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WO2008107771A2 - 2',3'-di-o-acyl-5-fluoronucléosides - Google Patents

2',3'-di-o-acyl-5-fluoronucléosides Download PDF

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Publication number
WO2008107771A2
WO2008107771A2 PCT/IB2008/000482 IB2008000482W WO2008107771A2 WO 2008107771 A2 WO2008107771 A2 WO 2008107771A2 IB 2008000482 W IB2008000482 W IB 2008000482W WO 2008107771 A2 WO2008107771 A2 WO 2008107771A2
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WIPO (PCT)
Prior art keywords
fluorocytidine
acetyl
acyl
formula
immobilized
Prior art date
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Ceased
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PCT/IB2008/000482
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English (en)
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WO2008107771A3 (fr
Inventor
Massimo Pregnolato
Marco Terreni
Daniela Ubiali
Teodora Bavaro
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INNOVATE BIOTECHNOLOGY Srl
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INNOVATE BIOTECHNOLOGY Srl
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Priority to EP08719215A priority Critical patent/EP2176278A2/fr
Publication of WO2008107771A2 publication Critical patent/WO2008107771A2/fr
Publication of WO2008107771A3 publication Critical patent/WO2008107771A3/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
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical

Definitions

  • the present invention concerns new 2',3'-di-O-acyl-5-fluoronucleosides useful as intermediates in the preparation of 5'-deoxy-2',3'-di-O-acyl-5-fluoronucleosides which, by simple deacetylation in position 2' and 3', provide important medicaments such as for example capecitabine.
  • the invention refers to 2',3'-di-O-acetyl-5-fluorocytidine derivatives and to a process for their preparation by enzymatic hydrolysis of only the acetyl group in position 5' of the corresponding 2',3',5'-tri-O-acetyl-5- fluorocytidine.
  • ART is a chemotherapeutical agent used for the treatment of some tumoral forms, among which the advanced stage colon cancer, breast cancer, ovary cancer and tested in lung, bladder and pancreas carcinomas.
  • capecitabine is prepared by reaction of 5-fluorocytosine with 5-deoxy-tri-O-acetylribose in the presence of a silylating agent, in particular of hexamethyldisilazane, subsequent - reaction of the 5'-deoxy-2',3'-di-O-acetyl-5- fluorocytidine thus obtained with pentanoyloxycarbonyl chloride and final deacetylation, as described in Bioorg. Med. Chem. 2000, 8, 1697-1706.
  • Other methods described in the literature for example in US 4,966,891, US 5,472,949 and US 5,476,932, always involve a reaction with a 5-deoxyribose having its secondary hydroxyls differently protected.
  • the present invention concers new 2',3'-di-O-acyl-5-fiuoronucleosides, in particular the 2',3'-di-O-acetyl-5-fluorocytidine and its N 4 -derivatives (globally designated "2',3'-di-O-acetyl-5-fluorocytidine-derivatives", useful as intermediates in the preparation of capecitabine.
  • acyl designates an acyl containing from 2 to 9 carbon atoms such as acetyl, propionyl, butyroyl, pivaloyl, benzoyl, p-toluoyl, phenylacetyl, p-toluoylacetyl, the acetyl group being preferred.
  • Said 2',3'-di-O-acyl-5-fluorocytidine-derivative of formula I is prepared by a process which comprises submitting the corresponding 2',3',5'-tri-O-acyl-5-fluorocytidine- derivative of formula II
  • the starting 2',3',5'-tri-O-acyl-5-fluoronucleosides of formula II are known products or can easily be prepared by reaction of the corresponding tetra-O-acylribose with cytosine.
  • phosphate buffer is meant a KH 2 PO 4 buffer at a concentration which may vary between 10 and 100 mM and which will preferably be of about 25 mM), at a pH value from 4.0 to 9, advantageously from 6.5 to 7.5, optionally in the presence of an organic co-solvent at a concentration up to 50%, preferably at 10-30% of acetonitrile or acetone, at a temperature of from 0°C to 25°C.
  • organic co-solvent at a concentration up to 50%, preferably at 10-30% of acetonitrile or acetone, at a temperature of from 0°C to 25°C.
  • catalysts optionally immobilized hydrolases such as lipases of esterases may be used.
  • the lipase used as a catalyst for the selective hydrolysis is generally obtainable from a wild or recombinant micro-organism, for example of the genus Rhizomucor, Candida or Pseudomonas.
