WO2007015257A2 - Procede de preparation de gemcitabine utilisant de nouveaux intermediaires - Google Patents

Procede de preparation de gemcitabine utilisant de nouveaux intermediaires Download PDF

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Publication number
WO2007015257A2
WO2007015257A2 PCT/IN2005/000256 IN2005000256W WO2007015257A2 WO 2007015257 A2 WO2007015257 A2 WO 2007015257A2 IN 2005000256 W IN2005000256 W IN 2005000256W WO 2007015257 A2 WO2007015257 A2 WO 2007015257A2
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WO
WIPO (PCT)
Prior art keywords
compound
formula
substituted
carried out
unsubstituted phenyl
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/IN2005/000256
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English (en)
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WO2007015257A3 (fr
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Itiyala Srinivas Reddy
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Hetero Drugs Ltd
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Hetero Drugs Ltd
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Publication date
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Priority to PCT/IN2005/000256 priority Critical patent/WO2007015257A2/fr
Priority to ARP050103954A priority patent/AR051374A1/es
Priority to PE2006000283A priority patent/PE20070315A1/es
Publication of WO2007015257A2 publication Critical patent/WO2007015257A2/fr
Anticipated expiration legal-status Critical
Publication of WO2007015257A3 publication Critical patent/WO2007015257A3/fr
Ceased legal-status Critical Current

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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
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical

