WO2010061402A2 - An improved process for the preparation of capecitabine - Google Patents

An improved process for the preparation of capecitabine Download PDF

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Publication number
WO2010061402A2
WO2010061402A2 PCT/IN2009/000676 IN2009000676W WO2010061402A2 WO 2010061402 A2 WO2010061402 A2 WO 2010061402A2 IN 2009000676 W IN2009000676 W IN 2009000676W WO 2010061402 A2 WO2010061402 A2 WO 2010061402A2
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WO
WIPO (PCT)
Prior art keywords
deoxy
capecitabine
formula
preparation
compound
Prior art date
Application number
PCT/IN2009/000676
Other languages
French (fr)
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WO2010061402A3 (en
Inventor
Vishwanath Kannan
Original Assignee
Vishwanath Kannan
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Publication date
Application filed by Vishwanath Kannan filed Critical Vishwanath Kannan
Publication of WO2010061402A2 publication Critical patent/WO2010061402A2/en
Publication of WO2010061402A3 publication Critical patent/WO2010061402A3/en

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Classifications

    • 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 relates to an improved process for the preparation of capecitabine
  • Capecitabine is a fluoro carbomate with antineoplastic activity and commercially available in the market under the brand name XELODA, and chemically described as 5 - deoxy-5- fluoro-N-[ pentyloxy] carbonyl ] - cystine, represented by the chemical formula
  • Wo 2005/0080351 discloses a process for the preparation of capecitabine. Which provides a process for acylation at the nitrogen atom in 5-fluoro cytosine with n-pentyl chloromate to form N-[(pentylloxy) carbonyl] -5-flurocytosine.
  • WO 2008/131062 teaches about the process of preparing capecitabine comprising deprotecting the OH groups in the positions 2 and 3 are protected, which is carried out using amberlyst 15 catalysts.
  • novel process for producing derivatives of the known anti-tumor agent utilizes an intermediate the novel compound, and provided for selective elimination of only the carbonyl radical from its hydroxyl sugar part, due of the step of selective hydrolysis.
  • capecitabine In view of the above prior art mentioned the preparation of capecitabine, it is clearly apparent that there is no industrial feasible process, therefore the alleged invention describes for the preparation of capecitabine usin a new reactants such as acetic anhydride with a base under novel catalyst used novozyme (CaIb) which is not reported or published in the prior art.
  • acetic anhydride with a base under novel catalyst used novozyme (CaIb)
  • Very important object of the present invention is that to obtain a capecitabine using a novel enzyme catalyst novozyme the silent feature of this catalyst include the avoidance of silicon based compounds and avoidance of hazardous compound such as chloride, which itself generates toxic fumes of HCl,
  • the enzymatic catalyst selected is a highly versatile catalyst with activity towards a great variety of different substrate s.
  • the present invention direct to an improved process for the preparation of the compound 5-deoxy -2, 3-O-isopyridene -N- [(pentyloxy) carbonyl] - 5- fluorocystidine. of the formula
  • an adduct obtain at step ( a) is reacted with a bases such as pyridine to afford oxy carbonyl compound c) further the said compound reacted with pentyl chloroformate, along with suitable organic solvent such as pyridine, dichloromethane, the said reaction is carried out at temperature below -10 to -20C after completion of the reaction the Dichloromethane is washed and obtain a product Deoxy flurocystidine d) the product obtained at step ( c) Deoxy flurocystidine further treated with NaoH carried for a period of 60 to 70 minutes, at below -5C to obtain a capecitabine

Abstract

The present invention direct to an improved process for the preparation of the compound 5-deoxy -2, 3-O-isopyridene -N-[(pentyloxy) carbonyl]-5- fluorocystidine of the formula (I).

