KR20200099012A - Methods for preparing clopidogrel bisulphate and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a method for manufacturing a clopidogrel sulphate and a pharmaceutical composition including a clopidogrel sulphate manufactured by using the same, and more specifically, to a method for manufacturing a clopidogrel sulphate capable of obtaining clopidogrel sulphate type I crystals with a high yield and purity. The present invention provides the method for manufacturing a clopidogrel sulphate of a new process different from a conventional art. The present invention includes high particle uniformity and formulation stability by increasing the yield compared to a conventional clopidogrel sulphate manufactured by the manufacturing method of the present invention and increasing the purity by reducing contents of impurities such as a residual solvent or the like.

Description

Manufacturing method of clopidogrel sulfate and pharmaceutical preparation containing the same {METHODS FOR PREPARING CLOPIDOGREL BISULPHATE AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME}

The present invention relates to a method for preparing clopidogrel sulfate and a pharmaceutical preparation containing clopidogrel sulfate obtained by using the same, and specifically, clopidogrel sulfate type I crystals having excellent yield and purity can be obtained by applying a novel process different from the prior art. It relates to a method for preparing clopidogrel sulfate and a pharmaceutical preparation comprising the same.

Clopidogrel is an effective platelet aggregation inhibitor for the treatment of peripheral or coronary artery diseases such as stroke, thrombosis, embolism, and myocardial infarction.The chemical name is methyl (+)-(S)-α-(2-chlorophenyl)-6,7 -Dihydrothieno[3,2-c]pyridin-5(4H)-acetate.

Clopidogrel directly inhibits ADP binding to the adenosinediphosphate (ADP) receptor, which is known to play an important role in thrombus formation, followed by direct inhibition of ADP-mediated activation of the glycoprotein GPIIb/IIa complex. Thereby specifically inhibits ADP-induced platelet aggregation. In addition, clopidogrel inhibits platelet aggregation induced by agonists other than ADP by blocking amplification of platelet activation by released ADP.

The pharmacological action of clopidogrel is achieved by active metabolites formed by metabolism in the liver after clopidogrel is administered orally. This active metabolite selectively and irreversibly modifies the ADP receptor on platelets, thereby preventing ADP from binding to the ADP receptor. Therefore, the effect of clopidogrel is highly dependent on the enzyme that metabolizes clopidogrel in the liver.

The chemical name of clopidogrel sulfate (or clopidogrel bisulfate), a representative pharmaceutical ingredient of clopidogrel, is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c ]Pyridine-5(4H)-acetate sulfate (1:1), molecular weight is 419.9, and the empirical formula is C ₁₆ H ₁₆ ClNO ₂ S· ₂ SO ₄ .

Clopidogrel sulfate is a white to gray powder, insoluble in water with a neutral pH, but very high solubility at pH 1.0. It is also freely soluble in methanol, slightly soluble in methylene chloride, and hardly soluble in ethyl ether.

Clopidogrel sulfate reduces thrombotic events such as acute myocardial infarction (MI), acute stroke, or established arterial disease. It is prescribed for and has been shown to reduce the rate of new ischemic strokes, new MI, and other combined end points of vascular death. In patients with acute coronary syndrome, clopidogrel sulfate has been shown to reduce the rate of complex endpoints of cardiovascular death, MI, stroke, or refractory ischemia.

Meanwhile, the clopidogrel sulfate may be prepared in crystalline form I and crystalline form II depending on the crystalline form.

Crystalline Form I is basically in the form of a powder and has a high solubility when the particles are fine. However, there is a problem that formulation is difficult because the effect of physical interactions between particles such as static electricity acts greatly.

Crystalline Form II is an orthorhombic form, which is denser and higher in stability than Crystalline Form I, and is advantageous in terms of formulation. On the other hand, there is a disadvantage that the solubility is relatively inferior to that of crystalline form I.

In addition, in the case of crystalline form I, it can be easily transformed into a thermodynamically stable crystalline form II. Therefore, even if it is manufactured in crystalline form I, there is a problem that it becomes crystalline form II or mixed crystalline forms I and II.

