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WO2008105593A1 - Procédé pour la préparation stéréosélective et la séparation de tri-o-acétyl-5-désoxy-b-d-ribofuranose - Google Patents

Procédé pour la préparation stéréosélective et la séparation de tri-o-acétyl-5-désoxy-b-d-ribofuranose Download PDF

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Publication number
WO2008105593A1
WO2008105593A1 PCT/KR2008/000969 KR2008000969W WO2008105593A1 WO 2008105593 A1 WO2008105593 A1 WO 2008105593A1 KR 2008000969 W KR2008000969 W KR 2008000969W WO 2008105593 A1 WO2008105593 A1 WO 2008105593A1
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WO
WIPO (PCT)
Prior art keywords
anomer
formula
solvent
ribofuranose
compound
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2008/000969
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English (en)
Inventor
Jaeheon Lee
Gha Seung Park
Weon Ki Yang
Jin Hee Kim
Chul Hyun Park
Yong-Hoon An
Chang-Ju Choi
Young-Kil Chang
Gwan Sun Lee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
Original Assignee
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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.)
Filing date
Publication date
Application filed by Hanmi Pharmaceutical Co Ltd, Hanmi Pharmaceutical Industries Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Publication of WO2008105593A1 publication Critical patent/WO2008105593A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch

Definitions

  • the present invention relates to a method for the stereoselective preparation and separation of tri-O-acetyl-5-deoxy- ⁇ -D-ribofuranose, which is useful as an intermediate in preparing capecitabine.
  • Capecitabine a nucleoside having a ribofuranose backbone, is an anti-tumor agent orally administered it to treat metastatic breast cancer and rectal cancer, and has the stereochemical structure shown below wherein the
  • 5-fiuorocytosine moiety attached at position 1 of the ribofuranose has ⁇ - orientation.
  • the capecitabine can be prepared by glycosylating tri-O-acetyl-5-deoxy- ⁇ -D-ribofuranose with fluorocytosine, and then subjecting the resulting product to carbamoylation and hydrolysis as shown in Reaction Scheme (A).
  • Reaction Scheme (A) Reaction Scheme (A)
  • tri-O-acetyl-5-deoxy- ⁇ -D- ribofuranose of formula (I) is prepared according to the method described in
  • the compound of formula (IV) is hydrolyzed to obtain a triol compound of formula (III);
  • the triol compound of formula (III) is acetylated using acetic anhydride in pyridine to obtain tri-O-acetyl-5-deoxy-D-ribofuranose of formula (II) which is a ⁇ -/ ⁇ -anomer mixture with respect with the acetyl at position 1;
  • the reaction mixture is subjected to vacuum distillation to purify the ⁇ -/ ⁇ -anomer mixture; and
  • ⁇ -anomer of formula (I) is separated from the mixture.
  • the present inventors have attempted to develop an improved method of preparing tri-O-acetyl-5-deoxy- ⁇ -D-ribofuranose, and have found that the ⁇ -/ ⁇ -anomer ratio can be markedly improved by using alkylamine or cyclic amine bases instead of pyridine during the acetylation.
  • an object of the present invention to provide a method for preparing tri-O-acetyl-5-deoxy- ⁇ -D-ribofuranose in a high ⁇ - anomer ratio. It is another object of the present invention to provide a simple and easy method for separating pure ⁇ -anomer of tri-O-acetyl-5- deoxy-D-ribofuranose from a ⁇ -/ ⁇ -anomer mixture thereof.
  • a method for preparing tri-O-acetyl-5-deoxy- ⁇ -D-ribofuranose of formula (I) which comprises the steps of:
  • triol compound of formula (III) in the form of an ⁇ - / ⁇ -anomer mixture having an ⁇ - to ⁇ - ratio of about 1 :1 to 2:1.
  • the anomers may be optionally separated by column chromatography for use in the next step.
