KR20090132281A - A method for preparing docetaxel and new intermediates for preparing the same - Google Patents

A method for preparing docetaxel and new intermediates for preparing the same Download PDF

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KR20090132281A
KR20090132281A KR1020080058477A KR20080058477A KR20090132281A KR 20090132281 A KR20090132281 A KR 20090132281A KR 1020080058477 A KR1020080058477 A KR 1020080058477A KR 20080058477 A KR20080058477 A KR 20080058477A KR 20090132281 A KR20090132281 A KR 20090132281A
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oxazolidine
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김경수
박영준
이인숙
박성준
이진서
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주식회사 카이로제닉스
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Abstract

PURPOSE: A method for preparing a docetaxel and a novel intermediate for preparing the docetaxel are provided to prepare the docetaxel of high purity and high yield. CONSTITUTION: A method for preparing a docetaxel of chemical formula I comprises: a step of performing coupling reaction of (4S,5R)-2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt of chemical formula VI with 7,10-bis(aryloxycarbonyl)-10-deaetylbaccatin III of chemical formula III to obtain 7,10-bis(aryloxycarbonyl)-13-((4S,5R)-2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl)-10-deacetylbaccatin III of chemical formula VII; a step of reacting the compound of chemical formula VII and removing phenylisoserine protection group; a step of reacting with di-t-butyl dicarbonate under the presence of base to obtain 7,10-bis(aryloxycarbonyl)-docetaxel of chemical formula VIII; and a step of reacting 7,10-bis(aryloxycarbonyl)-docetaxel under the presence of reaction solvent.

Description

도세탁셀의 제조방법 및 도세탁셀의 제조를 위한 신규한 중간체{A method for preparing docetaxel and new intermediates for preparing the same}A method for preparing docetaxel and new intermediates for preparing the same}

본 발명은 도세탁셀의 제조방법 및 도세탁셀의 제조를 위한 신규한 중간체에 관한 것이다. 보다 구체적으로 본 발명은 온화한 조건에서 용이하게 제거되는 보호기들을 포함하며 도세탁셀의 제조에 유용하게 사용될 수 있는 신규한 중간체 및 이들 중간체를 이용하여 간편하고 경제적으로 도세탁셀을 고 수율과 고 순도로 제조하는 방법에 관한 것이다. The present invention relates to a process for the preparation of docetaxel and to novel intermediates for the production of docetaxel. More specifically, the present invention includes novel intermediates that include protecting groups that are easily removed under mild conditions and can be useful for the preparation of docetaxel, and a method for producing docetaxel in high yield and high purity simply and economically using these intermediates. It is about.

도세탁셀(Docetaxel)은 광범위 항암효능을 갖는 것으로 잘 알려진 강력한 항암성분으로 하기 구조식 (I)로 표현된다. Docetaxel (Docetaxel) is a powerful anticancer component well known to have a wide range of anticancer efficacy and is represented by the following structural formula (I).

Figure 112008044389145-PAT00002
Figure 112008044389145-PAT00002

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

도세탁셀은 천연물에서 얻어지는 화학식 (II)로 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 formula (II) obtained from natural products.

Figure 112008044389145-PAT00003
Figure 112008044389145-PAT00003

도세탁셀을 제조하기 위해서는 출발물질인 10-데아세틸바카틴 III의 13번 위치에 페닐아이소세린 유도체를 도입해야 한다. 그러나 10-데아세틸바카틴 III에는 모두 4개의 하이드록시기가 존재하며 이들 중 7번과 10번의 하이드록시기가 13번의 하이드록시기 보다 더 좋은 반응성을 가지고 있어서 13번의 하이드록시기에 페닐아이소세린 유도체를 도입하기 위해서는 반응에 앞서 7번과 10번의 하이드록시기를 보호해야 한다. 이러한 10-데아세틸바카틴 III의 7번과 10번 하이드록시기를 보호하기 위해 트라이에틸실릴기와 2,2,2-트라이클로로에톡시카보닐기 등의 보호기를 도입하는 방법이 공지되어 있다(미국특허 제5,254,703호, 한국특허출원 제1987-0007752호).To prepare docetaxel, a phenylisoserine derivative should be introduced at position 13 of the starting material 10-deacetylbaccatin III. However, there are 4 hydroxyl groups in 10-deacetylbaccatin III, and 7 and 10 hydroxy groups have better reactivity than 13 hydroxy groups. To be introduced, the hydroxy groups 7 and 10 must be protected prior to the reaction. In order to protect the 7- and 10-hydroxy groups of 10-deacetyl-bacatin III, a method of introducing a protecting group such as triethylsilyl group and 2,2,2-trichloroethoxycarbonyl group is known (US patent). 5,254,703, Korean Patent Application No. 1987-0007752).

또한 페닐아이소세린 유도체를 10-데아세틸바카틴 III에 도입하는 과정에서도 페닐아이소세린의 아미노기와 하이드록시기를 적절히 보호하는 과정이 필요하다. 고리화되지 않은 페닐아이소세린 유도체의 경우 10-데아세틸바카틴 III와의 커플링반응이 용이하지 않을 뿐만 아니라 하이드록시기가 결합된 탄소원자의 입체구조가 라세미화되기 때문에 대부분의 선행기술의 경우 고리화된 페닐아이소세린 유도체를 반응에 사용하고 있다. In addition, in the process of introducing a phenylisoserine derivative into 10-deacetylbaccatin III, a process of properly protecting the amino group and the hydroxy group of phenylisoserine is necessary. In the case of the uncyclized phenylisoserine derivatives, the coupling reaction with 10-deacetylbaccatin III is not easy, and since the conformation of the hydroxy group-bonded carbon atom is racemicized, most of the prior art is cyclized. Phenylisoserine derivatives are used in the reaction.

대한민국특허등록 206457호와 대한민국특허공개 1995-7004286호, 대한민국특허등록 255460호, 대한민국특허등록 311198호 등에는 하기 화학식 (X)으로 표시되는 고리화된 페닐아이소세린 유도체와 하기 화학식 (XI)로 표시되며 2,2,2-트라이클로로에톡시카보닐기로 보호된 10-데아세틸바카틴 III 유도체를 반응시켜 도세탁셀을 제조하고 있다. Korea Patent Registration No. 206457, Republic of Korea Patent Publication No. 1995-7004286, Republic of Korea Patent Registration No. 255460, Republic of Korea Patent Registration No. 311198 are represented by the cyclic phenylisoserine derivative represented by the following formula (X) and the following formula (XI) And docetaxel is prepared by reacting a 10-deacetylbaccatin III derivative protected with a 2,2,2-trichloroethoxycarbonyl group.

Figure 112008044389145-PAT00004
Figure 112008044389145-PAT00004

상기 식에서 R1과 R2는 하나 이상의 아릴(페닐)라디칼로 임의로 치환된 C1-C4를 함유하는 알킬 라디칼, 또는 아릴(페닐)을 나타내고, 또는 대안적으로 R1과 R2는 그들이 연결되어 있는 탄소 원자와 함께 4 내지 7-환의 고리를 형성한다. G1과 G2는 2,2,2-트라이클로로에톡시카보닐 라디칼 또는 2,2,2-트라이클로로에톡시카보닐 라디칼로 전환될 수 있는 라디칼이다. Wherein R 1 and R 2 represent an alkyl radical containing C 1 -C 4 optionally substituted with one or more aryl (phenyl) radicals, or aryl (phenyl), or alternatively R 1 and R 2 together with the carbon atom to which they are linked To form a 4 to 7-ring ring. G1 and G2 are radicals that can be converted into 2,2,2-trichloroethoxycarbonyl radicals or 2,2,2-trichloroethoxycarbonyl radicals.

화학식 (XI)로 표시되는 10-데아세틸바카틴 III 유도체를 제조하는 방법은 대한민국특허등록 90972호에 자세히 기재되어 있다. 구체적으로는 상기 특허등록 공보에는 화학식 (II)로 표시되는 10-데아세틸바카틴 III와 2,2,2-트라이클로로에틸클로로포메이트를 반응시켜 7번과 10번의 하이드록시기가 2,2,2-트라이클로로에톡시카보닐기로 보호된 10-데아세틸바카틴 III를 93%의 수율로 얻었다고 기재되어 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 산성 조건을 사용하는 문제가 있으며, 이러한 문제들로 인하여 예기치 않은 부산물이 다량 생성되어 최종 화합물의 정제에 어려움이 있다. 도세탁셀을 제조하는 과정에서 다양한 부산물이 생성된다는 사실은 선행문헌(R.Vasu Dev 등, Journal of Pharmaceutical And Biomedical Analysis 40 (2006) 614-622)에 잘 기재되어 있다. The method for preparing the 10-deacetylbaccatin III derivative represented by Formula (XI) is described in detail in Korean Patent Registration No. 90972. Specifically, the patent publication discloses the reaction of 10-deacetylbaccatin III represented by the formula (II) with 2,2,2-trichloroethylchloroformate and the hydroxy groups of Nos. 7 and 10. It is described that 10-deacetylbacatin III protected with 2-trichloroethoxycarbonyl group was obtained 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 acidic condition in the protecting group removal reaction, and due to these problems it is difficult to purify the final compound due to the generation of unexpected by-products. The fact that various byproducts are produced in the process of preparing docetaxel is well described in R. Vasu Dev et al., Journal of Pharmaceutical And Biomedical Analysis 40 (2006) 614-622.

상기 화학식 (X)으로 표시되는 고리화된 페닐아이소세린 유도체 또한 보호기 제거반응에서 격렬한 산성조건을 필요로 하며 이 때문에 아미노기에 결합되어 있는 t-부톡시카보닐기가 함께 제거되는 문제점을 가지고 있다. 또한 도세탁셀과 같은 탁산계 화합물들은 강산성뿐만 아니라 약염기성의 반응조건에서도 불안정하기 때문에 이러한 조건에 노출될 경우 많은 부산물을 생성하는 심각한 문제점을 가지고 있다.The cyclized phenylisoserine derivative represented by the above formula (X) also requires vigorous acidic conditions in the protecting group removal reaction, and thus has a problem in that the t-butoxycarbonyl group bonded to the amino group is removed together. In addition, taxane-based compounds such as docetaxel have a serious problem of generating many by-products when exposed to such conditions because they are unstable under not only strong acidity but also weakly basic reaction conditions.

대한민국특허등록 297197호와 대한민국특허등록 301237호에서는 각각 하기 화학식 (XII)로 표시되는 페닐아이소세린 유도체와 하기 화학식 (XIII)으로 표시되는 페닐아이소세린 유도체를 이용하여 도세탁셀을 제조하고 있다. 이들 유도체들은 상기 화학식 (X)으로 표시되는 페닐아이소세린 유도체보다 상대적으로 온화한 조건에서 페닐아이소세린의 보호기를 제거할 수 있었으나 보호기 제거공정에서 10-데아세틸바카틴 III의 보호기로 사용된 2,2,2-트라이클로로에톡시카보닐기를 제거하기 위해 여전히 강산성의 격렬한 반응조건을 사용해야 하는 문제점을 가지고 있다. Korean Patent Registration No. 297197 and Korean Patent Registration No. 301237 prepare docetaxel using phenylisoserine derivatives represented by the following formula (XII) and phenylisoserine derivatives represented by the following formula (XIII), respectively. These derivatives were able to remove the protecting group of phenylisoserine under relatively mild conditions than the phenylisoserine derivative represented by the formula (X), but 2,2 used as a protecting group of 10-deacetylbaccatin III in the protecting group removing step. In order to remove the, 2-trichloroethoxycarbonyl group, there is still a problem in that vigorous acidic reaction conditions must be used.

Figure 112008044389145-PAT00005
Figure 112008044389145-PAT00005

상기 식에서 R1은 벤조일 라디칼 또는 R2-O-CO-라디칼을 나타내고(R2의 정의 는 상기 특허등록공보 참고), R3는 수소원자 또는 임의로 치환된 알릴 라디칼을 나타낸다. Wherein R 1 represents a benzoyl radical or R 2 —O—CO-radical (for definition of R 2 refer to the above patent publication), and R 3 represents a hydrogen atom or an optionally substituted allyl radical.

Figure 112008044389145-PAT00006
Figure 112008044389145-PAT00006

상기 식에서 R4는 수소 원자를 나타내거나 벤조일 라디칼 또는 라디칼 R2-O-CO-을 나타내고(R2의 정의는 상기 특허등록공보 참고), R3는 트라이할로메틸 라디칼 또는 트라이할로메틸 라디칼에 의해 치환된 페닐 라디칼을 나타낸다. Wherein R4 represents a hydrogen atom or represents a benzoyl radical or a radical R2-O-CO- (for definition of R2, see above patent registration), and R3 is substituted by a trihalomethyl radical or trihalomethyl radical Phenyl radicals.

국제특허공개 2006-135692호에서는 하기 화학식 (XIV)로 표시되는 베타락탐 화합물과 하기 화학식 (XV)로 표시되는 10-데아세틸바카틴 III 유도체를 반응시켜 도세탁셀을 제조하고 있다. In International Patent Publication No. 2006-135692, docetaxel is prepared by reacting a betalactam compound represented by the following formula (XIV) with a 10-deacetylbaccatin III derivative represented by the following formula (XV).