Regarding the manufacturing method of clopidogrel sulfate type I crystal, International Publication No. WO 2004-048385 (Patent Document 1) discloses that in order to obtain high purity clopidogrel sulfate type I crystal, clopidogrel sulfate crystal was dissolved in a solvent and then tertiary- A method of stirring by adding butyl methyl ether dropwise is described.

On the other hand, Korean Patent Application Publication No. 10-2016-0142578 (Patent Document 2) specifically provides a method for preparing spherical particles of clopidogrel sulfate crystalline form I type having a dense, low-static property, and uniform particle size. .

The formulation and stability problems of clopidogrel sulfate crystalline form I have been mostly solved by suggesting a method of improving the process technology for uniformly manufacturing the particle shape in a spherical shape and increasing stability from the prior literature and the prior art.

However, the spherical particles of the crystalline form I of clopidogrel sulfate according to the conventional manufacturing method have poor compressibility and flow properties, and when mixing, there is a problem that it is difficult to formulate because static electricity is strongly generated on the surface of the particles.

In addition, since there is a problem in that substances causing toxicity in the body such as organic solvents remain even after crystals are prepared, there is still a need for improvement of a manufacturing method for obtaining a high yield while further increasing the purity by removing impurities.

International Publication No. WO 2004-048385 Korean Patent Publication No. 10-2016-0142578

In the production of clopidogrel sulfate, the present invention provides a method of obtaining high-purity clopidogrel sulfate type I crystals in which the yield is high and the content of impurities such as residual solvent is further reduced through a novel process different from the conventional method.

In addition, the present invention provides a method for preparing clopidogrel sulfate more suitable for use in pharmaceutical use, and a pharmaceutical formulation using the same, by improving the difficult-to-form properties of the clopidogrel sulfate crystal prepared by the conventional method.

In order to achieve the above object, the method for producing clopidogrel sulfate of the present invention may include the following steps s1 to s4.

Dissolving crude clopidogrel sulfate in a solvent to prepare a clopidogrel sulfate solution (s1);

Preparing tertiary-butyl methyl ether (s2);

Adding the clopidogrel sulfate solution prepared in step s1 dropwise to the tertiary-butyl methyl ether and then stirring to generate clopidogrel sulfate crystals (s3);

The clopidogrel sulfate crystal is filtered, washed with tertiary-butyl ether, dried, and recrystallized (s4).

At this time, the crude clopidogrel sulfate of step s1,

Preparing clopidogrel camposulfonic acid salt from (+)-(2-chlorophenyl)[2-(2-cynyl)aminoethyl]methylester hydrochloride; And

After dissolving the clopidogrel camposulfonic acid salt in a solvent, adding a weak base, stirring, and adding sulfuric acid; can be prepared by a method comprising.

In addition, the weak base may be used by selecting one or two or more selected from the group consisting of sodium hydrogen carbonate, sodium carbonate, potassium carbonate, ammonium hydroxide, and magnesium hydroxide. By adding the weak base, the total pH can be adjusted to be weakly basic, and according to an embodiment of the present invention, when the pH is adjusted with sodium hydrogen carbonate, desirable results can be obtained.

The solvent in step s1 may be used by selecting an appropriate one of organic solvents. Specifically, one or two or more types may be selected from the group consisting of ethanol, isopropyl alcohol, methanol, and butanol. Among these, ethanol and/or isopropyl alcohol may be preferably used, and more preferably, ethanol may be used.

The volume ratio of the solvent used in step s1 and the tertiary-butylmethyl ether in step s2 may be preferably 1: 3 to 1: 8, more preferably 1: 4 to 1: 6. The present invention is prepared by adding a small amount of clopidogrel sulfate solution dropwise to a relatively large amount of tertiary-butylmethyl ether, unlike the prior art.If the volume is out of the above range, the yield and/or purity of the prepared clopidogrel sulfate may decrease. have.