  • the methylacetonide compound of formula (IV) can be easily prepared by the method described in US Patent No. 4,340,729.
  • an alkylamine or a cyclic amine may be used in an amount of 3 mole equivalents or more based on the compound of formula (HI) to achieve a highly stereoselective reaction of the triol compound with the acetic anhydride:
  • the product, tri-O-acetyl-5-deoxy-D-ribofuranose of formula (II) contains a marked high ⁇ -anomer content, the ⁇ - to ⁇ -anomer ratio being
  • This ⁇ -anomer-rich product can be subjected to recrystallization using a solvent or an anti-solvent to obtain highly pure ⁇ - anomer of formula (I) in a high yield of 99.5 % and more.
  • the present inventive method gives tri-O-acetyl-5-deoxy-D-ribofuranose having a high ⁇ -anomer content, which is carried out using an equivalent amount of an alkylamine or a cyclic amine, together with the organic solvent. Therefore, the work up process after the reaction is greatly simplified. That is, pure tri-O-acetyl-5-deoxy- ⁇ - D-ribofuranose can be recovered from the acetylation reaction mixture, and can be easily obtained in a high yield of 80 % and more by simple recrystallization using a solvent and an anti-solvent, instead of conducting high vacuum distillation employed in the conventional method.
  • the organic solvent used in the acetylation according to the present invention may be selected from the group consisting of tetrahydrofuran, acetonitrile, methylene chloride, chloroform, dibromoethane, dichloroethane, ethylacetate, toluene and a mixture thereof, preferably methylene chloride.
  • the alkylamine or cyclic amine used in the present invention may be selected from the group consisting of triethylamine, n-tributylamine, dicyclohexylamine, tetramethylethylenediamine, diisopropylethylamine, N- methylmorphorine and a mixture thereof, preferably triethylamine.
  • the selectivity of the ⁇ -anomer over the ⁇ -anomer increases from at least 10:1 to 15:1, in which the use of triethylamine is preferred, while piperidine is ineffective.
  • the amount of the alkylamine or cyclic amine may be 3 to 12 mole equivalents, preferably 4 to 5 mole equivalents based on the compound of formula (HI).
  • the acetylation according to the present invention may be carried out at 10 to 50 0 C, preferably 5 to 25 ° C for 6 to 24 hours.
  • the tri-O-acetyl-5-deoxy-D-ribofuranose product of formula (II) is obtained as a solid due to its high ⁇ -anomer content, unlike the product obtained by the conventional method using pyridine is an oil or semi-solid.
  • Tri-O-acetyl-5-deoxy-D-ribofuranose of formula (II) obtained by the inventive acetylation method is composed mainly of the desired ⁇ -anomer, the ⁇ -anomer content being only 6 to 9 %.
  • the ⁇ -anomer can be removed by recrystallization in accordance with any of the conventional methods.
  • pure ⁇ -anomer may be easily separated by adding an anti-solvent to a solution obtained by dissolving the anomer mixture in an appropriate solvent, filtering to remove the filtrate containing the ⁇ -anomer, and collecting pure ⁇ -anomer as a solid.
  • the appropriate solvent used in the recrystallization may be a polar organic solvent, which is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, acetone, acetonitrile, tetrahydrofiiran, chloroform, methylene chloride, ethylacetate, diethyl ether and a mixture thereof, preferably isopropanol.
  • a polar organic solvent which is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, acetone, acetonitrile, tetrahydrofiiran, chloroform, methylene chloride, ethylacetate, diethyl ether and a mixture thereof, preferably isopropanol.