Definitions

  • the present invention provides a commercially viable process for preparing gemcitabine and its pharmaceutically acceptable acid addition salts thereof in high yield and purity using novel intermediates.
  • U. S. Patent No. 4,808,614 disclosed difluoro antivirals and their derivatives thereof. These compounds are antiviral agents, and are useful in the treatment of various cancers and Herpes viral infections in mammals.
  • gemcitabine chemically 2 1 -deoxy-2',2'-difluorocytidine is a pyrimidine antimetabolite with broad spectrum activity against murine leukemias, murine solid tumors, and human tumor xenografts.
  • gemcitabine is represented by the following structure:
  • Patent No. 688783 B1 described a process for preparation of gemcitabine using benzoyl protection of intermediates.
  • the present invention is an improved, simple and commercially viable process that avoids multiple crystallizations and multiple chromatographic purifications that are associated with process described in the prior art.
  • One object of the present invention is to provide a novel process for preparing gemcitabine and pharmaceutically acceptable acid addition salts of gemcitabine in high purity and in high yield using novel intermediates.
  • R is C 1 - C 6 - alkyl, substituted or unsubstituted phenyl provided that at least one of R groups is substituted or unsubstituted phenyl; in presence of a base to give silyl protected lactone compound of formula IV:
  • R r ⁇ -vi wherein X is halo and R 1 is selected from Ci - C 6 - alkylsulfonyl and unsubstituted or substituted phenylsulfonyl; in presence of a base to give the compound of formula VII:
  • step (e) separating isomer from the mixture of isomers of the compound of formula IX obtained in step (e) by column chromatographic technique to give gemcitabine of formula I and optionally converting gemcitabine formed into the pharmaceutically acceptable acid addition salt of gemcitabine.
  • R is independently tert-butyl or phenyl.
  • the base used in step (a) is selected from imidazole, lutidine and pyridine. More preferable base is imidazole.
  • the reaction in step (a) is carried out in an inert solvent selected from the group consisting of hydrocarbon solvents such as toluene, xylene, n-hexane and cyclohexane; chlorinated hydrocarbon solvents such as methylene chloride, ethylene dichloride, chloroform and carbon tetrachloride; ketonic solvents such as acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone and methyl tert-butyl ketone; ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate, ethyl formate and methyl formate; ether solvents such as diethyl ether, diisopropyl ether and tert-butyl methyl ether; dimethylformamide; N, N-dimethyl hydrocarbon
  • reaction in step (a) is preferably carried out at ambient temperatures in the range from about -25 0 C to 100 0 C, more preferably at about O 0 C to 90 0 C and still more preferably at about O 0 C to 80 0 C.
  • Preferable reducing agent used in step (b) is diisobutyl aluminum hydride or lithium aluminum hydride and most preferable reducing agent is diisobutyl aluminum hydride.
  • the reduction is preferably carried out in the temperature range of about -100 0 C to -20 0 C, more preferably at about -85 0 C to -50 0 C and still more preferably at about -80 0 C to -65 0 C.
  • the reduction is preferably carried out in a solvent with a very low freezing point such as toluene and ether solvents such as diethyl ether. Most preferable solvent is toluene.
  • Preferable halo group used in step (c) is chloro, bromo or iodo and more preferable being chloro.
  • Ci - C 6 - alkylsulfonyl group is methane sulfonyl.
  • substituents of substituted phenylsulfonyl group are CrCa-alkyl and nitro; and more preferable substituted phenylsulfonyl groups are toluene sulfonyl and p- nitrobenzene sulfonyl.
  • R-i is methane sulfonyl.
  • Preferable base used in step (c) is an amine base and most preferable amine base is triethyl amine.
  • step (c) is preferably carried out in a chlorinated hydrocarbon solvent such as methylene chloride, ethylene dichloride and chloroform; and most preferable solvent is methylene chloride.
  • a chlorinated hydrocarbon solvent such as methylene chloride, ethylene dichloride and chloroform; and most preferable solvent is methylene chloride.
  • the compound of formula X is coupled with the compound of formula VII to obtain the compound of formula VIII (step- d).
  • P 1 is trimethylsilyl and P 2 is H or acetyl.
  • reaction between the compound of formula VII and the base is preferably carried out at an elevated temperature in the range of from about
  • the coupling reaction is preferably carried out in an inert reaction solvent, as defined above, may be used to temperatures in the range of from about ambient to about 100 0 C.
  • the preferable protected cytosine base of formula X used in step (d) is N-acetyl cytosine, bis(trimethylsilyl)-N-acetyl cytosine or bis(trimethylsilyl) cytosine.
  • Preferable silyl protecting agent is hexamethyl disilazane.
  • the step (e) of the reaction is the removal of the protecting groups.
  • Most silyl protecting groups are easily cleaved by contact with water, an alcohol, an acid or tetrabutyl ammonium fluoride.
  • the deprotection reaction is preferably carried out in alcoholic solvents; especially aqueous alcoholic solvents; polyols such as ethylene glycol and cyclic ether solvents such as tetrahydrofuran.
  • the isomers of formula IX obtained after deprotection are conveniently separated by column chromatography. Usually single run can effectively separate gemcitabine from the other three isomers.
  • the gemcitabine obtained above can be converted to a pharmaceutically acceptable salt by a conventional method.
  • Preferable pharmaceutically acceptable acid addition salts of gemcitabine are selected from salts obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and organic acids such as methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, acetic acid, citric acid, maleic acid, fumaric acid and tartaric acid. More preferable pharmaceutically acceptable acid addition salt is hydrochloric acid.
  • the process of the present invention can conveniently be monitor by High Performance Liquid Chromatography (HPLC) as against the process described in U.S. Patent No. 4,808,614, which cannot be monitored by HPLC.
  • HPLC High Performance Liquid Chromatography
  • Acetonitrile 1000 ml
  • trifluoroacetic acid 10 ml
  • water 260 ml
  • ethyl 2,2-difluoro-3-hydroxy-3-(2,2-dimethyl-dioxolan-4-yl)propionate 100 gm
  • the solvent is distilled and co-distilled with toluene to remove water completely from the reaction mass to give 66 gm of 2-desoxy-2,2-difluoro-1-oxoribose as residue.
  • step-l The residue obtained in step-l is added to dimethylformamide (200 ml) at 25 - 30 0 C and then imidazole (90 gm) is added to form a clear solution.
  • the solution is cooled to 10 0 C, the solution of tert-butyldiphenylsilyl chloride (200 gm) in dimethylformamide (50 ml) is added drop wise and then stirred for 24 hours at reflux.
  • the reaction mass is heated to 60 - 65 0 C for 3 hours and then cooled to 25 - 30 0 C.
  • the mass is poured into water (1000 ml) and extracted with ethyl acetate (500 ml).
  • the aqueous layer is separated and again extracted with ethyl acetate (250 ml). Then combined the two ethyl acetate layers, washed with 5% sodium bicarbonate solution (300 ml), again washed with water (200 ml) and then with saturated sodium chloride solution (200 ml). The resulting organic layer is dried on Na 2 SO 4 and then distilled under vacuum to give 240 gm of residue. The residue was purified by column chromatography to give 84 gm of 3,5-bis(tert-butyldiphenylsilyloxy)-2-desoxy-2,2-difluoro-1-oxoribose.
  • step-ll The residue (24 gm, obtained in step-ll) is added to toluene (300 ml), cooled to -78 0 C and then 20% solution of diisobutylaluminum hydride (66 gm) in hexane is added drop wise for 1 hour at -75 0 C.
  • the reaction mass is stirred for 45 minutes at -75 to -70 0 C to complete disappearance of starting material.
  • methanol 60 ml is added drop wise at -75 to -70 0 C and then stirred for 10 minutes.
  • N-acetyl cytosine (18 gm) and ethylene dichloride (400 ml) is stirred for 10 minutes, hexamethyl disilazane (32 ml) and trimethylsilyl chloride (4 ml) are added and then the contents are heated to 80 0 C to form a clear solution.
  • the solution is stirred for 1 hour at 80 0 C and then distilled completely to obtain a solid.
  • To the resulting solid ethylene dichloride (125 ml) is added and stirred for 10 minutes to form a clear solution.
  • reaction mass is cooled to 20 0 C and then the solution of trimethyl silyl triflate (20 ml) in ethylene dichloride (100 ml) is added drop wise at 20 - 25 0 C for 15 minutes.
  • the contents are stirred for 20 minutes and then the solution of the residue (20 gm, obtained in step-IV) in ethylene dichloride (100 ml) is added drop wise for 10 minutes at 20 - 25 0 C.
  • the resulting mass is heated to reflux for 18 hours and then cooled to 25 - 30 0 C.
  • aqueous hydrochloric acid is added at 10 - 15 0 C to adjust the pH to 5.5 - 6.5.
  • the aqueous layer is then subjected to carbon treatment at 50 0 C and co-distillation of the filtrate with isopropyl alcohol (3 x 150 ml) under vacuum.
  • the residue obtained is then subjected to column chromatography to obtain 3.5 gm of gemcitabine free base as residue (HPLC Purity: 92.6%).
  • Step-VII The residue (3.5 gm, obtained in step-VI) is dissolved in isopropyl alcohol (50 ml), the pH is adjusted to 2 with 20% hydrochloric acid at 0 - 5 0 C and then distilled the solvent to get residue. To the residue acetone (60 ml) is added and stirred for 5 minutes. The separated solid is filtered, washed three times with acetone (50 ml) and then dissolved in water (1 ml). To this solution added acetone (15 ml). The separated solid is filtered and dried to give 2.5 gm of gemcitabine hydrochloride (HPLC Purity: 99.6%).