Description

Title: - An improved process for the preparation of capecitabine,
Filed: - The present invention relates to an improved process for the preparation of capecitabine,
Prior art;-
Capecitabine is a fluoro carbomate with antineoplastic activity and commercially available in the market under the brand name XELODA, and chemically described as 5 - deoxy-5- fluoro-N-[ pentyloxy] carbonyl ] - cystine, represented by the chemical formula
Figure imgf000002_0001
Wo 2005/0080351 discloses a process for the preparation of capecitabine. Which provides a process for acylation at the nitrogen atom in 5-fluoro cytosine with n-pentyl chloromate to form N-[(pentylloxy) carbonyl] -5-flurocytosine.
Journal of medical chemistry 1997, which describes about the process for the preparation of 2, 3-o-isopropylidene-5- fluorocytidine, which is useful in the preparation of 5- fluorocytosine with 2, 2-dimethoxy propane. WO 2008/131062 teaches about the process of preparing capecitabine comprising deprotecting the OH groups in the positions 2 and 3 are protected, which is carried out using amberlyst 15 catalysts.
Provides novel process for producing derivatives of the known anti-tumor agent; said process utilizes an intermediate the novel compound, and provided for selective elimination of only the carbonyl radical from its hydroxyl sugar part, due of the step of selective hydrolysis.
In view of the above prior art mentioned the preparation of capecitabine, it is clearly apparent that there is no industrial feasible process, therefore the alleged invention describes for the preparation of capecitabine usin a new reactants such as acetic anhydride with a base under novel catalyst used novozyme (CaIb) which is not reported or published in the prior art.
Object of the Invention:-
Very important object of the present invention is that to obtain a capecitabine using a novel enzyme catalyst novozyme the silent feature of this catalyst include the avoidance of silicon based compounds and avoidance of hazardous compound such as chloride, which itself generates toxic fumes of HCl,
Description:- The present invention relates to an improved process for the preparation of capecitabine, unless define otherwise; all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention addressed. Any methods and materials similar or equivalent to those described herein can be used in the practice.
The described embodiment embodiments of the invention and the disclosed examples are given for the purpose of illustration rather limitation of the invention as set in the claims.
Therefore in the present invention provided an inventive process for the preparation of the compound 5-deoxy -2, 3-O-isopyridene - N-[(pentyloxy) carbonyl] - 5- fluorocystidine.
Therefore in one embodiment of the alleged invention, there is provided a process for the preparation of capecitabine which process comprising the following steps, reacting
Figure imgf000004_0001
With an innovative catalytic enzyme (calb) Novozyme 435, in the presence of organic solvent, the enzymatic catalyst selected is a highly versatile catalyst with activity towards a great variety of different substrate s. the enzyme used in particular as a powerful enanatio selelctive catalyst in the synthesis' s of optically active alcohols, amines and carboxylic acids,, the organic solvents selected to carry out the reaction using the bases such as pyridine to afford oxy carbonyl compound of formula, further the said compound reacted with pentyl chloroformate, along with suitable organic solvent such as pyridine, dichloromethane, the said reaction is carried out at temperature below -1OC to -20C after completion of the reaction the Dichloromethane is washed.
The product obtained Deoxy flurocystidine which is further treated with NaoH carried out the reaction for a period of upto 60 to 70 minutes, at below -5 C to obtain a capecitabine
The present invention direct to an improved process for the preparation of the compound 5-deoxy -2, 3-O-isopyridene -N- [(pentyloxy) carbonyl] - 5- fluorocystidine. of the formula
Figure imgf000005_0001
General formula
comripsing the following steps,
a) reacting a formula-a
Figure imgf000005_0002
Formula-A
with an enanatio selelctive catalyst such as enzyme Novozyme, in the presence of organic solvent, gives adduct of optically active alcohols, amines and carboxylic acids,,
b) an adduct obtain at step ( a) is reacted with a bases such as pyridine to afford oxy carbonyl compound c) further the said compound reacted with pentyl chloroformate, along with suitable organic solvent such as pyridine, dichloromethane, the said reaction is carried out at temperature below -10 to -20C after completion of the reaction the Dichloromethane is washed and obtain a product Deoxy flurocystidine d) the product obtained at step ( c) Deoxy flurocystidine further treated with NaoH carried for a period of 60 to 70 minutes, at below -5C to obtain a capecitabine
Reaction mechanism
Figure imgf000007_0002
Innovative enzyme catalyst)
Figure imgf000007_0001
Figure imgf000007_0003
Capecitabiiie
Q