  • the anti-solvent used in the recrystallization may be a nonpolar organic solvent, which is selected from the group consisting of n-hexane, heptane, octane, nonane, petroleum ether, isopropyl ether and a mixture thereof, or water, preferably n-hexane or water.
  • the recrystallization may be carried out at - 60 to 30 ° C, preferably - 10 to 5 °C, and the amounts of the solvent and anti-solvent may be 2 to 5 times (v/wt) and 5 to 40 times (v/wt) based on tri-O-acetyl-5-deoxy-D- ribofuranose of formula (II), respectively.
  • the ⁇ -anomer obtained after the recrystallization has a purity of at least 99.5 %, the ⁇ -anomer content being less than 0.5 %.
  • the inventive method for the stereoselective preparation of tri-O-acetyl-5-deoxy- ⁇ -D-ribofuranose of formula (I) shows markedly improved stereoselectivity as compared with the conventional method, and gives a high yield of at least 75 %, as compared with less than
  • 100 g of methyl-2,3-O-isopropylidene-5-deoxy- ⁇ -D-ribofuranose was added to 500 ml of 0.02 M sulfuric acid, and stirred at 80 to 85 ° C for 2 hours. The temperature was lowered to 45 to 50 ° C, and water was removed therefrom under a reduced pressure until the total volume was reduced by 2/3 to 1/2. 500 ml of 0.02 M sulfuric acid was added to the resulting solution, and stirred at 80 to 85 " C for 1 hour. The temperature was lowered to room temperature, the resulting solution was neutralized to pH 5.3 to 5.5 with 0.2 M sodium carbonate, and concentrated under a reduced pressure.
  • the resulting residue was suspended in 1,000 ml of acetonitrile, 50 g of anhydrous sodium sulfate was added thereto, and stirred for 1 hour.
  • the resulting mixture was filtered through a cellite column, which was then washed with 100 ml of acetonitrile, the filtrate and the wash were combined, and concentrated under a reduced pressure to remove the solvent.
  • 1,000 ml of methylene chloride and 370 ml of triethylamine were added to the resulting residue, and while keeping the temperature at 5 " C, 235.5 ml of acetic anhydride was added thereto, and stirred for 20 hours.
  • the resulting residue was suspended in 50 ml of acetonitrile, 5 g of anhydrous sodium sulfate was added thereto, and stirred for 1 hour.
  • the resulting mixture was filtered through a cellite column, which was then washed with 5 ml of acetonitrile, the filtrate and wash were combined, and concentrated under a reduced pressure.
  • 11.8 ml of acetic anhydride and 25 ml of pyridine were added to the resulting residue, and stirred for 12 hours. After completion of the reaction, 100 ml of water was added thereto, stirred for 1 hour, and the resulting solution was extracted with 100 ml of methylene chloride.
  • ⁇ -anomer content 99.7 % ( ⁇ -anomer content: 0.05 %)
  • Comparative Example 1 obtained by using pyridine as an organic base was dissolved in 13.6 ml of isopropanol, and 40.8 ml of hexane was added dropwise thereto. The resulting solution was aged at 0 to 5 " C for 3 hours, and filtered to obtain the title compound as a cream white solid (2.5 g; total yield: 36.2 %).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Materials Engineering (AREA)
  • Polymers & Plastics (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention concerne un procédé pour préparer du tri-O-acétyl-5-désoxy-b-D-ribofuranose extrêmement pur qui comporte une étape d'acétylation fortement stéréosélective de 1-méthylacétonide, et le b-anomère pur ainsi obtenu peut être avantageusement utilisé pour la préparation de la capécitabine.
PCT/KR2008/000969 2007-02-28 2008-02-19 Procédé pour la préparation stéréosélective et la séparation de tri-o-acétyl-5-désoxy-b-d-ribofuranose Ceased WO2008105593A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020070020336A KR100908363B1 (ko) 2007-02-28 2007-02-28 트라이-Ｏ-아세틸-5-데옥시-β-Ｄ-라이보퓨라노즈의입체선택적 제조방법 및 이의 분리방법
KR10-2007-0020336 2007-02-28

