KR101009467B1 - Taxan derivative useful for synthesizing docetaxel and a method for preparing the same - Google Patents

Taxan derivative useful for synthesizing docetaxel and a method for preparing the same Download PDF

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KR101009467B1
KR101009467B1 KR1020060023121A KR20060023121A KR101009467B1 KR 101009467 B1 KR101009467 B1 KR 101009467B1 KR 1020060023121 A KR1020060023121 A KR 1020060023121A KR 20060023121 A KR20060023121 A KR 20060023121A KR 101009467 B1 KR101009467 B1 KR 101009467B1
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tribromoacetyl
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김경수
박영준
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주식회사 셀트리온화학연구소
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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B66HOISTING; LIFTING; HAULING
    • B66CCRANES; LOAD-ENGAGING ELEMENTS OR DEVICES FOR CRANES, CAPSTANS, WINCHES, OR TACKLES
    • B66C1/00Load-engaging elements or devices attached to lifting or lowering gear of cranes or adapted for connection therewith for transmitting lifting forces to articles or groups of articles
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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B66HOISTING; LIFTING; HAULING
    • B66CCRANES; LOAD-ENGAGING ELEMENTS OR DEVICES FOR CRANES, CAPSTANS, WINCHES, OR TACKLES
    • B66C1/00Load-engaging elements or devices attached to lifting or lowering gear of cranes or adapted for connection therewith for transmitting lifting forces to articles or groups of articles
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Abstract

본 발명은 도세탁셀의 합성에 유용한, 하기 화학식 (I)로 표시되는 신규한 탁산 유도체, 이 유도체의 제조방법, 및 도세탁셀의 제조방법에 관한 것이다. 본 발명에 따른 신규한 탁산 유도체는 10-데아세틸바카틴 III의 7번 및 10번 위치에 트리브로모아세틸 치환체를 갖는다. The present invention relates to novel taxane derivatives represented by the following general formula (I), useful for the synthesis of docetaxel, a process for preparing the derivatives, and a process for preparing docetaxel. The novel taxane derivatives according to the invention have tribromoacetyl substituents at positions 7 and 10 of 10-deacetylbacatin III.

Figure 112008043689619-pat00001
Figure 112008043689619-pat00001

7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III, 도세탁셀, 트리브로모아세틸 브로마이드, 10-데아세틸바카틴 III 7,10-bis (tribromoacetyl) -10-deacetylbacatin III, docetaxel, tribromoacetyl bromide, 10-deacetylbacatin III

Description

도세탁셀의 합성에 유용한 탁산 유도체 및 그 제조방법{Taxan derivative useful for synthesizing docetaxel and a method for preparing the same} Taxane derivative useful for synthesizing docetaxel and a method for preparing the same}

본 발명은 화학식 (II)로 표시되는 도세탁셀의 합성에 유용하게 사용될 수 있는 10-데아세틸바카틴 III의 유도체와 그 유도체의 제조방법에 관한 것이다. 보다 구체적으로 본 발명은 도세탁셀의 합성에 유용하게 사용될 수 있도록 10-데아세틸바카틴 III의 7번과 10번 히드록시기를 트리브로모아세틸기로 보호한 유도체 및 그 제조방법에 관한 것이다. The present invention relates to a derivative of 10-deacetylbaccatin III which can be usefully used for the synthesis of docetaxel represented by the formula (II) and a method of preparing the derivative. More specifically, the present invention relates to derivatives in which the hydroxy groups 7 and 10 of 10-deacetylbaccatin III are protected by tribromoacetyl group so as to be useful in the synthesis of docetaxel, and a method of preparing the same.

도세탁셀(Docetaxel)은 광범위한 항암효능을 갖는 잘 알려진 강력한 항암성분으로 하기 구조식 (II)로 표현된다. Docetaxel (Docetaxel) is a well-known strong anticancer component having a wide range of anticancer efficacy and is represented by the following structural formula (II).

Figure 112006017498481-pat00002
Figure 112006017498481-pat00002

상기 화합물을 함유한 약제학적 제제는 비소세포 폐암이나 여성의 난소암과 유방암 등의 치료에 유용하게 사용되고 있다. Pharmaceutical formulations containing such compounds are useful for the treatment of non-small cell lung cancer, ovarian cancer and breast cancer in women.

도세탁셀은 천연물에서 얻어지는 하기 화학식 (III)으로 표시되는 10-데아세틸바카틴 III를 출발물질로 하는 반합성법에 의해 제조되어 진다. Docetaxel is prepared by a semisynthetic method starting from 10-deacetylbaccatin III represented by the following general formula (III) obtained from natural products.

Figure 112006017498481-pat00003
Figure 112006017498481-pat00003

도세탁셀을 제조하기 위해서는 출발물질인 10-데아세틸바카틴 III의 13번 위치에 페닐이소세린 유도체를 도입해야 한다. 그러나 10-데아세틸바카틴 III에는 모두 4개의 히드록시기가 존재하며 이들 중 7번과 10번의 히드록시기가 13번의 히드록시기 보다 더 좋은 반응성을 가지고 있어서 13번의 히드록시기에 페닐이소세린 유도체를 도입하기 위해서는 반응에 앞서 7번과 10번의 히드록시기를 보호해야 한다. 이러한 10-데아세틸바카틴 III의 7번과 10번 히드록시기를 보호하기 위해 사용되는 보호기로는 트리에틸실릴기와 2,2,2-트리클로로에톡시카르보닐기가 있다.To prepare docetaxel, a phenylisoserine derivative should be introduced at position 13 of the starting material 10-deacetylbaccatin III. However, there are four hydroxy groups in 10-deacetylbaccatin III, and among them, 7 and 10 hydroxy groups have better reactivity than 13 hydroxy groups, so in order to introduce phenylisoserine derivatives into 13 hydroxy groups, 7 and 10 hydroxyl groups should be protected. The protecting groups used to protect the 7 and 10 hydroxy groups of 10-deacetylbaccatin III include triethylsilyl group and 2,2,2-trichloroethoxycarbonyl group.