Figure 112008044389145-PAT00007
Figure 112008044389145-PAT00007

그러나 이 방법은 베타락탐을 이용하여 커플링 반응을 용이하게 수행할 수 있다는 우수성에도 불구하고, 베타락탐 화합물 자체의 합성이 어렵고, 커플링 반응 시 무수 조건하에 -45℃정도의 저온에서 반응을 수행하여야 하며, 10-데아세틸바카틴 III의 보호기로 사용된 실릴기를 제거하는 과정에서 강산성의 산을 사용해야 하는 문제점을 지니고 있다. However, this method is difficult to synthesize the beta lactam compound itself, despite the superiority that the coupling reaction can be easily carried out using beta lactam, the reaction is carried out at a low temperature of about -45 ℃ under anhydrous conditions during the coupling reaction. The problem is that a strong acid should be used in removing the silyl group used as a protecting group of 10-deacetylbaccatin III.

대한민국특허공개 2007-62533호에서는 하기 화학식 (XVI)으로 표시되는 페닐아이소세린 유도체와 하기 화학식 (XVII)로 표시되는 10-데아세틸바카틴 III 유도체를 반응시켜 도세탁셀을 제조하고 있다. In Korean Patent Publication No. 2007-62533, docetaxel is prepared by reacting a phenylisoserine derivative represented by Formula (XVI) with a 10-deacetylbaccatin III derivative represented by Formula (XVII).

Figure 112008044389145-PAT00008
Figure 112008044389145-PAT00008

그러나 이 반응공정에서 사용되는 10-데아세틸바카틴 III의 보호기가 도입단계 및 제거단계의 반응에서 낮은 수율을 보여주고 있으며 화학식 (XVI)으로 표시되는 페닐아이소세린 유도체의 제조에 다수의 추가공정을 필요로 하는 문제점을 지니고 있다. 또한 10-데아세틸바카틴 III의 보호기로 사용된 트라이클로로아세틸기가 약염기성의 조건에서도 매우 불안정해지는 문제점도 발견되고 있다. However, the protecting group of 10-deacetylbaccatin III used in this reaction process shows a low yield in the reaction of the introduction step and the removal step, and a number of additional steps have been taken in the preparation of the phenylisoserine derivative represented by the formula (XVI). It has a problem that it needs. In addition, a problem has been found that the trichloroacetyl group used as a protecting group for 10-deacetylbaccatin III becomes very unstable even under weakly basic conditions.

미국특허 5,254,703호에는 10-데아세틸바카틴 III의 보호기로 트라이에틸실릴기를 사용하고 있다. 도세탁셀 합성의 마지막 단계에서 이 보호기를 제거하기 위 해서는 강산인 염산을 사용하고 있으며 이때의 수율은 90%이다. 그러나 10-데아세틸바카틴 III의 하이드록시기들의 트라이에틸실릴 클로라이드와의 반응성은 7번>13번>>10번의 순서로 7번과 10번의 하이드록시기만을 선택적으로 보호하기에는 적합하지 못하다. 실제로 10-데아세틸바카틴 III와 트라이에틸실릴 클로라이드를 반응시켜 7번과 10번이 보호된 10-데아세틸바카틴 III가 얻어지는 수율은 14%에 불과하다(참고문헌: Tetrahedron 55 (1999) 6567~6576). U.S. Patent 5,254,703 uses triethylsilyl groups as protecting groups for 10-deacetylbaccatin III. At the end of the docetaxel synthesis, a strong acid hydrochloric acid is used to remove this protecting group, yielding 90%. However, the reactivity of the hydroxy groups of 10-deacetylbaccatin III with triethylsilyl chloride is not suitable for the selective protection of only 7 and 10 hydroxy groups in the order of 7> 13> 10. In fact, the yield of 10-deacetylbaccatin III protected with 7 and 10 by the reaction of 10-deacetylbaccatin III with triethylsilyl chloride is only 14% (Tetrahedron 55 (1999) 6567 ~ 6576).

이에 본 발명자들은 상기와 같은 공지 기술의 문제점을 해결하여 도세탁셀의 제조에 사용하기 더욱 용이한 페닐아이소세린과 10-데아세틸바카틴 III의 새로운 보호기를 개발하기 위하여 연구를 계속한 결과, 페닐아이소세린 유도체의 2번 위치의 하이드록시기와 3번 위치의 아미노기가 1,1-다이클로로아세톤에 의해 동시에 보호된 신규한 옥사졸리딘 유도체를 7번 및 10번 위치의 하이드록시기가 알릴옥시카보닐기에 의해 보호된 신규한 탁산유도체와 커플링시키면 커플링반응 후 보호기 제거반응이 매우 온화한 조건에서 수행됨으로써 간편하게 도세탁셀을 제조할 수 있음을 알 수 있었다. Therefore, the present inventors solved the problems of the known technique as described above, and continued the research to develop a new protecting group of phenylisoserine and 10-deacetylbacatin III which are easier to use in the preparation of docetaxel, and thus, phenylisoserine The new oxazolidine derivatives in which the hydroxyl group at position 2 and the amino group at position 3 were simultaneously protected by 1,1-dichloroacetone were replaced by the aryl group at position 7 and 10 by the allyloxycarbonyl group. Coupling with the protected new taxane derivative showed that docetaxel could be easily prepared by performing the protecting group removal reaction under a very mild condition after the coupling reaction.

즉, 본 발명자들은 페닐아이소세린 유도체의 2번 위치의 하이드록시기와 3번 위치의 아미노기가 1,1-다이클로로아세톤에 의해 동시에 보호된 신규한 옥사졸리딘 유도체를 사용하면 3번 위치의 아미노기의 친핵성 반응성이 여전히 남아 있는 상태에서 탁산유도체와의 커플링반응이 원활하게 수행될 수 있다는 사실을 발견하였다. 또한, 본 발명자들은 10-데아세틸바카틴 III의 7번과 10번 하이드록시기가 알릴옥시카보닐기 보호기에 의하여 선택적으로 용이하게 보호될 뿐만 아니라 온화한 조건에서도 용이하게 보호기 제거반응이 수행될 수 있다는 사실을 발견하고, 신규한 탁산 유도체와 그의 합성법을 개발하였다. That is, the inventors of the present invention have found that when the hydroxy group at position 2 of the phenylisoserine derivative and the amino group at position 3 are protected by 1,1-dichloroacetone simultaneously, It has been found that coupling reactions with taxane derivatives can be performed smoothly with nucleophilic reactivity remaining. In addition, the inventors have found that the hydroxy groups 7 and 10 of 10-deacetylbaccatin III are not only easily protected by allyloxycarbonyl group protecting groups, but also that the protecting group removal reaction can be easily performed even under mild conditions. And new taxane derivatives and their synthesis were developed.

본 발명의 목적은 강력한 항암 효과를 갖는 도세탁셀의 제조에 유용하게 사용될 수 있는 신규한 중간체인 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리 딘-5-카복실산 트라이알킬아민염(VI), 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III(III), 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III(VII), 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III(IX), 7,10-비스(알릴옥시카보닐)-도세탁셀(VIII)을 제공하기 위한 것이다. An object of the present invention is a novel intermediate (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid that can be usefully used in the preparation of docetaxel having a strong anticancer effect. Trialkylamine Salt (VI), 7,10-bis (allyloxycarbonyl) -10-deacetylbacatin III (III), 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R ) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III (VII), 13-[(4S, 5R) -2-dichloro To provide methyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III (IX), 7,10-bis (allyloxycarbonyl) -docetaxel (VIII) It is for.

본 발명의 다른 목적은 도세탁셀의 신규한 중간체 제조방법을 제공하기 위한 것이다.Another object of the present invention is to provide a novel method for preparing intermediates of docetaxel.

본 발명의 또 다른 목적은 신규한 중간체를 이용하여 경제적으로 고 수율과 고 순도의 도세탁셀을 제조하는 방법을 제공하기 위한 것이다. It is yet another object of the present invention to provide a process for the production of docetaxel with high yield and high purity economically using novel intermediates.

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 발명에 따른 도세탁셀의 제조방법은:The method for preparing docetaxel according to the present invention is:

(i) 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염을 하기 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III와 커플링반응시켜 하기 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 제조하는 1 단계; (i) The (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by the formula (VI) is represented by the following formula (III) Coupling reaction with 7,10-bis (allyloxycarbonyl) -10-deacetylbacatin III to 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III;

(iia) 상기 1 단계에서 얻어진 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데 아세틸바카틴 III를 용매 중에서 산 존재하에 페닐아이소세린의 보호기를 제거하고 염기 존재하에 다이-t-부틸 다이카보네이트와 반응시켜 하기 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀을 제조하는 2a 단계; (iia) 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl- represented by the formula (VII) obtained in the step 1; Oxazolidine-5-carbonyl] -10-de acetylbacatin III is removed in the solvent with a protecting group of phenylisoserine in the presence of an acid and reacted with di-t-butyl dicarbonate in the presence of a base to formula (VIII) Step 2a to prepare the indicated 7,10-bis (allyloxycarbonyl) -docetaxel;

(iiia) 상기 2a 단계에서 얻어진 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀의 7번과 10번 위치의 보호기를 반응용매 중에서 팔라듐촉매로 제거하는 3a 단계를 포함하여 이루어지거나; 또는 (iiia) a step 3a of removing the protecting groups at positions 7 and 10 of 7,10-bis (allyloxycarbonyl) -docetaxel represented by Formula (VIII) obtained in step 2a with a palladium catalyst in a reaction solvent; Or by; or

(iib) 상기 1 단계에서 얻어진 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III의 7번과 10번 위치의 보호기를 반응용매 중에서 팔라듐촉매로 제거하여 하기 화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 제조하는 2b 단계; (iib) 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl- represented by the formula (VII) obtained in the step 1; The protecting groups at positions 7 and 10 of oxazolidine-5-carbonyl] -10-deacetylbaccatin III are removed with a palladium catalyst in the reaction solvent to form 13-[(4S, 5R) Step 2b to prepare) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III;

(iiib) 상기 2b 단계에서 얻어진 화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 용매 중에서 산 존재하에 페닐아이소세린의 보호기를 제거하고 염기 존재하에 다이-t-부틸 다이카보네이트와 반응시키는 3b 단계를 포함하여 이루어진다. (iiib) 13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10- represented by formula (IX) obtained in step 2b. Deacetylbaccatin III comprises a 3b step of removing the protecting group of phenylisoserine in a solvent in the presence of an acid and reacting with di-t-butyl dicarbonate in the presence of a base.

Figure 112008044389145-PAT00009
Figure 112008044389145-PAT00010
Figure 112008044389145-PAT00009
Figure 112008044389145-PAT00010

Figure 112008044389145-PAT00011
Figure 112008044389145-PAT00012
Figure 112008044389145-PAT00011
Figure 112008044389145-PAT00012

Figure 112008044389145-PAT00013
Figure 112008044389145-PAT00014
Figure 112008044389145-PAT00013
Figure 112008044389145-PAT00014

상기 식에서 R1, R2 및 R3은 각각 독립적으로 C1-C4 알킬 또는 페닐알킬을 나타내거나, R1 및 R2가 함께 4 내지 7환의 사이클릭체인을 형성할 수 있고, 바람직하기는 R1, R2 및 R3이 에틸이다. Wherein R 1, R 2 and R 3 each independently represent C 1 -C 4 alkyl or phenylalkyl, or R 1 and R 2 together may form a 4 to 7 ring cyclic chain, preferably R 1, R 2 and R 3 are ethyl to be.

본 발명에 따른 도세탁셀의 제조방법은 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염(VI)과 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III(III)의 커플링 반응을 이용함으로써 10-데아세틸바카틴 III로의 보호기 도입과정과 상기 화합물 간의 커플링반응이 매우 용이하게 진행할 뿐만 아니라, 보호기 제거단계에서는 선행기술과 같이 강산을 사용하거나, 유독성 기체를 발생시키는 시약을 사용하지 않고도, 중성의 온화한 조건 하에서 보호기를 용이하게 제거할 수 있는 장점을 갖는다. 결국 이러한 장점들은 도세탁셀의 대량합성공정을 더욱 용이하게 하고 있다. Method for preparing docetaxel according to the present invention is (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt (VI) and 7,10-bis ( By using the coupling reaction of allyloxycarbonyl) -10-deacetylbaccatin III (III), the introduction of the protecting group into 10-deacetylbaccatin III and the coupling reaction between the compounds are very easy, The removal step has the advantage that the protecting group can be easily removed under mild and mild conditions without the use of strong acids or reagents that generate toxic gases as in the prior art. These advantages, in turn, facilitate the bulk synthesis process of docetaxel.

본 발명의 단순한 변형 내지 변경은 이 분야의 통상의 지식을 가진 자에 의 하여 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.

본 발명은 출발물질로 하기 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염과 하기 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III를 사용하여 이들 화합물을 커플링반응시켜 하기 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 제조한 다음, 화합물 (VII)의 보호기를 제거하여 도세탁셀을 제조한다.The present invention relates to (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by the following general formula (VI) as a starting material and the following general formula (III) These compounds were subjected to coupling reaction using 7,10-bis (allyloxycarbonyl) -10-deacetylbaccatin III represented by) to 7,10-bis (allyloxycarbon) represented by the following general formula (VII). Yl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III, followed by compound ( VII) is removed to prepare docetaxel.

