WO2010035985A2 - Method for producing taxane derivatives - Google Patents

Method for producing taxane derivatives Download PDF

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WO2010035985A2
WO2010035985A2 PCT/KR2009/005279 KR2009005279W WO2010035985A2 WO 2010035985 A2 WO2010035985 A2 WO 2010035985A2 KR 2009005279 W KR2009005279 W KR 2009005279W WO 2010035985 A2 WO2010035985 A2 WO 2010035985A2
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formula
compound
reaction
butoxycarbonyl
butyl
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PCT/KR2009/005279
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French (fr)
Korean (ko)
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WO2010035985A3 (en
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김문성
유무희
이재걸
김용직
최준호
성시영
임홍규
차대원
손병화
류기문
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동아제약 주식회사
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Priority to JP2011528922A priority Critical patent/JP5552489B2/en
Publication of WO2010035985A2 publication Critical patent/WO2010035985A2/en
Publication of WO2010035985A3 publication Critical patent/WO2010035985A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a method for preparing a taxane derivative having anticancer activity.
  • Taxane derivatives represented by the following formula (1) are important cancer chemotherapeutic agents having anti-leukemia and anti-tumor activity.
  • Representative drugs include paclitaxel and docetaxel, and the drugs have been recognized for their activity. It is marketed as a therapeutic agent for ovarian cancer and breast cancer.
  • R is t-butoxy or phenyl and G is hydrogen or acetyl.
  • the taxane derivative includes a baccatin III derivative represented by the following formula (2).
  • G1 and G2 represent an alcohol protecting group.
  • the taxane derivative represented by Chemical Formula 1 may be a condensation reaction of a 3-amino-2-hydroxy propionic acid derivative called isocerine with a baccatin III derivative represented by Chemical Formula 2, as shown in Reaction Scheme 1 below.
  • the derivatives are produced and then subjected to a deprotection step.
  • the introduction of this isoserine is disclosed in numerous patents and documents.
  • the yield in the process of deprotection after introduction of isocerine is as low as 60% and harmful to the environment by using heavy metals such as acid and zinc in the reaction.
  • a method of introducing cinnamic acid as a reactant has been proposed as a method for preparing a taxane derivative, which is a compound of Formula 1, using a baccatin III derivative.
  • Korean Patent Publication No. 1998-1625 discloses a derivative obtained by reacting a baccatin III derivative of Formula 2 with cinnamic acid in the presence of a tertiary butanol solution of osmium tetraoxide and nitric acid in the presence of t.
  • Taxane derivatives of the following Chemical Formula 1 are prepared by the step of using -butyl N-chlorocarbamate sodium salt.
  • the reaction is very low in the reaction yield of less than 20% in the process of introducing the amino hydroxy radicals, not only requires a long reaction time of 48 hours in the light-blocked dark room, but also the use of silver nitrate in the human body and the environment There is a problem in that it is a very harmful manufacturing method.
  • Taxane a compound of formula 1, comprising two steps of deprotection and then BOC protection after introducing propionic acid into International Publication No. 91/09589 and Korean Patent Publication No. 199-702324
  • a method for preparing a derivative is disclosed, which is shown in Ref.
  • a primary amine is generated in the process of deprotecting the amine and the alcohol, so that the reaction process is increased, and additional raw materials and reaction time are required.
  • a dicyclohexyl carbodiimide as a condensation reaction in the condensation reaction with the baccatin III derivative of the formula (2), the reaction proceeds by heating at a high temperature of 70 °C or more dicyclourea which is a by-product produced after the reaction There is a problem that must be removed and purified.
  • the method for preparing the taxane derivatives and intermediates of the general formula (1) prepared by the prior art produces a low yield and many by-products, and requires a long reaction time.
  • a demanding reaction condition such as a dark room reaction and a high temperature reaction condition is required, and there are problems that are harmful to the human body and the environment.
  • the present inventors use cinnamic acid or propionic acid as a reactant by using a new compound, phenyl oxazinane dione, as a reactant as a substance reacting with a baccatin III derivative of Formula 2 to prepare a taxane derivative of Formula 1.
  • a new compound phenyl oxazinane dione
  • a reactant as a substance reacting with a baccatin III derivative of Formula 2
  • the problems of the intermediate compounds produced using derivatives, low yield, reaction time of high temperature and time, and reaction processes in which many by-products are produced are solved.
  • the present invention provides a method for preparing a taxane derivative, which can solve the problems caused by the reaction process of the intermediate compound in which a high temperature reaction and a long time reaction, a low yield, and a large number of by-products are produced. It aims to provide.
  • an object of the present invention is to provide a novel reactant that reacts with a bacatin III derivative in the preparation of an intermediate compound of a taxane derivative using a bacatin III derivative.
  • the present invention relates to a method for preparing the taxane derivative represented by the following formula (1).
  • R is t-butoxy or phenyl and G is hydrogen or acetyl.
  • the present invention in preparing the taxane derivative of Chemical Formula 1, the bacterin III derivative of Chemical Formula 2, which is generally used, is used as a starting material. At this time, the present invention provides a method for preparing a taxane derivative represented by Chemical Formula 1, which is prepared by introducing a compound represented by Chemical Formula 3, which is a new compound, as a substance reacting with a baccatin III derivative.
  • R 1 is an amine protecting group of the t- butoxycarbonyl or benzoyl
  • R 3 is substituted with C 1 ⁇ C 6 alkyl or alkoxy or unsubstituted C 1 ⁇ C 6 alkyl, silyl, tetrahydropyranyl Or benzyl; -C (O) -R 5 or -C (O), and -OR 5
  • R 5 is an alkyl of C 1 ⁇ C 6 substituted by alkoxy or halogen or unsubstituted C 1 ⁇ C 6
  • G1 is Alcohol protecting group is shown.
  • Reaction Scheme 1 shows a method for preparing a taxane derivative represented by Chemical Formula 1 according to the present invention.
  • the present invention is to introduce a compound represented by the formula (3) to the bacterin III derivative of the formula (2) as a reactant to condensate them to obtain a compound of the formula (4), which is a hydroxy protecting group Taxane derivatives of Formula 1 having antitumor properties may be prepared, including the step of deprotection.
  • the compound of formula 2 and compound of formula 3 are prepared under one or more solvents selected from toluene, benzene, chlorobenzene, allylbenzene, tertiary butylbenzene, acetonitrile, heptane, dimethylformamide, tetrahydrofuran and anisole.
  • 4-dimethylaminopyridine or 4-pyrrolidinopyridine is selected as an activator in the temperature range of 0 ° C to 120 ° C to proceed with the reaction to prepare a compound of Chemical Formula 4.
  • hydroxy protecting group of the compound of Formula 4 is deprotected to prepare a taxane derivative of the compound of Formula 1, trimethylsilyl bromide, tribromoborane, tetrabutylammonium fluoride, tetrabutylammonium hydroxide, potassium hydroxide, zinc It can be carried out under one or more solvents selected using acetic acid, acetic acid, aqueous hydrochloric acid solution, trifluoroacetic acid, pyridinium P-toluenesulfonate, dichlorodicyanoquinone, ethanolamine, hydrazine.
  • the present invention is to provide a compound of formula (3) as a novel compound as a reactant useful for preparing a taxane derivative by reacting with the baccatin III derivative of formula (2).
  • the compound of Chemical Formula 3 is a phenyloxazinane dione compound, which is prepared from a propionic acid compound represented by the following Chemical Formula 5.
  • R 1 , R 3 are as defined in Formula 3
  • R 2 is a t-butoxycarbonyl, such as R 1 or an amine protecting group of benzoyl
  • R 1 and R 2 are the same as or different from each other Can be.
  • the compound of Formula 5 is a novel compound
  • the present invention provides a compound of Formula 5 is a novel compound capable of producing a compound of Formula 3 useful in the preparation of taxane derivatives by reacting with the Bacatin III derivative of Formula 2 .
  • the compound of Chemical Formula 5 is prepared from a compound represented by Chemical Formula 7 by reacting with di-t-butyl dicarbonate using the compound represented by Chemical Formula 6 as a starting material.
  • R 1 and R 2 are each t-butoxycarbonyl or benzoyl, which may be the same or different from each other
  • R 3 is methoxymethyl, methyl, 1-ethoxyethyl, trimethylsilyl, t-butyldimethylsilyl, Triethylsilyl, 2-tetrahydropyranyl, 4-methoxybenzyl, acetyl, pivaloyl, trichloroacetyl, 2-methoxy acetyl, 2,2,2-trichloroethoxycarbonyl, ethoxycarbonyl , t-butoxycarbonyl
  • R 4 is a protecting group of a carboxy group selected from C 1 to C 6 alkyl and benzyl radicals.
  • Compound of Formula 3 which is a novel compound useful for preparing taxane derivatives by reacting with Bacatin III derivative of Formula 2 according to the present invention, is a di-t-butyl dica as a starting material. Reacting with carbonate to synthesize the compound of Formula 7 having a tertiary amine substituted with the substituent R 2 , and then deprotecting the carboxyl group of the substituent R 4 through a hydrogenation or hydrolysis reaction Manufacture.
  • the prepared acid compound of Formula 5 may be prepared by the cyclization reaction using oxalyl chloride or thionyl chloride and dimethylformamide to produce a compound of Formula 3, which is a reactant, the compound of Formula 3 thus prepared
  • An anhydride-activated structure exhibits very good reactivity with the baccatin III derivatives of formula (2).
  • the method for producing a taxane derivative according to the present invention has a mild reaction conditions, a short reaction time, excellent reaction yield can be usefully used in the manufacture of anti-tumor therapeutics.
  • Characteristic of the manufacturing method of the present invention is a taxane derivative of formula 1 produced using cinnamic acid as a reactant and the baccatin III derivative of formula 2 which is a problem according to the conventional method for preparing a taxane derivative is a low yield of 20 ⁇ 53% The yield is more than 80% and can be produced in a very good yield. In addition, it has excellent process efficiency even if it is manufactured in one step without the process of protecting with BOC after two steps of deprotection after introducing propionic acid. .
  • the condensation reaction between the bacterin III derivative of formula 2 and the compound of formula 3 may terminate the reaction within a short time at room temperature, unlike the prior art, and is the final compound after the condensation reaction.
  • the present invention prepares the final compound in a short time by one step at room temperature reaction. The yield is excellent, there is no consumption of time and raw materials, no by-products generated after the reaction, and also harmless to human body and environment.
  • the present invention provides a novel reactant, which is a phenyloxazinane dione compound of formula (3) and a propionic acid compound of formula (5) in a method for preparing a taxane derivative, and introduces it into a reactant reacting with a bacatin III derivative, thereby providing a simple and gentle reaction. It can be usefully used to prepare taxane derivatives in a good yield in a short time under conditions.
  • Step 1 Preparation of (2R, 3S) -benzyl-3- (t-butoxy carbonylamino) -2- (methoxymethoxy) -3-phenylpropionate
  • Step 2 Preparation of (2R, 3S) -benzyl-3- (bis (t-butoxycarbonyl) amino) -2- (methoxymethoxy) -3-phenylpropionate
  • the mixture was concentrated under reduced pressure to remove the solvent, diluted with ethyl acetate, and washed with water, saturated citric acid aqueous solution and saturated aqueous sodium hydrogen carbonate solution. After washing with saturated brine and distilling under reduced pressure, the obtained compound was purified by column chromatography to obtain 680 mg (90%) of white crystals.
  • Step 3 Preparation of (2R, 3S) -3- (bis (t-butoxycarbonyl) amino) -2- (methoxymethoxy) -3-phenylpropionate (Formula 5)
  • Step 4 Preparation of (4S, 5R) -t-butyl-5- (methoxymethoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate (Formula 3) Manufacture)
  • Step 5 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1-hydroxy-9-oxo-7 ⁇ , 10 ⁇ -bis [(2,2,2-trichloroethoxy) carbonyloxy] Preparation of -11-Taxene-13 ⁇ -yl- (2R, 3S) -3-t-butoxycarbonylamino-3- (4-methylphenyl) -2- (methoxymethoxy) propionate Produce)
  • Step 6 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1-hydroxy-9-oxo-7 ⁇ , 10 ⁇ -bis [(2,2,2-trichloroethoxy) carbonyloxy] Preparation of -11-Taxene-13 ⁇ -yl (2R, 3S) -3-t-butoxycarbonylamino-3- (4-methylphenyl) -2-hydroxy propionate
  • Step 7 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1,7 ⁇ , 10 ⁇ -trihydroxy-9-oxo-11-taxen-13 ⁇ -yl (2R, 3S) -3-t- Preparation of Butoxycarbonylamino-3- (4-methylphenyl) -2-hydroxy propionate
  • reaction mixture was concentrated under reduced pressure, diluted with 20 ml of ethyl acetate, and washed with water, saturated sodium bicarbonate solution and saturated citric acid solution. After washing with saturated brine and distillation under reduced pressure, the obtained compound was purified by column chromatography to give 0.25g (84%) of a white solid title compound.
  • Example 1 using the above (4S, 5R) -t-butyl-5- (trimethylsilyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1, using tetrabutylammonium fluoride instead of trimethylsilyl bromide in step 6.