미국특허 제5,254,703호는 10-데아세틸바카틴 III의 보호기로 트리에틸실릴기를 사용하였다. 도세탁셀 합성의 마지막 단계에서 이 보호기를 제거하기 위해서는 강산인 염산을 사용하고 있으며 이때의 수율은 90%이다. 그러나 10-데아세틸바카틴 III 의 히드록시기들 중 트리에틸실릴 클로라이드와의 반응성은 7번>13번>>10번의 순서로 7번과 10번의 히드록시기만을 선택적으로 보호하는 것이 매우 어렵다. 실제로 10-데아세틸바카틴 III와 트리에틸실릴 클로라이드를 반응시켜 7번과 10번이 보호된 10-데아세틸바카틴 III가 얻어지는 수율은 14%에 불과하다(참고문헌: Tetrahedron 55 (1999) pp. 6567~6576).U.S. Patent 5,254,703 uses triethylsilyl groups as protecting groups for 10-deacetylbaccatin III. To remove this protecting group at the end of docetaxel synthesis, hydrochloric acid, a strong acid, is used and the yield is 90%. However, the reactivity with triethylsilyl chloride in the hydroxy groups of 10-deacetylbaccatin III is very difficult to selectively protect only the hydroxy groups 7 and 10 in the order of 7> 13> 10. In fact, the yield of 10-deacetylbaccatin III protected with 7 and 10 by reacting 10-deacetylbaccatin III with triethylsilyl chloride is only 14% (Tetrahedron 55 (1999) pp. 6567-6576).

한국특허출원 제1987-0007752호는 10-데아세틸바카틴 III와 2,2,2-트리클로로에틸클로로포르메이트를 반응시켜 7번과 10번의 히드록시기가 2,2,2-트리클로로에톡시카르보닐기로 보호된 10-데아세틸바카틴 III를 93%의 수율로 얻었다고 기재하고 있다. 또한 도세탁셀 합성의 마지막 단계에서 보호기를 제거하는 반응은 초산을 반응용매로 사용하고 아연과 60℃에서 반응시켜 90%의 수율로 보호기를 제거하고 있다. 그러나, 이 방법 또한 보호기 제거반응에서 매우 격렬한 강산성 조건을 사용한다는 문제가 있으며, 이러한 문제들로 인하여 최종 화합물의 정제에 어려움이 있고 예기치 않은 부산물을 발생시키는 원인이 되고 있다. 도세탁셀을 제조하는 과정에서 다양한 부산물이 생성된다는 사실은 선행 기술 문헌(R.Vasu Dev 등, Jouranl of Pharmaceutical And Biomedical Analysis 40 (2006) pp. 614-622)에 잘 기재되어 있다. Korean Patent Application No. 1987-0007752 has reacted 10-deacetylbaccatin III with 2,2,2-trichloroethylchloroformate, so that the hydroxy groups of Nos. 7 and 10 are 2,2,2-trichloroethoxycarbonyl groups. Protected 10-deacetylbaccatin III in 93% yield. In the final step of docetaxel synthesis, the reaction to remove the protecting group removes the protecting group in 90% yield by using acetic acid as a reaction solvent and reacting with zinc at 60 ° C. However, this method also has a problem of using a very violent strong acidic condition in the protecting group removal reaction, and these problems are difficult to purify the final compound and cause an unexpected byproduct. The fact that various byproducts are produced in the process of preparing docetaxel is well described in the prior art document (R. Vasu Dev et al., Jouranl of Pharmaceutical And Biomedical Analysis 40 (2006) pp. 614-622).

이에 본 발명자들은 상기와 같은 공지 기술의 문제점을 해결하여 도세탁셀의 제조에 사용하기 더욱 용이한 10-데아세틸바카틴 III의 새로운 보호기를 개발하기 위하여 연구를 계속한 결과, 10-데아세틸바카틴 III의 7번과 10번 히드록시기를 트리브 로모아세틸기로 보호한 유도체(화학식 I)가 도세탁셀의 합성에 유용하게 사용될 수 있음을 알 수 있었다. Accordingly, the present inventors solved the problems of the known technology as described above, and continued the research to develop a new protecting group of 10-deacetylbacatin III which is easier to use in the preparation of docetaxel. It was found that derivatives (formula I) protecting hydroxy groups 7 and 10 of the tribromoacetyl group may be useful for the synthesis of docetaxel.

즉, 본 발명자들은 10-데아세틸바카틴 III의 7번과 10번 히드록시기를 선택적으로 용이하게 보호하고, 보호기 제거반응 조건이 온화한 새로운 유도체와 그의 합성법을 개발하였다. 특히 본 발명자들은 도세탁셀과 같은 탁산 유도체들이 강산이나 염기성 등에 불안정하다는 점을 고려하여 보호기 제거반응이 거의 중성조건 하에서도 용이하게 진행될 수 있는 신규한 10-데아세틸바카틴 III 유도체를 찾는데 중점을 두고 연구하였다. That is, the present inventors have developed a novel derivative and its synthesis method to easily protect the 7 and 10 hydroxy groups of 10-deacetyl baccatin III, and mildly protecting group removal reaction conditions. In particular, the present inventors focused on finding a novel 10-deacetylbaccatin III derivative in which a protecting group removal reaction can be easily performed under almost neutral conditions, considering that taxane derivatives such as docetaxel are unstable in strong acids or basicity. It was.

