KR20110080931A - Method for manufacturing crystalline form (i) of clopidogrel hydrogen sulphate - Google Patents

Method for manufacturing crystalline form (i) of clopidogrel hydrogen sulphate Download PDF

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KR20110080931A
KR20110080931A KR1020100001379A KR20100001379A KR20110080931A KR 20110080931 A KR20110080931 A KR 20110080931A KR 1020100001379 A KR1020100001379 A KR 1020100001379A KR 20100001379 A KR20100001379 A KR 20100001379A KR 20110080931 A KR20110080931 A KR 20110080931A
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clopidogrel
crystalline form
hydrogen sulfate
clopidogrel hydrogen
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오윤석
신동혁
정진용
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동화약품주식회사
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    • C07ORGANIC CHEMISTRY
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Abstract

PURPOSE: A method for preparing a crystalline form of clopidogrel hydrogen sulphate(I) is provided to prepare a crystal with excellent fluidity and to minimize cracking. CONSTITUTION: A method for preparing a crystalline form of clopidogrel hydrogen sulphate comprises: a step of reacting clopidogrel free base with dark sulfuric acid under the presence of mixture solvent of 2-butanol and water. The use of waer is 5-14 weight% based on a weight of clopidogrel free base. The method additionally comprises a step of seeding the crystalline form(I) of clopidogrel hydrogen sulphate.

Description

클로피도그렐 황산수소염 결정형(I)의 제조방법{Method for manufacturing crystalline form (I) of Clopidogrel hydrogen sulphate}Method for manufacturing crystalline form (I) of Clopidogrel hydrogen sulphate}

본 발명은 클로피도그렐 황산수소염의 결정형 (I) 제조방법에 관한 것이다.The present invention relates to a process for preparing crystalline Form (I) of clopidogrel hydrogen sulfate.

하기 [화학식 1]의 (+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트(이하, ‘클로피도그렐’이라합니다) 황산수소염은 혈소판 응집 저해효과 및 항혈전 효과가 있는 약물로서 뇌졸중, 혈전, 색전 등의 말초동맥질환 및 심근경색, 협심증 등의 관상동맥 질환 치료에 사용되는 유용한 약물로 PLAVIX®정제로 시판되고 있다. (+)-(S) -α- (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate of Formula 1 Hydrogen sulfate is a drug that has a platelet aggregation inhibitory effect and an antithrombotic effect. Commercially available as PLAVIX ® tablets.

[화학식 1][Formula 1]

Figure pat00001
Figure pat00001

미국특허 제 4529596호에는 화학식 1의 라세미 화합물이 기재되어 있으며 유럽특허 제 0281459호는 테트라히드로 티에노 피리딘 유도체의 광학활성체를 분리하는 기술이 기재되어 있으며, 상기 화학식 1의 클로피도그렐 황산수소염이 개시되어 있다. 이 유럽특허에는 라세미 클로피도그렐을 (R)-(-)-10-캄파 술폰산을 이용하여 염을 형성한 다음, 목적 비선광도 값을 갖는 생성물을 얻기 위해 아세톤에서 환류 교반시키고 재결정하여, 우선성의 이성질체를 형성한 후 아세톤 용매 하에서 농축황산을 이용하여 상기 화학식 1을 침전시켜 수득하는 것을 기술하고 있다. US Patent No. 4529596 describes a racemic compound of Formula 1 and European Patent No. 0281459 describes a technique for separating the optically active agent of a tetrahydro thienopyridine derivative, and the clopidogrel hydrogen sulfate of Formula 1 is disclosed. It is. This European patent discloses racemic clopidogrel with (R)-(-)-10-campa sulfonic acid to form a salt, followed by reflux stirring and recrystallization in acetone to obtain a product having the desired non-photoluminescence value, thereby giving preference to the preferred isomers. It is described that after the formation of precipitate by the formula (1) using concentrated sulfuric acid in acetone solvent.

또한, 유럽특허 제 1087976호에서는 상기 화학식 1의 결정형 (I)과 (II)에 관한 기술을 하고 있다. 유럽특허 제 0281459호의 합성 방법에 의한 제조는 클로피도그렐 황산수소염 결정형 (I)만 합성 가능하다고 명기하고 있으며 결정형 (II)는 높은 열역학적 안정성을 가지며, 결정형 (I)의 결정은 불규칙한 평판이고 결정형 (II)의 결정은 덩어리 형태이며 결정형 (I) 보다 결정형 (II)가 낮은 정전기를 갖는다고 기술하고 있다.In addition, European Patent No. 1087976 describes the crystalline forms (I) and (II) of the general formula (1). Preparation by the synthesis method of EP 0281459 specifies that only Clopidogrel Hydrogen Sulfate Crystalline Form (I) can be synthesized, Form (II) has high thermodynamic stability, and Crystal of Form (I) is irregular plate and Form (II) It is described that the crystals are in the form of agglomerates and have lower static electricity than crystalline form (I).

국제 특허출원 WO03051362호은 클로피도그렐 황산수소염의 신규 결정형 (III), (IV), (V) 및 (VI) 및 비결정형의 제조방법을 기술하고 있으며, 특히 결정형 (I)을 메틸 t-부틸 메틸에테르 또는 디에틸에테르 하에서 제조하는 방법을 개시하고 있다. International patent application WO03051362 describes a process for the preparation of novel crystalline forms (III), (IV), (V) and (VI) and amorphous forms of clopidogrel hydrogen sulfate, in particular crystalline form (I) is methyl t-butyl methyl ether or A process for preparing under diethyl ether is disclosed.

