a high yield and high purity through a significantly simpler process compared to the production method according to the prior art, and thus economical in mass production of clarithromycin. To maximize.

Claims (5)

Reacting erythromycin A of formula 2 with acetic anhydride in the presence of triethylamine to prepare a 2'-acetoxy erythromycin A derivative of formula 3; Preparing a 6-O-methyl-2'-acetoxy-erythromycin derivative of Chemical Formula 4 by methylating the 2'-acetoxy erythromycin A derivative of Chemical Formula 3; And By reacting the 6-O-methyl-2'-acetoxy-erythromycin derivative of Chemical Formula 4 under methanol to prepare clarithromycin of Chemical Formula 1 in the form of a second crystalline form. The preparation method for the second crystalline form of clarithromycin represented by the following Scheme 4. Scheme 4 The method of claim 1, wherein the methylation of the 2'-acetoxy erythromycin A derivative of Formula 3 is carried out by reacting the 2'-acetoxy erythromycin A derivative of Formula 3 with methyliodine in the presence of potassium hydroxide. A process for producing the second crystalline form of clarithromycin, characterized in that 3. The process according to claim 2, wherein the methylation reaction proceeds under a mixed solvent of butylene oxide and dimethyl sulfoxide. The method of claim 1, wherein the preparing of the 2'-acetoxy erythromycin A derivative of Chemical Formula 3 is carried out using acetone as a solvent for the second crystalline form of clarithromycin. A second crystalline form of clarithromycin prepared according to the process according to any one of claims 1 to 4.