그 결과 본 발명자들은 화학식 (III)으로 표시되는 10-데아세틸바카틴 III를 염기의 존재하에 트리브로모아세틸 클로라이드와 반응시켜 화학식 (I)로 표시되는, 7번과 10번의 히드록시기가 트리브로모아세틸기로 보호된 10-데아세틸바카틴 III 유도체를 제조하고, 보호기 제거반응 단계에서 보호기를 중성이나 약 염기성의 온화한 조건으로 제거할 수 있는 새로운 방법을 개발하게 되었다.As a result, the present inventors reacted 10-deacetylbaccatin III represented by the formula (III) with tribromoacetyl chloride in the presence of a base to form a tribromo hydroxy group 7 and 10 represented by the formula (I). A 10-deacetylbaccatin III derivative protected by an acetyl group was prepared, and a new method was developed to remove the protecting group under mild or mild basic conditions in the protecting group removing step.

따라서 본 발명에 따르면 선행기술에서 사용된 강산을 사용하거나, 유독성 기체를 발생시키는 시약을 사용하지 않으면서도 도세탁셀을 용이하게 제조할 수 있는 신규한 10-데아세틸바카틴 III 유도체를 개발할 수 있었다. Therefore, according to the present invention, it was possible to develop a novel 10-deacetylbaccatin III derivative which can easily prepare docetaxel without using a strong acid used in the prior art or using a reagent that generates a toxic gas.

본 발명의 목적은 유망한 항암제의 핵심성분인 도세탁셀의 새로운 중간체인 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III를 제공하고, 그의 새로운 제조방법을 제공하기 위한 것이다.It is an object of the present invention to provide 7,10-bis (tribromoacetyl) -10-deacetylbacatin III, a new intermediate of docetaxel, which is a key component of promising anticancer agents, and to provide a new method for its preparation.

본 발명의 다른 목적은 도세탁셀의 제조에 보다 간편하고 경제적으로 이용 가능한 새로운 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III를 제공하고, 그의 새로운 제조방법을 제공하기 위한 것이다.Another object of the present invention is to provide a new 7,10-bis (tribromoacetyl) -10-deacetylbaccatin III, which is simpler and more economically available for the preparation of docetaxel, and to provide a new method for its preparation. .

본 발명의 또 다른 목적은 도세탁셀의 새로운 제조방법을 제공하기 위한 것이다.Another object of the present invention is to provide a new method for producing docetaxel.

본 발명의 상기 및 기타의 목적들은 하기 설명되는 본 발명에 의하여 모두 달성될 수 있다.The above and other objects of the present invention can be achieved by the present invention described below.

본 발명은 하기 화학식 (I)로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III 및 그 제조방법을 제공하기 위한 것이다.The present invention is to provide 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by the following general formula (I) and a preparation method thereof.

Figure 112006017498481-pat00004
Figure 112006017498481-pat00004

7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III(I)는 하기 화학식 (III)으로 표시되는 10-데아세틸바카틴 III를 염기의 존재하에 트리브로모아세틸 클로라이드와 반응시켜 제조된다(반응식 1).7,10-bis (tribromoacetyl) -10-deacetylbacatin III (I) is reacted with tribromoacetyl chloride in the presence of a base 10-deacetylbacatin III represented by the formula (III) It is prepared by (Scheme 1).

Figure 112006017498481-pat00005
Figure 112006017498481-pat00005

상기한 바와 같이 화학식 (III)으로 표시되는 10-데아세틸바카틴 III에 트리브로모아세틸기를 새로운 보호기로 도입함으로써, 도세탁셀 제조를 위하여 강산을 사용하거나, 유독성 기체를 발생시키는 시약을 사용하지 않고 중성이나 약 염기성의 온화한 조건으로 보호기를 용이하게 제거할 수 있는 방법을 제공할 수 있다.
또한, 본 발명은 약염기성 또는 중성의 조건하에서 화학식 (IV)로 표시되는 탁산유도체의 7번과 10번의 트리브로모아세틸 보호기를 각각 제거하여 화학식 (II)로 표시되는 도세탁셀을 제조하는 방법을 제공한다(반응식 2). 화학식 (IV)로 표시되는 13-[(2R,3S)-3-tert-부톡시카르보닐아미노-2-하이드록시-3-이소부틸-프로파노일]-7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III은 화학식 (I)로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III로부터 당해 기술분야에 공지된 기술에 따라 용이하게 제조될 수 있다.
By introducing a tribromoacetyl group into a new protecting group in 10-deacetylbaccatin III represented by the formula (III) as described above, it is possible to use neutral acid for the preparation of docetaxel without using a strong acid or a reagent that generates a toxic gas. However, a mildly basic mild condition can provide a method for easily removing the protecting group.
The present invention also provides a method for preparing docetaxel represented by the formula (II) by removing the 7 and 10 tribromoacetyl protecting groups of the taxane derivative represented by the formula (IV) under weakly basic or neutral conditions, respectively. (Scheme 2). 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromo) represented by formula (IV) Acetyl) -10-deacetylbacatin III is readily prepared according to techniques known in the art from 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by formula (I) Can be.

본 발명의 바람직한 구체예를 하기 반응식 1과 반응식 2에 도시하였다.Preferred embodiments of the invention are shown in Schemes 1 and 2 below.

Figure 112006017498481-pat00006
Figure 112006017498481-pat00006

Figure 112006017498481-pat00007
Figure 112006017498481-pat00007

7번과 10번 위치의 히드록시기가 트리브로모아세틸기로 보호된, 화학식 (I)로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III는 새로운 탁산 유도체로서, 본 발명은 화학식 (I)로 표시되는 신규한 탁산 유도체를 제공함을 목적으로 한다. 화학식 (I)로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III는 반응용매 중에서 염기의 존재하에 트리브로모아세틸 클로라이드와 반응시켜 제조할 수 있으며, 이 제조방법 또한 본 발명의 대상이 된다. 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by the formula (I), wherein the hydroxy groups at positions 7 and 10 are protected with tribromoacetyl groups, is a new taxane derivative. The present invention aims to provide a novel taxane derivative represented by the formula (I). 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by the formula (I) can be prepared by reacting with tribromoacetyl chloride in the presence of a base in a reaction solvent. It is also a subject of the present invention.