  • Step 1 Preparation of (2R, 3S) -benzyl-3- (t-butoxycarbonylamino) -2- (acetoxy) -3-phenylpropionate
  • Step 2 Preparation of (2R, 3S) -benzyl-3- (bis (t-butoxycarbonyl) amino) -2- (acetoxy) -3-phenylpropionate
  • Step 3 Preparation of (2R, 3S) -3- (bis- (t-butoxycarbonyl) amino) -2- (acetoxy) -3-phenylpropionic acid (Formula 5)
  • Step 4 Preparation of (4S, 5R) -t-butyl-5- (acetoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate (Preparation of Formula 3) )
  • Step 5 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1-hydroxy-9-oxo-7 ⁇ , 10 ⁇ -bis- (trichloroacetoxy) -11-taxen-13 ⁇ -yl- ( Preparation of 2R, 3S) -3-t-butoxycarbonylamino-3- (4-methylphenyl) -2- (acetoxy) propionate (Preparation of Formula 4)
  • Step 6 4-acetoxy-2 ⁇ -benzoyloxy-5 ⁇ , 20-epoxy-1,7 ⁇ , 10 ⁇ -trihydroxy-9-oxo-11-taxen-13 ⁇ -yl (2R, 3S) -3-t- Preparation of Butoxycarbonylamino-3- (4-methylphenyl) -2-hydroxy propionate
  • Example 11 docetaxel using (4S, 5R) -t-butyl-5- (trichloroacetoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Manufacture
  • Example 1 using the above (4S, 5R) -t-butyl-5- (ethoxycarboxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1, using potassium hydroxide instead of trimethylsilyl bromide in step 6 and hydrazine in place of zinc and acetic acid in step 7.

Abstract

The present invention relates to a method for producing taxane derivatives with anticancer activity. The method of the present invention produces taxane derivatives in a short time under mild conditions by employing phenyl oxazinan dione compounds which are novel compounds, as a reactant, such that the phenyl oxazinan dione compounds react to baccatin III derivatives.

Description

탁산 유도체의 제조방법Method for preparing taxane derivative
본 발명은 항암작용을 갖는 탁산 유도체의 제조방법에 관한 것이다.The present invention relates to a method for preparing a taxane derivative having anticancer activity.
하기 화학식 1로 표시되는 탁산 유도체는 항백혈병 및 항종양 활성을 갖는 중요한 암 화학요법제로서, 대표적인 약물로는 파클리탁셀(Paclitaxel)과 도세탁셀(Docetaxel) 등이 있으며, 상기 약물은 그 활성을 인정받아 폐암, 난소암, 유방암 등의 치료제로 시판되고 있다.Taxane derivatives represented by the following formula (1) are important cancer chemotherapeutic agents having anti-leukemia and anti-tumor activity. Representative drugs include paclitaxel and docetaxel, and the drugs have been recognized for their activity. It is marketed as a therapeutic agent for ovarian cancer and breast cancer.
<화학식 1> <Formula 1>
Figure PCTKR2009005279-appb-I000001
Figure PCTKR2009005279-appb-I000001
이 때, R은 t-부톡시 또는 페닐이며, G는 수소 또는 아세틸이다.Wherein R is t-butoxy or phenyl and G is hydrogen or acetyl.
상기, 탁산 유도체는 하기 화학식 2로 표시되는 바카틴 Ⅲ(baccatin Ⅲ) 유도체를 포함한다.The taxane derivative includes a baccatin III derivative represented by the following formula (2).
<화학식 2><Formula 2>
Figure PCTKR2009005279-appb-I000002
Figure PCTKR2009005279-appb-I000002
이 때, G1, G2는 알코올 보호기를 나타낸다.At this time, G1 and G2 represent an alcohol protecting group.
상기 화학식 1 화합물로 표시되는 탁산 유도체의 제조방법은 유럽 특허공보 제0253738호, 국제공개공보 제94/07878호, 제03/087077호, 대한민국 특허공개공보 제1993-702324호, 제1992-703560호, 제1995-700267호 등의 특허 이외에도 많은 문헌들에 개시되어 있다.Method for producing a taxane derivative represented by the formula (1) is European Patent Publication No. 0253738, International Publication No. 94/07878, 03/087077, Republic of Korea Patent Publication No. 1993-702324, 1992-703560 In addition to patents, such as US Pat.
일반적으로 상기 화학식 1 화합물로 표시되는 탁산 유도체는 하기 참고반응식 1에 나타낸 바와 같이, 이소세린으로 불리는 3-아미노-2-히드록시 프로피온산 유도체와 상기 화학식 2 화합물인 바카틴Ⅲ 유도체의 축합반응을 통해 유도체를 생성한 후 탈보호화 단계를 거쳐 제조된다. 상기 이소세린의 도입은 수많은 특허와 문헌들에 개시되어 있다.In general, the taxane derivative represented by Chemical Formula 1 may be a condensation reaction of a 3-amino-2-hydroxy propionic acid derivative called isocerine with a baccatin III derivative represented by Chemical Formula 2, as shown in Reaction Scheme 1 below. The derivatives are produced and then subjected to a deprotection step. The introduction of this isoserine is disclosed in numerous patents and documents.
<참고반응식 1><Reference Scheme 1>
Figure PCTKR2009005279-appb-I000003
Figure PCTKR2009005279-appb-I000003
상기 이소세린을 도입하여 화학식 1의 탁산 유도체 및 중간체를 제조하는 종래기술은 12시간 이상의 장시간의 반응시간이 필요하며, 반응 후 디시클로우레아와 같은 다량의 부산물이 생성되어 정제해야 문제가 있다.The prior art of preparing the taxane derivatives and intermediates of Formula 1 by introducing the isoserine requires a long reaction time of 12 hours or more, and a large amount of by-products such as dicyclourea are generated and purified after the reaction.
또한, 이소세린 도입 후 탈보호화 하는 과정에서의 수율이 60% 정도로 저조하며 반응에 산 및 아연과 같은 중금속을 사용하여 환경에 유해하다.In addition, the yield in the process of deprotection after introduction of isocerine is as low as 60% and harmful to the environment by using heavy metals such as acid and zinc in the reaction.
상기 화학식 2 화합물인 바카틴Ⅲ 유도체를 이용한 화학식 1 화합물인 탁산유도체의 제조방법으로 신남산을 반응물질로 도입하는 방법이 제안되었다.A method of introducing cinnamic acid as a reactant has been proposed as a method for preparing a taxane derivative, which is a compound of Formula 1, using a baccatin III derivative.
대한민국 특허공개공보 제1998-1625호에는 하기 참고 반응식2에 나타낸 바와 같이, 상기 화학식 2 화합물인 바카틴Ⅲ 유도체를 신남산과 반응시켜 얻은 유도체를 사산화오스뮴의 3차 부탄올 용액과 질산은 존재하에 t-부틸 N-클로로카르바메이트 나트륨염을 사용하는 단계를 거쳐 하기 화학식 1 화합물인 탁산유도체를 제조한다.Korean Patent Publication No. 1998-1625 discloses a derivative obtained by reacting a baccatin III derivative of Formula 2 with cinnamic acid in the presence of a tertiary butanol solution of osmium tetraoxide and nitric acid in the presence of t. Taxane derivatives of the following Chemical Formula 1 are prepared by the step of using -butyl N-chlorocarbamate sodium salt.
<참고반응식 2><Reference Scheme 2>
Figure PCTKR2009005279-appb-I000004
Figure PCTKR2009005279-appb-I000004
상기 반응은 아미노 히드록시 라디칼을 도입하는 과정에서 반응수율이 20% 이하로 매우 저조하며, 빛이 차단된 암실에서 48시간의 장시간의 반응시간이 필요할 뿐만 아니라, 반응에 질산은을 사용하므로써 인체 및 환경에 매우 유해한 제조방법인 점에 문제점이 있다.The reaction is very low in the reaction yield of less than 20% in the process of introducing the amino hydroxy radicals, not only requires a long reaction time of 48 hours in the light-blocked dark room, but also the use of silver nitrate in the human body and the environment There is a problem in that it is a very harmful manufacturing method.
다른 방법으로 국제공개공보 제91/09589호 및 대한민국 특허공개공보 제1993-702324호에 프로피온산을 도입한 후 2단계의 탈보호화 과정을 하고 다시 BOC으로 보호화 하는 과정을 포함하는 화학식 1 화합물인 탁산 유도체의 제조방법이 개시되어 있으며, 이를 하기 참고반응식 3으로 나타내었다.Taxane, a compound of formula 1, comprising two steps of deprotection and then BOC protection after introducing propionic acid into International Publication No. 91/09589 and Korean Patent Publication No. 199-702324 A method for preparing a derivative is disclosed, which is shown in Ref.
<참고반응식 3>Reference Scheme 3
Figure PCTKR2009005279-appb-I000005
Figure PCTKR2009005279-appb-I000005
상기 화학식 1 화합물인 탁산 유도체의 제조방법은 아민과 알코올을 탈보호화 하는 과정에서 1차 아민이 생성되어 반응공정이 늘어나 추가의 원료와 반응시간이 필요하다. 또한 상기 화학식 2 화합물인 바카틴Ⅲ 유도체와의 축합반응에서 디시클로헥실카보디이미드를 축합반응제로 사용하여 70℃ 이상의 고온에서 가열하여 반응을 진행시키며 반응 후 생성되는 다량의 부산물인 디시클로우레아를 제거하고 정제해야 하는 문제점이 있다.In the method for preparing the taxane derivative of Chemical Formula 1, a primary amine is generated in the process of deprotecting the amine and the alcohol, so that the reaction process is increased, and additional raw materials and reaction time are required. In addition, by using a dicyclohexyl carbodiimide as a condensation reaction in the condensation reaction with the baccatin III derivative of the formula (2), the reaction proceeds by heating at a high temperature of 70 ℃ or more dicyclourea which is a by-product produced after the reaction There is a problem that must be removed and purified.
상기에서 살펴 본 바와 같이, 종래기술에 의하여 제조되는 화학식 1의 탁산 유도체 및 중간체를 제조하는 방법은 낮은 수율과 많은 부산물이 생성되며, 장시간의 반응시간이 필요하다. 또한 암실반응, 고온의 반응조건과 같은 까다로운 반응조건이 필요하고, 인체 및 환경적으로도 유해한 문제 등이 있다.As described above, the method for preparing the taxane derivatives and intermediates of the general formula (1) prepared by the prior art produces a low yield and many by-products, and requires a long reaction time. In addition, a demanding reaction condition such as a dark room reaction and a high temperature reaction condition is required, and there are problems that are harmful to the human body and the environment.
따라서 상기 화학식 1 화합물인 탁산 유도체를 제조하기 위한 새로운 중간체 및 중간체 화합물에 의한 제조방법이 요구되어 왔다.Therefore, there has been a need for a new intermediate and a method for preparing the intermediate compound for the preparation of the taxane derivative of the formula (1).
이에 본 발명자들은 상기 화학식 1 화합물인 탁산 유도체를 제조하기 위하여 상기 화학식 2 화합물인 바카틴Ⅲ 유도체와 반응하는 물질로서 신규 화합물인 페닐 옥사지난 디온화합물을 반응물질로 이용함으로써 반응물질로 신남산 또는 프로피온산 유도체를 사용하여 생성되는 중간체 화합물의 문제점인 낮은 수율과 고온 및 시간의 반응시간, 많은 부산물이 생성되는 반응공정들의 문제점을 해결하였다.Accordingly, the present inventors use cinnamic acid or propionic acid as a reactant by using a new compound, phenyl oxazinane dione, as a reactant as a substance reacting with a baccatin III derivative of Formula 2 to prepare a taxane derivative of Formula 1. The problems of the intermediate compounds produced using derivatives, low yield, reaction time of high temperature and time, and reaction processes in which many by-products are produced are solved.
본 발명은 바카틴Ⅲ 유도체를 이용한 탁산 유도체의 제조방법에 있어서, 고온 반응 및 장시간의 반응, 낮은 수율 및 많은 부산물이 생성되는 중간체 화합물의 반응공정에 따른 문제점을 해결할 수 있는 탁산 유도체의 제조방법을 제공하는 것을 목적으로 한다.The present invention provides a method for preparing a taxane derivative, which can solve the problems caused by the reaction process of the intermediate compound in which a high temperature reaction and a long time reaction, a low yield, and a large number of by-products are produced. It aims to provide.
또한, 본 발명은 바카틴Ⅲ 유도체를 이용한 탁산 유도체의 중간체 화합물을 제조하는 데 있어서, 바카틴Ⅲ 유도체와 반응하는 신규 반응물질을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a novel reactant that reacts with a bacatin III derivative in the preparation of an intermediate compound of a taxane derivative using a bacatin III derivative.
본 발명은 하기 화학식 1로 표시되는 탁산 유도체의 제조방법에 관한 것이다.The present invention relates to a method for preparing the taxane derivative represented by the following formula (1).
<화학식 1><Formula 1>
Figure PCTKR2009005279-appb-I000006
Figure PCTKR2009005279-appb-I000006
이 때, R은 t-부톡시 또는 페닐이며, G는 수소 또는 아세틸이다.Wherein R is t-butoxy or phenyl and G is hydrogen or acetyl.
본 발명에서는 상기 화학식 1 화합물인 탁산 유도체를 제조함에 있어서, 일반적으로 사용되는 하기 화학식 2 화합물인 바카틴Ⅲ 유도체를 출발물질로 이용한다. 이 때, 화학식 2 화합물인 바카틴Ⅲ 유도체와 반응하는 물질로서 신규 화합물인 하기 화학식 3으로 표시되는 화합물을 도입하여 제조되는 상기 화학식 1로 표시되는 탁산 유도체의 제조방법을 제공한다.In the present invention, in preparing the taxane derivative of Chemical Formula 1, the bacterin III derivative of Chemical Formula 2, which is generally used, is used as a starting material. At this time, the present invention provides a method for preparing a taxane derivative represented by Chemical Formula 1, which is prepared by introducing a compound represented by Chemical Formula 3, which is a new compound, as a substance reacting with a baccatin III derivative.
