WO2010035985A2 - Procédé de production de dérivés de taxane - Google Patents

Procédé de production de dérivés de taxane Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
formula
compound
reaction
butoxycarbonyl
butyl
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PCT/KR2009/005279
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English (en)
Korean (ko)
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WO2010035985A3 (fr
Inventor
김문성
유무희
이재걸
김용직
최준호
성시영
임홍규
차대원
손병화
류기문
Original Assignee
동아제약 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by 동아제약 주식회사 filed Critical 동아제약 주식회사
Priority to JP2011528922A priority Critical patent/JP5552489B2/ja
Publication of WO2010035985A2 publication Critical patent/WO2010035985A2/fr
Publication of WO2010035985A3 publication Critical patent/WO2010035985A3/fr

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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

La présente invention concerne un procédé de production de dérivés de taxane avec une activité anticancéreuse. Le procédé de la présente invention produit des dérivés de taxane en peu de temps dans des conditions moyennes par l'utilisation de composés phényle oxazinan dione qui sont de nouveaux composés, en tant que réactif, de sorte que les composés phényle oxazinan dione réagissent à des dérivés de baccatine III.
PCT/KR2009/005279 2008-09-26 2009-09-17 Procédé de production de dérivés de taxane WO2010035985A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2011528922A JP5552489B2 (ja) 2008-09-26 2009-09-17 タキサン誘導体の製造方法

Applications Claiming Priority (2)

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KR1020080094529A KR101014438B1 (ko) 2008-09-26 2008-09-26 탁산 유도체의 제조방법
KR10-2008-0094529 2008-09-26

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WO2010035985A2 true WO2010035985A2 (fr) 2010-04-01
WO2010035985A3 WO2010035985A3 (fr) 2010-06-17

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0170430A1 (fr) * 1984-07-05 1986-02-05 The Wellcome Foundation Limited Composés pharmaceutiques hétérocycliques, leur préparation et leur application
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 (fr) * 1996-10-24 1998-04-30 Institute Armand-Frappier Famille de taxanes canadensol, preparation semi-synthetique et usage therapeutique de ces derniers
WO1999014209A1 (fr) * 1997-09-17 1999-03-25 Kabushiki Kaisha Yakult Honsha Nouveaux derives de taxane
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 (fr) * 1986-09-26 1989-01-06 Stela Inox Procede de traitement du poisson par depecage et dispositif pour la mise en oeuvre du procede
FR2687150B1 (fr) * 1992-02-07 1995-04-28 Rhone Poulenc Rorer Sa Procede de preparation de derives du taxane.
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 (fr) * 1984-07-05 1986-02-05 The Wellcome Foundation Limited Composés pharmaceutiques hétérocycliques, leur préparation et leur application
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 (fr) * 1996-10-24 1998-04-30 Institute Armand-Frappier Famille de taxanes canadensol, preparation semi-synthetique et usage therapeutique de ces derniers
WO1999014209A1 (fr) * 1997-09-17 1999-03-25 Kabushiki Kaisha Yakult Honsha Nouveaux derives de taxane

Also Published As

Publication number Publication date
JP5552489B2 (ja) 2014-07-16
JP2012503646A (ja) 2012-02-09
KR20100035261A (ko) 2010-04-05
WO2010035985A3 (fr) 2010-06-17
KR101014438B1 (ko) 2011-02-14

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