이하에서, 본 발명을 더욱 상세히 설명한다. In the following, the present invention is described in more detail.

반응식 1: 7,10-Scheme 1: 7,10- 비스Vis (( 트리브로모아세틸Tribromoacetyl )-10-) -10- 데아세틸바카틴Deacetylbacatin IIIIII (화학식 I)의 제조: 보호기의 도입Preparation of Formula (I): Introduction of Protecting Groups

화학식 (III)으로 표시되는 10-데아세틸바카틴 III를 반응용매중에서 염기의 존재하에 트리브로모아세틸 클로라이드와 반응시켜 화학식 (I)로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III를 제조한다. 7,10-bis (tribromoacetyl) -10 represented by formula (I) by reacting 10-deacetylbaccatin III represented by formula (III) with tribromoacetyl chloride in the presence of a base in a reaction solvent Prepare deacetylbacatin III.

트리브로모아세틸 클로라이드는 화학식 (III)으로 표시되는 10-데아세틸바카틴 III 에 대하여 화학양론적양 이상으로, 바람직하게는 1 내지 1.5 당량배로 사용하다.Tribromoacetyl chloride is used in more than stoichiometric amount, preferably 1 to 1.5 equivalent times, relative to 10-deacetylbaccatin III represented by the formula (III).

이 반응에 사용가능한 용매로는 테트라하이드로푸란, 디이소프로필에테르, 메틸 t-부틸에테르, 디옥산 등의 에테르류, 메틸이소부틸케톤 등의 케톤류, 아세토니트릴 등의 니트릴류, 에틸아세테이트, 이소프로필아세테이트, n-부틸아세테이트 등의 에스테르류, 펜탄, 헥산, 헵탄 등의 지방족 탄화수소류, 디클로로메탄, 클로로포름, 1,2-디클로로에탄 등의 염화 탄화수소류, 벤젠, 톨루엔, 크실렌 등의 방향족 탄화수소류, 디메틸아세트아미드, 디메틸포름아미드 등의 아미드류, 피리딘 등의 염기성 용매 중에서 선택된 1 종 이상이 언급될 수 있는데, 용매로 피리딘을 사용하는 경우에는 별도의 염기를 가하지 않고 직접 반응시킬 수 있다. 또한 사용가능한 염기로는 피리딘, 트리에틸아민, 이미다졸, DBU, 디이소프로필에틸아민 등의 유기염기, 포타슘 t-부톡사이드, 소듐에톡사이드 등의 알콕사이드류, n-부틸리튬, 페닐리튬, 리튬디이소프로필아미드, 소듐하이드리드, 리튬비스트리메틸실릴아미드 등을 언급할 수 있다. 반응 온도는 -20 내지 60℃이며, 바람직하게는 10 내지 30℃이다. 반응 시간은 반응직후부터 12시간 사이이며, 바람직하게는 30분 내지 2시간이다. Solvents usable for this reaction include ethers such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether and dioxane, ketones such as methyl isobutyl ketone, nitriles such as acetonitrile, ethyl acetate and isopropyl Esters such as acetate and n-butyl acetate, aliphatic hydrocarbons such as pentane, hexane, heptane, chloride hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, One or more selected from amides such as dimethylacetamide and dimethylformamide, and basic solvents such as pyridine may be mentioned. When pyridine is used as the solvent, it can be directly reacted without adding a separate base. Further bases that can be used include organic bases such as pyridine, triethylamine, imidazole, DBU and diisopropylethylamine, alkoxides such as potassium t-butoxide and sodium ethoxide, n-butyllithium, phenyl lithium, Lithium diisopropylamide, sodium hydride, lithium bistrimethylsilylamide and the like. Reaction temperature is -20-60 degreeC, Preferably it is 10-30 degreeC. The reaction time is from immediately after the reaction to 12 hours, preferably 30 minutes to 2 hours.

상기한 바와 같은 반응을 통하여 얻어진 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III(화학식 I)는 용매를 감압하에서 농축시키고, 에틸아세테이트와 물을 가하여 추출하고, 농축한 후 톨루엔으로 재결정하거나, 추출과정 없이 바로 에틸아세테이트와 헥산을 용출액으로 사용한 컬럼 크로마토그라피로 회수할 수 있다. 7,10-bis (tribromoacetyl) -10-deacetylbacatin III (Formula I) obtained through the reaction as described above was concentrated under reduced pressure, extracted with ethyl acetate and water, and concentrated. After recrystallization with toluene or without extraction process can be recovered by column chromatography using ethyl acetate and hexane as eluent.

반응식 2: 화학식 (Scheme 2: Formula ( IVIV )로 표시되는 화합물의 보호기 제거The protecting group of the compound represented by