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WO2008105593A1 true WO2008105593A1 (fr) 2008-09-04

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KR (1) KR100908363B1 (fr)
AR (1) AR065305A1 (fr)
TW (1) TW200900417A (fr)
WO (1) WO2008105593A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2210895A1 (fr) * 2009-01-27 2010-07-28 F. Hoffmann-La Roche AG Procédé pour la récupération de béta-Acétylfuranoside
US8097706B2 (en) * 2007-11-19 2012-01-17 Hammi Holdings Co., Ltd Methods for preparing capecitabine and beta-anomer-rich trialkyl carbonate compound used therein
CN102344469A (zh) * 2011-07-26 2012-02-08 江西科技师范学院 固体酸SO42-/γ-AL2O3催化合成1, 2, 3-O-三乙酰基-5-脱氧-D-呋喃核糖的方法
CN112125939A (zh) * 2020-07-16 2020-12-25 中国人民解放军陆军防化学院 一种制备高纯度5-脱氧-d-核糖的方法
CN117229341A (zh) * 2023-11-07 2023-12-15 成都苑东生物制药股份有限公司 卡培他滨晶型i及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4340729A (en) * 1979-06-12 1982-07-20 Hoffmann-La Roche Inc. 5'-Deoxy-5-fluorouridine
US5252756A (en) * 1992-06-22 1993-10-12 Eli Lilly And Company Process for preparing beta-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl-arylsulfonates
US6831069B2 (en) * 1999-08-27 2004-12-14 Ribapharm Inc. Pyrrolo[2,3-d]pyrimidine nucleoside analogs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4340729A (en) * 1979-06-12 1982-07-20 Hoffmann-La Roche Inc. 5'-Deoxy-5-fluorouridine
US5252756A (en) * 1992-06-22 1993-10-12 Eli Lilly And Company Process for preparing beta-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl-arylsulfonates
US6831069B2 (en) * 1999-08-27 2004-12-14 Ribapharm Inc. Pyrrolo[2,3-d]pyrimidine nucleoside analogs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SAIRAM P. ET AL.: "Synthesis of 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose from D-ribose", CARBOHYDRATE RESEARCH, vol. 338, 2003, pages 303 - 306, XP004404435 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8097706B2 (en) * 2007-11-19 2012-01-17 Hammi Holdings Co., Ltd Methods for preparing capecitabine and beta-anomer-rich trialkyl carbonate compound used therein
EP2210895A1 (fr) * 2009-01-27 2010-07-28 F. Hoffmann-La Roche AG Procédé pour la récupération de béta-Acétylfuranoside
WO2010086247A1 (fr) * 2009-01-27 2010-08-05 F. Hoffmann-La Roche Ag Procédé de récupération de bêta-acétylfuranoside
CN102245621A (zh) * 2009-01-27 2011-11-16 霍夫曼-拉罗奇有限公司 用于回收β-乙酰基呋喃糖苷的方法
JP2012513970A (ja) * 2009-01-27 2012-06-21 エフ．ホフマン−ラ ロシュ アーゲー ベータ−アセチルフラノシドの回収方法
US20130072674A1 (en) * 2009-01-27 2013-03-21 Hoffmann-La Roche Inc. Novel Process for the Recovery of Beta Acetylfuranoside
CN106397503A (zh) * 2009-01-27 2017-02-15 霍夫曼-拉罗奇有限公司 用于回收β-乙酰基呋喃糖苷的方法
US9580455B2 (en) * 2009-01-27 2017-02-28 Hoffmann-La Roche Inc. Process for the recovery of beta acetylfuranoside
CN102344469A (zh) * 2011-07-26 2012-02-08 江西科技师范学院 固体酸SO42-/γ-AL2O3催化合成1, 2, 3-O-三乙酰基-5-脱氧-D-呋喃核糖的方法
CN112125939A (zh) * 2020-07-16 2020-12-25 中国人民解放军陆军防化学院 一种制备高纯度5-脱氧-d-核糖的方法
CN117229341A (zh) * 2023-11-07 2023-12-15 成都苑东生物制药股份有限公司 卡培他滨晶型i及其制备方法
CN117229341B (zh) * 2023-11-07 2024-02-09 成都苑东生物制药股份有限公司 卡培他滨晶型i及其制备方法

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Publication number Publication date
TW200900417A (en) 2009-01-01
AR065305A1 (es) 2009-05-27
KR20080079833A (ko) 2008-09-02
KR100908363B1 (ko) 2009-07-20

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