본 발명의 제1면에 따르면, 본 발명은According to the first aspect of the present invention, the present invention

(i) 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염을 하기 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III와 커플링반응시켜 하기 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 제조하는 1 단계; (i) The (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by the formula (VI) is represented by the following formula (III) Coupling reaction with 7,10-bis (allyloxycarbonyl) -10-deacetylbacatin III to 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III;

(iia) 하기 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 용매 중에서 산 존재하에 페닐아이소세린의 보호기를 제거하고 염기 존재하에 다이-t-부틸 다이카보네이트와 반응시켜 하기 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀을 제조하는 2a 단계; 및(iia) 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine- represented by the following general formula (VII) 5-carbonyl] -10-deacetylbaccatin III is removed by the protecting group of phenylisoserine in the presence of an acid in a solvent and reacted with di-t-butyl dicarbonate in the presence of a base to give the following formula (VIII). Step 2a to prepare 10-bis (allyloxycarbonyl) -docetaxel; And

(iiia) 하기 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀의 7번과 10번 위치의 보호기를 반응용매 중에서 팔라듐촉매로 제거하는 3a 단계를 포함하는 화학식 (I)의 도세탁셀의 제조방법이다.(iiia) Formula (I) comprising the step 3a of removing the protecting groups at positions 7 and 10 of 7,10-bis (allyloxycarbonyl) -docetaxel represented by formula (VIII) with a palladium catalyst in the reaction solvent ) Is a method for producing docetaxel.

본 발명의 제2면에 따르면, 본 발명은 According to a second aspect of the invention, the invention is

(i) 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염을 하기 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III와 커플링반응시켜 하기 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 제조하는 1 단계; (i) The (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by the formula (VI) is represented by the following formula (III) Coupling reaction with 7,10-bis (allyloxycarbonyl) -10-deacetylbacatin III to 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III;

(iib) 하기 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III의 7번과 10번 위치의 보호기를 반응용매 중에서 팔라듐촉매로 제거하여 하기 화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 제조하는 2b 단계; 및(iib) 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine- represented by the following general formula (VII) The protecting groups at positions 7 and 10 of 5-carbonyl] -10-deacetylbaccatin III were removed with a palladium catalyst from the reaction solvent to form 13-[(4S, 5R) -2- 2b preparing dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III; And

(iiib) 하기 화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 용매 중에서 산 존재하에 페닐아이소세린의 보호기를 제거하고 염기 존재하에 다이-t-부틸 다이카보네이트와 반응시키는 3b 단계를 포함하는 화학식 (I)의 도세탁셀의 제조 방법이다.(iiib) 13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin represented by the following general formula (IX) III is a process for the preparation of docetaxel of formula (I) comprising the step 3b of removing the protecting group of phenylisoserine in the presence of an acid in a solvent and reacting with di-t-butyl dicarbonate in the presence of a base.

Figure 112008044389145-PAT00015
Figure 112008044389145-PAT00016
Figure 112008044389145-PAT00015
Figure 112008044389145-PAT00016

Figure 112008044389145-PAT00017
Figure 112008044389145-PAT00018
Figure 112008044389145-PAT00017
Figure 112008044389145-PAT00018

Figure 112008044389145-PAT00019
Figure 112008044389145-PAT00020
Figure 112008044389145-PAT00019
Figure 112008044389145-PAT00020

상기 식에서 R1, R2 및 R3은 각각 독립적으로 C1-C4 알킬 또는 페닐알킬을 나타내거나, R1 및 R2가 함께 4 내지 7환의 사이클릭체인을 형성할 수 있고, 바람직하기는 R1, R2 및 R3이 에틸이다. Wherein R 1, R 2 and R 3 each independently represent C 1 -C 4 alkyl or phenylalkyl, or R 1 and R 2 together may form a 4 to 7 ring cyclic chain, preferably R 1, R 2 and R 3 are ethyl to be.

본 발명은 또한 도세탁셀의 제조를 위한 중간체로서 상기 화학식 (VI), (III), (VII), (VIII), 및 (IX)로 표시되는 신규한 화합물을 제공한다.The present invention also provides novel compounds represented by the formulas (VI), (III), (VII), (VIII), and (IX) as intermediates for the preparation of docetaxel.

이하, 본 발명에 따른 도세탁셀의 제조방법을 단계별로 더욱 상세히 설명한다. Hereinafter, the method for producing docetaxel according to the present invention will be described in more detail step by step.

제1단계: 7,10-Stage 1: 7,10- 비스Vis (( 알릴옥시카보닐Allyloxycarbonyl )-13-[(4S,5R)-2-) -13-[(4S, 5R) -2- 다이클로로메틸Dichloromethyl -2--2- 메틸methyl -4--4- 페닐Phenyl -- 옥사졸리딘Oxazolidine -5--5- 카보닐Carbonyl ]-10-] -10- 데아세틸바카틴Deacetylbacatin IIIIII (( VIIVII )의 제조Manufacturing

화학식 (VII)로 나타나는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III은 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염을 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III와 커플링반응시켜 제조한다. 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] represented by formula (VII)] -10-Deacetylbaccatin III is a compound of formula (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by formula (VI) It is prepared by coupling with 7,10-bis (allyloxycarbonyl) -10-deacetylbacatin III represented by III).

화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염은 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III에 대하여 당량 이상으로, 바람직하게는 3 내지 4.5 당량배로 사용한다.The (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by formula (VI) is 7,10- represented by formula (III). It is used in an equivalent amount or more, preferably 3 to 4.5 equivalent times, relative to bis (allyloxycarbonyl) -10-deacetylbaccatin III.

이 반응에 사용가능한 용매로는 테트라하이드로퓨란, 다이아이소프로필에테르, 메틸 t-부틸에테르, 디옥산 등의 에테르류, 메틸아이소부틸케톤 등의 케톤류, 아세토나이트릴 등의 나이트릴류, 에틸아세테이트, 아이소프로필아세테이트, n-부틸아세테이트 등의 에스터류, 다이클로로메탄, 클로로폼, 1,2-다이클로로에탄 등의 염화 탄화수소류, 벤젠, 톨루엔, 자일렌 등의 방향족 탄화수소류, 다이메틸아세트아마이드, 다이메틸포름아마이드 등의 아마이드류 로부터 선택된 1 종 이상이 사용될 수 있다. As a solvent which can be used for this reaction, ethers, such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, dioxane, ketones, such as methyl isobutyl ketone, nitriles, such as acetonitrile, ethyl acetate, and iso Esters such as propyl acetate and n-butyl acetate, chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, dimethylacetamide, die One or more kinds selected from amides such as methylformamide can be used.

커플링반응은 축합제의 존재하에 수행하며, 임의로 활성화제의 존재하에 바람직하게 수행할 수 있다. 사용가능한 축합제로는 다이사이클로헥실카보다이이미드, 다이아이소프로필카보다이이미드와 같은 카보다이이미드류 또는 2-다이피리딜카보네이트와 같은 반응성 카보네이트류가 있으며, 활성화제로는 4-다이메틸아미노피리딘 또는 4-피롤리디노피리딘과 같은 다이알킬아미노피리딘이 있다. 일반적으로 축합제는 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염에 대하여 당량으로 사용하고 활성화제는 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III에 대하여 당량 이하의 양으로 사용한다. 바람직한 반응온도는 0 내지 30℃이며 반응시간은 2 내지 5시간이다. The coupling reaction is carried out in the presence of a condensing agent, optionally in the presence of an activating agent. Condensing agents that can be used include dicyclohexylcarbodiimide, carbodiimides such as diisopropylcarbodiimide, or reactive carbonates such as 2-dipyridylcarbonate, and the activator is 4-dimethylaminopyridine or 4 Dialkylaminopyridine such as pyrrolidinopyridine. Condensing agents are generally used in equivalent amounts and activated against (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by formula (VI) The agent is used in an amount equal to or less than 7,10-bis (allyloxycarbonyl) -10-deacetylbacatin III represented by the formula (III). Preferable reaction temperature is 0-30 degreeC, and reaction time is 2-5 hours.

상기 방법으로 얻어진 생성물은 통상적인 방법에 따라 반응용매가 여과 및 농축되고, 추가로 정제될 수 있다. 예를 들면, 생성물의 반응용액을 셀라이트 패드에 여과하여 감압하에서 농축하고, 다이클로로메탄에 녹여 실리카겔에 흡착시킨 후 에틸아세테이트와 헥산을 용출용액으로 사용하여 칼럼크로마토그래피를 한 다음, 에틸아세테이트와 헥산으로 결정화하여 목적 화합물을 두 가지 이성질체의 혼합물 로 얻을 수 있다. The product obtained by the above method can be further purified, the reaction solvent is filtered and concentrated according to a conventional method. For example, the reaction solution of the product was filtered through a pad of celite, concentrated under reduced pressure, dissolved in dichloromethane and adsorbed onto silica gel, followed by column chromatography using ethyl acetate and hexane as eluent, followed by ethyl acetate and Crystallization with hexane can give the desired compound as a mixture of two isomers.

본 발명의 제1단계에서 출발물질로 사용하는 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염은 하기 화학식의 (IV)로 표시되는(2R,3S)-페닐아이소세린 에스터를 반응용매 중에서 산 촉매 존재하에 1,1-다이클로로아세톤과 반응시켜 하기 화학식의 (V)로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 에스터를 제조하고, 이를 수용성 염기를 사용하여 가수분해한 후 트라이알킬아민을 가하여 용이하게 제조할 수 있다.(4S, 5R) -2-Dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by formula (VI) used as starting material in the first step of the present invention (2R, 3S) -phenylisoserine ester represented by the following formula (IV) is reacted with 1,1-dichloroacetone in the presence of an acid catalyst in a reaction solvent to represent (4S, 5R) -2-Dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid ester can be prepared, easily hydrolyzed using a water soluble base, and then trialkylamine added. .

Figure 112008044389145-PAT00021
Figure 112008044389145-PAT00021

상기 식에서 R은 C1-C4 알킬이다.Wherein R is C1-C4 alkyl.

이때 사용할 수 있는 반응용매로는 테트라하이드로퓨란, 다이아이소프로필에테르, 메틸 t-부틸에테르, 디옥산 등의 에테르류, 아세토나이트릴 등의 나이트릴류, 에틸아세테이트, 아이소프로필아세테이트, n-부틸아세테이트 등의 에스터류, 다이클로로메탄, 클로로폼, 1,2-다이클로로에탄 등의 염화 탄화수소류, 벤젠, 톨루엔, 자일렌 등의 방향족 탄화수소류로부터 선택된 1 종 이상이 사용될 수 있고, 산 촉매로는 p-톨루엔 설폰산, 벤젠 설폰산, 피리디늄 p-톨루엔 설폰산 등이 사용될 수 있다. 반응온도는 30℃ 내지 반응용매의 비점 범위 내인 것이 바람직하다. The reaction solvent that can be used at this time is ether such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, dioxane, nitrile such as acetonitrile, ethyl acetate, isopropyl acetate, n-butyl acetate, etc. At least one selected from esters of hydrocarbons, dichloromethane, chloroform, chlorinated hydrocarbons such as 1,2-dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene may be used. Toluene sulfonic acid, benzene sulfonic acid, pyridinium p-toluene sulfonic acid and the like can be used. It is preferable that reaction temperature exists in the boiling point range of 30 degreeC-a reaction solvent.

상기 방법으로 얻어진 화학식 (V)로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 에스터는 수용성염기의 수용액을 사용하여 가수분해하고, 산성조건에서 유리산으로 전환시킨 다음, 트라이알킬아민과 반응시키면 상기 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염이 얻어진다. 사용될 수 있는 수용성 염기로는 수산화리튬, 수산화나트륨, 수산화칼륨 등의 알칼리금속 수산화물을 사용하며, 반응용매로는 메탄올, 에탄올, 이소프로판올, 테트라하이드로퓨란, 아세토나이트릴과 같은 물과 섞일 수 있는 용매와 물과의 혼합용매를 사용한다. 바람직한 반응온도는 0 내지 30℃이다. 가수분해된 화합물을 유리산으로 전환시켜주기 위해서는 산을 사용해야 하는데 이때 사용가능한 산으로는 염산, 포름산, 아세트산, 트라이플루오로아세트산 등이 있으며, 가수분해 반응에서 사용한 알칼리금속 수산화물과 같은 당량으로 사용한다. 이렇게 제조된 옥사졸리딘 화합물은 산에 불안정하므로 상기 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염과 같이 3차 유기염기와의 염형태로 보관되고 사용되는 것이 바람직하다.The (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid ester represented by the formula (V) obtained by the above method was hydrolyzed using an aqueous solution of a water-soluble base. , Converted to the free acid in acidic conditions, and then reacted with trialkylamine to form (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5 represented by the formula (VI). Carboxylic acid trialkylamine salts are obtained. Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide may be used as the water-soluble base, and the reaction solvent may be a solvent which may be mixed with water such as methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and the like. Use a mixed solvent with water. Preferable reaction temperature is 0-30 degreeC. In order to convert the hydrolyzed compound into free acid, an acid should be used. The available acids include hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid, etc., and are used in the same amount as the alkali metal hydroxide used in the hydrolysis reaction. . The oxazolidine compound thus prepared is (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine represented by the formula (VI) because it is acid-stable. It is preferably stored and used in salt form with a tertiary organic base, such as salts.