화학식 (IV)로 표시되는 13-[(2R,3S)-3-tert-부톡시카르보닐아미노-2-하이드록시-3-이소부틸-프로파노일]-7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III의 7번 및 10번 위치의 트리브로모아세틸 보호기는 암모니아 또는 암모니아와 약산과의 염으로 쉽게 제거할 수 있다. 이때, 암모니아로는 5 내지 40% 농도의 암모니아수나 동일농도의 암모니아-유기용매 용액을 사용하며, 암모니아의 양은 화학식 (IV) 화합물에 대해 화학양론적양 또는 그 이상의 양, 바람직하게는 1 내지 5 당량배 범위로 사용한다. 암모니아와 약산과의 염을 사용할 경우 화학식 (IV)로 표시되는 화합물에 대해 1 내지 5 당량배 범위로 사용하며, 이때 암모니아와 염을 형성할 수 있는 약산은 포름산, 아세트산, 프로피온산 등으로부터 선택하여 사용할 수 있다. 반응용매로는 메탄올, 에탄올, 이소프로필알코올 등의 알코올류, 테트라히드로푸란, n-부틸아세테이트 등의 에스테르류, 디클로로메탄, 클로로포름, 1,2-디클로로에탄 등의 염화탄화수소류, 벤젠, 톨루엔, 크실렌 등의 방향족 탄화수소류, 디메틸아세트아미드, 디메틸포름아미드 등의 아미드류로부터 선택된 1 종 이상을 사용할 수 있으며, 반응은 바람직하게는 0 내지 60℃의 온도범위에서 수행한다. 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromo) represented by formula (IV) Tribromoacetyl protecting groups at positions 7 and 10 of acetyl) -10-deacetylbacatin III can be easily removed with ammonia or a salt of ammonia with a weak acid. At this time, ammonia water of 5 to 40% concentration or ammonia-organic solvent solution of the same concentration is used as the ammonia, and the amount of ammonia is in stoichiometric amount or higher relative to the compound of formula (IV), preferably 1 to 5 equivalents Use as a ship range. When a salt of ammonia and a weak acid is used, it is used in a range of 1 to 5 equivalents based on the compound represented by the formula (IV), wherein a weak acid capable of forming a salt with ammonia is selected from formic acid, acetic acid, propionic acid, and the like. Can be. Examples of the reaction solvent include alcohols such as methanol, ethanol and isopropyl alcohol, esters such as tetrahydrofuran and n-butyl acetate, chloride hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, benzene, toluene, At least one selected from aromatic hydrocarbons such as xylene, amides such as dimethylacetamide and dimethylformamide may be used, and the reaction is preferably performed at a temperature range of 0 to 60 ° C.

본 발명을 통해 신규한 탁산 유도체를 제공함으로 인하여, 지금까지 통상적으로 탁산의 7번 및 10번 위치의 보호기를 제거하는데 매우 강한 산성조건을 요구했음에 비해 본 발명에서 제공하는 탁산 유도체들은 암모니아 용액 또는 암모니아와 약산과의 염을 이용한 약염기성 또는 중성의 조건에서 극히 용이하게 보호기들이 제거될 수 있게 되었다. By providing a novel taxane derivative through the present invention, the taxane derivatives provided in the present invention are ammonia solution or so far compared to conventionally required very strong acidic conditions to remove the protecting groups at positions 7 and 10 of the taxane. Protecting groups can be removed very easily in weakly basic or neutral conditions using salts of ammonia and weak acids.

상기한 바와 같은 반응을 통하여 얻어진 화학식 (II)로 표기되는 도세탁셀은 용매를 감압하여 농축시키고, 에틸아세테이트와 물을 가하여 추출하고, 농축한 후 톨루 엔으로 재결정하거나, 추출과정 없이 바로 에틸아세테이트와 헥산을 용출액으로 사용한 컬럼 크로마토그라피로 회수할 수 있다.Docetaxel represented by the formula (II) obtained through the reaction as described above was concentrated by depressurizing the solvent, extracted with ethyl acetate and water, concentrated and recrystallized with toluene, or immediately without ethyl acetate and hexane Can be recovered by column chromatography used as eluent.

상기한 바와 같이 본 발명에 따라, 화학식 (III)으로 표시되는 10-데아세틸바카틴 III를 반응용매중에서 염기의 존재하에 트리브로모아세틸 클로라이드과 반응시켜 화학식 (I)로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III를 제조하고, 보호기 제거반응 단계에서 보호기를 중성이나 약 염기성의 온화한 조건으로 용이하게 제거할 수 있는 새로운 방법을 개발하게 되었다. 화학식 (I)로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III는 도세탁셀을 제조하기 위하여, 당해 기술분야에 공지된 기술에 따라 화학식 (IV)로 표시되는 13-[(2R,3S)-3-tert-부톡시카르보닐아미노-2-하이드록시-3-이소부틸-프로파노일]-7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III으로 제조될 수 있다.As described above, according to the present invention, the 7,10-bis represented by the formula (I) by reacting 10-deacetylbaccatin III represented by the formula (III) with tribromoacetyl chloride in the presence of a base in the reaction solvent (Tribromoacetyl) -10-deacetylbaccatin III was prepared and a new method was developed to easily remove the protecting group in mild to neutral or mild basic conditions in the protecting group removing step. 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by formula (I) is represented by formula (IV) according to techniques known in the art to prepare docetaxel. -[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromoacetyl) -10-deacetylbacca It can be prepared as Tin III.

상기한 바와 같이 본 발명에서 제공하는 화학식 (I)로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III는 그 합성공정이 용이할 뿐만 아니라 보호기 제거단계에서 선행기술들과는 달리 매우 온화한 조건에서 보호기를 용이하게 제거할 수 있음으로 인하여 도세탁셀의 대량합성공정이 더욱 용이하다. As described above, the 7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by the formula (I) provided in the present invention not only facilitates the synthesis process but also prior art in the protecting group removal step. Unlike them, the bulk synthesis process of docetaxel is easier because the protecting group can be easily removed under very mild conditions.

본 발명은 하기의 실시예에 의하여 보다 더 잘 이해될 수 있으며, 하기의 실시예는 본 발명을 예시하기 위한 것이며 첨부된 특허청구범위에 의하여 한정되는 보호범위를 제한하고자 하는 것은 아니다. The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection defined by the appended claims.