국제 특허출원 WO2004020443호는 일차, 이차 또는 삼차 C1 내지 C5 알코올들의 시리즈 또는 C1내지 C4 카르복실산들에 의한 이들의 에스테르 또는 임의 혼합물들로부터 선택된 용매하에 유리염기 또는 염의 형태의 클로피도그렐과 황산을 반응 시켜 결정형 (I) 제조를 위한 방법을 개시한다. 특히 침전은 저온인 -5 내지 15℃의 온도에서 2-프로판올 용액에서 수행하는 것을 개시한다.International patent application WO2004020443 discloses a crystalline form by reacting clopidogrel and sulfuric acid in the form of a free base or salt in a solvent selected from a series of primary, secondary or tertiary C1 to C5 alcohols or their esters or any mixtures thereof with C1 to C4 carboxylic acids. (I) A method for preparation is disclosed. In particular, precipitation is carried out in a 2-propanol solution at a temperature of −5 to 15 ° C. at low temperature.

국제 특허출원 WO2005063708호는 C6-C12 알코올, 예를 들면, 헥산올, 2-헥산올, 3-헥산올, 이소헥산올, 헵탄올, 2-헵탄올, 3-헵탄올, 4-헵탄올, 옥탄올, 이소옥탄올, 데칸올 또는 이의 혼합물) 및 물의 혼합물 중에서 진한 황산으로 처리하여 결정형 (I)형의 결정을 분리하는 것을 기재하고 있다. International patent application WO2005063708 discloses C6-C12 alcohols such as hexanol, 2-hexanol, 3-hexanol, isohexanol, heptanol, 2-heptanol, 3-heptanol, 4-heptanol, The separation of crystals of crystalline Form (I) by treatment with concentrated sulfuric acid in a mixture of octanol, isooctanol, decanol or mixtures thereof) and water.

국제 특허출원 WO2006087729호는 (S)-클로피도그렐과 C1 내지 C5의 카르복실산등의 용매상에서 황산을 가하여 결정형 (I)형을 형성하는 방법을 기재하고 있다.International patent application WO2006087729 describes a method for forming crystalline Form (I) by adding sulfuric acid in a solvent such as (S) -clopidogrel and C1 to C5 carboxylic acid.

이외, 상기 방법들은 유럽특허 제 1087976호에서 명기하고 있는 불규칙한 평판이거나 결정모양이 둥글지 않아 정전기의 문제를 가지고 있는 문제점이 있다. In addition, the above methods have the problem of having an electrostatic problem due to irregular flat plates or crystal shapes not specified in EP 1087976.

그러나, 지금껏 공개된 결정형 (I)의 제조방법 중, C1-C4의 저가탄소 알코올 및 물 혼합용매를 사용하여 결정모양이 원형이고 유동성이 우수한 결정형 (I)을 제조한 방법은 없었다. However, none of the methods for preparing crystalline Form (I) disclosed until now has been prepared using a C1-C4 low-carbon carbon alcohol and water mixed solvent to form crystalline Form (I) having a circular crystal shape and excellent fluidity.

이에 본 발명자들은 그 제조방법이 보다 용이하고 고순도 및 우수한 물성을 갖는 클로피도그렐 황산수소염 결정형(I)을 제공하고자 한다. Accordingly, the present inventors are to provide a clopidogrel hydrogen sulfate crystalline form (I) having a more easy manufacturing method and high purity and excellent physical properties.

본 발명은 클로피도그렐 자유염기를 2-부탄올과 물의 혼합용매하에서 진한 황산과 반응시켜 클로피도그렐 황산수소염의 결정형 (I)을 제조하는 방법을 제공한다.The present invention provides a method for preparing crystalline Form (I) of clopidogrel hydrogen sulfate by reacting clopidogrel free base with concentrated sulfuric acid under a mixed solvent of 2-butanol and water.

이하, 본 발명에서, “클로피도그렐”은 “(+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트”을 의미하며, “라세미 클로피도그렐”은 “(±)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트”를 의미한다. Hereinafter, in the present invention, “clopidogrel” means “(+)-(S) -α- (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl- 5-methyl acetate ”and“ racemic clopidogrel ”means“ (±) -α- (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl -5-methyl acetate ”.

본 발명의 결정형 (I) 제조방법에서, 물의 사용량은 클로피도그렐 자유염기 중량기준으로 4 내지 14% 중량인 것이 바람직하며, 5 내지 14% 중량인 것이 보다 더 바람직하며, 7.5 내지 11%가 더욱 바람직하며, 8.6%가 가장 바람직하다. 물의 함량이 14%을 초과할 경우 결정형(I)이 아니거나, 결정형(I)이더라도 불규칙한 평판모양의 결정형(I)이 제조되며, 4% 미만인 경우 결정형(I)이더라도 불규칙한 평판모양이 이거나, 결정화가 매우 느려 수율이 매우 낮게 제조되는 문제점이 있다. In the preparation method of Form (I) of the present invention, the amount of water used is preferably 4 to 14% by weight, more preferably 5 to 14% by weight, even more preferably 7.5 to 11% by weight, based on the weight of clopidogrel free base. , 8.6% is most preferred. If the water content exceeds 14%, it is not a crystalline form (I), or even if the crystalline form (I), irregular plate-like crystalline form (I) is produced.If the content is less than 4%, even a crystalline form (I) is an irregular plate-shaped or crystallized. There is a problem that the production is very low yield very low.

본 발명의 결정형 (I) 제조방법에서, 클로피도그렐 황산수소염의 결정형(I)을 시딩(seeding)하여 결정형 (I)의 생성을 촉진시킬 수 있다. In the method for preparing Form (I) of the present invention, seeding of Form (I) of Clopidogrel Hydrogen Sulfate may promote the formation of Form (I).