본 발명의 제1단계에서 사용되는 출발물질인 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III는 하기 화학식의 (II)로 표시되는 10-데아세틸바카틴 III를 용매 중에서 알릴클로로포메이트 및 피리딘과 함께 반응시켜 용이하게 제조할 수 있다. 상기 알릴클로로포메이트는 10-데아세틸바카틴 III(II)에 대해 10 내지 20당량배로 사용하며, 피리딘은 10-데아세틸바카틴 III(II)에 대해 15 내지 30당량배로 사용한다. 이 반응에서 사용가능한 용매로는 테트라하이드로퓨란, 다이아이소프로필에테르, 메틸 t-부틸에테르, 디옥산 등의 에테르류, 아세토나이트릴 등의 나이트릴류, 에틸아세테이트, 아이소프로필아세테이트, n-부틸아세테이트 등의 에스터류, 다이클로로메탄, 클로로폼, 1,2-다이클로로에탄 등의 염화 탄화수소류, 벤젠, 톨루엔, 자일렌 등의 방향족 탄화수소류, 다이메틸아세트아마이드, 다이메틸포름아마이드 등의 아마이드류로부터 선택된 1 종 이상이 있다. 7,10-bis (allyloxycarbonyl) -10-deacetylbacatin III represented by the formula (III) which is a starting material used in the first step of the present invention is 10- represented by the following formula (II) Deacetylbacatin III can be readily prepared by reacting with allylchloroformate and pyridine in a solvent. The allylchloroformate is used in an amount of 10 to 20 equivalents based on 10-deacetylbaccatin III (II), and pyridine is used in an amount of 15 to 30 equivalents based on 10-deacetylbaccatin III (II). Solvents usable in this reaction include ethers such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether and dioxane, nitriles such as acetonitrile, ethyl acetate, isopropyl acetate, n-butyl acetate and the like. From esters, chlorohydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, and amides such as dimethylacetamide and dimethylformamide. There is at least one species selected.

Figure 112008044389145-PAT00022
Figure 112008044389145-PAT00022

제2a단계: 7,10-Step 2a: 7,10- 비스Vis (( 알릴옥시카보닐Allyloxycarbonyl )-)- 도세탁셀(VIII)의Of docetaxel (VIII) 제조 Produce

본 발명의 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀은 제1단계에서 얻어진 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III(VII)를 용매 중에서 산 존재하에 반응시켜 페닐아이소세린의 보호기를 제거하고, 염기의 존재하에 다이-t-부틸 다이카보네이트와 반응시켜 제조한다. 7,10-bis (allyloxycarbonyl) -docetaxel represented by Formula (VIII) of the present invention is 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R)-obtained in the first step. 2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III (VII) was reacted in the presence of an acid in a solvent to remove the protecting group of phenylisoserine Prepared by reacting with di-t-butyl dicarbonate in the presence of a base.

페닐아이소세린의 보호기를 제거하는 과정은 1당량배 이상의 산을 사용하여 10 내지 40분 동안 수행하여 용이하게 진행할 수 있으며, 이와 같이 강산성의 격렬한 반응조건이 아닌 소량을 산을 사용하는 온화한 조건에서 반응이 잘 이루어지는 것은 바로 출발물질로서 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염을 사용한 효과이다. The process of removing the protecting group of phenylisoserine can be easily performed by using 10 equivalents or more of acid for 10 to 40 minutes, and thus reaction is carried out under mild conditions using an acid rather than a vigorous acidic reaction condition. This is achieved by using the (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by the formula (VI) as a starting material. .

상기 반응에서 반응용액의 산도를 조절하기 위하여 사용가능한 산으로는 염산, 황산, 포름산, 질산, 아세트산, 트라이플루오로아세트산, p-톨루엔설폰산, 메탄설폰산 등이 있고, 산은 화학식 (VII)로 나타나는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 당량 이상의 양을 사용하는 것이 바람직하나, 가장 빠른 시간내에 반응을 완결하고 부반응을 최소화하기 위하여 1.5당량배 사용하는 것이 가장 바람직하다. 또한 상기 반응에 사용가능한 용매로는 테트라하이드로퓨란, 다이아이소프로필에테르, 메틸 t-부틸에테르, 디옥산 등의 에테르류, 메틸아이소부틸케톤 등의 케톤류, 아세토나이트릴 등의 나이트릴류, 에틸아세테이트, 아이소프로필아세테이트, n-부틸아세테이트 등의 에스터류, 다아클로로메탄, 클로로폼, 1,2-다이클로로에탄 등의 염화 탄화수소류, 벤젠, 톨루엔, 자일렌 등의 방향족 탄화수소류, 다이메틸아세트아마이드, 다이메틸포름아마이드 등의 아마이드류 로부터 선택된 1 종 이상이 있으며, 반응은 바람직하게는 -20 내지 60℃의 온도범위에서 수행한다. Acids usable for controlling the acidity of the reaction solution in the reaction include hydrochloric acid, sulfuric acid, formic acid, nitric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, and the like. 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetyl It is preferred to use an amount equivalent to or greater than Bacatin III, but most preferably 1.5 equivalents in order to complete the reaction and minimize side reactions in the earliest time. In addition, solvents usable for the reaction include ethers such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, dioxane, ketones such as methyl isobutyl ketone, nitriles such as acetonitrile, ethyl acetate, Esters such as isopropyl acetate and n-butyl acetate, chlorinated hydrocarbons such as diachloromethane, chloroform and 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, dimethylacetamide, There is at least one selected from amides such as dimethylformamide, and the reaction is preferably performed at a temperature range of -20 to 60 ° C.

얻어진 반응용액은 적절한 염기로 중화시키고 물을 가한 후 다이-t-부틸 다이카보네이트를 가하여 반응시키면 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀을 제조할 수 있다. 다이-t-부틸 다이카보네이트는 화학식 (VII) 로 나타나는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 당량으로, 구체적으로는 1 내지 1.2당량배로 사용하는 것이 바람직하며, 염기로는 물에 녹을 수 있는 염기로서 중탄산나트륨, 중탄산칼륨, 탄산나트륨, 탄산칼륨, 수산화나트륨, 수산화칼륨 및 수산화리튬 중에서 선택된 1종 이상을 화학식 (VII)로 나타나는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 과량으로, 바람직하게는 3 내지 20당량배로 사용한다. The obtained reaction solution is neutralized with an appropriate base, water is added, and then di-t-butyl dicarbonate is added to react to prepare 7,10-bis (allyloxycarbonyl) -docetaxel represented by the formula (VIII). Di-t-butyl dicarbonate is 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxa represented by formula (VII). It is preferable to use it as an equivalent with respect to zolidine-5-carbonyl] -10-deacetyl-bacatin III, specifically 1 to 1.2 equivalent times, and as a base, a base which can be dissolved in water is sodium bicarbonate and potassium bicarbonate. , At least one selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-di represented by formula (VII) It is used in excess, preferably 3 to 20 equivalent times, relative to chloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III.

상기 방법으로 얻어진 생성물은 반응용액의 유기층을 분리하여 감압하에서 농축하고, 에틸아세테이트와 헥산을 사용하여 결정화를 하면 목적화합물을 얻을 수 있다. The product obtained by the above method is separated from the organic layer of the reaction solution, concentrated under reduced pressure, and crystallized using ethyl acetate and hexane to obtain the target compound.

제3a단계: Step 3a: 도세탁셀(I)의Of docetaxel (I) 제조 Produce

화학식 (I)로 나타나는 도세탁셀은 제2a단계에서 얻어진 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀을 반응용매 중에서 팔라듐 촉매와 반응시켜 제조한다. Docetaxel represented by formula (I) is prepared by reacting 7,10-bis (allyloxycarbonyl) -docetaxel represented by formula (VIII) obtained in step 2a with a palladium catalyst in a reaction solvent.

탁산유도체인 화학식 (VIII)의 화합물의 7번과 10번 위치의 보호기를 제거하는 과정은 팔라듐-탄소 촉매와 암모늄포메이트를 반응시키거나 테트라키스트라이페닐포스핀-팔라듐 촉매와 친핵체로 사용될 수 있는 화합물을 반응시켜 용이하게 진행할 수 있으며, 이와 같이 탁산유도체의 안정성에 심각한 영향을 줄 수 있는 산성이나 염기성이 아닌 온화한 조건에서 반응이 잘 이루어지는 것은 바로 출발물질로 서 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III를 사용한 효과이다. Removing the protecting groups at positions 7 and 10 of the compound of the formula (VIII), which is a taxane derivative, can be used as a nucleophile by reacting a palladium-carbon catalyst with an ammonium formate or as a tetrakistriphenylphosphine-palladium catalyst. The reaction can be easily carried out by reacting the compound, and the reaction proceeds well under mild conditions that are not acidic or basic, which may seriously affect the stability of the taxane derivative. Effect of using 10-bis (allyloxycarbonyl) -10-deacetylbacatin III.

팔라듐 촉매로 팔라듐-탄소 촉매가 사용되는 경우에는 1 내지 30중량%까지 다양한 함량(순도)의 촉매가 사용될 수 있으며 이와 반응성이 유사한 팔라듐하이드록사이드-탄소 촉매나 수분이 포함되어 있는 데구사타입의 팔라듐-탄소 촉매도 사용될 수 있다. 반응에 사용되는 팔라듐 촉매의 양은 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀에 대한 중량비로 1 내지 20% 범위내에서 사용한다. 팔라듐 촉매로 팔라듐-탄소 촉매가 사용되는 경우에는 암모늄포메이트가 함께 사용되며, 암모늄포메이트는 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀에 대해 3 내지 7당량배로 사용한다. When a palladium-carbon catalyst is used as the palladium catalyst, a catalyst having various contents (purity) of 1 to 30% by weight may be used, and a palladium hydroxide-carbon catalyst having similar reactivity to that of a degussa type Palladium-carbon catalysts may also be used. The amount of palladium catalyst used in the reaction is used in the range of 1 to 20% by weight based on 7,10-bis (allyloxycarbonyl) -docetaxel represented by the formula (VIII). When a palladium-carbon catalyst is used as the palladium catalyst, ammonium formate is used together, and ammonium formate is 3 to 7 equivalents to 7,10-bis (allyloxycarbonyl) -docetaxel represented by the formula (VIII). Use by ship.

이 반응에 사용가능한 용매로는 메탄올, 에탄올, 프로판올, 아이소프로판올 등의 알코올류, 테트라하이드로퓨란, 디옥산 등의 에테르류, 아세토나이트릴 등의 나이트릴류, 다이메틸아세트아마이드, 다이메틸포름아마이드 등의 아마이드류 로부터 선택된 1 종 이상이 있다. 바람직한 반응온도는 20~40℃이며, 반응 시간은 1 내지 5시간이다. Solvents usable for this reaction include alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, dimethylacetamide, dimethylformamide and the like. There is at least one kind selected from amides of. Preferable reaction temperature is 20-40 degreeC, and reaction time is 1 to 5 hours.

팔라듐 촉매로 테트라키스트라이페닐포스핀-팔라듐 촉매가 사용되는 경우 반응에 사용되는 팔라듐 촉매의 양은 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀에 대해 0.05 내지 0.5당량배의 범위에서 사용한다. 팔라듐 촉매로 테트라키스트라이페닐포스핀-팔라듐 촉매가 사용되는 경우에는 친핵체의 역할을 할 수 있는 화합물이 함께 사용되며, 이 반응에서 사용가능한 친핵체로는 n-부틸아 민, t-부틸아민, 디메돈, 피리딘, 포름산, 아세트산, 포타슘 아세테이트, 2-에틸 헥산산으로부터 선택된 1 종 이상이 있으며, 이들 친핵체들은 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III에 대해 2 내지 5당량배로 사용한다. When tetrakistriphenylphosphine-palladium catalyst is used as the palladium catalyst, the amount of palladium catalyst used in the reaction is 0.05 to 0.5 equivalents to 7,10-bis (allyloxycarbonyl) -docetaxel represented by the formula (VIII). Used in the range of ships. When a tetrakistriphenylphosphine-palladium catalyst is used as the palladium catalyst, a compound that can act as a nucleophile is used together. The nucleophiles usable in this reaction are n-butylamine, t-butylamine, di There is at least one member selected from medon, pyridine, formic acid, acetic acid, potassium acetate, 2-ethyl hexanoic acid, and these nucleophiles are 7,10-bis (allyloxycarbonyl) -10-deacetyl represented by the formula (III). It is used 2 to 5 equivalent times with respect to Bacatin III.

또한 이 반응에 사용가능한 용매로는 테트라하이드로퓨란, 다이아이소프로필에테르, 메틸 t-부틸에테르, 디옥산 등의 에테르류, 아세토나이트릴 등의 나이트릴류, 에틸아세테이트, 아이소프로필아세테이트, n-부틸아세테이트 등의 에스터류, 다이클로로메탄, 클로로폼, 1,2-다이클로로에탄 등의 염화 탄화수소류 로부터 선택된 1 종 이상이 있다. 바람직한 반응온도는 20 내지 40℃이며, 반응 시간은 5 내지 40분이다. Moreover, as a solvent which can be used for this reaction, ethers, such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, dioxane, nitriles, such as acetonitrile, ethyl acetate, isopropyl acetate, n-butyl acetate And at least one selected from esters such as dichloromethane, chloroform and chlorinated hydrocarbons such as 1,2-dichloroethane. Preferable reaction temperature is 20-40 degreeC, and reaction time is 5-40 minutes.

상기 방법으로 얻어진 생성물은 반응용액을 셀라이트 패드에 여과하여 감압하에서 농축하고, 얻어진 잔사를 에틸아세테이트에 녹이고 물로 세척한 후 유기층을 분리하여 칼럼크로마토그래피를 한 다음, 다이클로로메탄과 헥산 및 에탄올과 물로 연속하여 결정화하면 순수한 목적 화합물을 얻을 수 있다. The product obtained by the above method was filtered through a celite pad and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with water, and the organic layer was separated and subjected to column chromatography. Then, dichloromethane, hexane, ethanol and Continuous crystallization with water gives a pure target compound.