실시예Example

실시예 1: 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III(화학식 I)의 제조Example 1 Preparation of 7,10-bis (tribromoacetyl) -10-deacetylbacatin III (Formula I)

클로로포름 225㎖에 10-데아세틸바카틴 III 5.0g (9.18mmol)을 용해시킨 다음, 피리딘 22.3㎖ (30eq.)를 적가한 후 10분 동안 교반하였다. 여기에 트리브로모아세틸 클로라이드 6.66g (21.11mmol)을 천천히 가하고 실온에서 1시간 동안 교반시켰다. 감압하에 용매를 제거한 후 잔류물에 물 100㎖를 가하고 에틸아세테이트 100㎖로 추출하였다. 유기층을 소금물로 세척하고 무수 황산마그네슘으로 수분을 제거한 후 감압증류하였다. 잔류물을 톨루엔 40㎖에 녹인 후 0℃로 냉각시켜 생성된 흰색의 고체를 여과한 후 헥산 30㎖로 세척하여 순수한 표제화합물 9.31g (수율 92%)을 수득하였다.5.0 g (9.18 mmol) of 10-deacetylbacatin III was dissolved in 225 ml of chloroform, and then 22.3 ml (30 eq.) Of pyridine was added dropwise and stirred for 10 minutes. 6.66 g (21.11 mmol) tribromoacetyl chloride was slowly added thereto and stirred at room temperature for 1 hour. After the solvent was removed under reduced pressure, 100 ml of water was added to the residue, followed by extraction with 100 ml of ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was dissolved in 40 mL of toluene, cooled to 0 ° C., the resulting white solid was filtered and washed with 30 mL of hexane to give 9.31 g (yield 92%) of the title compound.

1H NMR (CDCl3) δ=1.12 (s, 3H), 1.23 (s, 3H), 1.93 (s, 3H), 2.05 (m, 1H), 2.25 (s, 3H), 2.33 (m, 2H), 2.33 (s, 3H), 2.74 (m, 1H), 4.03 (d, J=6.4Hz, 1H), 4.18 (d, J=8.4Hz, 1H), 4.37 (d, J=8.4Hz, 1H), 4.94 (m, 1H), 5.00 (d, J=9.5Hz, 1H), 5.71 (d, J=7.0Hz, 1H), 5.74 (m, 1H), 6.54 (s, 1H), 7.50 (t, J=7.4Hz, 2H), 7.64 (t, J=7.4Hz, 1H), 8.12 (d, J=7.1Hz, 2H) 1 H NMR (CDCl 3 ) δ = 1.12 (s, 3H), 1.23 (s, 3H), 1.93 (s, 3H), 2.05 (m, 1H), 2.25 (s, 3H), 2.33 (m, 2H) , 2.33 (s, 3H), 2.74 (m, 1H), 4.03 (d, J = 6.4Hz, 1H), 4.18 (d, J = 8.4Hz, 1H), 4.37 (d, J = 8.4Hz, 1H) , 4.94 (m, 1H), 5.00 (d, J = 9.5 Hz, 1H), 5.71 (d, J = 7.0 Hz, 1H), 5.74 (m, 1H), 6.54 (s, 1H), 7.50 (t, J = 7.4Hz, 2H), 7.64 (t, J = 7.4Hz, 1H), 8.12 (d, J = 7.1Hz, 2H)

실시예Example 2: 13-[(2R,3S)-3-tert-부톡시카르보닐아미노-2-하이드록시-3-이소부틸-프로파노일]-7,10-비스(트리브로모아세틸)-10-데아세틸바카틴  2: 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromoacetyl) -10- Deacetylbacatin IIIIII (화학식 Formula IVIV )의 보호기 제거Protector removal

13-[(2R,3S)-3-tert-부톡시카르보닐아미노-2-하이드록시-3-이소부틸-프로파노일]-7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III 4.0g (2.93mmol)을 메탄올:테트라하이드로푸란 (3/1, v/v) 혼합용매 20㎖에 녹인 후 메탄올에 녹인 2.0M 암모니아 (2.93㎖, 5.86mmol)를 적가하였다. 상온에서 1시간동안 교반한 후, 반응용매를 감압증류하여 제거하였다. 잔류물에 물 100㎖를 가하고 에틸아세테이트 100㎖로 추출하였다. 유기층을 소금물로 세척하고 무수 황산마그네슘으로 수분을 제거한 후 감압증류하였다. 잔류물을 톨루엔 40㎖에 녹인 후 0℃로 냉각시켜 생성된 흰색의 고체를 여과한 후 헥산 30㎖로 세척하여 순수한 13-[(2R,3S)-3-tert-부톡시카르보닐아미노-2-하이드록시-3-이소부틸-프로파노일]-10-데아세틸바카틴 III (도세탁셀) 2.21g (수율 93%)을 수득하였다.13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromoacetyl) -10-deacetyl 4.0 g (2.93 mmol) of Bacatin III was dissolved in 20 ml of a methanol: tetrahydrofuran (3/1, v / v) mixed solvent, and 2.0 M ammonia (2.93 ml, 5.86 mmol) dissolved in methanol was added dropwise. After stirring for 1 hour at room temperature, the reaction solvent was removed by distillation under reduced pressure. 100 ml of water was added to the residue, followed by extraction with 100 ml of ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was dissolved in 40 ml of toluene, cooled to 0 ° C. and the resulting white solid was filtered and washed with 30 ml of hexane to obtain pure 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2. 2.21 g (yield 93%) of -hydroxy-3-isobutyl-propanoyl] -10-deacetylbacatin III (docetaxel) were obtained.