The clopidogrel sulfate solution of step s3 is preferably added dropwise at a rate of 10 to 30% by volume/hour, more preferably at a rate of 15 to 20% by volume/hour. If it is added dropwise faster than the above-described speed, the purity may decrease, and if it is out of the above-described speed range, the process speed may be delayed, resulting in a decrease in manufacturing efficiency or particle uniformity and purity.

On the other hand, the step s3 is preferably carried out in a temperature condition of 20 to 40 ℃, if less than 20 ℃ the process speed may be lowered, if it exceeds 40 ℃ the yield may be lowered.

When all of the clopidogrel sulfate solution is added in step s3, stirring is performed while controlling the speed so as not to deviate from the temperature range for 5 to 15 hours. If the stirring time is less than 5 hours, crystallization is not sufficiently performed, and the washing condition after recrystallization is poor, resulting in a decrease in purity. In addition, even if it is stirred for more than 15 hours, the yield or purity does not increase any more, so the process efficiency decreases.

The drying in step s4 is preferably carried out in a vacuum of 50 to 70°C. By performing in a vacuum state, it is possible to maintain high purity by blocking the inflow of external contaminants. In addition, drying at less than 50° C. lowers the drying rate, and drying at a temperature exceeding 70° C. may deteriorate components, which is not preferable.

After drying, the recrystallized clopidogrel sulfate can be obtained, in which case the yield is 92% or more, more preferably 95% or more, based on the amount of crude clopidogrel sulfate added.

In addition, the purity of the clopidogrel sulfate may be 99.3% or more, more preferably 99.5% or more, and most preferably 99.9% or more.

Meanwhile, the clopidogrel sulfate is characterized in that the particle size corresponding to 10% to 90% in the particle size normal distribution curve is uniform in a particle size distribution of 60 to 110 μm.

High purity clopidogrel sulfate can be prepared in a high yield by the above production method, and the obtained clopidogrel sulfate crystal is a spherical type I crystal and has excellent stability.

The present invention provides a method for producing clopidogrel sulfate in a novel process different from the prior art, and the method for producing clopidogrel sulfate of the present invention has a higher yield of clopidogrel sulfate crystals compared to the conventional method, while further reducing the content of impurities such as residual solvents. It is characterized by high purity.

In addition, clopidogrel sulfate crystals prepared by the method of the present invention are spherical I-type crystals, have high particle size uniformity, and have little difficulty in tabletting due to weight deviation, sticking, etc. when preparing tablets by the direct hitting method. In addition, since crystal form conversion to Form II hardly occurs, it is characterized by excellent stability even during long-term storage.

1 is an X-ray diffraction analysis graph of clopidogrel sulfate type I prepared in Example 1. FIG.
2 is a micrograph of clopidogrel sulfate particles prepared in Example 1.
3 is a graph showing the particle size distribution of clopidogrel sulfate prepared in Example 1.
4 is a micrograph of clopidogrel sulfate particles prepared in Comparative Example 1.
5 is a particle size distribution graph of clopidogrel sulfate prepared in Comparative Example 1.

Terms used in the present specification and claims are not limited to their usual or dictionary meanings and should not be interpreted, and that the inventor can appropriately define the concept of terms in order to describe his own invention in the best way. Based on the principle, it should be interpreted as a meaning and concept consistent with the technical idea of the invention. Therefore, the configuration described in the present specification and each embodiment is only one of the most preferred embodiments of the present invention and does not represent all the technical spirit of the present invention, and various equivalents and equivalents that can replace them at the time of the present application It should be understood that there may be variations.

The term ``crude clopidogrel sulfate'' used throughout the present specification is a clopidogrel sulfate substance in a state before being physically processed or purified after being first synthesized through chemical bonding, and refers to clopidogrel sulfate having physical properties that are not suitable for use for pharmaceutical purposes. do.

The terms "about" and "substantially" used throughout this specification are used as meanings at or close to the numerical values when manufacturing and material tolerances specific to the stated meanings are presented, and are accurate to aid understanding of the present application. Or absolute figures are used to prevent unfair use of the stated disclosure by unconscionable infringers.