<화학식 2><Formula 2>
Figure PCTKR2009005279-appb-I000007
Figure PCTKR2009005279-appb-I000007
<화학식 3><Formula 3>
Figure PCTKR2009005279-appb-I000008
Figure PCTKR2009005279-appb-I000008
상기 식에서, R1은 t-부톡시카르보닐 또는 벤조일의 아민 보호기이며, R3은 C1~C6의 알킬 또는 알콕시로 치환되거나 치환되지 않은 C1~C6의 알킬, 실릴, 테트라하이드로피란 또는 벤질; -C(O)-R5 또는 -C(O)-O-R5이며, R5는 C1~C6의 알콕시 또는 할로겐으로 치환되거나 치환되지 않은 C1~C6의 알킬이고, G1, G2는 알코올 보호기를 나타낸다.Wherein, R 1 is an amine protecting group of the t- butoxycarbonyl or benzoyl, R 3 is substituted with C 1 ~ C 6 alkyl or alkoxy or unsubstituted C 1 ~ C 6 alkyl, silyl, tetrahydropyranyl Or benzyl; -C (O) -R 5 or -C (O), and -OR 5, R 5 is an alkyl of C 1 ~ C 6 substituted by alkoxy or halogen or unsubstituted C 1 ~ C 6, G1, G2 is Alcohol protecting group is shown.
하기 반응식 1에 본 발명에 따른 화학식 1로 표시되는 탁산 유도체의 제조방법을 나타내었다.Reaction Scheme 1 shows a method for preparing a taxane derivative represented by Chemical Formula 1 according to the present invention.
<반응식 1><Scheme 1>
Figure PCTKR2009005279-appb-I000009
Figure PCTKR2009005279-appb-I000009
상기 반응식 1 에서 알 수 있는 바와 같이, 본 발명은 화학식 2 화합물인 바카틴 Ⅲ 유도체에 화학식 3으로 표시되는 화합물을 반응물질로 도입하여 이들을 축합 반응시켜 화학식 4의 화합물을 얻고, 이를 히드록시 보호기를 탈보호 반응시키는 단계를 포함하여 항종양성 특성 있는 화학식 1의 탁산 유도체를 제조할 수 있다.As can be seen in Scheme 1, the present invention is to introduce a compound represented by the formula (3) to the bacterin III derivative of the formula (2) as a reactant to condensate them to obtain a compound of the formula (4), which is a hydroxy protecting group Taxane derivatives of Formula 1 having antitumor properties may be prepared, including the step of deprotection.
본 발명에서 화학식 2의 화합물과 화학식 3의 화합물은 톨루엔, 벤젠, 클로로벤젠, 알릴벤젠, 3차 부틸벤젠, 아세토니트릴, 헵탄, 디메틸포름아미드, 테트라히드로퓨란, 아니솔 중에서 선택된 1종 이상의 용매 하에서, 0℃ 내지 120℃의 온도 범위에서 활성화제로서 4-디메틸아미노피리딘 또는 4-피로리디노피리딘을 하나 또는 모두 선택하여 반응을 진행하여 화학식 4의 화합물을 제조한다.In the present invention, the compound of formula 2 and compound of formula 3 are prepared under one or more solvents selected from toluene, benzene, chlorobenzene, allylbenzene, tertiary butylbenzene, acetonitrile, heptane, dimethylformamide, tetrahydrofuran and anisole. , 4-dimethylaminopyridine or 4-pyrrolidinopyridine is selected as an activator in the temperature range of 0 ° C to 120 ° C to proceed with the reaction to prepare a compound of Chemical Formula 4.
상기 화학식 4의 화합물의 히드록시 보호기를 탈보호 반응시켜 화학식 1 화합물인 탁산 유도체를 제조할 때에는 트리메틸실릴브로마이드, 트리브로모보란, 테트라부틸암모늄플로라이드, 테트라부틸암모늄히드록사이드, 수산화칼륨, 아연-초산, 초산, 염산수용액, 트리플로로아세틱에시드, 피리디늄 P-톨루엔설포네이트, 디클로로디시아노퀴논, 에탄올아민, 히드라진을 사용하여 선택된 1종 이상의 용매 하에서 실시할 수 있다.When the hydroxy protecting group of the compound of Formula 4 is deprotected to prepare a taxane derivative of the compound of Formula 1, trimethylsilyl bromide, tribromoborane, tetrabutylammonium fluoride, tetrabutylammonium hydroxide, potassium hydroxide, zinc It can be carried out under one or more solvents selected using acetic acid, acetic acid, aqueous hydrochloric acid solution, trifluoroacetic acid, pyridinium P-toluenesulfonate, dichlorodicyanoquinone, ethanolamine, hydrazine.
또한, 본 발명은 상기 화학식 2 화합물인 바카틴Ⅲ 유도체와 반응하여 탁산 유도체를 제조할 수 있는 데 유용한 반응물질로서 신규 화합물인 상기 화학식 3의 화합물을 제공하는 것이다.In addition, the present invention is to provide a compound of formula (3) as a novel compound as a reactant useful for preparing a taxane derivative by reacting with the baccatin III derivative of formula (2).
상기 화학식 3의 화합물은 페닐옥사지난 디온화합물로서, 하기 화학식 5로 표시되는 프로피온산 화합물로부터 제조된다.The compound of Chemical Formula 3 is a phenyloxazinane dione compound, which is prepared from a propionic acid compound represented by the following Chemical Formula 5.
<화학식 5><Formula 5>
Figure PCTKR2009005279-appb-I000010
Figure PCTKR2009005279-appb-I000010
이 때, R1, R3는 상기 화학식 3에서 정의한 바와 같으며, R2는 R1과 같은 t-부톡시카르보닐, 또는 벤조일의 아민보호기이며, R1과 R2는 각각 서로 같거나 다를 수 있다.In this case, R 1 , R 3 are as defined in Formula 3, R 2 is a t-butoxycarbonyl, such as R 1 or an amine protecting group of benzoyl, R 1 and R 2 are the same as or different from each other Can be.
또한, 상기 화학식 5의 화합물은 신규 화합물로서, 본 발명은 상기 화학식 2 화합물인 바카틴Ⅲ 유도체와 반응하여 탁산 유도체 제조에 유용한 화학식 3 화합물을 제조할 수 있는 신규 화합물인 화학식 5의 화합물을 제공한다.In addition, the compound of Formula 5 is a novel compound, the present invention provides a compound of Formula 5 is a novel compound capable of producing a compound of Formula 3 useful in the preparation of taxane derivatives by reacting with the Bacatin III derivative of Formula 2 .
상기 화학식 5의 화합물은 하기 화학식 6으로 표시되는 화합물을 출발물질로 하여 디-t-부틸 디카르보네이트와 반응시켜 하기 화학식 7로 표시되는 화합물로부터 제조된다.The compound of Chemical Formula 5 is prepared from a compound represented by Chemical Formula 7 by reacting with di-t-butyl dicarbonate using the compound represented by Chemical Formula 6 as a starting material.
<화학식 6><Formula 6>
Figure PCTKR2009005279-appb-I000011
Figure PCTKR2009005279-appb-I000011
<화학식 7><Formula 7>
Figure PCTKR2009005279-appb-I000012
Figure PCTKR2009005279-appb-I000012
상기 식에서, R1과 R2가 각각 서로 같거나 다를 수 있는 t-부톡시카르보닐 또는 벤조일이고, R3가 메톡시메틸, 메틸, 1-에톡시에틸, 트리메틸실릴, t-부틸디메틸실릴, 트리에틸실릴, 2-테트라하이드로피라닐, 4-메톡시벤질, 아세틸, 피발로일, 트리클로로아세틸, 2-메톡시 아세틸, 2,2,2-트리클로로에톡시카르보닐, 에톡시카보닐, t-부톡시카르보닐 중에서 선택되고, R4는 C1~C6의 알킬, 벤질 라디칼 중에서 선택되는 카르복시기의 보호기이다.Wherein R 1 and R 2 are each t-butoxycarbonyl or benzoyl, which may be the same or different from each other, R 3 is methoxymethyl, methyl, 1-ethoxyethyl, trimethylsilyl, t-butyldimethylsilyl, Triethylsilyl, 2-tetrahydropyranyl, 4-methoxybenzyl, acetyl, pivaloyl, trichloroacetyl, 2-methoxy acetyl, 2,2,2-trichloroethoxycarbonyl, ethoxycarbonyl , t-butoxycarbonyl, and R 4 is a protecting group of a carboxy group selected from C 1 to C 6 alkyl and benzyl radicals.
상기 화학식 2 화합물인 바카틴Ⅲ 유도체와 반응하여 탁산 유도체 제조에 유용한 신규 화합물인 상기 화학식 3 및 화학식 5의 화합물을 제조하는 개략적인 제조방법을 하기 반응식 2에 나타내었다.A schematic preparation method for preparing the compounds of Formula 3 and Formula 5, which is a novel compound useful for preparing taxane derivatives by reacting with the baccatin III derivative of Formula 2, is shown in Scheme 2 below.
<반응식 2><Scheme 2>
Figure PCTKR2009005279-appb-I000013
Figure PCTKR2009005279-appb-I000013
본 발명에 따른 상기 화학식 2 화합물인 바카틴Ⅲ 유도체와 반응하여 탁산 유도체 제조에 유용한 신규 화합물인 상기 화학식 3의 화합물은 출발물질인 상기 화학식 6의 화합물의 2차 아민 화합물을 디-t-부틸 디카르보네이트와 반응시켜 상기 치환기 R2로 치환된 3차 아민을 갖는 상기 화학식 7의 화합물을 합성한 후 수소화 반응 또는 가수분해 반응을 통하여 치환기 R4의 카르복시기를 탈보호하여 상기 화학식 5의 에시드 화합물을 제조한다.Compound of Formula 3, which is a novel compound useful for preparing taxane derivatives by reacting with Bacatin III derivative of Formula 2 according to the present invention, is a di-t-butyl dica as a starting material. Reacting with carbonate to synthesize the compound of Formula 7 having a tertiary amine substituted with the substituent R 2 , and then deprotecting the carboxyl group of the substituent R 4 through a hydrogenation or hydrolysis reaction Manufacture.
제조된 상기 화학식 5의 에시드 화합물은 옥살릴클로라이드 또는 티오닐클로라이드와 디메틸포름아미드를 사용하여 고리화 반응을 통해 반응물질인 상기 화학식 3의 화합물을 제조할 수 있으며, 이렇게 제조된 화학식 3의 화합물은 무수물형태의 활성화된 구조로 상기 화학식 2의 화합물인 바카틴 Ⅲ유도체와 매우 좋은 반응성을 나타낸다.The prepared acid compound of Formula 5 may be prepared by the cyclization reaction using oxalyl chloride or thionyl chloride and dimethylformamide to produce a compound of Formula 3, which is a reactant, the compound of Formula 3 thus prepared An anhydride-activated structure exhibits very good reactivity with the baccatin III derivatives of formula (2).
이상의 단계를 포함하는, 본 발명에 의한 탁산 유도체의 제조방법은 반응조건이 온화하고 반응시간이 짧으며, 반응수율이 우수하여 항종양 치료제 제조에 유용하게 사용될 수 있다.Including the above steps, the method for producing a taxane derivative according to the present invention has a mild reaction conditions, a short reaction time, excellent reaction yield can be usefully used in the manufacture of anti-tumor therapeutics.
본 발명의 제조방법의 특징은 종래 탁산 유도체의 제조방법에 따른 문제점인 화학식 2 화합물인 바카틴Ⅲ 유도체와 반응물질로 신남산을 사용하여 생성되는 화학식 1의 탁산유도체는 20 ~ 53%의 낮은 수율보다 수율이 80%이상으로 매우 우수한 수율로 제조할 수 있으며, 또한, 프로피온산을 도입한 후 2단계의 탈보호화 과정을 하고 다시 BOC으로 보호화 하는 과정없이 1 단계 공정으로 제조하더라도 우수한 공정효율성을 갖는다.Characteristic of the manufacturing method of the present invention is a taxane derivative of formula 1 produced using cinnamic acid as a reactant and the baccatin III derivative of formula 2 which is a problem according to the conventional method for preparing a taxane derivative is a low yield of 20 ~ 53% The yield is more than 80% and can be produced in a very good yield. In addition, it has excellent process efficiency even if it is manufactured in one step without the process of protecting with BOC after two steps of deprotection after introducing propionic acid. .
본 발명의 또 다른 특징은 화학식 2 화합물인 바카틴 Ⅲ유도체와 화학식 3 화합물의 축합반응은 종래 기술과는 달리 상온에서 1시간 이내의 단시간에 반응을 종결시킬 수 있으며, 또한 축합반응 후 최종 화합물인 탁산 유도체를 제조하기 위해 탈보호화하는 과정에서 여러 단계를 거쳐야 하기 때문에 수율이 감소되며 추가의 원료가 소모되는 종래의 제조방법과는 달리 본 발명은 한 단계의 상온반응으로 단 시간 내에 최종화합물을 제조하여 수율이 우수하고, 시간 및 원료의 소모가 없으며 반응 후 생성되는 부산물이 없고, 인체 및 환경적으로도 무해하다.Another characteristic of the present invention is that the condensation reaction between the bacterin III derivative of formula 2 and the compound of formula 3 may terminate the reaction within a short time at room temperature, unlike the prior art, and is the final compound after the condensation reaction. Unlike the conventional manufacturing method in which the yield is reduced and additional raw materials are consumed because several steps are required in the process of deprotecting to prepare the taxane derivative, the present invention prepares the final compound in a short time by one step at room temperature reaction. The yield is excellent, there is no consumption of time and raw materials, no by-products generated after the reaction, and also harmless to human body and environment.
본 발명은 탁산 유도체의 제조방법에 있어서, 화학식 3의 페닐옥사지난 디온화합물과 화학식 5의 프로피온산 화합물인 신규 반응물질을 제공하여 이를 바카틴Ⅲ 유도체와 반응하는 반응물질에 도입함으로써, 간편하고 온화한 반응조건에서 단시간 내에 우수한 수율로 탁산 유도체를 제조하는 데 유용하게 사용될 수 있다.The present invention provides a novel reactant, which is a phenyloxazinane dione compound of formula (3) and a propionic acid compound of formula (5) in a method for preparing a taxane derivative, and introduces it into a reactant reacting with a bacatin III derivative, thereby providing a simple and gentle reaction. It can be usefully used to prepare taxane derivatives in a good yield in a short time under conditions.