본 발명의 결정형 (I) 제조방법에서, 반응온도 및 결정온도가 15 내지 25℃인 것이 바람직하다. 즉, 본 발명의 결정형 (I) 제조방법은 결정을 생성시키기 위해 별도로 결정온도를 저온으로 할 필요가 없는 이점이 있다. In the method for producing crystalline form (I) of the present invention, the reaction temperature and the crystal temperature are preferably 15 to 25 ° C. That is, the manufacturing method of the crystalline form (I) of the present invention has the advantage that the crystal temperature does not need to be lowered separately to produce crystals.

본 발명의 결정형 (I) 제조방법에서, 클로피도그렐 자유염기 및 혼합용매의 중량비가 1: 14 내지 25인 것이 바람직하다. In the method for preparing Form (I) of the present invention, it is preferable that the weight ratio of clopidogrel free base and mixed solvent is 1:14 to 25.

본 발명의 결정형 (I) 제조방법에서, 반응 시간은 5 내지 15시간인 것이 바람직하다. In the method for preparing Form (I) of the present invention, the reaction time is preferably 5 to 15 hours.

본 발명의 결정형(I) 제조방법에서, 출발물질인 클로피도그렐 자유염기는 다른 화합물로부터 단리(isolation)된 것일 수도 있고, 클로피도그렐의 약제학적으로 허용되는 염으로부터 클로피도그렐 자유염기를 제조하기 위한 공정에서, 클로피도그렐 자유염기가 단리되지 않은 상태일 수 있다. 또한, 출발물질인 클로피도그렐 자유염기는 공지의 방법으로 제조될 수 있으며, 예를 들어 디클로로메탄 용매하에 클로피도그렐 캄파 술폰산염 및 탄산칼륨의 반응으로 제조된 것일 수 있다. In the method for preparing Form (I) of the present invention, the starting material clopidogrel free base may be isolated from other compounds, and in the process for preparing clopidogrel free base from the pharmaceutically acceptable salt of clopidogrel, clopidogrel Free base may be unisolated. In addition, the starting material clopidogrel free base may be prepared by a known method, for example, may be prepared by the reaction of clopidogrel camphor sulfonate and potassium carbonate in a dichloromethane solvent.

여기서, 본 발명의 출발물질인 클로피도그렐 자유염기를 제조하기 위한 클로피도그렐 캄파 술폰산염은 공지된 방법(예를 들어, 유럽특허 제 0281459호)으로 제조될 수 있으며, 본 발명에서 제공하는 다음과 같은 방법으로 제조된 것 일 수 있다.Here, the clopidogrel camphor sulfonate for preparing the clopidogrel free base, which is a starting material of the present invention, may be prepared by a known method (for example, European Patent No. 0281459), by the following method provided by the present invention. It may be manufactured.

따라서, 본 발명은 본 발명의 결정형 (I) 제조방법의 출발물질인 클로피도그렐 자유염기를 제조하기 위한 클로피도그렐 캄파 술폰산염을 라세미 클로피도그렐 염기 및 (R)-(-)-10-캄파 술폰산을 디클로로메탄, 디클로로에탄, 클로로포름 중에서 선택된 용매에 용해한 후, 1차, 2차, 3차의 C1-C5알킬 아세테이트 중 선택된 반용매(antisolvent)를 첨가 후 반응시켜 제조하는 방법을 제공한다. 여기서, 반용매는 에틸아세테이트 인 것이 바람직하다. 위와 같은 본 발명의 클로피도그렐 캄파 술폰산염은 공지된 방법(유럽특허 제0281459호)에 비해 높은 수율 및 고순도로 제공하는 이점이 있다(45%수율, e.e.>99.5%).Accordingly, the present invention is to prepare a clopidogrel camphor sulfonate for preparing clopidogrel free base, which is the starting material of the preparation method of crystalline form (I) of the present invention, racemic clopidogrel base and (R)-(-)-10-campa sulfonic acid are dichloromethane. It is prepared by dissolving in a solvent selected from dichloroethane and chloroform, and then adding and reacting an antisolvent selected from primary, secondary and tertiary C1-C5 alkyl acetates. Here, the antisolvent is preferably ethyl acetate. Clopidogrel camphor sulfonate of the present invention as described above has the advantage of providing a high yield and high purity compared to the known method (European Patent No. 0281459) (45% yield, e.e.> 99.5%).

본 발명의 제조방법은 공지된 클로피도그렐 황산수소염의 결정형 (I)의 개선된 제조 방법으로서 저온이 아닌 실온에서도 높은 광학순도를 가지며 결정이 둥글고(도 3) 유동성이 우수한 결정형 (I)을 제조하게 하는 이점이 있다. 따라서, 본발명에 의해 제조된 결정형 (I)은 정제 타정시 분쇄과정이 필요 없고, 유동성이 좋아 고르게 충전됨으로서 크래킹(Cracking)이나 스티킹(Sticking)을 최소화 할 수 있는 장점이 있다. The preparation method of the present invention is an improved preparation method of crystalline Form (I) of clopidogrel hydrogen sulfate, which has a high optical purity even at room temperature, not at low temperature, and has a round crystal (FIG. 3), which allows the preparation of Form (I) having excellent fluidity. There is an advantage. Therefore, the crystalline form (I) prepared by the present invention does not need a pulverization process during tablet tableting, and has an advantage of minimizing cracking or sticking by filling evenly with good fluidity.