1H NMR (CDCl3) δ=1.12 (s, 3H), 1.24(s, 3H), 1.35(s, 9H), 1.77(s, 3H), 1.87(s, 3H), 2.28(m, 2H), 2.58(m, 1H), 3.91(d, J=7Hz, 1H), 4.19(d, J=9Hz, 2H), 4.32(d, J=9Hz, 2H), 4.26(m, 1H), 4.62(d, J=2Hz, 1H), 4.94(d, J=9Hz, 1H), 5.22(s, 1H), 5.26(dd, J=9Hz 및 J=3Hz, 1H), 5.46(d, J=9Hz, 1H), 5.68(d, J=7Hz, 1H), 6.22(t, J=9Hz, 1H), 7.38(5H), 7.50, 7.60 및 8.12(5H) 1 H NMR (CDCl 3 ) δ = 1.12 (s, 3H), 1.24 (s, 3H), 1.35 (s, 9H), 1.77 (s, 3H), 1.87 (s, 3H), 2.28 (m, 2H) , 2.58 (m, 1H), 3.91 (d, J = 7 Hz, 1H), 4.19 (d, J = 9 Hz, 2H), 4.32 (d, J = 9 Hz, 2H), 4.26 (m, 1H), 4.62 ( d, J = 2 Hz, 1H), 4.94 (d, J = 9 Hz, 1H), 5.22 (s, 1H), 5.26 (dd, J = 9 Hz and J = 3 Hz, 1H), 5.46 (d, J = 9 Hz, 1H), 5.68 (d, J = 7 Hz, 1H), 6.22 (t, J = 9 Hz, 1H), 7.38 (5H), 7.50, 7.60, and 8.12 (5H)

실시예Example 3: 13-[(2R,3S)-3-tert-부톡시카르보닐아미노-2-하이드록시-3-이소부틸-프로파노일]-7,10-비스(트리브로모아세틸)-10-데아세틸바카틴  3: 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromoacetyl) -10- Deacetylbacatin IIIIII 의 보호기 제거Protector removal

13-[(2R,3S)-3-tert-부톡시카르보닐아미노-2-하이드록시-3-이소부틸-프로파노일]-7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III 4.0g (2.93mmol)을 메탄올:테트라하이드로푸란 (3/1, v/v) 혼합용매 30㎖에 녹인 후 암모늄아세테이트 0.84g(10.90mmol)을 가하였다. 상온에서 3시간동안 교반한 후, 반응용매를 감압증류하여 제거하였다. 잔류물에 물 100㎖를 가하고 에틸아세테이트 100㎖로 추출하였다. 유기층을 소금물로 세척하고 무수 황산마그네슘으로 수분을 제거한 후 감압증류하였다. 잔류물을 톨루엔 40㎖에 녹인 후 0℃로 냉각시켜 생성된 흰색의 고체를 여과한 후 헥산 30㎖로 세척하여 순수한 13-[(2R,3S)-3-tert-부톡시카르보닐아미노-2-하이드록시-3-이소부틸-프로파노일]-10-데아세틸바카틴 III (도세탁셀) 2.18g (수율 92%)을 수득하였다.13-[(2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl] -7,10-bis (tribromoacetyl) -10-deacetyl 4.0 g (2.93 mmol) of Bacatin III was dissolved in 30 ml of a methanol: tetrahydrofuran (3/1, v / v) mixed solvent, and 0.84 g (10.90 mmol) of ammonium acetate was added thereto. After stirring for 3 hours at room temperature, the reaction solvent was removed by distillation under reduced pressure. 100 ml of water was added to the residue, followed by extraction with 100 ml of ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was dissolved in 40 ml of toluene, cooled to 0 ° C. and the resulting white solid was filtered and washed with 30 ml of hexane to obtain pure 13-[(2R, 3S) -3-tert-butoxycarbonylamino-2. 2.18 g (yield 92%) of -hydroxy-3-isobutyl-propanoyl] -10-deacetylbacatin III (docetaxel) were obtained.

1H NMR (CDCl3) δ=1.12 (s, 3H), 1.24(s, 3H), 1.35(s, 9H), 1.77(s, 3H), 1.87(s, 3H), 2.28(m, 2H), 2.58(m, 1H), 3.91(d, J=7Hz, 1H), 4.19(d, J=9Hz, 2H), 4.32(d, J=9Hz, 2H), 4.26(m, 1H), 4.62(d, J=2Hz, 1H), 4.94(d, J=9Hz, 1H), 5.22(s, 1H), 5.26(dd, J=9Hz 및 J=3Hz, 1H), 5.46(d, J=9Hz, 1H), 5.68(d, J=7Hz, 1H), 6.22(t, J=9Hz, 1H), 7.38(5H), 7.50, 7.60 및 8.12(5H) 1 H NMR (CDCl 3 ) δ = 1.12 (s, 3H), 1.24 (s, 3H), 1.35 (s, 9H), 1.77 (s, 3H), 1.87 (s, 3H), 2.28 (m, 2H) , 2.58 (m, 1H), 3.91 (d, J = 7 Hz, 1H), 4.19 (d, J = 9 Hz, 2H), 4.32 (d, J = 9 Hz, 2H), 4.26 (m, 1H), 4.62 ( d, J = 2 Hz, 1H), 4.94 (d, J = 9 Hz, 1H), 5.22 (s, 1H), 5.26 (dd, J = 9 Hz and J = 3 Hz, 1H), 5.46 (d, J = 9 Hz, 1H), 5.68 (d, J = 7 Hz, 1H), 6.22 (t, J = 9 Hz, 1H), 7.38 (5H), 7.50, 7.60, and 8.12 (5H)

본 발명은 화학식 (I)로 표시되는 10-데아세틸바카틴 III로부터 용이하게 제조되고 보호기 제거가 용이한 화학식 (I)으로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III와 그의 제조방법을 제공하는 효과를 가진다.The present invention relates to 7,10-bis (tribromoacetyl) -10-deacetyl, which is easily prepared from 10-deacetylbaccatin III represented by formula (I) and represented by formula (I) that is easy to remove protecting groups. It has the effect of providing Bacatin III and its preparation.