In the entire specification of the present application, the term "combination(s) thereof" included in the expression of the Makushi form means one or more mixtures or combinations selected from the group consisting of the constituent elements described in the expression of the Makushi form, It means to include at least one selected from the group consisting of the above components.

In the entire specification of the present application, the description of "A and/or B" means "A or B or both".

Hereinafter, the present invention will be described in more detail.

Clopidogrel sulfate crystals according to the present invention can be prepared by crystallization and recrystallization using crude clopidogrel sulfate as a starting material.

The crude clopidogrel sulfate is a crude clopidogrel sulfate that has not been further purified or physically modified after the initial synthesis, and may be prepared by the following method.

Crude Clopidogrel Sulfate was prepared from (+)-(2-chlorophenyl)[2-(2-cynyl)aminoethyl]methyl ester hydrochloride, followed by stirring by adding a weak base, followed by further It can be obtained by adding sulfuric acid.

Specifically, first, clopidogrel camposulfonic acid salt is prepared from (+)-(2-chlorophenyl)[2-(2-cynyl)aminoethyl]methyl ester hydrochloride. As a preparation example, clopidogrel camposulfonic acid salt may be prepared as follows. (+)-(2-chlorophenyl)[2-(2-cynyl)aminoethyl]methyl ester hydrochloride, 35% formalin and methanol were added to a reactor and stirred to react. Purified water, dichloromethane, and sodium carbonate are added and stirred, and when layer separation is performed, the organic layer is separated. When dichloromethane is added again as a solvent and stirred to separate the layers again, the organic layer is separated, sodium sulfate is added, and then dehydration is performed by stirring. Then, after concentration, ethyl acetate and camposulfonic acid are added to crystallize. Finally, by filtration and washing, clopidogrel camposulfonic acid salt can be obtained.

Next, clopidogrel camposulfonate is dissolved in a solvent and then a weak base is added to prepare crude clopidogrel sulfate.

As a manufacturing example, the crude clopidogrel sulfate may be prepared as follows. Clopidogrel sulfonate, ethyl acetate, and sodium hydrogen carbonate as a weak base were added to a reactor and stirred to separate layers. After removing the aqueous layer, purified water, sodium sulfate and activated carbon were added and stirred to separate the layers again. After filtration and concentration, crystallization by adding acetone and sulfuric acid, filtration and drying, crude clopidogrel sulfate can be obtained.

At this time, the weak base may be used by selecting one or two or more selected from the group consisting of sodium hydrogen carbonate, sodium carbonate, potassium carbonate, ammonium hydroxide, and magnesium hydroxide. It is preferable to adjust the total pH to about 8.0 weakly by adding the weak base. As a result of the experiment by the applicant, when sodium hydrogen carbonate was added and used together with purified water, desirable results were obtained.

The preparation method of crude clopidogrel sulfate described above is illustrative of a preferred preparation method according to the present invention to aid the understanding of those skilled in the art, and crude clopidogrel sulfate may be synthesized by other methods other than the above method. Therefore, the entire gist of the present invention should not be interpreted by limiting it to the method for producing crude clopidogrel sulfate.

After obtaining crude clopidogrel sulfate, it was dissolved in a solvent to prepare a clopidogrel sulfate solution, and crystals were produced using tertary-butylmethyl ether. In the prior art including Patent Document 1 described above, in order to increase the yield and purity of the I-form crystal of clopidogrel sulfate, clopidogrel sulfate was first dissolved in a solvent, and then tertiary-butylmethyl ether was added dropwise, while the loss of clopidogrel sulfate was reduced. Minimization is used to increase the yield and minimize the content of impurities. This is a common method carried out to increase the yield and purity. However, as a result of the experiment conducted by the present applicant, there was a limit to increasing the purity with the above method. Although the method according to the prior art could be increased to about 99.12%, higher purity was not obtained even when the process conditions such as temperature, stirring speed and time, type of solvent, input amount, and input speed were changed. After repeated experiments, the applicant of the present invention found that, contrary to the conventional method, a large amount of tertiary-butyl methyl ether was slowly stirred while adding a large amount of clopidogrel sulfate, surprisingly, the purity increased to 99.5% or more, more preferably to 99.9%. I found it. Therefore, the clopidogrel sulfate according to the present invention is carried out by dropwise addition of a clopidogrel sulfate solution to tertiary-butylmethyl ether, contrary to the conventional known method.