  • Advantageous microbial lipases are those obtainable from micro-organisms of the Candida and Pseudomonas genus.
  • the lipase from Candida may be obtained from wild or recombinant Candida rugosa, Candida antarctica, Candida lipolytica, that from Candida rugosa, preferibly immobilized as described in WO 03/057894, being preferred.
  • An advantageous recombinant lipase is the isoform encoded by the gene lipl synthesized with an optimized nucleotide sequence in terms of heterologous expression in yeast, for example in Saccharomices cervisiae or in Pichia -pastoris as described by S. Brocca et al. in Protein Science, 1998, VoI 7, Issue 6, 1415-1422.
  • the lipase from Pseudomonas may be obtained from Pseudomonas putida, Pseudomonas cepacia or, advantageously, from Pseudomonas ⁇ uorescens, preferably immobilized as described in WO 03/057894.
  • the immobilization of the lipase is normally made on solid hydrophobic supports.
  • the immobilization of lipase may be made on a silicon matrix consisting of an organosilicon compound, namely of a compound containing at least a Si-C bond (US 6,080,402).
  • the immobilization may be made on a octyl agarose gel such as Octyl Sepharose ® CL-4B, or on polymetacrylate resins and a butyl character such as Sapebeads FP-BU or a decaoctyl character such as Sapebeads FP-RPOD (RP-OD) which are already totally derivatized with hydrophobic groups, i.e. butyl and, decaoctyl chains, respectively.
  • the hydrophobic immobilizing support is octyl-agarose or decaoctyl-Sapebeads RP-OD.
  • the immobilization may be made on a macroporous matrix of silica or silicates (EP 444092), on a matrix consisting of adsorbing, optionally reticulated acrylic-type resins such as Amberlite ® XAD-8 or Lewatit ® E 2001/85 (EP 529 424), of an amphiphilic support containing lipophilic chains (US 5,182,201), on a styrene and divinylbenzene matrix optionally containing epoxy groups such as Lewatit ® R 259 K or R 260 K or Diaion ® HP-40, on a polyacrylic resin containing epoxy groups such as FP 4000, on a polymethacrylic resin containing epoxy groups such as Sepabeads ® FP-EP or Eupergit ® C, suitably derivatized with hydrophobic groups.
  • a macroporous matrix of silica or silicates EP 444092
  • esterases enzymes of animal origin such as pig pancreas esterases or of fungi origin such as Aspergillus niger esterase immobilized on Eupergit C may be used.
  • the 2',3',5'-tri-O- acetyl-5-fluoronucleoside is dissolved in a buffer at the chosen pH, for example in a 25 mM phosphate buffer containing 20-30% acetonitrile or acetone kept at the desired pH value.
  • the solution thus obtained is treated with a preferably immobilized lipase from Candida rugosa or from Pseudomonas fluorescens or with an esterase from pig pancreas or from Aspergillus niger and left to incubate for a period of time from 12 to 120 hours, by controlling the hydrolysis reaction by HPLC.
  • the immobilization for example on octyl agarose, may be made as described in WO 03/57894.
  • the selective enzymatic hydrolysis of the acyloxy group in the position 5' showed to be a simple method characterized by mild experimental conditions, reduced percent of organic solvent in the aqueous solution and low temperature, for obtaining high yields in 2',3'-di-O-acyl-5-fluorocytidine- derivatives of formula I characterized by a free hydroxyl in position 5'.
  • the free hydroxyl in position 5' allows the conversion of the 2',3'-di-O-acyl-5- fluorocytidine-derivatives of formula I into the corresponding 5'-deoxy-2',3'-di-O- acyl-5-fluorocytidine-derivatives, for example via the corresponding sulfonic esters and iodo or bromo derivatives and subsequent replacement of the halogen by a hydrogen atom with consequent obtaining of the corresponding 5'-deoxy-2',3'-di-O- acyl-5-fluorocytidine-derivatives.
  • a 2',3'-di- O-acetyl-5-fluorocytidine-derivative of formula I is treated with an alkyl, aralkyl or aryl sulfonyl chloride, for example with methane sulfonyl chloride or with /(-toluene sulfonyl chloride in an organic solvent such as pyridine to obtain the corresponding, new 5'-O-(alkyl, aryl or aryl sulfonyl)-2',3'-di-O-acetyl-5-fluorocytidine-derivative which, by reaction with a brominating or iodinating agent, for example with a quaternary ammonium bromide such as tetra( «-butyl)ammonium bromide or sodium iodide in a polar aprotic solvent such as dimethylacetamide, dimethylformamide or dimethyl s