이하 본 발명의 실시예를 통하여 발명의 내용을 상세히 설명하고자 한다. 하기 실시예는 본 발명의 예시이며 본 발명의 범위를 한정하는 것은 아니다.Hereinafter, the contents of the present invention will be described in detail through embodiments of the present invention. The following examples are illustrative of the invention and do not limit the scope of the invention.
<실시예 1> (4S,5R)-t-부틸-5-(메톡시메톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 1 Docetaxel using (4S, 5R) -t-butyl-5- (methoxymethoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Manufacture
1 단계 : (2R,3S)-벤질-3-(t-부톡시 카르보닐아미노)-2-(메톡시메톡시)-3-페닐프로피오네이트의 제조Step 1: Preparation of (2R, 3S) -benzyl-3- (t-butoxy carbonylamino) -2- (methoxymethoxy) -3-phenylpropionate
(2R,3S)-벤질-3(t-부톡시카르보닐아미노)-2-히드록시-3-페닐프로피 오네이트 5g(13.5mmol)을 메틸렌클로라이드 67ml에 녹인 후 0℃ 로 냉각하였다. 반응물에 클로로메틸 메틸에테르 1.5ml(20mmol)을 가하고 디이소프로필에틸아민 4.7ml(26mmol)을 적가하였다. 반응물을 상온에서 6시간 교반하여 반응을 종결시킨 다음 물과 포화식염수로 세척하고 감압 농축하여 오일을 얻었다. 컬럼 크로마토그래피로 정제하여 흰색 결정 5.1g(91%)을 얻었다.5 g (13.5 mmol) of (2R, 3S) -benzyl-3 (t-butoxycarbonylamino) -2-hydroxy-3-phenylpropionate was dissolved in 67 ml of methylene chloride and cooled to 0 ° C. To the reaction was added 1.5 ml (20 mmol) of chloromethyl methyl ether and 4.7 ml (26 mmol) of diisopropylethylamine were added dropwise. The reaction was stirred for 6 hours at room temperature to terminate the reaction, washed with water and brine and concentrated under reduced pressure to give an oil. Purification by column chromatography yielded 5.1 g (91%) of white crystals.
1H-NMR(CDCl3) δ : 1.39(s, 9H), 2.80(s, 3H), 4.37(d, 1H), 4.45(s, 1H), 4.58(d, 1H), 5.12~5.22(q, 2H), 5.30(d, 1H), 5.53(d, 1H), 7.19~7.36(m, 10H)1H-NMR (CDCl3) δ: 1.39 (s, 9H), 2.80 (s, 3H), 4.37 (d, 1H), 4.45 (s, 1H), 4.58 (d, 1H), 5.12 ~ 5.22 (q, 2H ), 5.30 (d, 1H), 5.53 (d, 1H), 7.19-7.36 (m, 10H)
Mass(M+1) : 416Mass (M + 1): 416
2 단계 : (2R,3S)-벤질-3-(비스(t-부톡시카르보닐)아미노)-2-(메톡시메톡시)-3-페닐프로피오네이트의 제조Step 2: Preparation of (2R, 3S) -benzyl-3- (bis (t-butoxycarbonyl) amino) -2- (methoxymethoxy) -3-phenylpropionate
(2R,3S)-벤질-3-(t-부톡시카르보닐아미노)-2-(메톡시메톡시)-3-페닐프로피오네이트 600mg(1.4mmol)을 아세토니트릴 3ml에 녹인 다음 디-t-부틸 디카르보네이트 1.9g(3.6mmol)을 가한 뒤 교반하였다. 반응물에 4-(디메틸아미노)피리딘 20mg(0.14mmol)을 가하고 60℃의 온도에서 6시간 동안 교반하였다. 반응 종결 후 감압농축하여 용매를 제거한 다음 에틸아세테이트를 가하여 희석하고 물과 포화구연산 수용액, 포화 탄산수소나트륨수용액으로 세척하였다. 포화식염수로 세척 후 감압하여 얻은 화합물을 컬럼 크로마토그래피로 정제 하여 680mg(90%)의 흰색 결정을 얻었다.600 mg (1.4 mmol) of (2R, 3S) -benzyl-3- (t-butoxycarbonylamino) -2- (methoxymethoxy) -3-phenylpropionate was dissolved in 3 ml of acetonitrile and then di-t Butyl dicarbonate 1.9 g (3.6 mmol) was added and stirred. 20 mg (0.14 mmol) of 4- (dimethylamino) pyridine was added to the reaction and stirred at a temperature of 60 ° C. for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent, diluted with ethyl acetate, and washed with water, saturated citric acid aqueous solution and saturated aqueous sodium hydrogen carbonate solution. After washing with saturated brine and distilling under reduced pressure, the obtained compound was purified by column chromatography to obtain 680 mg (90%) of white crystals.
1H-NMR(CDCl3) δ : 1.38(s, 18H), 3.28(s, 3H), 4.70(s, 2H), 4.86~4.99(q, 2H), 5.06(d, 1H), 5.59(d, 1H), 7.03(m, 2H), 7.22(m, 6H), 7.37(m, 2H)1 H-NMR (CDCl 3) δ: 1.38 (s, 18H), 3.28 (s, 3H), 4.70 (s, 2H), 4.86-4.99 (q, 2H), 5.06 (d, 1H), 5.59 (d, 1H ), 7.03 (m, 2H), 7.22 (m, 6H), 7.37 (m, 2H)
Mass(M+1) : 516Mass (M + 1): 516
3 단계 : (2R,3S)-3-(비스(t-부톡시카르보닐)아미노)-2-(메톡시메톡시)-3-페닐프로피오닉에시드의 제조(화학식 5의 제조)Step 3: Preparation of (2R, 3S) -3- (bis (t-butoxycarbonyl) amino) -2- (methoxymethoxy) -3-phenylpropionate (Formula 5)
(2R,3S)-벤질-3-(비스(t-부톡시카르보닐)아미노)-2-(메톡시메톡시)-3-페닐프로피오네이트 240mg(0.47mmol)을 에틸아세테이트 4ml에 녹인 후 10% 팔라듐 카본 50mg(20% w.t)을 가했다. 상온에서 30분 동안 수소화 반응하여 반응을 종결시킨 후 셀라이트 필터로 팔라듐 카본을 제거하고 얻은 반응 후 용액을 농축하여 190mg(96%)의 흰색고체를 얻었다.240 mg (0.47 mmol) of (2R, 3S) -benzyl-3- (bis (t-butoxycarbonyl) amino) -2- (methoxymethoxy) -3-phenylpropionate was dissolved in 4 ml of ethyl acetate. 50 mg (20% wt) of 10% palladium carbon was added. After completion of the reaction by hydrogenation at room temperature for 30 minutes, palladium carbon was removed with a celite filter, and the reaction solution was concentrated to obtain 190 mg (96%) of white solid.
1H-NMR(CDCl3) δ : 1.36(s, 18H), 3.28(s, 3H), 4.70(s, 2H), 4.97(d, 1H), 5.58(d, 1H), 7.20(m, 3H), 7.36(m, 2H)1 H-NMR (CDCl 3) δ: 1.36 (s, 18H), 3.28 (s, 3H), 4.70 (s, 2H), 4.97 (d, 1H), 5.58 (d, 1H), 7.20 (m, 3H), 7.36 (m, 2 H)
Mass(M+1) : 426Mass (M + 1): 426
4 단계 : (4S,5R)-t-부틸-5-(메톡시메톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트의 제조(화학식 3의 제조)Step 4: Preparation of (4S, 5R) -t-butyl-5- (methoxymethoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate (Formula 3) Manufacture)
상온에서 디메틸포름아미드 546ul(7.1mmol)를 7.8ml의 아세토니트릴에 녹인 후 -20 ℃로 냉각한 뒤 옥살릴클로라이드 618ul(7.1mmol)을 서서히 적가하고 동일한 온도에서 30분 동안 교반하였다. (2R, 3S)-벤질-3-(비스(t-부톡시카르보닐)아미노)-2-(메톡시메톡시)-3-페닐프로피오닉에시드 0.5g(1.2mmol)와 피리딘 105ul (1.3mmol)을 4.7ml의 아세토니트릴에 녹인 후 교반하며 -20 ℃로 냉각하고 반응중인 -20 ℃의 디메틸포름아미드와 옥살릴클로라이드 반응물에 서서히 적가 하였다. 같은 온도에서 2시간 동안 교반 후 1시간에 걸쳐 실온으로 상온시키고 4시간 동안 교반하였다. 반응종결 후 에틸아세테이트로 희석한 다음 물과 포화식염수로 세척하고 감압농축하여 상기 표제화합물 0.39g(95%)을 얻었다.546 ul (7.1 mmol) of dimethylformamide was dissolved in 7.8 ml of acetonitrile at room temperature, cooled to −20 ° C., and 618 ul (7.1 mmol) of oxalyl chloride was slowly added dropwise and stirred at the same temperature for 30 minutes. (2R, 3S) -benzyl-3- (bis (t-butoxycarbonyl) amino) -2- (methoxymethoxy) -3-phenylpropionic acid 0.5 g (1.2 mmol) and pyridine 105 ul (1.3 mmol) ) Was dissolved in 4.7 ml of acetonitrile, stirred and cooled to -20 ° C, and slowly added dropwise to the reacted dimethylformamide and oxalyl chloride reactants at -20 ° C. After stirring for 2 hours at the same temperature, the mixture was allowed to warm to room temperature over 1 hour and stirred for 4 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed with water and brine, and concentrated under reduced pressure to obtain 0.39 g (95%) of the title compound.
1H-NMR(CDCl3) δ : 1.44(s, 9H), 3.45(s, 3H), 4.77(d, 1H), 4.83(d, 1H), 4. 89(d, 1H), 5.49(d, 1H), 7.23~7.36(m, 5H)1 H-NMR (CDCl 3) δ: 1.44 (s, 9H), 3.45 (s, 3H), 4.77 (d, 1H), 4.83 (d, 1H), 4. 89 (d, 1H), 5.49 (d, 1H ), 7.23-7.36 (m, 5H)
Mass(M+Na) : 374Mass (M + Na): 374
5 단계 : 4-아세톡시-2α-벤조일옥시-5β,20-에폭시-1-히드록시-9-옥소-7β,10β-비스[(2,2,2-트리클로로에톡시)카르보닐옥시]-11-탁센-13α-일-(2R,3S)-3-t-부톡시카르보닐아미노-3-(4-메틸페닐)-2-(메톡시메톡시)프로피오네이트의 제조(화학식 4의 제조)Step 5: 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-9-oxo-7β, 10β-bis [(2,2,2-trichloroethoxy) carbonyloxy] Preparation of -11-Taxene-13α-yl- (2R, 3S) -3-t-butoxycarbonylamino-3- (4-methylphenyl) -2- (methoxymethoxy) propionate Produce)
(4S,5R)-t-부틸-5-(메톡시메톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복시레이트 1g(2.8mmol)을 14ml의 톨루엔에 녹인 다음 4-아세톡시-2α-벤조일옥시-5β,20-에폭시-1,13σ-디히드록시-9-옥소-7β,10β-비스[(2,2,2-트리클로로에톡시)카르보닐옥시]-11-탁센 0.64g(0.7mmol)을 가하고 상온에서 교반하였다. 반응물에 4-(디메틸아미노)피리딘 0.41g (3.4mmol)을 가하고 80℃에서 8시간 동안 교반하여 반응을 종결시키고 실온으로 냉각한 뒤 감압 농축하여 얻은 반응물을 에틸아세테이트50ml로 희석하였다. 희석된 반응물을 포화 구연산수용액, 포화 탄산수소나트륨 수용액, 포화식염수로 세척한 뒤 감압 농축하였다. 얻어진 화합물을 컬럼크로마토그래피로 정제하여 흰색의 고체 표제화합물 0.55g(65%)를 얻었다.1 g (2.8 mmol) of (4S, 5R) -t-butyl-5- (methoxymethoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate is 14 ml of toluene Dissolved in 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1,13σ-dihydroxy-9-oxo-7β, 10β-bis [(2,2,2-trichloroethoxy) carb Bonyloxy] -11-taxene 0.64 g (0.7 mmol) was added and stirred at room temperature. 0.41 g (3.4 mmol) of 4- (dimethylamino) pyridine was added to the reaction mixture, which was then stirred at 80 ° C. for 8 hours to terminate the reaction, cooled to room temperature, and concentrated under reduced pressure. The reaction mixture was diluted with 50 ml of ethyl acetate. The diluted reaction was washed with saturated aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then concentrated under reduced pressure. The obtained compound was purified by column chromatography to give 0.55 g (65%) of a white solid title compound.