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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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention porte sur un processus commercialement viable permettant de préparer de la gemcitabine et ses sels d'addition d'acides pharmaceutiquement acceptables avec un rendement élevé et une grande pureté à l'aide de nouveaux intermédiaires.
PCT/IN2005/000256 2005-08-04 2005-08-04 Procede de preparation de gemcitabine utilisant de nouveaux intermediaires Ceased WO2007015257A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/IN2005/000256 WO2007015257A2 (fr) 2005-08-04 2005-08-04 Procede de preparation de gemcitabine utilisant de nouveaux intermediaires
ARP050103954A AR051374A1 (es) 2005-08-04 2005-09-21 Proceso de preparacion de gemcitabina y compuestos relacionados
PE2006000283A PE20070315A1 (es) 2005-08-04 2006-03-14 Procedimiento para la preparacion de gemcitabina

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000256 WO2007015257A2 (fr) 2005-08-04 2005-08-04 Procede de preparation de gemcitabine utilisant de nouveaux intermediaires

Publications (2)

Publication Number Publication Date
WO2007015257A2 true WO2007015257A2 (fr) 2007-02-08
WO2007015257A3 WO2007015257A3 (fr) 2008-04-10

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AR (1) AR051374A1 (fr)
PE (1) PE20070315A1 (fr)
WO (1) WO2007015257A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007117760A3 (fr) * 2006-02-06 2007-12-06 Reddys Lab Ltd Dr Préparation de gemcitabine
CN102659884A (zh) * 2012-04-23 2012-09-12 南京臣功制药股份有限公司 盐酸吉西他滨的提纯方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526988A (en) * 1983-03-10 1985-07-02 Eli Lilly And Company Difluoro antivirals and intermediate therefor
US7265096B2 (en) * 2002-11-04 2007-09-04 Xenoport, Inc. Gemcitabine prodrugs, pharmaceutical compositions and uses thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007117760A3 (fr) * 2006-02-06 2007-12-06 Reddys Lab Ltd Dr Préparation de gemcitabine
CN102659884A (zh) * 2012-04-23 2012-09-12 南京臣功制药股份有限公司 盐酸吉西他滨的提纯方法

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Publication number Publication date
PE20070315A1 (es) 2007-06-06
AR051374A1 (es) 2007-01-10
WO2007015257A3 (fr) 2008-04-10

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