To this end, clopidogrel sulfate solution is prepared by first adding clopidogrel sulfate and an appropriate organic solvent to the reactor. At this time, the solvent may be used by selecting an appropriate one of organic solvents, specifically one or two or more selected from the group consisting of ethanol, isopropyl alcohol, methanol, and butanol. Among these, ethanol and/or isopropyl alcohol may be preferably used, and more preferably, ethanol may be used. As a result of an experiment conducted by the present applicant, the purity could be increased to 99.5% when isopropyl alcohol was used as a solvent, and the purity was most preferably 99.9% when ethanol was used as a solvent.

Meanwhile, tertiary-butylmethyl ether is added to another reactor to prepare the prepared clopidogrel sulfate solution. Then, the clopidogrel sulfate solution is slowly added dropwise to the reactor into which tertiary-butylmethyl ether is added.

Accordingly, the volume ratio of the solvent in which clopidogrel sulfate is dissolved and tertiary-butylmethyl ether may be preferably 1: 3 to 1: 8, more preferably 1: 4 to 1: 6. That is, the present invention is prepared by dropwise addition of a crude clopidogrel sulfate solution dissolved in a small amount of a solvent to a relatively large amount of tertiary-butyl methyl ether, unlike the prior art, but if it is out of the volume range, the yield of the prepared clopidogrel sulfate And/or the purity may be lowered.

Clopidogrel sulfate solution is added dropwise to the tertiary-butyl methyl ether and stirred to primarily produce clopidogrel sulfate crystals.At this time, the introduction rate of the clopidogrel sulfate solution is preferably 10 to 30% by volume/hour, more preferably It is recommended to set the rate at 15 to 20% by volume/hour. If it is added dropwise faster than the above-described rate, the purity may decrease, and if it is added dropwise at a rate less than the above-described rate, the process speed may be delayed and manufacturing efficiency may decrease.

In addition, the first crystallization process is preferably carried out under a temperature condition of 20 to 40 ℃, if less than 20 ℃ the process speed may be lowered, if it exceeds 40 ℃ the yield may be lowered. When all of the clopidogrel sulfate solution is added, the mixture is stirred while controlling the speed so as not to deviate from the temperature range for 5 to 15 hours. If the stirring time is less than 5 hours, crystallization is not sufficiently performed, and the washing condition after recrystallization is poor, resulting in a decrease in purity. In addition, even if it is stirred for more than 15 hours, the yield or purity does not increase any more, so the process efficiency decreases.

Thereafter, the primary crystal of clopidogrel sulfate is filtered, washed with tertiary-butyl methyl ether, dried and recrystallized to obtain clopidogrel sulfate according to the present invention.

After washing with tert-butyl methyl ether, drying is preferably performed in a vacuum of 50 to 70°C. By performing in a vacuum state, it is possible to maintain high purity by blocking the inflow of external contaminants. In addition, drying at less than 50° C. lowers the drying rate, and drying at a temperature exceeding 70° C. may deteriorate components, which is not preferable.

After drying, clopidogrel sulfate crystals according to the present invention can be obtained. At this time, the yield of crude clopidogrel sulfate is 92% or more, more preferably 95% or more, which can be obtained in high yield.

In addition, the purity of the clopidogrel sulfate is 99.3% or more, more preferably 99.5% or more, and most preferably 99.9% or more according to an embodiment of the present invention.

The clopidogrel sulfate is characterized in that the particle size is uniform in that the particle size corresponding to 10% to 90% of the particle size normal distribution curve shows a particle size distribution of 60 to 110㎛.