도1은 실시예5에서 제조한 클로피도그렐 황산수소염의 결정형(I)의 X-선 회절분석 데이터이다.
도2는 실시예5에서 제조한 클로피도그렐 황산수소염의 결정형(I)의 FTIR의 스펙트럼이다.
도3은 실시예5에서 제조한 클로피도그렐 황산수소염의 결정형(I)의 광학현미경으로 본 50배 확대 사진이다.
도4는 비교예 1의 클로피도그렐 황산수소염의 결정형(I)의 광학현미경으로 본 50배 확대 사진이다.
도5는 실시예6의 클로피도그렐 황산수소염의 결정형(I)의 광학현미경으로 본 50배 확대 사진이다.
도6은 실시예 7의 클로피도그렐 황산수소염의 결정형(I)의 광학현미경으로 본 50배 확대 사진이다.
도7은 실시예 10의 클로피도그렐 황산수소염의 결정형(I)의 광학현미경으로 본 50배 확대 사진이다.
도8은 실시예 11의 클로피도그렐 황산수소염의 결정형(I),(II) 혼합물의 광학현미경으로 본 50배 확대 사진이다.
도9는 비교예2의 클로피도그렐 황산수소염의 결정형(I)의 광학현미경으로 본 50배 확대 사진이다.
1 is X-ray diffraction analysis data of crystalline Form (I) of clopidogrel hydrogen sulfate prepared in Example 5. FIG.
Fig. 2 is a spectrum of FTIR of crystalline Form (I) of clopidogrel hydrogen sulfate prepared in Example 5.
FIG. 3 is a 50 times magnified photograph seen by an optical microscope of crystalline Form (I) of clopidogrel hydrogen sulfate prepared in Example 5. FIG.
FIG. 4 is a 50 times magnified photograph seen by an optical microscope of crystalline Form (I) of Clopidogrel hydrogen sulfate of Comparative Example 1. FIG.
Fig. 5 is a magnified photograph 50 times as seen by an optical microscope of crystalline Form (I) of clopidogrel hydrogen sulfate in Example 6.
FIG. 6 is a 50 times magnified photograph seen by an optical microscope of Form (I) of Clopidogrel hydrogen sulfate of Example 7. FIG.
FIG. 7 is a 50-fold enlarged photograph seen by an optical microscope of crystalline Form (I) of clopidogrel hydrogen sulfate in Example 10; FIG.
FIG. 8 is a 50-fold enlarged photograph seen by an optical microscope of a crystalline form (I), (II) mixture of clopidogrel hydrogen sulfate of Example 11.
9 is a 50 times magnified photograph seen by an optical microscope of crystalline Form (I) of clopidogrel hydrogen sulfate of Comparative Example 2. FIG.

이하, 실시예를 통하여 본 발명을 상세히 설명하기는 하나, 다음의 실시예는 본 발명을 설명하기 위한 것일 뿐 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to the following examples, but the following examples are only intended to illustrate the present invention and do not limit the scope of the present invention.

하기 실시예에서 제조한 클로피도그렐 황산수소염 결정형 (I)의 X-선 회절분석 데이터 , IR 데이터, 순도는 분말용 X-선 회절분석기(PXRD,(Buker AXS(germany)사의 D8 focus(2.2kw)), 푸리에 변환 적외선 분광학(FTIR,(Thermo scientific사의 Nicolet 6700)) 및 HPLC(Agilent Technologies 사의 1200 series, Ultron ES-OVM, 15cm, 4.6mm I.D, particle size 5㎛의 컬럼)을 사용하여 측정하였다.
X-ray diffraction analysis data, IR data, and purity of Clopidogrel Hydrogen Sulfate Crystalline Form (I) prepared in the following Examples are powder X-ray diffractometer (PXRD, (D8 focus (2.2kw) of Bucker AXS (germany)) And Fourier Transform Infrared Spectroscopy (FTIR, Nicolet 6700 from Thermo Scientific) and HPLC (1200 series from Agilent Technologies, Ultron ES-OVM, 15 cm, 4.6 mm ID, column size particle size 5 μm).

<실시예 1>&Lt; Example 1 > 라세미 클로피도그렐(라세미 메틸 α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[Racemic clopidogrel (racemic methyl α- (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [ 3,2-c]피리딘3,2-c] pyridine -5-아세테이트) 자유 염기 제조-5-acetate) free base preparation

메탄올 600ml에 무수탄산나트륨 90.5g과 4,5,6,7-테트라히드로티에노[3,2-c]피리딘 염산염(제조사: Zhejiang Liaoyuan Pharm. Co.Ltd.) 100g을 넣고 60∼65℃에서 1시간 교반한 후 40∼45℃로 냉각하였다. 상기 용액에 브로모-(2-클로로페닐)-아세트산 메틸 에스테르(제조사: Jiacheng-Chem Enter. Ltd.) 165g과 메탄올 100ml을 넣고 60∼65℃에서 24시간 동안 교반하였다. 상기 반응액을 20∼25℃로 냉각하고 디클로로메탄 200ml을 넣고 여과하고 디클로로메탄 200ml으로 세척하였다. 90.5 g of anhydrous sodium carbonate and 100 g of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (manufactured by Zhejiang Liaoyuan Pharm. Co. Ltd.) were added to 600 ml of methanol. After stirring for an hour, the mixture was cooled to 40 to 45 ° C. 165 g of bromo- (2-chlorophenyl) -acetic acid methyl ester (manufacturer: Jiacheng-Chem Enter. Ltd.) and 100 ml of methanol were added and stirred at 60 to 65 ° C. for 24 hours. The reaction solution was cooled to 20-25 ° C., 200 ml of dichloromethane was added, filtered, and washed with 200 ml of dichloromethane.