제2b단계: 13-[(4S,5R)-2-Step 2b: 13-[(4S, 5R) -2- 다이클로로메틸Dichloromethyl -2--2- 메틸methyl -4--4- 페닐Phenyl -- 옥사졸리딘Oxazolidine -5--5- 카보닐Carbonyl ]-10-] -10- 데아세틸바카틴Deacetylbacatin III(IX)의 제조 Preparation of III (IX)

화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III는 화학식 (VII)로 나타나는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 반응용매 중에서 팔라듐 촉매와 반응시켜 제조한다. 13-[(4S, 5R) -2-Dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III represented by formula (IX) 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10 represented by VII) Prepared by reacting deacetylbacatin III with a palladium catalyst in a reaction solvent.

탁산유도체인 화학식 (VII)의 화합물의 7번과 10번 위치의 보호기를 제거하는 과정은 팔라듐-탄소 촉매와 암모늄아세테이트를 반응시키거나 테트라키스트라이페닐포스핀-팔라듐 촉매와 친핵체로 사용될 수 있는 화합물을 반응시켜 용이하게 진행할 수 있으며, 이와 같이 탁산유도체의 안정성에 심각한 영향을 줄 수 있는 산성이나 염기성 아닌 온화한 조건에서 반응이 잘 이루어지는 것은 바로 출발물질로서 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III를 사용한 효과이다. Removing the protecting groups at positions 7 and 10 of the compound of formula (VII), which is a taxane derivative, may react with a palladium-carbon catalyst and an ammonium acetate, or may be used as a nucleophile with a tetrakistriphenylphosphine-palladium catalyst. The reaction proceeds easily, and the reaction proceeds well under mild conditions that are not acidic or basic, which may seriously affect the stability of the taxane derivative. As a starting material, 7,10-bis represented by the formula (III) It is an effect using (allyloxycarbonyl) -10-deacetylbacatin III.

팔라듐 촉매로 팔라듐-탄소 촉매가 사용되는 경우에는 1 내지 30중량% 까지 다양한 함량의 촉매가 사용될 수 있으며 이와 반응성이 유사한 팔라듐하이드록사이드-탄소 촉매나 수분이 포함되어 있는 데구사타입의 팔라듐-탄소 촉매도 사용될 있다. 반응에 사용되는 팔라듐 촉매의 양은 화학식 (VII)로 나타나는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 중량비로 1 내지 20% 범위내에서 사용한다. 팔라듐 촉매로 팔라듐-탄소 촉매가 사용되는 경우에는 암모늄포메이트가 함께 사용되며, 암모늄포메이트는 화학식 (VII)로 나타나는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 3 내지 7당량배로 사용한다. When a palladium-carbon catalyst is used as the palladium catalyst, various catalysts may be used in amounts ranging from 1 to 30% by weight, and palladium hydroxide-carbon having similar reactivity or degussa-type palladium-carbon containing water. Catalysts may also be used. The amount of palladium catalyst used for the reaction was 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxa represented by formula (VII). It is used in the range of 1 to 20% by weight relative to zolidine-5-carbonyl] -10-deacetylbacatin III. When a palladium-carbon catalyst is used as the palladium catalyst, ammonium formate is used together, and ammonium formate is 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) represented by formula (VII). 2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III in 3-7 equivalents.

이 반응에 사용가능한 용매로는 메탄올, 에탄올, 프로판올, 아이소프로판올 등의 알코올류, 테트라하이드로퓨란, 디옥산 등의 에테르류, 아세토나이트릴 등의 나이트릴류, 다이메틸아세트아마이드, 다이메틸포름아마이드 등의 아마이드류 로부 터 선택된 1 종 이상이 있다. 바람직한 반응온도는 20 내지 40℃이며, 반응 시간은 1 내지 5시간이다. Solvents usable for this reaction include alcohols such as methanol, ethanol, propanol and isopropanol, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, dimethylacetamide, dimethylformamide and the like. There is at least one species selected from amides. Preferable reaction temperature is 20-40 degreeC, and reaction time is 1 to 5 hours.

팔라듐 촉매로 테트라키스트라이페닐포스핀-팔라듐 촉매가 사용되는 경우 반응에 사용되는 팔라듐 촉매의 양은 화학식 (VII)로 나타나는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 0.05 내지 0.5당량배의 범위에서 사용한다. 팔라듐 촉매로 테트라키스트라이페닐포스핀-팔라듐 촉매가 사용되는 경우에는 친핵체의 역할을 할 수 있는 화합물이 함께 사용되며, 이 반응에서 사용가능한 친핵체로는 n-부틸아민, t-부틸아민, 디메돈, 피리딘, 포름산, 아세트산, 포타슘 아세테이트, 2-에틸 헥산산으로부터 선택된 1 종 이상이 있으며, 이들 친핵체들은 화학식 (VII)로 나타나는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 2 내지 5당량배로 사용한다. When a tetrakistriphenylphosphine-palladium catalyst is used as the palladium catalyst, the amount of the palladium catalyst used in the reaction is 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) represented by the formula (VII). 2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III in the range of 0.05 to 0.5 equivalent times. When a tetrakistriphenylphosphine-palladium catalyst is used as the palladium catalyst, a compound that can act as a nucleophile is used together. The nucleophiles usable in this reaction are n-butylamine, t-butylamine and dimethone. , Pyridine, formic acid, acetic acid, potassium acetate, 2-ethyl hexanoic acid, and these nucleophiles are 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III at 2 to 5 equivalent times.

또한 이 반응에 사용가능한 용매로는 테트라하이드로퓨란, 다이아이소프로필에테르, 메틸 t-부틸에테르, 디옥산 등의 에테르류, 아세토나이트릴 등의 나이트릴류, 에틸아세테이트, 아이소프로필아세테이트, n-부틸아세테이트 등의 에스터류, 다이클로로메탄, 클로로폼, 1,2-다이클로로에탄 등의 염화 탄화수소류 로부터 선택된 1 종 이상이 있다. 바람직한 반응온도는 20~40℃이며, 반응 시간은 5 내지 40분이다. Moreover, as a solvent which can be used for this reaction, ethers, such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, dioxane, nitriles, such as acetonitrile, ethyl acetate, isopropyl acetate, n-butyl acetate And at least one selected from esters such as dichloromethane, chloroform and chlorinated hydrocarbons such as 1,2-dichloroethane. Preferable reaction temperature is 20-40 degreeC, and reaction time is 5-40 minutes.

상기 방법으로 얻어진 생성물은, 반응용액을 셀라이트 패드에 여과하여 감압하에서 농축하고, 얻어진 잔사를 에틸아세테이트에 녹이고 물로 세척한 후 유기층 을 분리하여 칼럼크로마토그래피를 통해 목적 화합물을 얻을 수 있다. The product obtained by the above method, the reaction solution is filtered through a pad of celite and concentrated under reduced pressure, the obtained residue is dissolved in ethyl acetate and washed with water and then separated by an organic layer to obtain the target compound through column chromatography.

제3b단계: Step 3b: 도세탁셀(I)의Of docetaxel (I) 제조 Produce

본 발명의 화학식 (I)로 나타나는 도세탁셀은 상기 화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 용매 중에서 산 존재하에 반응시켜 페닐아이소세린의 보호기를 제거하고, 염기의 존재하에 다이-t-부틸 다이카보네이트와 반응시켜 제조한다. Docetaxel represented by Formula (I) of the present invention is 13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl represented by Formula (IX) ] -10-deacetylbacatin III is reacted in the presence of an acid in a solvent to remove the protecting group of phenylisoserine and is reacted with di-t-butyl dicarbonate in the presence of a base.

페닐아이소세린의 보호기를 제거하는 과정은 1.5당량배의 산을 사용하는 완화한 조건에서 10 내지 40분 동안 수행하여 용이하게 진행할 수 있으며, 이와 같이 강산성의 격렬한 반응조건이 아닌 온화한 조건에서 반응이 잘 이루어지는 것은 바로 출발물질로서 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염을 사용한 효과이다. The process of removing the protecting group of phenylisoserine can be easily carried out by performing for 10 to 40 minutes under mild conditions using 1.5 equivalents of acid. In this way, the reaction is well reacted under mild conditions rather than vigorous acidic reaction conditions. It is the effect of using (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by general formula (VI) as starting material.

반응액의 산도를 조절하기 위하여 사용가능한 산으로는 염산, 황산, 포름산, 질산, 아세트산, 트라이플루오로아세트산, p-톨루엔설폰산, 메탄설폰산 등이 있고, 산은 화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 당량의 양을 사용하는 것이 바람직하나, 가장 빠른 시간내에 반응을 완결하고 부반응을 최소화하기 위하여 1.5당량배를 사용한다. 또한 이 반응에 사용가능한 용매로는 테트라하이드로퓨란, 다이아이소프로필에테르, 메틸 t-부틸에테르, 디옥산 등의 에테르류, 메틸아이소부틸케톤 등의 케톤류, 아세토나이트릴 등의 나이트릴류, 에틸아세테이트, 아이소프로필아세테이트, n-부틸아세테이트 등의 에스터류, 다이클로로메탄, 클로로폼, 1,2-다이클 로로에탄 등의 염화 탄화수소류, 벤젠, 톨루엔, 자일렌 등의 방향족 탄화수소류, 다이메틸아세트아마이드, 다이메틸포름아마이드 등의 아마이드류 로부터 선택된 1 종 이상이 있으며, 반응은 바람직하게는 -20 내지 60℃의 온도범위에서 수행한다. 얻어진 반응용액을 적절한 염기로 중화시키고 물을 가한 후 다이-t-부틸 다이카보네이트를 가하여 반응시키면 화학식 (I)로 표시되는 도세탁셀을 제조할 수 있다. 반응에 사용되는 다이-t-부틸 다이카보네이트는 화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 당량으로, 구체적으로는 1 내지 1.2당량배로 사용하는 것이 바람직하며, 염기로는 물에 녹을 수 있는 염기로서 중탄산나트륨, 중탄산칼륨, 탄산나트륨, 탄산칼륨, 수산화나트륨, 수산화칼륨 및 수산화리튬 중에서 선택된 1종 이상을 화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 과량으로, 바람직하게는 3 내지 20당량배로 사용한다. Acids usable for controlling the acidity of the reaction solution include hydrochloric acid, sulfuric acid, formic acid, nitric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, and the like. It is preferred to use an equivalent amount of-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III In this case, 1.5 equivalents are used to complete the reaction in the earliest time and to minimize side reactions. As the solvent usable for this reaction, ethers such as tetrahydrofuran, diisopropyl ether, methyl t-butyl ether, dioxane, ketones such as methyl isobutyl ketone, nitriles such as acetonitrile, ethyl acetate, Esters such as isopropyl acetate and n-butyl acetate, chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, dimethylacetamide And at least one selected from amides such as dimethylformamide, and the reaction is preferably performed at a temperature range of -20 to 60 ° C. Docetaxel represented by the formula (I) can be prepared by neutralizing the obtained reaction solution with an appropriate base, adding water, and then reacting with di-t-butyl dicarbonate. The di-t-butyl dicarbonate used for the reaction is 13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl represented by the formula (IX). ] 10-deacetylbacatin III is used in the equivalent amount, specifically 1 to 1.2 equivalent times, and the base is a water soluble base as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, hydroxide At least one selected from sodium, potassium hydroxide and lithium hydroxide is selected from 13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbo represented by formula (IX) It is used in excess of Neil] -10-deacetylbaccatin III, preferably 3 to 20 equivalent times.

상기 방법으로 얻어진 생성물은, 반응용액의 유기층을 분리하여 감압하에서 농축하고, 얻어진 잔사를 에틸아세테이트에 녹이고 물로 세척한 후 유기층을 분리하여 칼럼크로마토그래피를 한 다음, 에틸아세테이트와 헥산 및 에탄올과 물로 연속하여 결정화 하면 순수한 목적 화합물을 얻을 수 있다. The product obtained by the above method was separated from the organic layer of the reaction solution, concentrated under reduced pressure, the residue obtained was dissolved in ethyl acetate, washed with water, and the organic layer was separated and subjected to column chromatography, followed by ethyl acetate, hexane, ethanol, and water. When crystallized to obtain a pure target compound.

상기한 바와 같이 본 발명에서 제공하는 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염과 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III는 커플 링반응이 매우 용이하게 진행할 뿐만 아니라 보호기 제거단계에서 선행기술들과는 달리 매우 온화한 조건에서 보호기를 용이하게 제거할 수 있음으로 하여 도세탁셀의 대량합성공정을 더욱 용이하게 할 수 있다. As described above, (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by formula (VI) provided in the present invention and 7,10-bis (allyloxycarbonyl) -10-deacetylbacatin III, represented by III), facilitates the coupling reaction very easily and facilitates protecting under very mild conditions unlike prior arts in the protecting group removal step. It can be removed to facilitate the mass synthesis process of docetaxel more easily.

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: (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 메틸에스터(V)의 제조Example 1: Preparation of (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid methyl ester (V)

(2R,3S)-페닐아이소세린 에스터 51.76g(0.27mol)과 피리디늄 p-톨루엔설포네이트 2.67g(0.01mol)을 톨루엔 700㎖에 녹인 후, 1,1-다이클로로아세톤 34.57g(0.32mol)을 적가한 후 딘-스탁 트랩(Dean-Stark trap)을 설치하고 3시간 동안 환류시켰다. 반응이 완결된 후 탄산수소나트륨 5.1g을 포화 소금물 200㎖에 녹인 혼합수용액을 반응용액에 가하고 유기층을 분리하였다. 물층을 에틸아세테이트 700㎖로 추출한 후 유기층을 모두 합하여 무수 황산 마그네슘으로 건조시키고 감압하에서 농축시켜 표제 화합물(V) 76.62g을 얻었다. 2가지 이성질체의 혼합물로 얻어진 수율은 95%였다.51.76 g (0.27 mol) of (2R, 3S) -phenylisoserine ester and 2.67 g (0.01 mol) of pyridinium p-toluenesulfonate were dissolved in 700 ml of toluene, followed by 34.57 g (0.32 mol) of 1,1-dichloroacetone. ) Was added dropwise and Dean-Stark trap was installed and refluxed for 3 hours. After the reaction was completed, a mixed aqueous solution of 5.1 g of sodium bicarbonate dissolved in 200 ml of saturated brine was added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted with 700 ml of ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 76.62 g of the title compound (V). The yield obtained with a mixture of two isomers was 95%.