High purity clopidogrel sulfate can be prepared in a high yield by the above production method, and the obtained clopidogrel sulfate crystal is a spherical type I crystal and has excellent stability.

Hereinafter, a manufacturing method according to an embodiment of the present invention will be sequentially summarized and described. In addition, different processes and results from the prior art will be described in more detail through Examples and Comparative Examples.

<Method for producing Crude Clopidogrel Sulfate>

Step 1: Synthesis of Clopidogrel Camposulfonate

(+)-(2-chlorophenyl)[2-(2-cynyl)aminoethyl]methyl ester hydrochloride, 35% formalin, and methanol were added to the reactor, followed by stirring at room temperature for about 30 minutes. After circulating hot water, heating it to 35 to 50°C and reacting for 20 hours or more, it is confirmed through TLC whether the reaction is complete (TLC condition ethyl acetate: hexane = 1: 8). When the reaction was completed, after cooling to room temperature, 294.5 g of purified water and 390.4 g of dichloromethane were added, followed by stirring for 30 minutes. After stirring, a saturated sodium hydrogen carbonate solution prepared by mixing purified water and sodium hydrogen carbonate was slowly added to adjust the pH to 8, stirred for 30 minutes, and the organic layer was separated.

Dichloromethane is added as a solvent to the aqueous layer, stirred for about 30 minutes, and the aqueous layer is removed and then combined with the previous organic layer. Anhydrous sodium sulfate was added, dehydrated for about 30 minutes, filtered through a Nuche filter, and the residue was concentrated under reduced pressure. Ethyl acetate was added to the concentrated oil, stirred and cooled to room temperature, and camphorsulfonic acid was slowly added over about 2 hours. After crystallization is complete, the mixture is stirred for 2 to 5 hours.

The resulting crystals were filtered and washed with ethyl acetate. After washing, drying at 40° C. for 3 hours or more to obtain clopidogrel camposulfonic acid salt.

Step 2: Synthesis of Crude Clopidogrel Sulfate

After dissolving clopidogrel camposulfonic acid salt and ethyl acetate as a solvent, a saturated sodium hydrogen carbonate solution prepared by mixing purified water and sodium hydrogen carbonate was added to the reactor, adjusted to pH 8, stirred for 1 hour, and the layers were separated. The aqueous layer is separated and removed, purified water is added to the organic layer, stirred, and allowed to stand. The layer is separated again to remove the aqueous layer. Sodium sulfate and activated carbon were added to the organic layer, stirred for 30 minutes to 3 hours, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Acetone is added to the concentrated solution to dissolve, and then stirred at room temperature for about 30 minutes to prepare a reaction solution.

Sulfuric acid was added dropwise to the reaction solution at room temperature over 2 to 8 hours, followed by stirring for 8 hours or more. Then, it was filtered under reduced pressure and washed with acetone. Take out the crystals, put them in a fluid bed dryer, and dry them at 25 to 40°C for 6 hours or longer to obtain crude clopidogrel sulfate.

Step 3: Synthesis of Clopidogrel Sulfate

Crude clopidogrel sulfate and organic solvent are added to the reactor and heated to completely dissolve to prepare a crude clopidogrel sulfate solution. Tertiary-butyl methyl ether was added to another reactor, transferred to the crystallization tank through the housing filter, and then the crude clopidogrel sulfate solution was slowly added dropwise to the solvent prepared in the crystallization tank for 5 to 20 hours, followed by stirring for 4 to 9 hours. The crystals are filtered and washed with tert-butyl methyl ether. Take out the crystals, put them in a fluid bed dryer, and dry them at 50 to 80°C for 7 hours or longer to obtain clopidogrel sulfate.

Hereinafter, a manufacturing method for obtaining clopidogrel sulfate according to the present invention of high yield and high purity from crude clopidogrel sulfate described in step 3 will be described in detail with reference to Examples and Comparative Examples. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited by the following examples. The embodiments of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.

Example 1

In the reactor (A), 10.5 g of crude clopidogrel sulfate prepared according to step 2 was completely dissolved while heating in 26 mL of ethanol to prepare a clopidogrel sulfate solution.