상기 여과된 반응 여액에 정제수 300ml을 넣고 아세트산으로 용액의 pH를 7.0∼7.2로 보정한 후 유기층을 분리하고, 물층을 한 번 더 디클로로메탄 200ml으로 추출하였다. 추출된 두 유기층을 합하여 정제수로 세척하였다. 세척된 디클로로메탄 용액을 증류하여 라세미 클로피도그렐 염기(라세미 메틸 α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리딘-5-아세테이트)을 183g을 얻었다.
300 ml of purified water was added to the filtered reaction filtrate, the pH of the solution was corrected to 7.0-7.2 with acetic acid, the organic layer was separated, and the water layer was extracted with 200 ml of dichloromethane. The two extracted organic layers were combined and washed with purified water. Distilled washed dichloromethane solution to racemic clopidogrel base (racemic methyl α- (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-acetate) 183 g was obtained.

<< 실시예Example 2>  2> 클로피도렐Clopidora 캄파Kampa 술폰산염( Sulfonates ( 메틸methyl (+)-(S)-α-(2- (+)-(S) -α- (2- 클로로페닐Chlorophenyl )-4,5,6,7-) -4,5,6,7- rim 트라히드로티에노[Trahydrothieno [ 3,2-c]피리딘3,2-c] pyridine -5-아세테이트 -5-acetate 캄파Kampa 술폰산염Sulfonate )의 제조 Manufacturing

실시예1에서 제조한 라세미 클로피도그렐 염기 183g에 20∼25℃에서 디클로로메탄 150ml과 (R)-(-)-10-캄파 술폰산 132.2g을 넣고 용해하였다. 상기 반응액에 에틸아세테이트 225ml을 주입하고 20∼25℃에서 2시간 동안 교반하였다. 상기 반응액을 40∼45℃로 가열하여 1시간 교반 한 후 20∼25℃로 냉각하여 3시간 동안 교반하였다. 생성된 결정을 여과하고 아세톤 100ml으로 세척한 다음 건조하여 클로피도그렐 캄파 술폰산염 142g을 얻었다(수율: 45%). 이때 얻어진 여액은 실시예 3에서 사용하였다. To 183 g of racemic clopidogrel base prepared in Example 1, 150 ml of dichloromethane and 132.2 g of (R)-(-)-10-campa sulfonic acid were dissolved at 20 to 25 ° C. 225 ml of ethyl acetate was added to the reaction solution, and the mixture was stirred at 20 to 25 ° C. for 2 hours. The reaction solution was heated to 40-45 ° C., stirred for 1 hour, cooled to 20-25 ° C., and stirred for 3 hours. The resulting crystals were filtered, washed with 100 ml of acetone and dried to give 142 g of clopidogrel camphor sulfonate (yield: 45%). The filtrate obtained at this time was used in Example 3.

specific O.R. : 25.5o (c=1.68, 메탄올, 25℃) e.e.>99.5%
specific OR: 25.5 o (c = 1.68, methanol, 25 ° C) ee> 99.5%

<< 실시예Example 3>  3> 클로피도렐Clopidora 캄파Kampa 술폰산염( Sulfonates ( 메틸methyl (+)-(S)-α-(2- (+)-(S) -α- (2- 클로로페닐Chlorophenyl )-4,5,6,7-) -4,5,6,7- 테트라히드로티에노[3,2-c]피리딘Tetrahydrothieno [3,2-c] pyridine -5-아세테이트 -5-acetate 캄파Kampa 술폰산염Sulfonate ) 제조 ) Produce

실시예 2에서 여과된 여액을 증류하고 디클로로메탄 250ml을 넣고 용해한 후 정제수 220ml에 수산화나트륨 13.4g을 용해하여 만든 수산화나트륨 수용액을 서서히 주입하여 pH 7.0∼7.2으로 보정한 후 층 분리하였다. 분리된 유기층을 정제수로 세척하였다. 세척된 유기층을 증류하여 용매를 제거하고 메탄올 400ml과 소디움메톡시드 7.7g을 넣고 60∼65℃에서 4시간정도 교반하였다. 상기 반응액을 증류하여 용매를 제거하고 20∼25℃에서 디클로로메탄 200ml와 정제수 200ml을 넣고 아세트산으로 pH 7.0∼7.2로 보정한 후 유기층을 분리하고 정제수로 세척하였다. 세척된 유기층을 증류하여 용매를 제거하고 농축된 잔류물에 20∼25℃에서 디클로로메탄 82ml과 (R)-(-)-10-캄파 술폰산 72.7g을 넣고 용해하였다. 상기 반응액에 에틸아세테이트 124ml을 주입하고 20∼25℃에서 2시간정도 교반하였다. 상기 반응액을 40∼45℃로 가열하여 1시간정도 교반 한 후 20∼25℃로 냉각하여 3시간정도 교반하였다. 생성된 결정을 여과하고 아세톤으로 세척한 다음 건조하여 클로피도그렐 캄파 술폰산염 70g을 얻었다(수율: 실시예 2의 여액으로부터 22%).The filtrate filtered in Example 2 was distilled, dissolved in 250 ml of dichloromethane, and then slowly injected with an aqueous sodium hydroxide solution prepared by dissolving 13.4 g of sodium hydroxide in 220 ml of purified water, followed by correction to pH 7.0 to 7.2, followed by layer separation. The separated organic layer was washed with purified water. The washed organic layer was distilled to remove the solvent, 400 ml of methanol and 7.7 g of sodium methoxide were added thereto, and the mixture was stirred at 60 to 65 ° C. for about 4 hours. The reaction solution was distilled off to remove the solvent, 200 ml of dichloromethane and 200 ml of purified water were added at 20 to 25 ° C., and the pH was adjusted to 7.0 to 7.2 with acetic acid. The organic layer was separated and washed with purified water. The washed organic layer was distilled off to remove the solvent, and dissolved in a concentrated residue with 82 ml of dichloromethane and 72.7 g of (R)-(-)-10-campa sulfonic acid at 20 to 25 ° C. 124 ml of ethyl acetate was added to the reaction solution, and the mixture was stirred at 20 to 25 ° C. for about 2 hours. The reaction solution was heated to 40-45 ° C., stirred for about 1 hour, cooled to 20-25 ° C., and stirred for 3 hours. The resulting crystals were filtered, washed with acetone and dried to give 70 g of clopidogrel camphor sulfonate (yield: 22% from the filtrate of Example 2).