1H NMR (400MHz, CDCl3) :δ= 7.41-7.32(5H, m), 5.96(1H, s), 4.61(1H, t), 4.50(1H, d), 3.74(3H, s), 2.65(1H, d), 1.76(3H, s) (이상 TLC에서 위에 나타나 는 이성질체) 1 H NMR (400 MHz, CDCl 3 ): δ = 7.41-7.32 (5H, m), 5.96 (1H, s), 4.61 (1H, t), 4.50 (1H, d), 3.74 (3H, s), 2.65 (1H, d), 1.76 (3H, s) (isomers appearing above in TLC above)

1H NMR (400MHz, CDCl3) :δ= 7.48-7.28(5H, m), 5.55(1H, s), 4.67(1H, m), 4.60(1H, d), 3.73(3H, s), 2.90(1H, d), 1.76(3H, s) (이상 TLC에서 아래에 나타나는 이성질체) 1 H NMR (400 MHz, CDCl 3 ): δ = 7.48-7.28 (5H, m), 5.55 (1H, s), 4.67 (1H, m), 4.60 (1H, d), 3.73 (3H, s), 2.90 (1H, d), 1.76 (3H, s) (isomers appearing below in TLC above)

실시예 2: (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이에틸아민염(VI)의 제조Example 2: Preparation of (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid triethylamine salt (VI)

실시예 1에서 얻어진 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 메틸에스터 76.62g(0.25mol)을 메탄올 400㎖에 녹인 후, 3.0N-수산화리튬 수용액 125㎖을 적가하였다. 실온에서 30분 동안 교반한 후 감압하에서 농축하였다. 얻어진 잔사를 에틸아세테이트 300㎖와 물 200㎖에 녹인 후 물층을 추출하였다. 유기층을 물 100㎖로 다시 추출하여 물층을 합한 후, 에틸아세테이트 500㎖를 가하고 3N-염산 125㎖를 서서히 적가하였다. 유기층을 분리한 후 물층을 에틸아세테이트 100㎖로 2회 추출하였다. 유기층을 합하여 트라이에틸아민 76.39g(0.76mol)을 적가한 후, 무수 황산 마그네슘으로 건조하고 감압하에서 농축하여 표제 화합물(VI) 83.79g을 얻었다. 얻어진 수율은 85%였다.After dissolving 76.62 g (0.25 mol) of (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid methyl ester obtained in Example 1 in 400 ml of methanol, 3.0 N 125 ml of an aqueous lithium hydroxide solution was added dropwise. Stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The obtained residue was dissolved in 300 ml of ethyl acetate and 200 ml of water, and then the water layer was extracted. The organic layer was extracted again with 100 mL of water, the water layers were combined, 500 mL of ethyl acetate was added, and 125 mL of 3N hydrochloric acid was slowly added dropwise. The organic layer was separated and the aqueous layer was extracted twice with 100 ml of ethyl acetate. The organic layers were combined, 76.39 g (0.76 mol) of triethylamine was added dropwise, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 83.79 g of the title compound (VI). The yield obtained was 85%.

실시예Example 3: 7,10- 3: 7,10- 비스Vis (( 알릴옥시카보닐Allyloxycarbonyl )-10-) -10- 데아세틸바카틴Deacetylbacatin IIIIII (( IIIIII )의 제조Manufacturing

10-데아세틸바카틴 III 30g(0.06mol)과 피리딘 87.15g(1.10mol)을 클로로폼 300㎖에 녹인 후 반응용액의 온도를 0℃로 낮추고 알릴클로로포메이트 66.40g(0.83mol)을 온도를 0℃로 유지하면서 3시간 동안 서서히 적가하였다. 반응 이 완결된 후 감압하에서 농축하고 에틸아세테이트 500㎖에 녹인 후 3N-염산 수용액 600㎖를 가하였다. 유기층을 분리한 후 무수 황산 마그네슘으로 건조하고 감압하에서 농축하였다. 얻어진 고체는 에틸아세테이트 500㎖에 50℃로 가열하면서 녹인 후 용액의 부피를 감압하에서 200㎖로 농축하고 헥산 700㎖를 서서히 가하여 생성되는 흰색의 분말을 여과하여 표제 화합물(III) 37.30g을 얻었다. 얻어진 수율은 95%였다.30-g (0.06 mol) of 10-deacetyl-bacatin III and 87.15 g (1.10 mol) of pyridine were dissolved in 300 ml of chloroform, and the temperature of the reaction solution was lowered to 0 ° C and 66.40 g (0.83 mol) of allylchloroformate was heated. It was slowly added dropwise for 3 hours while maintaining at 0 ° C. After the reaction was completed, the mixture was concentrated under reduced pressure, dissolved in 500 ml of ethyl acetate, and 600 ml of 3N hydrochloric acid solution was added thereto. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was dissolved in 500 ml of ethyl acetate while heating to 50 ° C., the volume of the solution was concentrated to 200 ml under reduced pressure, and 700 ml of hexane was gradually added to filter the resulting white powder to obtain 37.30 g of the title compound (III). The yield obtained was 95%.

1H NMR (400MHz, CDCl3) :δ= 8.10(2H, d), 7.61(1H, t), 7.49(2H, t), 6.25(1H, s), 6.01-5.94(2H, m), 5.63(1H, d), 5.53(1H, dd), 5.41-5.22(4H, m), 4.98(1H, d), 4.88(1H, m), 4.67-4.63(4H, m), 4.33((1H, d), 4.15(1H, d), 3.99(1H, d), 2.67-2.59(1H, m) 2.30(3H, s), 2.28(2H, m), 2.17(3H, s), 2.11(1H, d), 1.97(1H, m), 1.82(3H, s), 1.46(3H, s), 1.09(3H, s) 1 H NMR (400 MHz, CDCl 3 ): δ = 8.10 (2H, d), 7.61 (1H, t), 7.49 (2H, t), 6.25 (1H, s), 6.01-5.94 (2H, m), 5.63 (1H, d), 5.53 (1H, dd), 5.41-5.22 (4H, m), 4.98 (1H, d), 4.88 (1H, m), 4.67-4.63 (4H, m), 4.33 ((1H, d), 4.15 (1H, d), 3.99 (1H, d), 2.67-2.59 (1H, m) 2.30 (3H, s), 2.28 (2H, m), 2.17 (3H, s), 2.11 (1H, d), 1.97 (1H, m), 1.82 (3H, s), 1.46 (3H, s), 1.09 (3H, s)

실시예Example 4: 7,10- 4: 7,10- 비스Vis (( 알릴옥시카보닐Allyloxycarbonyl )-13-[(4S,5R)-2-) -13-[(4S, 5R) -2- 다이클로로메틸Dichloromethyl -2--2- 메틸methyl -4--4- 페닐Phenyl -- 옥사졸리딘Oxazolidine -5--5- 카보닐Carbonyl ]-10-] -10- 데아세틸바카틴Deacetylbacatin IIIIII (( VIIVII )의 제조 Manufacturing

실시예 3에서 얻어진 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III(III) 37.30g(0.05mol)을 다이사이클로헥실카보다이이미드 43.19g(0.21mmol) 및 4-다이메틸아미노피리딘 1.28g(0.01mol)과 함께 톨루엔 1000㎖에 녹인 후 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이에틸아민염(VI) 81.92g(0.21mol)을 톨루엔 500㎖에 녹인 용액을 0℃에서 서서히 적가하였다. 반응용액의 온도를 실온까지 서서히 올리면서 3시간 동안 교반하였다. 반응이 완결된 후 반응용액을 셀라이트 패드에 여과하여 불용성 물질을 제거하고, 감압하에서 농축하였다. 37.30 g (0.05 mol) of 7,10-bis (allyloxycarbonyl) -10-deacetylbacatin III (III) obtained in Example 3 was added to 43.19 g (0.21 mmol) of dicyclohexylcarbodiimide and 4-di (4S, 5R) -2-Dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid triethylamine salt (VI) dissolved in 1000 ml of toluene with 1.28 g (0.01 mol) of methylaminopyridine ) A solution of 81.92 g (0.21 mol) in 500 ml of toluene was slowly added dropwise at 0 ° C. The reaction solution was stirred for 3 hours while gradually raising the temperature to room temperature. After the reaction was completed, the reaction solution was filtered through a pad of celite to remove insoluble matters, and concentrated under reduced pressure.

얻어진 잔사를 350㎖의 다이클로로메탄에 녹여 130g의 실리카겔에 흡착시킨 후 칼럼크로마토그래피를 통해 화합물을 분리 정제하였다. 사용한 칼럼의 직경은 2.7인치이며 70-230mesh의 실리카겔 500g을 사용하였다. 화합물을 로딩한 후 에틸아세테이트/헥산=1:5 혼합용매 1.5L와 에틸아세테이트/헥산=1:4 혼합용매 1.2L, 에틸아세테이트/헥산=1:3 혼합용매 1.5L로 연속하여 용출시키면 목적 화합물이 나오고 시작하며 에틸아세테이트/헥산=1:3 혼합용매 11L로 용출시키면 목적 화합물이 모두 나왔다. 목적화합물이 포함된 용출용액을 모두 합하여 감압하에서 농축하고, 얻어진 조생성물을 에틸아세테이트 150㎖에 녹인 후 헥산 1000㎖를 가하여 결정화하고, 여과하여 표제 화합물(VII) 45.36g을 얻었다. 2가지 이성질체의 혼합물로 얻어진 수율은 88%였다. The obtained residue was dissolved in 350 ml of dichloromethane and adsorbed onto 130 g of silica gel, and then the compound was separated and purified through column chromatography. The diameter of the column used was 2.7 inches and 500-g silica gel of 70-230mesh was used. After loading the compound, eluting with 1.5L ethyl acetate / hexane = 1: 5 mixed solvent, 1.2L ethyl acetate / hexane = 1: 4 mixed solvent, and 1.5L ethyl acetate / hexane = 1: 3 mixed solvent This was started and eluted with 11 L of ethyl acetate / hexane = 1: 3 mixed solvent to give all the target compounds. All the elution solutions containing the target compound were combined and concentrated under reduced pressure. The crude product was dissolved in 150 ml of ethyl acetate, and 1000 ml of hexane was added to crystallize. The resulting mixture was filtered to give 45.36 g of the title compound (VII). The yield obtained with a mixture of two isomers was 88%.

1H NMR (400MHz, CDCl3) :δ= 8.03(2H, d), 7.65(1H, t), 7.52-7.49(3H, m), 7.42-7.36(3H, m), 6.23(1H, t), 6.22(1H, s), 6.02-5.91(2H, m), 5.77(1H, s), 5.65(1H, dd), 5.49(1H, dd), 5.45-5.22(4H, m), 4.90(1H, d), 4.75(1H, t), 4.66-4.62(4H, m), 4.53(1H, d), 4.26(1H, d), 4.11(1H, d), 3.88(1H, d), 2.62-2.55(1H, m), 2.17-2.14(2H, m), 2.09(3H, s), 1.91(3H, s), 1.81(3H, s), 1.80(3H, s), 1.75(1H, m), 1.25(3H, s), 1.15(3H, s) (이상 TLC에서 위에 나타나는 이성질체) 1 H NMR (400 MHz, CDCl 3 ): δ = 8.03 (2H, d), 7.65 (1H, t), 7.52-7.49 (3H, m), 7.42-7.36 (3H, m), 6.23 (1H, t) , 6.22 (1H, s), 6.02-5.91 (2H, m), 5.77 (1H, s), 5.65 (1H, dd), 5.49 (1H, dd), 5.45-5.22 (4H, m), 4.90 (1H , d), 4.75 (1H, t), 4.66-4.62 (4H, m), 4.53 (1H, d), 4.26 (1H, d), 4.11 (1H, d), 3.88 (1H, d), 2.62- 2.55 (1H, m), 2.17-2.14 (2H, m), 2.09 (3H, s), 1.91 (3H, s), 1.81 (3H, s), 1.80 (3H, s), 1.75 (1H, m) , 1.25 (3H, s), 1.15 (3H, s) (isomers appearing above in TLC)

1H NMR (400MHz, CDCl3) :δ= 8.03-8.01(2H, m), 7.65(1H, t), 7.53-7.48(2H, t), 7.46-7.36(5H, m), 6.28(1H, t), 6.20(1H, s), 6.01(1H, s), 6.00-5.90(2H, m), 5.63(1H, d), 5.45(1H, dd), 5.41-5.21(4H, m), 4.87(1H, d), 4.69(1H, m), 4.69-4.62(4H, m), 4.41(1H, d), 4.24(1H, d), 4.09(1H, d), 3.86(1H, d), 2.61-2.53(1H, m), 2.14-2.11(2H, m), 2.02(3H, s), 1.93(1H, m), 1.83(3H, s), 1.78(3H, s), 1.67(3H, s), 1.23(3H, s), 1.16(3H, s) (이상 TLC에서 아래에 나타나는 이성질체) 1 H NMR (400 MHz, CDCl 3 ): δ = 8.03-8.01 (2H, m), 7.65 (1H, t), 7.53-7.48 (2H, t), 7.46-7.36 (5H, m), 6.28 (1H, t), 6.20 (1H, s), 6.01 (1H, s), 6.00-5.90 (2H, m), 5.63 (1H, d), 5.45 (1H, dd), 5.41-5.21 (4H, m), 4.87 (1H, d), 4.69 (1H, m), 4.69-4.62 (4H, m), 4.41 (1H, d), 4.24 (1H, d), 4.09 (1H, d), 3.86 (1H, d), 2.61-2.53 (1H, m), 2.14-2.11 (2H, m), 2.02 (3H, s), 1.93 (1H, m), 1.83 (3H, s), 1.78 (3H, s), 1.67 (3H, s), 1.23 (3H, s), 1.16 (3H, s) (isomers appearing below in TLC above)