  • the mobile phases were of 10% acetonitrile in 1OmM KH2PO4 buffer at spontaneous pH and 10% H2O in acetonitrile; the mobile phases were filtered and de-gased before the use; the flux was of 1 mL/minute. Monitoring was made using TLC on silica gel 60 (0.25 mm, E. Merck, Darmstadt, Germany).
  • the immobilization process is based on the principle of the interface absorption on strongly hydrophobic supports, said absorption being performed at a low ionic strength.
  • the process consists of dissolving the calculated amount of enzymatic extract in water buffered at neutral pH with 25 mM phosphate buffer under stirring and continuing stirring (oscillating mixer) for 30 minutes.
  • the suspension is added stirring the immobilizing support, previously washed and conditioned with the same buffer and stirring is continued for 2 hours.
  • the suspension is filtered under reduced pressure and the enzymatic material is washed with distilled water.
  • the amount of immobilized enzyme is calculated by spectrophotometry by determining the concentration of the residual supernatant enzyme in the immobilization suspension according to the Bredford method based on the absorbance of the enzyme/Bradford reagent complex at 595 nm (Bradford M: A rapid, sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem, 1976, 72:248-254). PREPARATION II
  • a solution of 7.4 mL of lipase from Candida rugosa lip 1 wild-type (containing 16.1 U/mL of solution) in 4.6 ml of phosphate buffer 25 mM at pH 7 is let under stirring for about 30 minutes at room temperature, then 600 mg of gel octyl agarose (Octyl Sepharose® CL-4B, Pharmacia Biotech) or decaoctyl sepabeads (Sepabeads® FP- RPOD, Resindion) previously washed first with water and, then, with the immobilizing buffer (phosphate buffer 25 mM at pH 7), is added thereto. The mixture is let under stirring for about two hours at room temperature then filtered.
  • gel octyl agarose Octyl Sepharose® CL-4B, Pharmacia Biotech
  • decaoctyl sepabeads Sepabeads® FP- RPOD, Resindion
  • the enzyme was removed by filtration, the 2',3'-di-O-acetyl-5-fluorocytidine thus obtained was isolated by removing the possibly present organic solvent and extracting the product from the aqueous solution by ethyl acetate. After evaporation of the collected extracts under reduced pressure, the residue was purified using a chromatographic silica gel column by using a (CH2C12 100- CH 2 Cl 2 -MeOH 97:3) mixture as an eluent, thus obtaining the 2',3'-di- O-acetyl-5-fluorocytidine. Global yield 85%.
  • the enzyme was removed by filtration, the 2',3'-di-O-acetyl-N 4 ( «- pentyloxycarbonyl)-5-fluorocytidine thus obtained was isolated by removing the possibly present organic solvent and extracting the product from the aqueous solution with ethyl acetate. After evaporation of the collected extracts under reduced pressure, the 2',3'-di-O-acetil-N 4 ( «-pentyloxycarbonyl)-5-fluorocytidine was obtained.
  • HPLC Rt 14.90 minutes (A: 10 mM buffer K 2 HPO 4 90%/CH 3 CN 10%, B: CH 3 CN 90%/H 2 O 10%, spontaneous pH; Method: 0-3 minutes 75% A-25% B, 3-10 minutes 60% A-40% B, 10-11 minutes 60% A-40% B, 11-12 minutes 50% A-50% B, 12-18 minutes 50% A-50% B,18-23 minutes 75% A-25% B, Flux: 1 mL/ninute, ⁇ : 240 nm, column: RP- 18 Shiseido Capcell Pak).
  • a solution of 2',3',5'-tri-O-acetyl-5-fluorocytidine (10 mM) in a buffer consisting of KH 2 PO 4 25 mM 90% and acetonitrile 10% at pH 7 is added with commercial Candida rugosa lipase (CRL) immobilized on Octyl-Sepharose (Example 3); or commercial Candida rugosa lipase (CRL) immobilized on Decaoctyl-Sepabeads RP- OD (Example 4); or recombinant Candida rugosa lipl lipase (CRL lipl) immobilized on Octyl-Sepharose (Example 5); or recombinant Candida rugosa lipl lipase (CRL lipl) immobilized on Decaoctyl-Sepabeads RP-OD (Example 6), or Protease N (Amano Pharmaceutical Co.) immobilized on de
  • Example 7-10 A solution of 2',3',5'-tri-O-acetil-N 4 -(n-pentyloxycarbonyl)-5-fluorocytidine (10 mM) in a buffer consisting of KH 2 PO 4 25 mM 90% and acetonitrile 10% at pH 7 is added with commercial Candida rugosa lipase (CRL) immobilized on Octyl- Sepharose (Example 7), or recombinant Candida rugosa lipl lipase (CRL lipl) immobilized on Decaoctyl-Seapabeads (Example 8), or commercial Pseudomonas fluorescens lipase (PFL) immobilized on Octyl-Sepharose (Example 9); or Protease N (EC 3.4.21.66, Amano Pharmaceutical Co.) immobilized on decaoctyl-Sepabeads (Sepabeads RP-OD