1H-NMR(CDCl3) δ : 1.13(s, 3H), 1.23(s, 3H), 1.34(s, 9H), 1.70(s, 1H), 1.75(s, 3H), 1.87(s, 3H), 1.88(s, 1H), 2.26(d, 2H), 2.61(m, 1H), 2.98(s, 3H), 3.90(d, 1H), 4.18(d, 1H), 4.30(d, 1H), 4.44(d, 1H), 4.52(s, 1H), 4.58(d, 1H), 4.62(s, 1H), 4.75(d, 2H), 4.85(d, 1H), 4.95(d, 1H), 5.25(s, 1H), 5.38(d, 1H), 5.58(t, 1H), 5.65(d, 1H), 6.20(t, 1H), 7.35(m, 1H), 7.39(m, 4H), 7.48(m, 2H), 7.62(m, 1H), 8.10(d, 2H)1 H-NMR (CDCl 3) δ: 1.13 (s, 3H), 1.23 (s, 3H), 1.34 (s, 9H), 1.70 (s, 1H), 1.75 (s, 3H), 1.87 (s, 3H), 1.88 (s, 1H), 2.26 (d, 2H), 2.61 (m, 1H), 2.98 (s, 3H), 3.90 (d, 1H), 4.18 (d, 1H), 4.30 (d, 1H), 4.44 (d, 1H), 4.52 (s, 1H), 4.58 (d, 1H), 4.62 (s, 1H), 4.75 (d, 2H), 4.85 (d, 1H), 4.95 (d, 1H), 5.25 ( s, 1H), 5.38 (d, 1H), 5.58 (t, 1H), 5.65 (d, 1H), 6.20 (t, 1H), 7.35 (m, 1H), 7.39 (m, 4H), 7.48 (m , 2H), 7.62 (m, 1H), 8.10 (d, 2H)
Mass(M+Na) : 1224Mass (M + Na): 1224
6 단계 : 4-아세톡시-2α-벤조일옥시-5β,20-에폭시-1-히드록시-9-옥소-7β,10β-비스[(2,2,2-트리클로로에톡시)카르보닐옥시]-11-탁센-13α-일(2R,3S)-3-t-부톡시카르보닐아미노-3-(4-메틸페닐)-2-히드록시 프로피오네이트의 제조Step 6: 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-9-oxo-7β, 10β-bis [(2,2,2-trichloroethoxy) carbonyloxy] Preparation of -11-Taxene-13α-yl (2R, 3S) -3-t-butoxycarbonylamino-3- (4-methylphenyl) -2-hydroxy propionate
4-아세톡시-2α-벤조일옥시-5β,20-에폭시-1-히드록시-9-옥소-7β,10β-비스(2,2,2-트리클로로에톡시)카르보닐옥시]-11-탁센-13α-일(2R,3S)-3-t-부톡시카르보닐아미노-3-(4-메틸페닐)-2-(메톡시메톡시)프로피오네이트 2g(1.7mmol)을 디클로로메탄 20ml에 녹인 후 -30℃로 냉각하였다. 트리메틸실릴브로마이드0.88ml(6.7mmol)를 서서히 적하하고 동일한 온도에서 1시간동안 교반 후 0℃에서 3시간동안 교반하였다. 탄산수소나트륨수용액으로 반응을 종결 시킨 다음 물과 포화식염수로 세척하고 감압 증류하여 얻은 화합물을 컬럼크로마토그래피로 정제하여 흰색의 고체 표제화합물 1.3g(70%)를 얻었다.4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-9-oxo-7β, 10β-bis (2,2,2-trichloroethoxy) carbonyloxy] -11-taxene 2 g (1.7 mmol) of -13α-yl (2R, 3S) -3-t-butoxycarbonylamino-3- (4-methylphenyl) -2- (methoxymethoxy) propionate was dissolved in 20 ml of dichloromethane. Then cooled to -30 ° C. 3.88 ml (6.7 mmol) of trimethylsilyl bromide was slowly added dropwise, stirred at the same temperature for 1 hour, and then stirred at 0 ° C. for 3 hours. The reaction was terminated with an aqueous solution of sodium hydrogen carbonate, washed with water and brine, and distilled under reduced pressure to obtain a white solid title compound (1.3g, 70%).
1H-NMR(CDCl3) δ :1.13(s, 3H), 1.23(s, 3H), 1.34(s, 9H), 1.70(s, 1H), 1.75(s, 3H), 1.87(s, 3H), 1.88(s, 1H), 2.26(d, 2H), 2.61(m, 1H), 3.35(d, 1H), 3.90(d, 1H), 4.18(d, 1H), 4.30(d, 1H), 4.58(d, 1H), 4.62(b, 1H), 4.75(s, 2H), 4.85(d, 1H), 4.95(d, 1H), 5.25(s, 1H), 5.38(d,1H), 5.58(t, 1H), 5.65(d, 1H), 6.20(t, 1H), 7.35(m, 1H), 7.39(m, 4H), 7.48(m, 2H), 7.62(m, 1H), 8.10(d, 2H)1 H-NMR (CDCl 3) δ: 1.13 (s, 3H), 1.23 (s, 3H), 1.34 (s, 9H), 1.70 (s, 1H), 1.75 (s, 3H), 1.87 (s, 3H), 1.88 (s, 1H), 2.26 (d, 2H), 2.61 (m, 1H), 3.35 (d, 1H), 3.90 (d, 1H), 4.18 (d, 1H), 4.30 (d, 1H), 4.58 (d, 1H), 4.62 (b, 1H), 4.75 (s, 2H), 4.85 (d, 1H), 4.95 (d, 1H), 5.25 (s, 1H), 5.38 (d, 1H), 5.58 ( t, 1H), 5.65 (d, 1H), 6.20 (t, 1H), 7.35 (m, 1H), 7.39 (m, 4H), 7.48 (m, 2H), 7.62 (m, 1H), 8.10 (d , 2H)
Mass(M+Na) : 1180Mass (M + Na): 1180
7 단계 : 4-아세톡시-2α-벤조일옥시-5β,20-에폭시-1,7β,10β-트리히드록시-9-옥소-11-탁센-13α-일(2R,3S)-3-t-부톡시카르보닐아미노-3-(4-메틸페닐)-2-히드록시 프로피오네이트의 제조Step 7: 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1,7β, 10β-trihydroxy-9-oxo-11-taxen-13α-yl (2R, 3S) -3-t- Preparation of Butoxycarbonylamino-3- (4-methylphenyl) -2-hydroxy propionate
4-아세톡시-2α-벤조일옥시-5β,20-에폭시-1-히드록시-9-옥소-7β,10β-비스[(2,2,2-트리클로로에톡시)카르보닐옥시]-11-탁센-13α-일(2R,3S)-3-t-부톡시카르보닐아미노-3-(4-메틸페닐)-2-히드록시프로피오네이트 0.5g을 메틸알콜 10ml에 녹인 후 아세틱에시드 10ml를 가하고 교반하였다. 반응물에 아연 1g을 가하고 60℃에서 30분 동안 교반하여 반응을 종결시킨 후 감압농축하고 에틸아세테이트 20ml로 희석한 뒤 물과 포화 탄산수소나트륨 용액, 포화 구연산수용액으로 세척하였다. 포화식염수로 세척하고 감압증류하여 얻은 화합물을 컬럼크로마토그래피로 정제하여 흰색의 고체 표제화합물 0.25g(84%)를 얻었다.4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-9-oxo-7β, 10β-bis [(2,2,2-trichloroethoxy) carbonyloxy] -11- 0.5 g of taxane-13α-yl (2R, 3S) -3-t-butoxycarbonylamino-3- (4-methylphenyl) -2-hydroxypropionate was dissolved in 10 ml of methyl alcohol, and then 10 ml of acetic acid was added. Added and stirred. 1 g of zinc was added to the reaction mixture and stirred at 60 ° C. for 30 minutes to complete the reaction. The reaction mixture was concentrated under reduced pressure, diluted with 20 ml of ethyl acetate, and washed with water, saturated sodium bicarbonate solution and saturated citric acid solution. After washing with saturated brine and distillation under reduced pressure, the obtained compound was purified by column chromatography to give 0.25g (84%) of a white solid title compound.
1H-NMR(CDCl3) δ : 1.13(s, 3H), 1.23(s, 3H), 1.34(s, 9H), 1.70(s, 1H), 1.75(s, 3H), 1.87(s, 3H), 1.88(s, 1H), 2.26(d, 2H), 2.39(s, 3H),2.61(m, 1H), 3.35(d, 1H), 3.90(d, 1H), 4.18(m, 3H), 4.32(d, 1H), 4.62(s, 1H), 4.92(d, 1H), 5.21(s, 1H), 5.27(d, 1H), 5.42(d, 1H), 5.65(d, 1H), 6.20(t,1H), 7.35(m, 1H), 7.39(m, 4H), 7.48(m, 2H), 7.62(m, 1H), 8.10(d, 2H)1 H-NMR (CDCl 3) δ: 1.13 (s, 3H), 1.23 (s, 3H), 1.34 (s, 9H), 1.70 (s, 1H), 1.75 (s, 3H), 1.87 (s, 3H), 1.88 (s, 1H), 2.26 (d, 2H), 2.39 (s, 3H), 2.61 (m, 1H), 3.35 (d, 1H), 3.90 (d, 1H), 4.18 (m, 3H), 4.32 (d, 1H), 4.62 (s, 1H), 4.92 (d, 1H), 5.21 (s, 1H), 5.27 (d, 1H), 5.42 (d, 1H), 5.65 (d, 1H), 6.20 ( t, 1H), 7.35 (m, 1H), 7.39 (m, 4H), 7.48 (m, 2H), 7.62 (m, 1H), 8.10 (d, 2H)
Mass(M+Na) : 830Mass (M + Na): 830
<실시예 2> (4S,5R)-t-부틸-5-메톡시-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 2 Preparation of docetaxel using (4S, 5R) -t-butyl-5-methoxy-2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate
1) 실시예 1의 1 단계에서 클로로메틸 메틸에테르 대신 메틸 아이오다이드를사용하여 실시예 1에서와 동일한 방법으로 (4S,5R)-t-부틸-5-메톡시-2,6-디옥소-4- 페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) In the same manner as in Example 1, using methyl iodide instead of chloromethyl methyl ether in step 1 of Example 1, (4S, 5R) -t-butyl-5-methoxy-2,6-dioxo- 4-Phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 1.44(s, 9H), 3.62(s, 3H), 4.38(d, 1H), 5.58(d, 1H),7.23~7.36(m, 5H)1H-NMR (CDCl3) δ: 1.44 (s, 9H), 3.62 (s, 3H), 4.38 (d, 1H), 5.58 (d, 1H), 7.23 ~ 7.36 (m, 5H)
2) 상기 1)에서 제조된 (4S,5R)-t-부틸-5-메톡시-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트 화합물을 이용하여 실시예 1의 6 단계에서 트리메틸실릴 브로마이드 대신 트리브로모보란을 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) using (4S, 5R) -t-butyl-5-methoxy-2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate compound prepared in 1) above Docetaxel was prepared in the same manner as in Example 1 using tribromoborane instead of trimethylsilyl bromide in Step 6 of Example 1.
<실시예 3> (4S,5R)-t-부틸-5-(1-에톡시에톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 3 (4S, 5R) -t-butyl-5- (1-ethoxyethoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Preparation of Docetaxel
1) 실시예 1의 1 단계와 동일한 방법으로 클로로메틸메틸에테르 대신 에틸비닐에테르를 사용하여 (4S,5R)-t-부틸-5-(1-에톡시에톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) (4S, 5R) -t-butyl-5- (1-ethoxyethoxy) -2,6-dioxo using ethyl vinyl ether instead of chloromethyl methyl ether in the same manner as in step 1 of Example 1 4-Phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 1.25(t, 3H), 1.38(d, 3H), 1.44(s, 9H), 3.60(q, 3H), 4.85(q, 2H), 5.05(d, 1H), 5.62(d, 1H),7.23~7.36(m, 5H)1 H-NMR (CDCl 3) δ: 1.25 (t, 3H), 1.38 (d, 3H), 1.44 (s, 9H), 3.60 (q, 3H), 4.85 (q, 2H), 5.05 (d, 1H), 5.62 (d, 1H), 7.33 ~ 7.36 (m, 5H)
2) 상기 1)에서 제조된 (4S,5R)-t-부틸5-(1-에톡시에톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예 1의 6 단계에서 트리메틸실릴 브로마이드 대신 0.5N 염산수용액을 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) (4S, 5R) -t-butyl5- (1-ethoxyethoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxyl prepared in 1) above Docetaxel was prepared in the same manner as in Example 1 using 0.5 N aqueous hydrochloric acid solution instead of trimethylsilyl bromide in step 6 of Example 1 using the rate.
<실시예 4> (4S,5R)-t-부틸-5-(트리메틸실릴옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 4 of docetaxel using (4S, 5R) -t-butyl-5- (trimethylsilyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Produce
1) 실시예 1의 1 단계에서 클로로메틸 메틸에테르 대신 트리메틸 실릴클로라이드를 사용하여 실시예 1에서와 동일한 방법으로 (4S,5R)-t-부틸-5-(트리메틸실릴옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) (4S, 5R) -t-butyl-5- (trimethylsilyloxy) -2,6- in the same manner as in Example 1, using trimethyl silylchloride instead of chloromethyl methyl ether in step 1 of Example 1 Dioxo-4-phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 0.08(s, 9H), 1.46(s, 9H),4.85(d, 1H), 5.35(d, 1H),7.20(m, 2H), 7.32~7.39(m, 3H)1H-NMR (CDCl3) δ: 0.08 (s, 9H), 1.46 (s, 9H), 4.85 (d, 1H), 5.35 (d, 1H), 7.20 (m, 2H), 7.32 ~ 7.39 (m, 3H )
2) 상기 (4S,5R)-t-부틸-5-(트리메틸실릴옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예 1의 6 단계에서 트리메틸실릴 브로마이드 대신 테트라부틸암모늄플로라이드를 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) Example 1 using the above (4S, 5R) -t-butyl-5- (trimethylsilyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1, using tetrabutylammonium fluoride instead of trimethylsilyl bromide in step 6.