비선광도 값 : 24.8o (c=1.68, 메탄올, 23도)
Specific luminance value: 24.8 o (c = 1.68, methanol, 23 degrees)

<< 실시예Example 4> 4> 클로피도그렐Clopidogrel 자유염기 제조 Free base manufacturing

디클로로메탄 400ml에 실시예 2에서 제조한 클로피도그렐 캄파 술폰산염 100g을 넣고 10℃이하에서 교반하였다. 상기 반응액에 정제수 300ml에 탄산칼륨 20g을 녹여 만든 탄산칼륨 수용액을 10℃이하를 유지하며 서서히 주입한 후 40분정도 교반하였다. 상기 반응액에서 유기층을 분리하고 정제수 300ml으로 분리된 유기층을 세척하였다. 세척된 유기층에 무수황산나트륨과 활성탄 0.5g을 넣고 20∼25℃에서 교반한 후 여과하고 디클로로메탄 25ml으로 세척하였다. 상기 여과한 여액을 증류하고 2-부탄올 50ml을 넣고 추가로 증류하여 용매를 제거하여 정량적으로 순수한 클로피도그렐 자유염기 58g을 얻었다.
100 g of clopidogrel camphor sulfonate prepared in Example 2 was added to 400 ml of dichloromethane, and the mixture was stirred at 10 ° C. or less. Potassium carbonate aqueous solution prepared by dissolving 20 g of potassium carbonate in 300 ml of purified water was slowly injected while maintaining the temperature below 10 ° C., and then stirred for about 40 minutes. The organic layer was separated from the reaction solution and the organic layer separated with 300 ml of purified water was washed. Anhydrous sodium sulfate and activated carbon 0.5g were added to the washed organic layer, stirred at 20-25 ° C., filtered, and washed with 25 ml of dichloromethane. The filtered filtrate was distilled, 50 ml of 2-butanol was added thereto, and further distilled to remove the solvent, thereby obtaining 58 g of pure clopidogrel free base.

<< 실시예Example 5>  5> 클로피도그렐Clopidogrel 황산수소염의Hydrogen sulfate 결정형 (I) 제조(화학식 1) Preparation of Form (I) (Formula 1)

실시예 4에서 얻은 클로피도그렐 자유 염기 58g에 2-부탄올 1100ml와 정제수 5ml을 넣고 15∼20℃에서 교반하였다. 상기 반응액에 20∼25℃를 유지하며 황산 16.8g을 서서히 주입하고 30분정도 교반한 후 클로피도그렐 황산수소염 결정형 (I)을 1g 가한 후 20∼25℃에서 12시간 교반하였다. 생성된 결정을 여과하고 아세톤으로 세척한 후 건조하여 클로피도그렐 황산수소염 결정형 (I)을 40g(수율 : 53%) 얻었다. To 58 g of clopidogrel free base obtained in Example 4, 1100 ml of 2-butanol and 5 ml of purified water were added and stirred at 15 to 20 ° C. 16.8 g of sulfuric acid was slowly added to the reaction solution while stirring and stirred for about 30 minutes, and then 1 g of clopidogrel hydrogen sulfate crystalline form (I) was added, followed by stirring at 20 to 25 ° C. for 12 hours. The resulting crystals were filtered, washed with acetone and dried to obtain 40 g (yield: 53%) of clopidogrel hydrogen sulfate crystalline form (I).

이때 수득한 결정형 (I)의 X-선 회절 분석 데이타 및 IR 데이터 값은 도1 및 도2와 같다.X-ray diffraction analysis data and IR data values of Crystal Form (I) thus obtained are shown in FIGS. 1 and 2.

specific O.R. : 56.3o (c=1.891, 메탄올, 24도) e.e. > 99.9%specific OR: 56.3 o (c = 1.891, methanol, 24 degrees) ee> 99.9%

impurity A : 0.015%, impurity B : 0.03%, impurity C : 0.025%, 건조검량 : 0.1%impurity A: 0.015%, impurity B: 0.03%, impurity C: 0.025%, dry inspection weight: 0.1%

또한, 수득한 결정형 (I)을 광학현미경(Zeiss사의 Axiovert 25)으로 50배 확대하여 본 결과, 균일한 크기의 둥근 결정모양이었다.(도 3). In addition, the obtained crystalline Form (I) was magnified 50 times with an optical microscope (Axiovert 25 manufactured by Zeiss). As a result, it was a round crystal of uniform size.

클로피도그렐 자유염기 중량을 기준 물(정제수)의 함량 변화에 따른 클로피도그렐 황산수소염 결정의 변화를 확인하기 위해 실시예 5와 동일한 조건으로 정제수의 함량을 다양하게 변화하여 클로피도그렐 황산수소염을 제조하였다.Clopidogrel hydrogen sulfate was prepared by variously changing the content of purified water under the same conditions as in Example 5 to confirm the change of clopidogrel hydrogen sulfate crystals according to the change in the content of reference water (purified water) based on the weight of clopidogrel free base.