150 mL of tert-butyl methyl ether was added to another reactor (B), and the temperature was adjusted to 25 to 30°C.

The crude clopidogrel sulfate solution prepared in the reactor (A) was added dropwise to the reactor (B) into which tert-butylmethyl ether was added at a rate of 15 to 20% by volume/hour, followed by stirring. Stirring was performed for 6 hours while controlling the stirring speed so that the temperature was maintained at 25 to 30° C. to produce primary crystals of clopidogrel sulfate.

After filtering the primary crystals of clopidogrel sulfate, the crystals were washed with 10 mL of tert-butyl methyl ether. The washed crystals were dried in a vacuum at a temperature of 60° C. to obtain 10 g of clopidogrel sulfate (CLO-CF I) of type I with uniform distribution of spherical particles.

Example 2

10.5 g of crude clopidogrel sulfate, which was the same as in Example 1, was completely dissolved while heating in 35 mL of isopropyl alcohol to prepare a clopidogrel sulfate solution.

150 mL of tert-butyl methyl ether was added to another reactor (B), and the temperature was adjusted to 25 to 30°C.

The crude clopidogrel sulfate solution prepared in the reactor (A) was stirred while being added dropwise to the reactor (B) in which tert-butylmethyl ether was added at a rate of 15 to 20% by volume/hour. Stirring was performed for 6 hours while controlling the stirring speed so that the temperature was maintained at 25 to 30° C. to produce primary crystals of clopidogrel sulfate.

After filtering the primary crystals of clopidogrel sulfate, the crystals were washed with 10 mL of tert-butyl methyl ether. The washed crystals were dried in a vacuum at a temperature of 60° C. to obtain 9.8 g of clopidogrel sulfate (CLO-CF II) of type I with uniform spherical particles.

Comparative Example 1

(S)-(+)-α-(2-chlorophenyl)-4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine-5-acetate 3.25g was dissolved in 20 mL of ethanol and then cooled to 0°C. . 1.0 g of 96% sulfuric acid was added while maintaining the temperature at 0 to 5°C.

After the reaction solution was stirred for 30 minutes, 30 mL of tertiary-butyl methyl ether was slowly added dropwise to the reaction solution. After stirring at 0 to 10°C for 10 hours, the crystals were filtered, and the crystals were washed with 15 mL of tert-butyl methyl ether.

The wet body was vacuum-dried at 20 to 40°C to obtain 3.8 g of crystals having a melting point of 182°C.

Comparative Example 2

321.8 g (1.0 mol) of clopidogrel base was dissolved in 2.0 L of cyclohexane and 2.0 L of isopropanol, and 107.9 (1.1 mol) of sulfuric acid was added at 10 to 15°C, followed by stirring for 1 to 3 hours.

The reaction mixture was heated to 10 to 22° C. and stirred for 5 hours, and the resulting crystals were filtered and washed to obtain 389.9 g of Form I of crystalline clopidogrel.

Results and Discussion

The yield, purity, and crystal form of clopidogrel sulfate prepared according to each of the Examples and Comparative Examples are shown in Table 1 below.

division yield(%) water(%) Crystal form Example 1
(CLO-CF I) 95.2 99.9 I type Example 2
(CLO-CF II) 93.3 99.5 I type Comparative Example 1 - 99.12 Type I + Type II Comparative Example 2 - 95 I type

As shown in Table 1, the crystal of Clopidogrel Sulfate Form I according to the method of the present invention has a high yield as well as a very high purity, so there is little side effect or toxicity in the body due to residual impurities.

In addition, the particle size distribution of the particles of Example 1 and Comparative Example 1 was measured by a dry particle size analysis method using Malvern MASTERSIZE 3000 equipment, and the results are shown in Table 2 below and FIGS. 3 and 5.