<실시예 5> (4S,5R)-t-부틸-5-(t-부틸디메틸실릴옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 5 (4S, 5R) -t-butyl-5- (t-butyldimethylsilyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Preparation of Docetaxel
1) 실시예 1의 1 단계에서 클로로메틸 메틸에테르 대신 t-부틸디메틸실릴클로라이드를 사용하여 실시예 1에서와 동일한 방법으로 (4S,5R)-t-부틸-5-(t-부틸 디메틸실릴옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) (4S, 5R) -t-butyl-5- (t-butyl dimethylsilyloxy in the same manner as in Example 1, using t-butyldimethylsilylchloride instead of chloromethyl methyl ether in step 1 of Example 1 ) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 0.05(s, 3H), 0.06(s, 3H), 0.88(s, 9H), 1.44(s, 9H),4.78(d, 1H), 5.38(d, 1H),7.20(m, 2H), 7.32~7.39(m, 3H)1 H-NMR (CDCl 3) δ: 0.05 (s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 1.44 (s, 9H), 4.78 (d, 1H), 5.38 (d, 1H), 7.20 (m, 2H), 7.32-7.39 (m, 3H)
2) 상기 (4S,5R)-t-부틸-5-(t-부틸디메틸실릴옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예 1의 6 단계에서 트리메틸실릴 브로마이드 대신 테트라부틸암모늄플로라이드를 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) using (4S, 5R) -t-butyl-5- (t-butyldimethylsilyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1 using tetrabutylammonium fluoride instead of trimethylsilyl bromide in step 6 of Example 1.
<실시예 6> (4S,5R)-t-부틸-5-(트리에틸실릴옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 6 Docetaxel using (4S, 5R) -t-butyl-5- (triethylsilyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Manufacture
1) 실시예 1의 1 단계에서 클로로메틸 메틸에테르 대신 트리에틸실릴 클로라이드를 사용하여 실시예 1에서와 동일한 방법으로 (4S,5R)-t-부틸-5-(트리에틸실릴옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) In the same manner as in Example 1, using triethylsilyl chloride instead of chloromethyl methyl ether in step 1 of Example 1, (4S, 5R) -t-butyl-5- (triethylsilyloxy) -2, 6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 0.51~0.72(m, 6H), 0.89~0.98(m, 9H), 1.44(s, 9H),4.78(d, 1H), 5.38(d, 1H),7.23~7.42(m, 5H)1 H-NMR (CDCl 3) δ: 0.51 to 0.72 (m, 6H), 0.89 to 0.98 (m, 9H), 1.44 (s, 9H), 4.78 (d, 1H), 5.38 (d, 1H), 7.33 to 7.42 (m, 5H)
2) 상기 (4S,5R)-t-부틸-5-(트리에틸실릴옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예 1의 6 단계에서 트리메틸실릴 브로마이드 대신 초산을 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) Example using (4S, 5R) -t-butyl-5- (triethylsilyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1 using acetic acid instead of trimethylsilyl bromide in step 6 of 1.
<실시예 7> (4S,5R)-t-부틸-5-(2-테트라하이드로피라닐옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 7 (4S, 5R) -t-Butyl-5- (2-tetrahydropyranyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel production
1) 실시예 1의 1 단계에서 클로로메틸 메틸에테르 대신 3,4-디히드로-2H-피란을 사용하여 실시예 1에서와 동일한 방법으로 (4S,5R)-t-부틸-5-(2-테트라하이드로피라닐옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) In the same manner as in Example 1, using 3,4-dihydro-2H-pyran instead of chloromethyl methyl ether in step 1 of Example 1, (4S, 5R) -t-butyl-5- (2- Tetrahydropyranyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 1.44(s, 9H),1.49~1.61(m, 4H), 1.78~1.85(m, 2H), 3.55(m, 1H), 4.03(m, 1H), 4.75(d, 1H), 4.95(d, 1H), 5.56(d, 1H),7.23~7.42(m, 5H)1 H-NMR (CDCl 3) δ: 1.44 (s, 9H), 1.49 to 1.61 (m, 4H), 1.78 to 1.85 (m, 2H), 3.55 (m, 1H), 4.03 (m, 1H), 4.75 (d , 1H), 4.95 (d, 1H), 5.56 (d, 1H), 7.33-7.42 (m, 5H)
2) 상기 (4S,5R)-t-부틸-5-(2-테트라하이드로피라닐옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예 1의 6 단계에서 트리메틸실릴 브로마이드 대신 피리디늄 P-톨루엔설포네이트를 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) using (4S, 5R) -t-butyl-5- (2-tetrahydropyranyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1, using pyridinium P-toluenesulfonate instead of trimethylsilyl bromide in step 6 of Example 1.
<실시예 8> (4S,5R)-t-부틸-5-(4-메톡시벤질옥시)-2,6-디옥소-4-페닐-1,3-옥사지 난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 8 (4S, 5R) -t-Butyl-5- (4-methoxybenzyloxy) -2,6-dioxo-4-phenyl-1,3-oxazane egg-3-carboxylate Docetaxel production
1) 실시예 1의 1 단계에서 클로로메틸 메틸에테르 대신 4-메톡시벤질 브로마이드를 사용하여 실시예 1에서와 동일한 방법으로 (4S,5R)-t-부틸-5-(4-메톡시벤질옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) (4S, 5R) -t-butyl-5- (4-methoxybenzyloxy in the same manner as in Example 1, using 4-methoxybenzyl bromide instead of chloromethyl methyl ether in step 1 of Example 1 ) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 1.44(s, 9H), 3.92(s, 3H), 4.41(d, 1H), 4.72(d, 1H), 4. 89(d, 1H), 5.39(d, 1H), 6.91(d, 2H), 7.23~7.41(m, 7H)1 H-NMR (CDCl 3) δ: 1.44 (s, 9H), 3.92 (s, 3H), 4.41 (d, 1H), 4.72 (d, 1H), 4. 89 (d, 1H), 5.39 (d, 1H ), 6.91 (d, 2H), 7.23-7.41 (m, 7H)
2) 상기 (4S,5R)-t-부틸-5-(4-메톡시벤질옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예 1의 6 단계에서 트리메틸실릴 브로마이드 대신 디클로로디시아노퀴논을 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) using (4S, 5R) -t-butyl-5- (4-methoxybenzyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1, using dichlorodicyanoquinone instead of trimethylsilyl bromide in Step 6 of Example 1.
<실시예 9> (4S,5R)-t-부틸-5-(아세톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 9 Preparation of docetaxel using (4S, 5R) -t-butyl-5- (acetoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate
1 단계: (2R,3S)-벤질-3-(t-부톡시카르보닐아미노)-2-(아세톡시)-3-페닐프로피오네이트의 제조Step 1: Preparation of (2R, 3S) -benzyl-3- (t-butoxycarbonylamino) -2- (acetoxy) -3-phenylpropionate
(2R,3S)-벤질-3-(t-부톡시카르보닐아미노)-2-히드록시-3-페닐프로피오네이트 3g(8.1mmol)을 메틸렌클로라이드 30ml에 녹인 후 무수아세트산 0.91ml(9.7mmol)을 가하고 0℃로 냉각하였다. 반응물에 피리딘1.3ml(16mmol)을 서서히 적가하고 상온에서 4시간 동안 교반하였다. 반응종결 후 물과 포화식염수로 세척한 다음 감압농축하여 오일을 얻었다. 컬럼크로마토그래피로 정제하여 흰색 결정 3.0g(91%)을 얻었다.3 g (8.1 mmol) of (2R, 3S) -benzyl-3- (t-butoxycarbonylamino) -2-hydroxy-3-phenylpropionate was dissolved in 30 ml of methylene chloride, and then 0.91 ml (9.7 mmol) of acetic anhydride. ) Was added and cooled to 0 ° C. Pyridine 1.3 ml (16 mmol) was slowly added dropwise to the reaction and stirred at room temperature for 4 hours. After completion of the reaction, washed with water and brine and concentrated under reduced pressure to give an oil. Purified by column chromatography to give 3.0g (91%) of white crystals.
1H-NMR(CDCl3) δ : 1.42(s, 9H), 2.05(s, 3H), 5.12~5.22(q, 2H), 5.35(d, 1H), 5.41(d, 1H), 7.19~7.36(m, 10H)1 H-NMR (CDCl 3) δ: 1.42 (s, 9H), 2.05 (s, 3H), 5.12 to 5.22 (q, 2H), 5.35 (d, 1H), 5.41 (d, 1H), 7.19 to 7.36 (m , 10H)
Mass(M+1) : 414Mass (M + 1): 414
2 단계: (2R,3S)-벤질-3-(비스(t-부톡시카르보닐)아미노)-2-(아세톡시)-3-페닐프로피오네이트의 제조Step 2: Preparation of (2R, 3S) -benzyl-3- (bis (t-butoxycarbonyl) amino) -2- (acetoxy) -3-phenylpropionate
(2R,3S)-벤질-3-(t-부톡시카르보닐아미노)-2-(아세톡시)-3-페닐프로피오네이트 2g(4.8mmol)을 실시예 1의 2단계와 동일한 방법으로 반응을 종결시키고 컬럼크로마토그래피로 정제하여 2.3g(93%)의 흰색 결정을 얻었다.2 g (4.8 mmol) of (2R, 3S) -benzyl-3- (t-butoxycarbonylamino) -2- (acetoxy) -3-phenylpropionate was reacted in the same manner as in step 2 of Example 1. Was terminated and purified by column chromatography to obtain 2.3 g (93%) of white crystals.
1H-NMR(CDCl3) δ : 1.41(s, 18H), 2.15(s, 3H), 4.90~5.02(q, 2H), 5.68(d, 1H), 6.05(d, 1H), 7.03(m, 2H), 7.22(m, 6H), 7.37(m, 2H)1 H-NMR (CDCl 3) δ: 1.41 (s, 18H), 2.15 (s, 3H), 4.90 to 5.02 (q, 2H), 5.68 (d, 1H), 6.05 (d, 1H), 7.03 (m, 2H ), 7.22 (m, 6H), 7.37 (m, 2H)
Mass(M+1) : 514Mass (M + 1): 514
3 단계: (2R,3S)-3-(비스-(t-부톡시카르보닐)아미노)-2-(아세톡시)-3-페닐프로피오닉에시드의 제조(화학식 5의 제조)Step 3: Preparation of (2R, 3S) -3- (bis- (t-butoxycarbonyl) amino) -2- (acetoxy) -3-phenylpropionic acid (Formula 5)
(2R,3S)-벤질-3-(비스(t-부톡시카르보닐)아미노)-2-(아세톡시)-3-페닐프로피오네이트 2.3g(4.5mol)을 실시예 1의 3단계와 동일한 방법으로 수소화 반응하여 반응을 종결시킨 후 셀라이트 필터로 팔라듐 카본을 제거하고 얻은 반응 후 용액을 농축하여 2g(98%)의 흰색고체를 얻었다.2.3 g (4.5 mol) of (2R, 3S) -benzyl-3- (bis (t-butoxycarbonyl) amino) -2- (acetoxy) -3-phenylpropionate and In the same manner, the reaction was terminated by hydrogenation, and then palladium carbon was removed with a celite filter. After the reaction, the solution was concentrated to give 2 g (98%) of white solid.
1H-NMR(CDCl3) δ : 1.38(s, 18H), 2.11(s, 3H), 5.75(d, 1H), 6.01(d, 1H), 7.25(m, 3H), 7.45(m, 2H)1 H-NMR (CDCl 3) δ: 1.38 (s, 18H), 2.11 (s, 3H), 5.75 (d, 1H), 6.01 (d, 1H), 7.25 (m, 3H), 7.45 (m, 2H)
Mass(M+1) : 424Mass (M + 1): 424
4 단계: (4S,5R)-t-부틸-5-(아세톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트의 제조(화학식 3의 제조)Step 4: Preparation of (4S, 5R) -t-butyl-5- (acetoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate (Preparation of Formula 3) )
(2R,3S)-3-(비스-(t-부톡시카르보닐)아미노)-2-(아세톡시)-3-페닐프로피오닉에시드 2g(4.7mmol)을 실시예 1의 4단계와 동일한 방법으로 반응을 종결시켰다. 반응물을 에틸아세테이트로 희석한 후 물과 포화식염수로 세척하고 감압 농축하여 상기 표제화합물 1.6g(94%)을 얻었다.2 g (4.7 mmol) of (2R, 3S) -3- (bis- (t-butoxycarbonyl) amino) -2- (acetoxy) -3-phenylpropionic acid was prepared in the same manner as in Step 4 of Example 1. The reaction was terminated. The reaction was diluted with ethyl acetate, washed with water and brine, and concentrated under reduced pressure to obtain 1.6 g (94%) of the title compound.
1H-NMR(CDCl3) δ : 1.44(s, 9H), 2.18(s, 3H), 5.58(d, 1H), 5.81(d, 1H),7.20(m, 2H), 7.40(m, 3H)1 H-NMR (CDCl 3) δ: 1.44 (s, 9H), 2.18 (s, 3H), 5.58 (d, 1H), 5.81 (d, 1H), 7.20 (m, 2H), 7.40 (m, 3H)
Mass(M+1) : 350Mass (M + 1): 350
5 단계: 4-아세톡시-2α-벤조일옥시-5β,20-에폭시-1-히드록시-9-옥소-7β,10β-비스-(트리클로로아세톡시)-11-탁센-13α-일-(2R,3S)-3-t-부톡시카르보닐아미노-3-(4-메틸페닐)-2-(아세톡시)프로피오네이트의 제조(화학식 4의 제조)Step 5: 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-9-oxo-7β, 10β-bis- (trichloroacetoxy) -11-taxen-13α-yl- ( Preparation of 2R, 3S) -3-t-butoxycarbonylamino-3- (4-methylphenyl) -2- (acetoxy) propionate (Preparation of Formula 4)
(4S,5R)-t-부틸-5-(아세톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트 2g(5.7mmol)을 14ml의 아니솔에 녹인 후 4-아세톡시-2α-벤조일옥시-5β,20-에폭시-1,13σ-디히드록시-9-옥소-7β,10β-비스-(트리클로로아세톡시)-11-탁센 1.2g(1.4mmol)과 4-(디메틸아미노) 피리딘 0.018g(0.14mmol)을 가하고 상온에서 1시간 교반하였다. 반응종결 후 감압 농축하여 얻은 반응물을 에틸아세테이트100ml로 희석하고 포화 구연산수용액, 포화 탄산수소나트륨수용액, 포화식염수로 세척한 뒤 감압 농축하였다. 얻어진 화합물을 컬럼크로마토그래피로 정제하여 흰색의 고체 표제화합물 2.4g(89%)를 얻었다.14 g of anisole (2 g (5.7 mmol) of (4S, 5R) -t-butyl-5- (acetoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate After dissolving in 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1,13σ-dihydroxy-9-oxo-7β, 10β-bis- (trichloroacetoxy) -11-taxene 1.2 g ( 1.4 mmol) and 0.018 g (0.14 mmol) of 4- (dimethylamino) pyridine were added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with 100 ml of ethyl acetate, washed with saturated citric acid solution, saturated sodium bicarbonate solution and saturated brine, and concentrated under reduced pressure. The obtained compound was purified by column chromatography to give 2.4 g (89%) of a white solid title compound.