[표 1]TABLE 1

Figure pat00002
Figure pat00002

본 발명의 결정형 (I) 제조방법에서, 물의 사용량은 클로피도그렐 자유염기 중량기준으로 4 내지 14% 중량인 것이 바람직하며, 물의 함량이 14%를 초과할 경우 결정형 (I)이 아니거나, 결정형 (I)이더라도 불규칙한 평판모양의 결정형 (I)이 제조되며, 4% 미만인 경우 결정형 (I)이더라도 불규칙한 평판모양이 이거나, 결정화가 매우 느려 수율이 매우 낮게 제조되는 문제점이 있다.
In the preparation method of Form (I) of the present invention, it is preferable that the amount of water used is 4 to 14% by weight based on the weight of clopidogrel free base, and if the content of water exceeds 14%, it is not Form (I) or Form (I). Irregular plate-like crystalline form (I) is prepared even if less than 4%, even if the crystalline form (I) is irregular plate-shaped, or the crystallization is very slow, there is a problem that the yield is very low.

<실시예 12> 클로피도그렐 황산수소염의 결정형 (I) 제조(화학식 1)Example 12 Preparation of Form (I) of Clopidogrel Hydrogen Sulfate (Formula 1)

클로피도그렐 자유 염기 46g에 2-부탄올 800ml와 정제수 5ml을 넣고 15∼20℃에서 교반하였다. 상기 반응액에 20∼25℃를 유지하며 황산 14.1g을 서서히 주입하고 20∼25℃에서 7시간 교반하였다. 생성된 결정을 여과하고 아세톤으로 세척한 후 건조하여 클로피도그렐 황산수소염 결정형 (I)을 31.3g(수율 : 52%)을 얻었다.Into 46 g of clopidogrel free base, 800 ml of 2-butanol and 5 ml of purified water were added and stirred at 15 to 20 ° C. 14.1 g of sulfuric acid was slowly added thereto while maintaining the reaction solution at 20 to 25 ° C., and stirred at 20 to 25 ° C. for 7 hours. The resulting crystals were filtered, washed with acetone and dried to obtain 31.3 g (yield: 52%) of clopidogrel hydrogen sulfate crystalline form (I).

<실시예 13> 클로피도그렐 황산수소염의 결정형 (I) 제조(화학식 1)Example 13 Preparation of Form (I) of Clopidogrel Hydrogen Sulfate (Formula 1)

클로피도그렐 자유 염기(출처 :Jiacheng-Chem Enterprises Limited) 50g에 2-부탄올 1000ml와 정제수 4.3ml을 넣고 15∼20℃에서 교반하였다. 상기 반응액에 20∼25℃를 유지하며 황산 15.2g을 서서히 주입하고 30분정도 교반한 후 클로피도그렐 황산수소염 결정형 (I)을 0.9g 가한 후 20∼25℃에서 14시간 교반하였다. 생성된 결정을 여과하고 아세톤으로 세척한 후 건조하여 클로피도그렐 황산수소염 결정형 (I)을 33.5g(수율 : 51.3%)을 얻었다.
1000 g of 2-butanol and 4.3 ml of purified water were added to 50 g of clopidogrel free base (source: Jiacheng-Chem Enterprises Limited) and stirred at 15 to 20 ° C. 15.2 g of sulfuric acid was slowly added to the reaction solution while stirring and stirred for about 30 minutes, and 0.9 g of clopidogrel hydrogen sulfate crystal form (I) was added thereto, followed by stirring at 20 to 25 ° C. for 14 hours. The resulting crystals were filtered, washed with acetone and dried to obtain 33.5 g (yield: 51.3%) of clopidogrel hydrogen sulfate crystalline form (I).

<< 비교예Comparative example 2>  2> 클로피도그렐Clopidogrel 황산수소염의Hydrogen sulfate 결정형 (I) 제조( Form (I) Preparation WO2005063708WO2005063708 of 실시예Example 12) 12)

디클로로메탄 450ml에 클로피도그렐 캄파 술폰산염 86.1g을 넣고 25∼30℃에서 중탄산나트륨 수용액(10%, 650ml)를 넣고 10분간 교반하였다. 상기 반응액에서 유기층을 분리하고 디클로로메탄 90ml로 수층을 다시 추출하였다. 정제수 180ml으로 분리된 두 유기층을 세척하였다. 세척된 유기층에 무수황산나트륨으로 건조한 후 증류하여 클로피도그렐 자유염기을 얻었다.86.1 g of clopidogrel camphor sulfonate was added to 450 ml of dichloromethane, and an aqueous sodium bicarbonate solution (10%, 650 ml) was added at 25 to 30 ° C, followed by stirring for 10 minutes. The organic layer was separated from the reaction solution, and the aqueous layer was extracted again with 90 ml of dichloromethane. Two organic layers separated with 180 ml of purified water were washed. The washed organic layer was dried over anhydrous sodium sulfate and distilled to obtain a clopidogrel free base.