The particle size distribution can be said to be better as the values of D ₁₀ /D ₅₀ and D ₅₀ /D ₉₀ used as indicators are larger. Here, D ₁₀ , D ₅₀ , D ₉₀ refer to the particle diameters of particles corresponding to the order of 10%, 50%, and 90% of the total number of particles, respectively, when the measured particles are ordered from small to large. do.

division Particle size distribution (㎛) D ₁₀ / D ₅₀ D ₅₀ / D ₉₀ Example 1 Dv(10): 64.6
Dv(50): 83.5
Dv(90): 108 0.774 0.773 Comparative Example 1 Dv(10): 3.56
Dv(50): 31.5
Dv(90): 444 0.113 0.071

The particles of Example 1 are spherical homogeneous and stable crystals as shown in FIG. 2, which have excellent dispersibility and flow properties, and are suitable for use in formulation purposes, and have a narrow particle size distribution as shown in FIG.

On the other hand, in the case of Comparative Example 1 prepared by the method of the prior art (Patent Document 1) in which tertiary-butyl methyl ether was added dropwise to the clopidogrel sulfate solution, the purity was lower than that of the method according to the present invention, and shown in FIG. As can be seen, the crystals are not homogeneous, and as shown in FIG. 5, the particle size distribution is wide, indicating that the crystal size is irregular.

In addition, in the case of Comparative Example 2 prepared by the method described in Patent Document 2, the purity was significantly lower than that of the present invention.

Claims (14)

Dissolving crude clopidogrel sulfate in a solvent to prepare a clopidogrel sulfate solution (s1);
Preparing tertiary-butyl methyl ether (s2);
Adding the clopidogrel sulfate solution prepared in step s1 dropwise to the tertiary-butyl methyl ether, and then stirring to generate clopidogrel sulfate crystals (s3);
Filtering the crystals of clopidogrel sulfate, washing with tertiary-butyl ether, drying and recrystallization (s4); method for producing clopidogrel sulfate comprising a.
The method of claim 1,
Crude clopidogrel sulfate of the step s1,
Preparing clopidogrel camposulfonic acid salt from (+)-(2-chlorophenyl)[2-(2-cynyl)aminoethyl]methyl ester hydrochloride; And
Dissolving the clopidogrel camphorsulfonate in a solvent, adding a weak base, stirring, and adding sulfuric acid; the method for producing clopidogrel sulfate.
The method of claim 2,
The weak base is one or two or more selected from the group consisting of sodium hydrogen carbonate, sodium carbonate, potassium carbonate, ammonium hydroxide, and magnesium hydroxide.
The method of claim 1,
The solvent of step s1 is one or more organic solvents selected from the group consisting of ethanol, isopropyl alcohol, methanol, and butanol.
The method of claim 1,
The volume ratio of the solvent in step s1 and the tertiary-butylmethyl ether in step s2 is 1: 3 to 1: 8, wherein the method for producing clopidogrel sulfate.
The method of claim 1,
The method for producing clopidogrel sulfate, wherein the clopidogrel sulfate solution of step s3 is added dropwise at a rate of 10 to 30% by volume/hour.
The method of claim 1,
The s3 step is a method of producing clopidogrel sulfate that is performed under a temperature condition of 20 to 40°C.
The method of claim 1,
The stirring time in the step s3 is 5 to 15 hours, the method for producing clopidogrel sulfate.
The method of claim 1,
The drying in step s4 is a method of producing clopidogrel sulfate that is performed in a vacuum state of 50 to 70°C.
The method of claim 1,
Clopidogrel sulfate recrystallized in the step s4 is a method for producing clopidogrel sulfate having a particle diameter corresponding to 10% to 90% in a particle size normal distribution curve of 60 to 110 μm.
The method of claim 1,
The production method of clopidogrel sulfate that the yield of clopidogrel sulfate recrystallized in step s4 is 92% or more.
The method of claim 1,
The purity of clopidogrel sulfate recrystallized in step s4 is 99.3% or more.
Clopidogrel sulfate pharmaceutical preparation comprising clopidogrel sulfate prepared by the method of claim 1.
The method of claim 13,
The clopidogrel sulfate is a pharmaceutical preparation of clopidogrel sulfate that is in the form I crystal form.

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