1H-NMR(CDCl3) δ : 1.15(s, 3H), 1.22(s, 3H), 1.34(s, 9H), 1.73(s, 1H), 1.75(s, 3H), 1.87(s, 3H), 1.88(s, 1H), 2.10(s, 3H), 2.26(d, 2H), 2.43(s, 3H),2.70(m, 1H), 3.90(d, 1H), 4.18(m, 3H), 4.32(d, 1H), 4.98(d, 1H), 5.21(s, 1H), 5.25(d, 1H), 5.40(d,1H), 5.65(d, 1H), 6.20(t, 1H), 6.48(s, 1H), 7.35(m, 1H), 7.39(m, 4H), 7.48(m, 2H), 7.62(m, 1H), 8.10(d, 2H)1 H-NMR (CDCl 3) δ: 1.15 (s, 3H), 1.22 (s, 3H), 1.34 (s, 9H), 1.73 (s, 1H), 1.75 (s, 3H), 1.87 (s, 3H), 1.88 (s, 1H), 2.10 (s, 3H), 2.26 (d, 2H), 2.43 (s, 3H), 2.70 (m, 1H), 3.90 (d, 1H), 4.18 (m, 3H), 4.32 (d, 1H), 4.98 (d, 1H), 5.21 (s, 1H), 5.25 (d, 1H), 5.40 (d, 1H), 5.65 (d, 1H), 6.20 (t, 1H), 6.48 ( s, 1H), 7.35 (m, 1H), 7.39 (m, 4H), 7.48 (m, 2H), 7.62 (m, 1H), 8.10 (d, 2H)
Mass(M+Na) : 1162Mass (M + Na): 1162
6 단계: 4-아세톡시-2α-벤조일옥시-5β,20-에폭시-1,7β,10β-트리히드록시-9-옥소-11-탁센-13α-일(2R,3S)-3-t-부톡시카르보닐아미노-3-(4-메틸페닐)-2-히드록시 프로피오네이트의 제조Step 6: 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1,7β, 10β-trihydroxy-9-oxo-11-taxen-13α-yl (2R, 3S) -3-t- Preparation of Butoxycarbonylamino-3- (4-methylphenyl) -2-hydroxy propionate
4-아세톡시-2α-벤조일옥시-5β,20-에폭시-1-히드록시-9-옥소-7β,10β-비스-(트리클로로아세톡시)-11-탁센-13α-일(2R,3S)-3-t-부톡시카르보닐아미노-3-(4-메틸페닐)-2-(아세톡시)프로피오네이트 0.55g(0.48mmol)을 30ml의 에탄올에 녹인 후 히드라진 0.4ml를 적가하였다. 상온에서 1시간 동안 교반하여 반응을 종결시킨 후 감압농축하고 에틸아세테이트 20ml로 희석한 뒤 염화암모늄수용액과 포화식염수로 세척하였다. 감압 증류하여 얻은 화합물을 컬럼크로마토그래피로 정제하여 흰색의 고체 표제화합물 0.33g(85%)를 얻었다.4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1-hydroxy-9-oxo-7β, 10β-bis- (trichloroacetoxy) -11-taxen-13α-yl (2R, 3S) 0.55 g (0.48 mmol) of 3-t-butoxycarbonylamino-3- (4-methylphenyl) -2- (acetoxy) propionate was dissolved in 30 ml of ethanol and 0.4 ml of hydrazine was added dropwise. After completion of the reaction by stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, diluted with 20 ml of ethyl acetate, and washed with an aqueous ammonium chloride solution and saturated brine. Compound obtained by distillation under reduced pressure was purified by column chromatography to give 0.33 g (85%) of a white solid title compound.
1H-NMR(CDCl3) δ : 1.13(s, 3H), 1.23(s, 3H), 1.34(s, 9H), 1.70(s, 1H), 1.75(s, 3H), 1.87(s, 3H), 1.88(s, 1H), 2.26(d, 2H), 2.39(s, 3H),2.61(m, 1H), 3.35(d, 1H), 3.90(d, 1H), 4.18(m, 3H), 4.32(d, 1H), 4.62(s,1H), 4.92(d, 1H), 5.21(s, 1H), 5.27(d, 1H), 5.42(d, 1H), 5.65(d, 1H), 6.20(t, 1H), 7.35(m, 1H), 7.39(m, 4H), 7.48(m, 2H), 7.62(m, 1H), 8.10(d, 2H)1 H-NMR (CDCl 3) δ: 1.13 (s, 3H), 1.23 (s, 3H), 1.34 (s, 9H), 1.70 (s, 1H), 1.75 (s, 3H), 1.87 (s, 3H), 1.88 (s, 1H), 2.26 (d, 2H), 2.39 (s, 3H), 2.61 (m, 1H), 3.35 (d, 1H), 3.90 (d, 1H), 4.18 (m, 3H), 4.32 (d, 1H), 4.62 (s, 1H), 4.92 (d, 1H), 5.21 (s, 1H), 5.27 (d, 1H), 5.42 (d, 1H), 5.65 (d, 1H), 6.20 ( t, 1H), 7.35 (m, 1H), 7.39 (m, 4H), 7.48 (m, 2H), 7.62 (m, 1H), 8.10 (d, 2H)
Mass(M+Na) : 830Mass (M + Na): 830
<실시예 10> (4S,5R)-t-부틸-5-(피발로일옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 10 Docetaxel using (4S, 5R) -t-butyl-5- (pivaloyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Manufacture
1) 실시예 9의 1 단계에서 무수아세트산 대신 피발로일클로라이드를 사용하여 실시예 9에서와 동일한 방법으로 (4S, 5R)-t-부틸-5-(피발로일옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) (4S, 5R) -t-butyl-5- (pivaloyloxy) -2,6- in the same manner as in Example 9, using pivaloylchloride instead of acetic anhydride in step 1 of Example 9 Dioxo-4-phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 1.18(s, 9H), 1.44(s, 9H), 5.55(d, 1H), 5.81(d, 1H),7.19(m, 2H), 7.36(m, 3H)1 H-NMR (CDCl 3) δ: 1.18 (s, 9H), 1.44 (s, 9H), 5.55 (d, 1H), 5.81 (d, 1H), 7.19 (m, 2H), 7.36 (m, 3H)
2) 상기 (4S, 5R)-t-부틸-5-(피발로일옥시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예 1의 6 단계에서 트리메틸실릴 브로마이드 대신 테트라부틸암모늄히드록사이드를, 7 단계에서 아연과 초산 대신 히드라진을 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) Example using the above (4S, 5R) -t-butyl-5- (pivaloyloxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1, using tetrabutylammonium hydroxide instead of trimethylsilyl bromide in step 6 of 1, and hydrazine in place of zinc and acetic acid in step 7.
<실시예 11> (4S,5R)-t-부틸-5-(트리클로로아세톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 11 docetaxel using (4S, 5R) -t-butyl-5- (trichloroacetoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Manufacture
1) 실시예 9의 1 단계에서 무수아세트산 대신 무수트리클로로아세트산을 사용하여 실시예 9에서와 동일한 방법으로 (4S,5R)-t-부틸-5-(트리클로로아세톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) In the same manner as in Example 9, using trichloroacetic anhydride instead of acetic anhydride in step 1 of Example 9, (4S, 5R) -t-butyl-5- (trichloroacetoxy) -2,6- Dioxo-4-phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 1.44(s, 9H), 5.65(d, 1H), 5.85(d, 1H), 7.23~7.36(m, 5H)1H-NMR (CDCl3) δ: 1.44 (s, 9H), 5.65 (d, 1H), 5.85 (d, 1H), 7.23 ~ 7.36 (m, 5H)
2) 상기 (4S,5R)-t-부틸-5-(트리클로로아세톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예 9에서와 동일한 방법으로 도세탁셀을 제조하였다.2) Example using (4S, 5R) -t-butyl-5- (trichloroacetoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in 9.
<실시예 12> (4S,5R)-t-부틸-5-(2-메톡시아세톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 12 (4S, 5R) -t-butyl-5- (2-methoxyacetoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Preparation of Docetaxel
1) 실시예 9의 1 단계에서 무수아세트산 대신 메톡시아세틸클로라이드를 사용하여 실시예 9에서와 동일한 방법으로 (4S,5R)-t-부틸-5-(2-메톡시아세톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) (4S, 5R) -t-butyl-5- (2-methoxyacetoxy) -2, in the same manner as in Example 9, using methoxyacetylchloride instead of acetic anhydride in step 1 of Example 9 6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 1.18(s, 9H), 1.44(s, 9H),5.55(d, 1H), 5.81(d, 1H),7.19(m, 2H), 7.36(m, 3H)1 H-NMR (CDCl 3) δ: 1.18 (s, 9H), 1.44 (s, 9H), 5.55 (d, 1H), 5.81 (d, 1H), 7.19 (m, 2H), 7.36 (m, 3H)
2) 상기 (4S,5R)-t-부틸-5-(2-메톡시아세톡시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예 1의 6 단계에서 트리메틸실릴 브로마이드 대신 에탄올아민을, 7 단계에서 아연과 초산 대신 히드라진을 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) using (4S, 5R) -t-butyl-5- (2-methoxyacetoxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1, using ethanolamine instead of trimethylsilyl bromide in step 6 of Example 1, and hydrazine in place of zinc and acetic acid in step 7.
<실시예 13> (4S,5R)-t-부틸-5-(에톡시카르복시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 13 of docetaxel using (4S, 5R) -t-butyl-5- (ethoxycarboxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Produce
1) 실시예 9의 1 단계에서 무수아세트산 대신 에틸클로로포메이트를 사용하여 실시예 9와 동일한 방법으로 (4S,5R)-t-부틸-5-(에톡시카르복시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) (4S, 5R) -t-butyl-5- (ethoxycarboxy) -2,6-dioxo in the same manner as in Example 9 using ethylchloroformate instead of acetic anhydride in step 1 of Example 9 4-Phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 1.35(t, 3H), 1.44(s, 9H),4.28(q, 2H), 5.65(q, 2H),7.19(m, 2H), 7.36(m, 3H)1 H-NMR (CDCl 3) δ: 1.35 (t, 3H), 1.44 (s, 9H), 4.28 (q, 2H), 5.65 (q, 2H), 7.19 (m, 2H), 7.36 (m, 3H)
2) 상기 (4S,5R)-t-부틸-5-(에톡시카르복시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예1의 6 단계에서 트리메틸실릴 브로마이드 대신 수산화칼륨을, 7 단계에서 아연과 초산 대신 히드라진을 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) Example 1 using the above (4S, 5R) -t-butyl-5- (ethoxycarboxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1, using potassium hydroxide instead of trimethylsilyl bromide in step 6 and hydrazine in place of zinc and acetic acid in step 7.
<실시예 14> (4S,5R)-t-부틸-5-(t-부톡시카복시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 14 (4S, 5R) -t-butyl-5- (t-butoxycarboxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Preparation of Docetaxel
1) 실시예 9의 1 단계에서 무수아세트산 대신 디-t-부틸 디카르보네이트를 사용하여 실시예 9에서와 동일한 방법으로 (4S,5R)-t-부틸-5-(t-부톡시카복시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) (4S, 5R) -t-butyl-5- (t-butoxycarboxy) in the same manner as in Example 9, using di-t-butyl dicarbonate instead of acetic anhydride in step 1 of Example 9 -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 1.44(s, 18H), 5.82(d, 2H), 6.01(d, 2H),7.21(m, 5H)1 H-NMR (CDCl 3) δ: 1.44 (s, 18H), 5.82 (d, 2H), 6.01 (d, 2H), 7.21 (m, 5H)
2) 상기 (4S,5R)-t-부틸-5-(t-부톡시카복시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예1의 6 단계에서 트리메틸실릴 브로마이드 대신 트리플로로아세트산을, 7 단계에서 아연과 초산 대신 히드라진을 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) using (4S, 5R) -t-butyl-5- (t-butoxycarboxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate Docetaxel was prepared in the same manner as in Example 1, using trifluoroacetic acid instead of trimethylsilyl bromide in step 6 of Example 1 and hydrazine in place of zinc and acetic acid in step 7.
<실시예 15> (4S,5R)-t-부틸-5-(2,2,2-트리클로로에톡시카르복시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용한 도세탁셀의 제조Example 15 (4S, 5R) -t-Butyl-5- (2,2,2-trichloroethoxycarboxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3 -Preparation of Docetaxel Using Carboxylate
1) 실시예 9의 1 단계에서 무수아세트산 대신 2,2,2-트리클로로에틸 클로로포메이트를 사용하여 실시예 9와 동일한 방법으로 (4S,5R)-t-부틸-5-(2,2,2-트리클로로에톡시카르복시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 제조하였다.1) (4S, 5R) -t-butyl-5- (2,2 in the same manner as in Example 9, using 2,2,2-trichloroethyl chloroformate instead of acetic anhydride in Step 1 of Example 9 , 2-trichloroethoxycarboxy) -2,6-dioxo-4-phenyl-1,3-oxazinane-3-carboxylate was prepared.