실시예 5: 7,10-비스(알릴옥시카보닐)-도세탁셀(VIII)의 제조 Example 5: Preparation of 7,10-bis (allyloxycarbonyl) -docetaxel (VIII)

실시예 4에서 얻어진 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III 45.36g(0.05mol)을 에틸아세테이트 400㎖에 녹인 후 진한 염산 5.76㎖(0.075mol)를 적가하고, 상온에서 30분 동안 교반하였다. 반응용액에 탄산수소나트륨 42.56g(0.55mol)을 가하여 중화시키고, 물 1L를 가한 후 다이-t-부틸 다이카보네이트 12.06g(0.06mol)을 가하였다. 상온에서 2.5시간 동안 교반시킨 후 유기층을 분리하고, 물층을 에틸아세테이트 500㎖로 2회 추출하였다. 유기층을 합하여 무수 황산 마그네슘으로 건조하고 감압하에서 농축하였다. 얻어진 잔사를 아세톤 100㎖에 녹이고 헥산 700㎖를 서서히 가한 후 생성된 흰색고체를 여과하여 표제 화합물(VIII) 42.70g을 얻었다. 얻어진 수율은 95%였다. 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] obtained in Example 4 45.36 g (0.05 mol) of 10-deacetylbaccatin III was dissolved in 400 ml of ethyl acetate, and then 5.76 ml (0.075 mol) of concentrated hydrochloric acid was added dropwise, and stirred at room temperature for 30 minutes. 42.56 g (0.55 mol) of sodium hydrogen carbonate was added to the reaction solution and neutralized. 1 L of water was added thereto, and then 12.06 g (0.06 mol) of di-t-butyl dicarbonate was added thereto. After stirring for 2.5 hours at room temperature, the organic layer was separated, and the water layer was extracted twice with 500 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 100 ml of acetone, 700 ml of hexane was slowly added, and the produced white solid was filtered to give 42.70 g of the title compound (VIII). The yield obtained was 95%.

1H NMR (400MHz, CDCl3) :δ= 8.10(2H, d), 7.61(1H, t), 7.50(2H, t), 7.42-7.37(4H, m), 7.35-7.31(1H, m), 6.22(1H, s), 6.19(1H, t), 6.02-5.91(2H, m), 5.68(1H, d), 5.47(1H, dd), 5.41-5.22((4H+2H, m), 4.94(1H, d), 4.70-4.60(4H+1H, m) 4.32(1H, d), 4.17(1H, d), 3.91(1H, d), 3.34(1H, d), 2.65-2.57(1H, m), 2.38(3H, s), 2.32(2H, brs), 2.00(1H, m), 1.94(3H, s), 1.83(3H, s), 1.35(9H, s), 1.26(3H, s), 1.19(3H, s) 1 H NMR (400 MHz, CDCl 3 ): δ = 8.10 (2H, d), 7.61 (1H, t), 7.50 (2H, t), 7.42-7.37 (4H, m), 7.35-7.31 (1H, m) , 6.22 (1H, s), 6.19 (1H, t), 6.02-5.91 (2H, m), 5.68 (1H, d), 5.47 (1H, dd), 5.41-5.22 ((4H + 2H, m), 4.94 (1H, d), 4.70-4.60 (4H + 1H, m) 4.32 (1H, d), 4.17 (1H, d), 3.91 (1H, d), 3.34 (1H, d), 2.65-2.57 (1H , m), 2.38 (3H, s), 2.32 (2H, brs), 2.00 (1H, m), 1.94 (3H, s), 1.83 (3H, s), 1.35 (9H, s), 1.26 (3H, s), 1.19 (3H, s)

실시예Example 6:  6: 도세탁셀(I)의Of docetaxel (I) 제조 1 Manufacture 1

실시예 5에서 얻어진 7,10-비스(알릴옥시카보닐)-도세탁셀 42.70g(0.04mol)을 메탄올 1L에 녹이고 팔라듐-탄소 촉매 4.27g과 암모늄포메이트 13.79g(0.22mol)을 가하였다. 반응용액을 35℃에서 3시간 동안 교반하여 반응이 완결된 후, 반응용액을 셀라이트 패드에 여과하였다. 반응용액을 감압하에서 농축한 후 에틸아세테이트 500㎖에 녹이고 물 300㎖를 가하여 유기층을 추출하였다. 얻어진 유기층을 무수 황산 마그네슘으로 건조하고 감압하에서 농축한 후 칼럼크로마토그래피를 통해 화합물을 분리 정제하였다. 사용한 칼럼의 직경은 2.7인치이며 70-230mesh의 실리카겔 500g을 사용하였다. 화합물을 로딩한 후 다이클로로메탄 1L와 에틸아세테이트/헥산=1:1 혼합용매 4L로 연속하여 용출시키면 목적 화합물이 나오기 시작하며 에틸아세테이트/헥산=3:2 혼합용매 5L로 용출시키면 목적 화합물이 모두 나왔다. 목적화합물이 포함된 용출용액을 모두 합하여 감압하에서 농축하고, 얻어진 조생성물을 다이클로로메탄 180㎖에 녹인 후 헥산 80㎖를 가하여 결정화하고, 생성된 흰색 고 체를 여과하였다. 얻어진 고체를 다시 에탄올 700㎖에 녹인 후 물 3L를 가하여 결정화하고 여과하여 순수한 도세탁셀(I) 30.12g을 얻었다. 얻어진 수율은 85%였다. 42.70 g (0.04 mol) of 7,10-bis (allyloxycarbonyl) -docetaxel obtained in Example 5 was dissolved in 1 L of methanol, and 4.27 g of palladium-carbon catalyst and 13.79 g (0.22 mol) of ammonium formate were added thereto. After the reaction was completed by stirring the reaction solution at 35 ° C. for 3 hours, the reaction solution was filtered through a pad of celite. The reaction solution was concentrated under reduced pressure, dissolved in 500 ml of ethyl acetate, and 300 ml of water was added to extract the organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the compound was separated and purified through column chromatography. The diameter of the column used was 2.7 inches and 500-g silica gel of 70-230mesh was used. After loading the compound, eluting with 1L of dichloromethane and 4L of ethyl acetate / hexane = 1: 1 mixed solvent, the target compound starts to come out and eluted with 5L of ethyl acetate / hexane = 3: 2 mixed solvent. Came out. The elution solution containing the target compound was combined and concentrated under reduced pressure. The obtained crude product was dissolved in 180 ml of dichloromethane, and 80 ml of hexane was added to crystallize. The resulting white solid was filtered. The obtained solid was again dissolved in 700 ml of ethanol, and 3 L of water was added to crystallize and filtered to obtain 30.12 g of pure docetaxel (I). The yield obtained was 85%.

1H NMR (400MHz, CDCl3) :δ= 8.11(2H, d), 7.62(1H, t), 7.50(2H, t), 7.42-7.31(5H, m), 6.22(1H, t), 5.68(1H, d), 5.42(1H, d), 5.27((1H, brd), 5.21(1H, d), 4.95(1H, d), 4.62(1H, brs), 4.32(1H, d), 4.25-4.20(1H, m), 4.20(1H, s), 4.19(1H, d), 3.92(1H, d), 3.34(1H, d), 2.62(1H, m), 2.38(3H, s), 2.27(2H, brd), 1.85(3H, s), 1.85(1H, m), 1.76(3H, s), 1.35(9H, s), 1.24(3H, s), 1.14(3H, s) 1 H NMR (400 MHz, CDCl 3 ): δ = 8.11 (2H, d), 7.62 (1H, t), 7.50 (2H, t), 7.42-7.31 (5H, m), 6.22 (1H, t), 5.68 (1H, d), 5.42 (1H, d), 5.27 ((1H, brd), 5.21 (1H, d), 4.95 (1H, d), 4.62 (1H, brs), 4.32 (1H, d), 4.25 -4.20 (1H, m), 4.20 (1H, s), 4.19 (1H, d), 3.92 (1H, d), 3.34 (1H, d), 2.62 (1H, m), 2.38 (3H, s), 2.27 (2H, brd), 1.85 (3H, s), 1.85 (1H, m), 1.76 (3H, s), 1.35 (9H, s), 1.24 (3H, s), 1.14 (3H, s)

실시예Example 7:  7: 도세탁셀(I)의Of docetaxel (I) 제조 2 Manufacture 2

실시예 5에서 얻어진 7,10-비스(알릴옥시카보닐)-도세탁셀 10.00g(10.25mmol)을 다이클로로메탄 600㎖에 녹이고 테트라키스트라이페닐포스핀-팔라듐(Pd(PPh3)4) 2.36g(2.05mmol)과 아닐린 9.54g(102.50mmol)을 가하였다. 반응용액을 실온에서 30분 동안 교반하고 반응이 완결된 후 물 500㎖를 넣고 유기층을 추출하였다. 얻어진 유기층은 무수 황산 마그네슘으로 건조하고, 감압하에서 농축한 후 실시예 6에서와 같은 방법으로 정제과정을 거쳐 순수한 도세탁셀(I) 7.00g을 얻었다. 얻어진 수율은 84%였다. 10.00 g (10.25 mmol) of 7,10-bis (allyloxycarbonyl) -docetaxel obtained in Example 5 was dissolved in 600 ml of dichloromethane, and 2.36 g of tetrakistriphenylphosphine-palladium (Pd (PPh 3 ) 4 ). (2.05 mmol) and 9.54 g (102.50 mmol) of aniline were added. The reaction solution was stirred at room temperature for 30 minutes, and after completion of the reaction, 500 ml of water was added and the organic layer was extracted. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified to obtain 7.00 g of pure docetaxel (I) in the same manner as in Example 6. The yield obtained was 84%.

실시예Example 8: 13-[(4S,5R)-2- 8: 13-[(4S, 5R) -2- 다이클로로메틸Dichloromethyl -2--2- 메틸methyl -4--4- 페닐Phenyl -- 옥사졸리딘Oxazolidine -5--5- 카보닐Carbonyl ]-10-] -10- 데아세틸바카틴Deacetylbacatin III(IX)의 제조 Preparation of III (IX)

실시예 4에서 얻어진 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로 메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III(VII) 20g (20.03mmol)을 다이클로로메탄 600㎖에 녹인 후 테트라키스트라이페닐포스핀-팔라듐(Pd(PPh3)4) 2.3g(2.03mmol)과 t-부틸아민 7.40g(100.15mmol)을 가하였다. 반응용액을 실온에서 5분 동안 교반하고, 반응이 완결된 후 물 500㎖를 가하고 유기층을 추출하였다. 얻어진 유기층을 무수 황산 마그네슘으로 건조하여 감압하에서 농축하고 칼럼크로마토그래피를 통해 화합물을 분리 정제하여 표제 화합물(IX) 13.2g을 얻었다. 얻어진 수율은 80%였다. 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] obtained in Example 4 20 g (20.03 mmol) of 10-deacetylbacatin III (VII) was dissolved in 600 ml of dichloromethane, followed by 2.3 g (2.03 mmol) of tetrakistriphenylphosphine-palladium (Pd (PPh 3 ) 4 ) and t-butyl 7.40 g (100.15 mmol) of amine were added. The reaction solution was stirred at room temperature for 5 minutes, and after completion of the reaction, 500 ml of water was added and the organic layer was extracted. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified through column chromatography to obtain 13.2 g of the title compound (IX). The yield obtained was 80%.