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Saccharide Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

L'invention concerne de nouveaux 2',3'-di-O-acyl-5-fluoronucléosides utiles comme intermédiaires dans la préparation de 5'-désoxy-2'-3'-di-O-acyl-5-fluoronucléosides.
PCT/IB2008/000482 2007-03-05 2008-03-04 2',3'-di-o-acyl-5-fluoronucléosides Ceased WO2008107771A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08719215A EP2176278A2 (fr) 2007-03-05 2008-03-04 2',3'-di-o-acyl-5-fluoronucléosides

Applications Claiming Priority (2)

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ITMI2007A000435 2007-03-05
ITMI20070435 ITMI20070435A1 (it) 2007-03-05 2007-03-05 2',3'-di-o-acil-5-fluoronucleosidi

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WO2008107771A3 WO2008107771A3 (fr) 2008-10-30

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102212095A (zh) * 2010-04-08 2011-10-12 上海医药工业研究院 卡培他滨及其中间体的制备方法
CN102424697A (zh) * 2011-10-27 2012-04-25 齐鲁天和惠世制药有限公司 2′，3′-二-o-乙酰基-5′-脱氧-5-氟胞苷鎓盐类化合物及其制备方法
CN103897004A (zh) * 2012-12-27 2014-07-02 鲁南制药集团股份有限公司 一种卡培他滨的合成方法
CN101993464B (zh) * 2009-08-19 2014-07-23 成都弘达药业有限公司 一种卡培他滨的制备方法
CN112876526A (zh) * 2021-01-15 2021-06-01 山东铂源药业有限公司 一种卡培他滨关键中间体的制备方法