1H-NMR(CDCl3) δ : 1.44(s, 9H), 4.75(q, 2H), 5.65(d, 1H), 5.81(d, 1H), 7.21(m, 5H)1 H-NMR (CDCl 3) δ: 1.44 (s, 9H), 4.75 (q, 2H), 5.65 (d, 1H), 5.81 (d, 1H), 7.21 (m, 5H)
2) 상기 (4S,5R)-t-부틸-5-(2,2,2-트리클로로 에톡시카르복시)-2,6-디옥소-4-페닐-1,3-옥사지난-3-카르복실레이트를 이용하여 실시예 1의 6 단계에서 트리메틸실릴 브로마이드 대신 아연과 초산을, 7 단계에서 아연과 초산 대신 히드라진을 사용하여 실시예 1에서와 동일한 방법으로 도세탁셀을 제조하였다.2) Said (4S, 5R) -t-butyl-5- (2,2,2-trichloro ethoxycarboxy) -2,6-dioxo-4-phenyl-1,3-oxazinan-3-carbox Docetaxel was prepared in the same manner as in Example 1, using zinc and acetic acid in place of trimethylsilyl bromide in step 6 of Example 1, and hydrazine in place of zinc and acetic acid in step 7, using a carboxylate.

Claims (9)

  1. 하기 화학식 2로 표시되는 화합물과 하기 화학식 3으로 표시되는 화합물을 축합 반응시켜 하기 화학식 4로 표시되는 화합물을 제조한 다음 이를 히드록시 보호기를 탈보호 반응시키는 단계를 포함하여 항종양성 특성 있는 하기 화학식 1의 탁산 유도체의 제조방법.To prepare a compound represented by the formula (4) by condensation reaction of the compound represented by the formula (2) and the compound represented by the formula (3), and then to deprotection reaction of the hydroxy protecting group comprising the following formula 1 Process for the preparation of the taxane derivatives.
    <화학식 1> <Formula 1>
    Figure PCTKR2009005279-appb-I000014
    Figure PCTKR2009005279-appb-I000014
    <화학식 2><Formula 2>
    Figure PCTKR2009005279-appb-I000015
    Figure PCTKR2009005279-appb-I000015
    <화학식 3><Formula 3>
    Figure PCTKR2009005279-appb-I000016
    Figure PCTKR2009005279-appb-I000016
    <화학식 4><Formula 4>
    Figure PCTKR2009005279-appb-I000017
    Figure PCTKR2009005279-appb-I000017
    상기 식에서, R1은 t-부톡시카르보닐 또는 벤조일 중에서 선택되는 아민 보호기이고, R3은 C1~C6의 알킬 또는 알콕시로 치환되거나 치환되지 않은 C1~C6의 알킬, 실릴, 테트라하이드로피란 또는 벤질; -C(O)-R5 또는 -C(O)-O-R5 중에서 선택되며, 여기서 R5는 C1~C6의 알콕시 또는 할로겐으로 치환되거나 치환되지 않은 C1~C6의 알킬이고, G는 수소 또는 아세틸이며, G1 및 G2는 알코올 보호기이다.Wherein, R 1 is an amine protecting group selected from t- butoxycarbonyl or benzoyl, R 3 is substituted with C 1 ~ C 6 alkyl or alkoxy or unsubstituted C 1 ~ C 6 alkyl, silyl, tetra Hydropyrans or benzyl; Is selected from -C (O) -R 5 or -C (O) -OR 5 , wherein R 5 is C 1 -C 6 alkyl substituted or unsubstituted with C 1 -C 6 alkoxy or halogen, G Is hydrogen or acetyl and G1 and G2 are alcohol protecting groups.
  2. 제 1 항에 있어서, 화학식 2의 화합물과 화학식 3의 화합물의 축합 반응을 진행함에 있어서 활성화제로서 4-디메틸아미노피리딘 또는 4-피로리디노피리딘을 1 또는 모두 사용하는 화학식 1의 탁산 유도체의 제조방법.The preparation of the taxane derivative of formula (I) according to claim 1, wherein in the condensation reaction of the compound of formula (2) and the compound of formula (3), one or both of 4-dimethylaminopyridine or 4-pyrrolidinopyridine is used as an activator. Way.
  3. 제 1 항에 있어서, 화학식 2의 화합물과 화학식 3의 화합물의 축합 반응을 진행함에 있어서 0℃ 내지 120℃의 온도범위에서 반응 용매로서 톨루엔, 벤젠, 클로로벤젠, 알릴벤젠, 3차 부틸벤젠, 아세토니트릴, 헵탄, 디메틸포름아미드, 테트라히드로퓨란, 아니솔 중에서 1종 이상 선택되는 용매를 사용하는 화학식 1의 탁산 유도체의 제조방법.According to claim 1, Toluene, benzene, chlorobenzene, allylbenzene, tertiary butylbenzene, aceto as a reaction solvent in the temperature range of 0 ℃ to 120 ℃ in the condensation reaction of the compound of Formula 2 and the compound of Formula 3 A process for preparing the taxane derivative of formula (I) using a solvent selected from at least one of nitrile, heptane, dimethylformamide, tetrahydrofuran and anisole.
  4. 하기 화학식 3로 표시되는 화합물.A compound represented by the following formula (3).
    <화학식 3><Formula 3>
    Figure PCTKR2009005279-appb-I000018
    Figure PCTKR2009005279-appb-I000018
    상기 식에서, R1 및 R3는 상기 청구항 1에서 정의한 바와 같다.Wherein R 1 and R 3 are as defined in claim 1 above.
  5. 제 4 항에 있어서, R1이 t-부톡시카르보닐 또는 벤조일인 화합물.The compound of claim 4, wherein R 1 is t-butoxycarbonyl or benzoyl.
  6. 하기 화학식 5로 표시되는 에시드 화합물을 옥살릴클로라이드 또는 티오닐클로라이드와 디메틸포름아미드를 사용하여 고리화 반응을 통해 하기 화학식 3으로 표시되는 화합물의 제조방법.A method for preparing a compound represented by the following Chemical Formula 3 through a cyclization reaction using an oxalyl chloride or thionyl chloride and dimethylformamide as an acid compound represented by the following Chemical Formula 5.
    <화학식 3><Formula 3>
    Figure PCTKR2009005279-appb-I000019
    Figure PCTKR2009005279-appb-I000019
    Figure PCTKR2009005279-appb-I000020
    Figure PCTKR2009005279-appb-I000020
    상기 식에서, R1과 R2는 t-부톡시카르보닐, 벤조일 중에서 선택되는 아민 보호기로 각각 서로 같거나 다를 수 있으며, R3는 C1~C6의 알킬 또는 알콕시로 치환되거나 치환되지 않은 C1~C6의 알킬, 실릴, 테트라하이드로피란 또는 벤질; -C(O)-R5 또는 -C(O)-O-R5 중에서 선택되며, 여기서 R5는 C1~C6의 알콕시 또는 할로겐으로 치환되거나 치환되지 않은 C1~C6의 알킬이다.Wherein R 1 and R 2 may be the same as or different from each other with an amine protecting group selected from t-butoxycarbonyl and benzoyl, and R 3 may be substituted or unsubstituted with C 1 to C 6 alkyl or alkoxy. Alkyl, silyl, tetrahydropyran or benzyl of 1 to C 6 ; -C (O) is selected from -R 5, or -C (O) -OR 5, where R 5 is alkyl of C 1 ~ non-substituted alkoxy or halogen-substituted C 6 or C 1 ~ C 6.
  7. 하기 화학식 5로 표시되는 화합물.A compound represented by the following formula (5).
    <화학식 5><Formula 5>
    Figure PCTKR2009005279-appb-I000021
    Figure PCTKR2009005279-appb-I000021
    상기 식에서, R1, R2 및 R3는 청구항 6에서 정의한 바와 같다.Wherein R 1 , R 2 and R 3 are as defined in claim 6.
  8. 제 7 항에 있어서, R1과 R2가 각각 서로 같거나 다를 수 있는 t-부톡시카르보닐 또는 벤조일이고, R3가 메톡시메틸, 메틸, 1-에톡시에틸, 트리메틸실릴, t-부틸디메틸실릴, 트리에틸실릴, 2-테트라하이드로피라닐, 4-메톡시벤질, 아세틸, 피발로일, 트리클로로아세틸, 2-메톡시 아세틸, 2,2,2-트리클로로에톡시카르보닐, 에톡시카보닐, t-부톡시카르보닐 중에서 선택되는 화합물.8. A compound according to claim 7, wherein R 1 and R 2 are each t-butoxycarbonyl or benzoyl, which may be the same or different from each other, and R 3 is methoxymethyl, methyl, 1-ethoxyethyl, trimethylsilyl, t-butyl Dimethylsilyl, triethylsilyl, 2-tetrahydropyranyl, 4-methoxybenzyl, acetyl, pivaloyl, trichloroacetyl, 2-methoxy acetyl, 2,2,2-trichloroethoxycarbonyl, e Methoxycarbonyl, t-butoxycarbonyl.
  9. 하기 화학식 6으로 표시되는 3-아미노-3-페닐프로피오네이트의 화합물을 디-t-부틸 디카르보네이트와 반응시켜 하기 화학식 7의 화합물을 제조한 후 수소화 반응 또는 가수분해 반응을 통하여 카르복시기를 탈보호하여 제조되는 하기 화학식 5로 표시되는 에시드 화합물의 제조방법.To react the compound of 3-amino-3-phenylpropionate represented by the formula (6) with di-t-butyl dicarbonate to prepare a compound of the formula (7) and then to remove the carboxyl group through a hydrogenation or hydrolysis reaction Method for preparing an acid compound represented by the formula (5) prepared by protecting.
    <화학식 5><Formula 5>
    Figure PCTKR2009005279-appb-I000022
    Figure PCTKR2009005279-appb-I000022
    <화학식 6><Formula 6>
    Figure PCTKR2009005279-appb-I000023
    Figure PCTKR2009005279-appb-I000023
    <화학식 7><Formula 7>
    Figure PCTKR2009005279-appb-I000024
    Figure PCTKR2009005279-appb-I000024
    상기 식에서, R1과 R2가 각각 서로 같거나 다를 수 있는 t-부톡시카르보닐 또는 벤조일이고, R3가 메톡시메틸, 메틸, 1-에톡시에틸, 트리메틸실릴, t-부틸디메틸실릴, 트리에틸실릴, 2-테트라하이드로피라닐, 4-메톡시벤질, 아세틸, 피발로일, 트리클로로아세틸, 2-메톡시 아세틸, 2,2,2-트리클로로에톡시카르보닐, 에톡시카보닐, t-부톡시카르보닐 중에서 선택되고, R4는 C1~C6의 알킬, 벤질 라디칼 중에서 선택되는 카르복시기의 보호기이다.Wherein R 1 and R 2 are each t-butoxycarbonyl or benzoyl, which may be the same or different from each other, R 3 is methoxymethyl, methyl, 1-ethoxyethyl, trimethylsilyl, t-butyldimethylsilyl, Triethylsilyl, 2-tetrahydropyranyl, 4-methoxybenzyl, acetyl, pivaloyl, trichloroacetyl, 2-methoxy acetyl, 2,2,2-trichloroethoxycarbonyl, ethoxycarbonyl , t-butoxycarbonyl, and R 4 is a protecting group of a carboxy group selected from C 1 to C 6 alkyl and benzyl radicals.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0170430A1 (en) * 1984-07-05 1986-02-05 The Wellcome Foundation Limited Heterocyclic pharmaceutical compounds, preparation and use
US5319105A (en) * 1989-12-22 1994-06-07 Abbott Laboratories Derivatives and anologs of monoethylglycinexylidide
US5532363A (en) * 1989-11-14 1996-07-02 Florida State University Heteroaryl substituted oxazinone compounds for the preparation of taxol
WO1998017656A1 (en) * 1996-10-24 1998-04-30 Institute Armand-Frappier A family of canadensol taxanes, the semi-synthetic preparation and therapeutic use thereof
WO1999014209A1 (en) * 1997-09-17 1999-03-25 Kabushiki Kaisha Yakult Honsha New taxane derivatives
US6911549B1 (en) * 1992-12-15 2005-06-28 Jackson B. Hester, Jr. Method of preparing a taxol derivative

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2604337B1 (en) * 1986-09-26 1989-01-06 Stela Inox PROCESS FOR TREATING FISH BY CUTTING OUT AND DEVICE FOR CARRYING OUT THIS METHOD
FR2687150B1 (en) * 1992-02-07 1995-04-28 Rhone Poulenc Rorer Sa PROCESS FOR THE PREPARATION OF TAXANE DERIVATIVES.
US20050288520A1 (en) * 2004-06-25 2005-12-29 Phytogen Life Sciences Inc. One pot synthesis of taxane derivatives and their conversion to paclitaxel and docetaxel

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0170430A1 (en) * 1984-07-05 1986-02-05 The Wellcome Foundation Limited Heterocyclic pharmaceutical compounds, preparation and use
US5532363A (en) * 1989-11-14 1996-07-02 Florida State University Heteroaryl substituted oxazinone compounds for the preparation of taxol
US5319105A (en) * 1989-12-22 1994-06-07 Abbott Laboratories Derivatives and anologs of monoethylglycinexylidide
US6911549B1 (en) * 1992-12-15 2005-06-28 Jackson B. Hester, Jr. Method of preparing a taxol derivative
WO1998017656A1 (en) * 1996-10-24 1998-04-30 Institute Armand-Frappier A family of canadensol taxanes, the semi-synthetic preparation and therapeutic use thereof
WO1999014209A1 (en) * 1997-09-17 1999-03-25 Kabushiki Kaisha Yakult Honsha New taxane derivatives

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