1H NMR (400MHz, CDCl3) :δ= 8.03(2H, d), 7.66(1H, t), 7.53-7.50(4H, m), 7.42-7.41(3H, m), 6.26(1H, t), 5.78(1H, s), 5.64(1H, d), 5.19(1H, s), 4.89(1H, d), 4.75(1H, t), 4.53(1H, d), 4.26(1H, d), 4.22(1H, s), 4.21(1H, m), 4.12(1H, d), 3.86(1H, d), 2.94(1H, d), 2.57-2.53(1H, m), 2.14-2.10(2H, m), 1.95(3H, s), 1.86(3H, s), 1.82(3H, s), 1.72(3H, s), 1.24(3H, s), 1.10(3H, s) (이상 TLC에서 위에 나타나는 이성질체) 1 H NMR (400 MHz, CDCl 3 ): δ = 8.03 (2H, d), 7.66 (1H, t), 7.53-7.50 (4H, m), 7.42-7.41 (3H, m), 6.26 (1H, t) , 5.78 (1H, s), 5.64 (1H, d), 5.19 (1H, s), 4.89 (1H, d), 4.75 (1H, t), 4.53 (1H, d), 4.26 (1H, d), 4.22 (1H, s), 4.21 (1H, m), 4.12 (1H, d), 3.86 (1H, d), 2.94 (1H, d), 2.57-2.53 (1H, m), 2.14-2.10 (2H, m), 1.95 (3H, s), 1.86 (3H, s), 1.82 (3H, s), 1.72 (3H, s), 1.24 (3H, s), 1.10 (3H, s) (above TLC Isomers)

1H NMR (400MHz, CDCl3) :δ= 8.02(2H, d), 7.05(1H, t), 7.51(2H, t), 7.51-7.41(5H, m), 6.28(1H, t), 6.01(1H, s), 5.63(1H, d), 5.19(1H, s), 4.86(1H, d), 4.60(1H, t), 4.40(1H, d), 4.23(1H, d), 4.22(1H, m), 4.16(1H, s), 4.10(1H, d), 3.85(1H, d),2.83(1H, d), 2.56-2.51(1H, m), 2.10(2H, m), 1.95(3H, s), 1.81(3H, s), 1.80(1H, m), 1.72(3H, s), 1.66(3H, s), 1.25(3H, s), 1.10(3H, s) (이상 TLC에서 아래에 나타나는 이성질체) 1 H NMR (400 MHz, CDCl 3 ): δ = 8.02 (2H, d), 7.05 (1H, t), 7.51 (2H, t), 7.51-7.41 (5H, m), 6.28 (1H, t), 6.01 (1H, s), 5.63 (1H, d), 5.19 (1H, s), 4.86 (1H, d), 4.60 (1H, t), 4.40 (1H, d), 4.23 (1H, d), 4.22 ( 1H, m), 4.16 (1H, s), 4.10 (1H, d), 3.85 (1H, d), 2.83 (1H, d), 2.56-2.51 (1H, m), 2.10 (2H, m), 1.95 (3H, s), 1.81 (3H, s), 1.80 (1H, m), 1.72 (3H, s), 1.66 (3H, s), 1.25 (3H, s), 1.10 (3H, s) (or more TLC Isomers that appear below in

실시예Example 9:  9: 도세탁셀(I)의Of docetaxel (I) 제조 Produce

실시예 8에서 얻어진 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III 13.2g(16.17mmol)을 에틸아세테이트 200㎖에 녹인 후 진한 염산 1.3㎖(24.25mmol)을 적가하고 상온에서 30분 동안 교반하였다. 반응이 완결된 후 반응용액에 탄산수소나트륨 13.58g(161.70mmol)을 가하여 중화시키고, 물 500㎖를 가하였다. 반응용액에 다이-t-부틸 다이카보네이트 4.23g(19.40mmol)을 가하고 상온에서 2.5시간 교반시킨 후 유기층을 분리하였다. 물층을 에틸아세테이트 300㎖로 2회 추출하고, 유기층을 합하여 무수 황산 마그네슘으로 건조한 후 유기층을 감압하에서 농축하였다. 얻어진 조생성물을 다이클로로메탄 80㎖에 녹인 후 헥산 26㎖를 가하여 결정화하였다. 얻어진 고체를 다시 에탄올 40㎖에 녹인 후 물 600㎖를 가하여 결정화하고 여과하여 순수한 도세탁셀(I) 12.41g을 얻었다. 얻어진 수율은 95%였다. 13.2 g (16.17 mmol) of 13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III obtained in Example 8 ) Was dissolved in 200 ml of ethyl acetate, and 1.3 ml (24.25 mmol) of concentrated hydrochloric acid was added dropwise, followed by stirring at room temperature for 30 minutes. After completion of the reaction, 13.58 g (161.70 mmol) of sodium bicarbonate was added to the reaction solution to neutralize it, and 500 ml of water was added thereto. 4.23 g (19.40 mmol) of di-t-butyl dicarbonate was added to the reaction solution, which was stirred at room temperature for 2.5 hours, and the organic layer was separated. The water layer was extracted twice with 300 ml of ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulfate, and the organic layer was concentrated under reduced pressure. The obtained crude product was dissolved in 80 ml of dichloromethane and crystallized by adding 26 ml of hexane. The obtained solid was dissolved in 40 ml of ethanol again, and 600 ml of water was added to crystallize and filtered to obtain 12.41 g of pure docetaxel (I). The yield obtained was 95%.

Claims (13)

하기 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염을 하기 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III와 커플링반응시켜 하기 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 제조하는 1 단계; 7, (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by the following general formula (VI) is represented by the following general formula (III) 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) represented by the following general formula (VII) by coupling with 10-bis (allyloxycarbonyl) -10-deacetylbacatin III 1 step of preparing 2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III; 1 단계에서 얻어진 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 용매 중에서 산 존재하에 반응시켜 페닐아이소세린의 보호기를 제거한 다음, 염기 존재하에 다이-t-부틸 다이카보네이트와 반응시켜 하기 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀을 제조하는 2a 단계; 및 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10 obtained in step 1 -Deacetylbaccatin III is reacted in the presence of an acid in a solvent to remove the protecting group of phenylisoserine, and then reacted with di-t-butyl dicarbonate in the presence of a base to form 7,10-bis (VIII) Step 2a to prepare allyloxycarbonyl) -docetaxel; And 2a 단계에서 얻어진 7,10-비스(알릴옥시카보닐)-도세탁셀을 반응용매 중에서 팔라듐촉매 존재 하에서 반응시키는 3a 단계:Step 3a, wherein the 7,10-bis (allyloxycarbonyl) -docetaxel obtained in step 2a is reacted in the presence of a palladium catalyst in a reaction solvent: 로 이루어지는 하기 화학식 (I)의 도세탁셀의 제조 방법.Method for producing docetaxel of formula (I) consisting of:
Figure 112008044389145-PAT00023
Figure 112008044389145-PAT00024
Figure 112008044389145-PAT00023
Figure 112008044389145-PAT00024
Figure 112008044389145-PAT00025
Figure 112008044389145-PAT00026
Figure 112008044389145-PAT00025
Figure 112008044389145-PAT00026
Figure 112008044389145-PAT00027
Figure 112008044389145-PAT00027
 상기 식에서 R1, R2 및 R3은 각각 독립적으로 C1-C4 알킬 또는 페닐알킬을 나타내거나, R1 및 R2가 함께 4 내지 7환의 사이클릭체인을 형성할 수 있음.Wherein R 1, R 2 and R 3 each independently represent C 1 -C 4 alkyl or phenylalkyl, or R 1 and R 2 may together form a 4 to 7 ring cyclic chain. 하기 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염을 하기 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III와 커플링반응시켜 하기 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 제조하는 1 단계; 7, (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by the following general formula (VI) is represented by the following general formula (III) 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) represented by the following general formula (VII) by coupling with 10-bis (allyloxycarbonyl) -10-deacetylbacatin III 1 step of preparing 2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III; 1 단계에서 얻어진 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III을 반응용매 중에서 팔라듐촉매 존재 하에서 반응시켜 상기 화합물(VII)의 7번과 10번 위치의 보호기를 제거하여 하기 화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페 닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 제조하는 2b 단계; 및7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10 obtained in step 1 -Deacetylbaccatin III is reacted in the presence of a palladium catalyst in a reaction solvent to remove the protecting groups at positions 7 and 10 of the compound (VII), and 13-[(4S, 5R)- 2b preparing 2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbaccatin III; And 2b 단계에서 얻어진 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III를 용매 중에서 산 존재하에 반응시켜 페닐아이소세린의 보호기를 제거한 다음, 염기 존재하에 다이-t-부틸 다이카보네이트와 반응시키는 3b 단계; 13-[(4S, 5R) -2-Dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III obtained in step 2b in the presence of an acid in a solvent Reacting to remove the protecting group of phenylisoserine and then reacting with di-t-butyl dicarbonate in the presence of a base; 로 이루어지는 하기 화학식 (I)의 도세탁셀의 제조 방법.Method for producing docetaxel of formula (I) consisting of:
Figure 112008044389145-PAT00028
Figure 112008044389145-PAT00029
Figure 112008044389145-PAT00028
Figure 112008044389145-PAT00029
Figure 112008044389145-PAT00030
Figure 112008044389145-PAT00031
Figure 112008044389145-PAT00030
Figure 112008044389145-PAT00031
Figure 112008044389145-PAT00032
Figure 112008044389145-PAT00032
 상기 식에서 R1, R2 및 R3은 각각 독립적으로 C1-C4 알킬 또는 페닐알킬을 나타내거나, R1 및 R2가 함께 4 내지 7환의 사이클릭체인을 형성할 수 있음. Wherein R 1, R 2 and R 3 each independently represent C 1 -C 4 alkyl or phenylalkyl, or R 1 and R 2 may together form a 4 to 7 ring cyclic chain. 제1항 또는 제2항에 있어서, 상기 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염이 (4S,5R)-2- 다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이에틸아민염인 도세탁셀의 제조 방법.The (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt of Claim 1 or 2 represented by the said General formula (VI) is The method for producing docetaxel, which is (4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid triethylamine salt. 제1항 또는 제2항에 있어서, 상기 1단계의 커플링반응은 축합제로 다이사이클로헥실카보다이이미드 또는 다이아이소프로필카보다이이미드를 사용하여 실시되는 것을 특징으로 하는 도세탁셀의 제조 방법.The method of claim 1 or 2, wherein the coupling reaction of the first step is carried out using dicyclohexylcarbodiimide or diisopropylcarbodiimide as a condensing agent. 제1항 또는 제2항에 있어서, 상기 2a단계와 상기 3b단계 반응에 사용되는 산이 염산, 황산, 포름산, 질산, 트라이플루오로아세트산, p-톨루엔설폰산, 또는 메탄설폰산 중에서 선택된 1 종 이상으로 상기 화학식 (VII)로 나타나는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III에 대해 1.5당량 사용하는 도세탁셀의 제조 방법.The method according to claim 1 or 2, wherein the acid used in the reaction of step 2a and 3b is at least one selected from hydrochloric acid, sulfuric acid, formic acid, nitric acid, trifluoroacetic acid, p-toluenesulfonic acid, or methanesulfonic acid. 7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbo represented by Formula (VII) above A method for preparing docetaxel using 1.5 equivalents of yl] -10-deacetylbaccatin III. 제1항 또는 제2항에 있어서, 상기 3a단계와 상기 2b단계 반응에 사용되는 팔라듐 촉매가 팔라듐-탄소 촉매, 팔라듐하이드록사이드-탄소 촉매, 또는 데구사타입의 팔라듐-탄소 촉매이며, 암모늄포메이트를 함께 사용하는 것을 특징으로 하는 도세탁셀의 제조 방법. The palladium catalyst used in the reaction of steps 3a and 2b is a palladium-carbon catalyst, a palladium hydroxide-carbon catalyst, or a degussa-type palladium-carbon catalyst. A method for producing docetaxel, characterized by using a mate together. 제1항 또는 제2항에 있어서, 상기 3a단계와 상기 2b단계 반응에 사용되는 팔라듐 촉매가 테트라키스트라이페닐포스핀-팔라듐 촉매이며, 친핵체로서 n-부틸아 민, t-부틸아민, 디메돈, 피리딘, 포름산, 아세트산, 포타슘 아세테이트, 2-에틸 헥산산 중에서 선택된 1 종 이상을 함께 사용하는 것을 특징으로 하는 도세탁셀의 제조 방법. The palladium catalyst used in the step 3a and the step 2b reaction is a tetrakistriphenylphosphine-palladium catalyst, and n-butylamine, t-butylamine, dimethone as nucleophiles. , Pyridine, formic acid, acetic acid, potassium acetate, 2-ethyl hexanoic acid. 하기 화학식 (VI)으로 표시되는 (4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카복실산 트라이알킬아민염:(4S, 5R) -2-Dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carboxylic acid trialkylamine salt represented by the following general formula (VI):
Figure 112008044389145-PAT00033
Figure 112008044389145-PAT00033
 상기 식에서 R1, R2 및 R3은 각각 독립적으로 C1-C4 알킬 또는 페닐알킬을 나타내거나, R1 및 R2가 함께 4 내지 7환의 사이클릭체인을 형성할 수 있음. Wherein R 1, R 2 and R 3 each independently represent C 1 -C 4 alkyl or phenylalkyl, or R 1 and R 2 may together form a 4 to 7 ring cyclic chain. 제8항에 있어서, R1, R2 및 R3이 에틸인 화합물.The compound of claim 8, wherein R 1, R 2 and R 3 are ethyl. 하기 화학식 (III)으로 표시되는 7,10-비스(알릴옥시카보닐)-10-데아세틸바카틴 III:7,10-bis (allyloxycarbonyl) -10-deacetylbacatin III represented by the following formula (III):
Figure 112008044389145-PAT00034
Figure 112008044389145-PAT00034
 하기 화학식 (VII)로 표시되는 7,10-비스(알릴옥시카보닐)-13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III:7,10-bis (allyloxycarbonyl) -13-[(4S, 5R) -2-dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbo represented by formula (VII) Nil] -10-deacetylbacatin III:
Figure 112008044389145-PAT00035
Figure 112008044389145-PAT00035
 하기 화학식 (VIII)로 표시되는 7,10-비스(알릴옥시카보닐)-도세탁셀:7,10-bis (allyloxycarbonyl) -docetaxel represented by the following formula (VIII):
Figure 112008044389145-PAT00036
Figure 112008044389145-PAT00036
 하기 화학식 (IX)로 표시되는 13-[(4S,5R)-2-다이클로로메틸-2-메틸-4-페닐-옥사졸리딘-5-카보닐]-10-데아세틸바카틴 III:13-[(4S, 5R) -2-Dichloromethyl-2-methyl-4-phenyl-oxazolidine-5-carbonyl] -10-deacetylbacatin III represented by the following formula (IX):
Figure 112008044389145-PAT00037
Figure 112008044389145-PAT00037
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