화학식 (III)으로 표시되는 10-데아세틸바카틴 III의 보호기를 도입하는 선행기술의 경우 7번과 10번 위치를 선택적으로 보호하는 과정이 매우 낮은 수율로 얻어지거나 과량의 시약을 필요로 하며, 보호기 제거과정에서 매우 강한 산성조건이 요구되는 문제점이 있다. 그러나 본 발명은 보호기 도입과정이 용이하고, 보호기 제거단계에서 암모니아 용액 또는 암모니아와 약산과의 염을 이용한 약염기성 또는 중성의 조건에서 극히 용이하게 보호기들이 제거될 수 있는 장점을 갖는다. In the prior art in which the protecting group of 10-deacetylbaccatin III represented by the formula (III) is introduced, the process of selectively protecting positions 7 and 10 is obtained in very low yield or requires an excessive amount of reagent, There is a problem that a very strong acidic condition is required during the removal of the protecting group. However, the present invention has an advantage that the protecting group can be easily introduced, and the protecting groups can be easily removed in a weakly basic or neutral condition using an ammonia solution or a salt of ammonia and a weak acid in the protecting group removing step.

본 발명의 단순한 변형 내지 변경은 이 분야의 통상의 지식을 가진 자에 의하여 용이하게 이해될 수 있으며, 이러한 변형이나 변경은 모두 본 발명의 영역에 포함되는 것으로 볼 수 있다.Simple modifications and variations of the present invention can be readily understood by those skilled in the art, and all such variations or modifications can be considered to be included within the scope of the present invention.

Claims (7)

하기 화학식 (I)로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III.7,10-bis (tribromoacetyl) -10-deacetylbacatin III represented by formula (I) below.
Figure 112006017498481-pat00008
Figure 112006017498481-pat00008
하기 화학식 (III)으로 표시되는 10-데아세틸바카틴 III를 반응용매중에서 염기의 존재하에 트리브로모아세틸 클로라이드와 반응시키는 것을 특징으로 하는 제1항에 정의된 화학식 (I)로 표시되는 7,10-비스(트리브로모아세틸)-10-데아세틸바카틴 III를 제조하는 방법.7, represented by formula (I) according to claim 1, characterized in that 10-deacetylbaccatin III represented by formula (III) is reacted with tribromoacetyl chloride in the presence of a base in a reaction solvent. A process for preparing 10-bis (tribromoacetyl) -10-deacetylbacatin III.
Figure 112006017498481-pat00009
Figure 112006017498481-pat00009
제2항에 있어서, 반응에 사용되는 용매가 테트라하이드로푸란, 디이소프로필에테르, 메틸 t-부틸에테르, 디옥산, 메틸이소부틸케톤, 아세토니트릴, 에틸아세테이트, 이소프로필아세테이트, n-부틸아세테이트, 디클로로메탄, 클로로포름, 1,2-디클로로에탄, 벤젠, 톨루엔, 크실렌, 디메틸아세트아미드, 디메틸포름아미드 중에서 선택된 1 종 이상인 방법.The solvent used in the reaction according to claim 2, wherein the solvent used for the reaction is tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, dioxane, methyl isobutyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, n-butyl acetate, At least one selected from dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, dimethylacetamide, dimethylformamide. 제2항에 있어서, 반응에 사용되는 염기가 피리딘, 트리에틸아민, 이미다졸, DBU, 디이소프로필에틸아민, 포타슘 t-부톡사이드, 소듐에톡사이드, n-부틸리튬, 페닐리튬, 리튬디이소프로필아미드, 소듐하이드리드, 및 리튬비스트리메틸실릴아미드 중에서 선택된 1종 이상인 방법.The base used in the reaction according to claim 2, wherein the base used for the reaction is pyridine, triethylamine, imidazole, DBU, diisopropylethylamine, potassium t-butoxide, sodium ethoxide, n-butyllithium, phenyllithium, lithium di At least one selected from isopropylamide, sodium hydride, and lithium bistrimethylsilylamide. 암모니아 또는 암모니아와 아세트산, 포름산 및 프로피온산으로 구성된 군에서 선택되는 1종의 약산의 염을 사용하여 하기 화학식 (IV)로 표시되는 탁산유도체의 7번과 10번의 트리브로모아세틸 보호기를 각각 제거하여 하기 화학식 (II)로 표시되는 도세탁셀을 제조하는 방법.Using a salt of one a weak acid selected from the group consisting of ammonia or ammonia and acetic acid, formic acid and propionic acid, the tribromoacetyl protecting groups 7 and 10 of the taxane derivative represented by the following formula (IV) are respectively removed A process for producing docetaxel represented by the formula (II).
Figure 112010051999211-pat00010
Figure 112010051999211-pat00011
Figure 112010051999211-pat00010
Figure 112010051999211-pat00011
제5항에 있어서, 5 내지 40% 농도의 암모니아를 화학식 (IV)로 표시되는 탁산유도체에 대해 1 내지 5당량배로 가하여 트리브로모아세틸 보호기를 제거하는 것을 특징으로 하는 제조 방법.The method according to claim 5, wherein 5 to 40% of ammonia is added in an amount of 1 to 5 equivalents to the taxane derivative represented by the formula (IV) to remove the tribromoacetyl protecting group. 제5항에 있어서, 암모니아와 아세트산, 포름산 및 프로피온산으로 구성된 군에서 선택되는 1종의 약산의 염을 화학식 (IV)로 표시되는 탁산유도체에 대해 1 내지 5당량배로 가하여 트리브로모아세틸 보호기를 제거하는 것을 특징으로 하는 제조 방법.The salt of one weak acid selected from the group consisting of ammonia and acetic acid, formic acid and propionic acid is added in an amount of 1 to 5 equivalents to the taxane derivative represented by the formula (IV) to remove the tribromoacetyl protecting group. The manufacturing method characterized by the above-mentioned.
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