클로피도그렐 자유염기을 n-헥산올 250ml와 물 1ml를 넣고 25∼30℃에서 교반하였다. 10∼15℃에서 진한황산을 넣고 결정형 (I)형을 접종하여 20∼25℃에서 10시간 교반 하였다. 22∼25℃에서 2시간정도 빠르게 교반하고, 6시간정도 느리게 교반하였다. 반응물을 여과하고 메틸 tert-부틸에스테르 150ml로 세척하고 건조하여 클로피도그렐 황산수소염 결정형 (I)을 11g(수율 : 17%)을 얻었다. {참고로, 특허 WO2005063708호에는 상기와 같은 방법으로 제조시, 85.95%의 수율이 나온다고 기재되어 있으나, 직접실시해본결과 수율은 17%였음}250 ml of n-hexanol and 1 ml of water were added to the clopidogrel free base, and the mixture was stirred at 25 to 30 ° C. Concentrated sulfuric acid was added at 10 to 15 ° C, and inoculated with crystalline form (I), followed by stirring at 20 to 25 ° C for 10 hours. Stirred rapidly at 22-25 ° C. for 2 hours and slowly for 6 hours. The reaction was filtered, washed with 150 ml of methyl tert-butyl ester and dried to give 11 g (yield: 17%) of Clopidogrel Hydrogen Sulfate Crystalline Form (I). {Reference, WO2005063708, when manufactured in the same manner as described above, yields of 85.95%, but the results of direct experiments yielded 17%}

또한, 수득한 결정형 (I)을 광학현미경(Zeiss사의 Axiovert 25)으로 50배 확대하여 본 결과, 분말형태의 결정형이었다(도 9).In addition, the obtained crystalline Form (I) was magnified 50 times with an optical microscope (Axiovert 25 manufactured by Zeiss), and found to be a powdered crystalline form (FIG. 9).

Claims (11)

클로피도그렐 자유염기를 2-부탄올과 클로피도그렐 자유염기 중량을 기준으로 4 내지 14%중량인 물의 혼합용매하에서 진한 황산과 반응시켜 클로피도그렐 황산수소염의 결정형(I)을 제조하는 방법.A method for preparing crystalline form (I) of clopidogrel hydrogen sulfate by reacting clopidogrel free base with concentrated sulfuric acid in a mixed solvent of water having 4 to 14% by weight based on the weight of 2-butanol and clopidogrel free base. 제1항에 있어서, 물의 사용량이 클로피도그렐 자유염기 중량기준으로 5 내지14% 중량인 클로피도그렐 황산수소염의 결정형 (I) 제조방법.The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 1, wherein the amount of water used is 5 to 14% by weight based on the weight of clopidogrel free base. 제2항에 있어서, 물의 사용량이 클로피도그렐 자유염기 중량기준으로 7.5 내지 11% 중량인 클로피도그렐 황산수소염의 결정형 (I) 제조방법.The method for preparing crystalline Form (I) of clopidogrel hydrogen sulfate according to claim 2, wherein the amount of water used is 7.5 to 11% by weight based on the weight of clopidogrel free base. 제3항에 있어서, 물의 사용량이 클로피도그렐 자유염기 중량기준으로 8.6% 중량인 클로피도그렐 황산수소염의 결정형 (I) 제조방법.The method for preparing crystalline Form (I) of clopidogrel hydrogen sulfate according to claim 3, wherein the amount of water used is 8.6% by weight based on the weight of clopidogrel free base. 제1항에 있어서, 클로피도그렐 황산수소염의 결정형(I)을 시딩(seeding)하는 단계를 추가로 포함하는 클로피도그렐 황산수소염의 결정형(I) 제조방법.The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 1, further comprising seeding crystalline form (I) of clopidogrel hydrogen sulfate. 제1항에 있어서, 반응온도 및 결정온도가 15 내지 25℃인 클로피도그렐 황산수소염의 결정형(I) 제조방법.The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 1, wherein the reaction temperature and the crystal temperature are 15 to 25 ° C. 제1항에 있어서, 클로피도그렐 자유염기 및 혼합용매의 중량비가 1: 14 내지 25인 클로피도그렐 황산수소염의 결정형(I) 제조방법.The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 1, wherein the weight ratio of clopidogrel free base and mixed solvent is 1:14 to 25. 제1항에 있어서, 반응 시간이 5 내지 15시간인 클로피도그렐 황산수소염의 결정형(I) 제조방법.The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 1, wherein the reaction time is 5 to 15 hours. 제1항 내지 제8항 중 어느 한 항에 있어서, 클로피도그렐 자유염기가 디클로로메탄 용매하에 클로피도그렐 캄파 술폰산염 및 탄산칼륨의 반응으로 제조된 것인 클로피도그렐 황산수소염의 결정형(I) 제조방법.The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to any one of claims 1 to 8, wherein the clopidogrel free base is prepared by the reaction of clopidogrel camphor sulfonate and potassium carbonate in a dichloromethane solvent. 제9항에 있어서, 클로피도그렐 캄파 술폰산염이 라세미 클로피도그렐 염기 및 (R)-(-)-10-캄파 술폰산을 디클로로메탄, 디클로로에탄, 클로로포름 중에서 선택된 용매에 용해한후, 1차, 2차, 3차의 C1-C5알킬 아세테이트 중 선택된 반용매(antisolvent)를 첨가후 반응시켜 제조된 것인 클로피도그렐 황산수소염의 결정형 (I) 제조방법. 10. The method according to claim 9, wherein the clopidogrel camphor sulfonate is dissolved in racemic clopidogrel base and (R)-(-)-10-campa sulfonic acid in a solvent selected from dichloromethane, dichloroethane, chloroform, followed by primary, secondary, 3 A process for preparing crystalline form (I) of clopidogrel hydrogen sulfate, which is prepared by addition and reaction of a selected antisolvent in C1-C5 alkyl acetate of tea. 제10항에 있어서, 반용매(antisolvent)가 에틸아세테이트인 클로피도그렐 황산수소염의 결정형(I) 제조방법. The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 10, wherein the antisolvent is ethyl acetate.
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