Claims

We Claim,
1. An improved process for the preparation of the compound 5- deoxy -2, 3-O-isopyridene -N-[(pentyloxy) carbonyl] - 5- fluorocystidine of the formula
Figure imgf000008_0001
General formula
comripsing the following steps,
a) reacting a formula-a
Figure imgf000008_0002
Formula-A
with an enanatio selelctive catalyst such as enzyme Novozyme, in the presence of organic solvent, gives adduct of optically active alcohols, amines and carboxylic acids,, b) an adduct obtain at step ( a) is reacted with a bases such as pyridine to afford oxy carbonyl compound c) further the said compound reacted with pentyl chloroformate, along with suitable organic solvent such as pyridine, dichloromethane, the said reaction is carried out at temperature below -10 to -20C after completion of the reaction the Dichloromethane is washed and obtain a product Deoxy flurocystidine d) the product obtained at step ( c) Deoxy flurocystidine further treated with NaoH carried for a period of 60 to 70 minutes, at below -5C to obtain a capecitabine
PCT/IN2009/000676 2008-11-25 2009-11-23 An improved process for the preparation of capecitabine WO2010061402A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2483/MUM/2008 2008-11-25
IN2483MU2008 2008-11-25

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WO2010061402A2 true WO2010061402A2 (en) 2010-06-03
WO2010061402A3 WO2010061402A3 (en) 2012-05-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2883959A1 (en) 2013-12-13 2015-06-17 Plasmia Biotech, S.L. Enzymatic production of cytosinic nucleoside analogues

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0602478A1 (en) * 1992-12-18 1994-06-22 F. Hoffmann-La Roche Ag Novel process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives
GB2403950A (en) * 2003-07-18 2005-01-19 Mitsui Chemicals Inc Pyrimidine nucleosides from reaction of sugar phosphate with pyrimidine base derivative & enzyme having cytosine nucleoside phosphorylase activity
WO2005063786A2 (en) * 2003-12-22 2005-07-14 F.Hoffman-La Roche Ag Process for fluorocytidine derivatives
WO2008131062A2 (en) * 2007-04-20 2008-10-30 Dr. Reddy's Laboratories Ltd. Process for preparing capecitabine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100383128C (en) * 2004-02-23 2008-04-23 上海迪赛诺医药发展有限公司 Ramification of N-carbethoxy cytosine and preparation method and application
CN100425617C (en) * 2006-10-31 2008-10-15 浙江海正药业股份有限公司 Fluoropyrimidine compound carbalkoxylation method

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0602478A1 (en) * 1992-12-18 1994-06-22 F. Hoffmann-La Roche Ag Novel process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives
GB2403950A (en) * 2003-07-18 2005-01-19 Mitsui Chemicals Inc Pyrimidine nucleosides from reaction of sugar phosphate with pyrimidine base derivative & enzyme having cytosine nucleoside phosphorylase activity
WO2005063786A2 (en) * 2003-12-22 2005-07-14 F.Hoffman-La Roche Ag Process for fluorocytidine derivatives
WO2008131062A2 (en) * 2007-04-20 2008-10-30 Dr. Reddy's Laboratories Ltd. Process for preparing capecitabine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS 2012 STN Database accession no. 2005:962225 & WO 2005 080351 A1 (SHANGHAI DESANO HPHARMACEUTICAL HOLDING CO., LTD) 01 September 2005 *
DATABASE CAPLUS 2012 STN Database accession no. 2007:363083 & CN 1 935 828 A (ZHEJIANG HAIZHENG PHARMACEUTICAL CO., LTD) 28 March 2007 *
DATABASE CASREACT 2012 STN: 'The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, Capecitabine' Database accession no. 133:252646 & SHIMMA, N. ET AL.: 'The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, Capecitabine' BIOORGANIC & MEDICINAL CHEMISTRY vol. 8, no. 7, 2000, pages 1697 - 1706 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2883959A1 (en) 2013-12-13 2015-06-17 Plasmia Biotech, S.L. Enzymatic production of cytosinic nucleoside analogues

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