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US4966891A (en) 1987-11-17 1990-10-30 Hoffmann-La Roche Inc. Fluorocytidine derivatives
EP0444092A1 (fr) 1988-11-16 1991-09-04 Novo Nordisk As Preparation de lipase immobilisee sur particules, son procede de production et son utilisation.
US5182201A (en) 1990-10-26 1993-01-26 Uop Lipase immobilization without covalent bonding on an amphiphilic support containing lipophilic alkyl chains
EP0529424A2 (fr) 1991-08-30 1993-03-03 Chemie Linz GmbH Procédé pour augmenter la sélectivité enantiomérique d'une lipase de Candida dans l'esterification des alcools chiraux et lipase immobilisée
US5472949A (en) 1992-12-18 1995-12-05 Hoffmann-La Roche Inc. N4 -(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine compounds, compositions and methods of using same
US5476932A (en) 1994-08-26 1995-12-19 Hoffmann-La Roche Inc. Process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives
US6080402A (en) 1994-03-11 2000-06-27 Studiengesellschaft Kohle Mbh Immobilization of lipases by entrapment in silica matrices
WO2003057894A1 (fr) 2002-01-14 2003-07-17 Innovate Biotechnology S.R.L. Processus d'hydrolyse enzymatique selective de polyesters nucleosidiques

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EP1706414B1 (fr) * 2003-12-22 2008-07-23 F.Hoffmann-La Roche Ag Procede de production de derives de fluorocytidine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4966891A (en) 1987-11-17 1990-10-30 Hoffmann-La Roche Inc. Fluorocytidine derivatives
EP0444092A1 (fr) 1988-11-16 1991-09-04 Novo Nordisk As Preparation de lipase immobilisee sur particules, son procede de production et son utilisation.
US5182201A (en) 1990-10-26 1993-01-26 Uop Lipase immobilization without covalent bonding on an amphiphilic support containing lipophilic alkyl chains
EP0529424A2 (fr) 1991-08-30 1993-03-03 Chemie Linz GmbH Procédé pour augmenter la sélectivité enantiomérique d'une lipase de Candida dans l'esterification des alcools chiraux et lipase immobilisée
US5472949A (en) 1992-12-18 1995-12-05 Hoffmann-La Roche Inc. N4 -(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine compounds, compositions and methods of using same
US6080402A (en) 1994-03-11 2000-06-27 Studiengesellschaft Kohle Mbh Immobilization of lipases by entrapment in silica matrices
US5476932A (en) 1994-08-26 1995-12-19 Hoffmann-La Roche Inc. Process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives
WO2003057894A1 (fr) 2002-01-14 2003-07-17 Innovate Biotechnology S.R.L. Processus d'hydrolyse enzymatique selective de polyesters nucleosidiques

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BIORG. MED. CHEM. LETT., vol. 12, no. 3, 2002, pages 483 - 486
BRADFORD M: "A rapid, sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein dye binding", ANAL BIOCHEM, vol. 72, 1976, pages 248 - 254
BROCCA ET AL., PROTEIN SCIENCE, vol. 7, no. 6, 1998, pages 1415 - 1422
BULL. KOREAN CHEM. SOC., vol. 26, no. 11, 2005, pages 1865 - 1868

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101993464B (zh) * 2009-08-19 2014-07-23 成都弘达药业有限公司 一种卡培他滨的制备方法
CN102212095A (zh) * 2010-04-08 2011-10-12 上海医药工业研究院 卡培他滨及其中间体的制备方法
CN102212095B (zh) * 2010-04-08 2016-03-30 上海医药工业研究院 卡培他滨及其中间体的制备方法
CN102424697A (zh) * 2011-10-27 2012-04-25 齐鲁天和惠世制药有限公司 2′，3′-二-o-乙酰基-5′-脱氧-5-氟胞苷鎓盐类化合物及其制备方法
CN103897004A (zh) * 2012-12-27 2014-07-02 鲁南制药集团股份有限公司 一种卡培他滨的合成方法
CN103897004B (zh) * 2012-12-27 2017-05-31 鲁南制药集团股份有限公司 一种卡培他滨的合成方法
CN112876526A (zh) * 2021-01-15 2021-06-01 山东铂源药业有限公司 一种卡培他滨关键中间体的制备方法

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ITMI20070435A1 (it) 2008-09-06
WO2008107771A3 (fr) 2008-10-30

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