WO2007112473A1 - Purification d'un anomère de difluoronucléoside au moyen d'une solution acide aqueuse - Google Patents

Purification d'un anomère de difluoronucléoside au moyen d'une solution acide aqueuse Download PDF

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Publication number
WO2007112473A1
WO2007112473A1 PCT/AU2006/000430 AU2006000430W WO2007112473A1 WO 2007112473 A1 WO2007112473 A1 WO 2007112473A1 AU 2006000430 W AU2006000430 W AU 2006000430W WO 2007112473 A1 WO2007112473 A1 WO 2007112473A1
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WO
WIPO (PCT)
Prior art keywords
process according
difluoronucleoside
crude
acid
anomer
Prior art date
Application number
PCT/AU2006/000430
Other languages
English (en)
Inventor
Huijan Zhong
Aifeng Lv
Raju Kalidindi
Song Lin
Xiping Su
Original Assignee
Mayne Pharma Limited
Chemwerth Inc
Jiangsu Hansen Pharmaceutical 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 Mayne Pharma Limited, Chemwerth Inc, Jiangsu Hansen Pharmaceutical Co Ltd filed Critical Mayne Pharma Limited
Priority to PCT/AU2006/000430 priority Critical patent/WO2007112473A1/fr
Publication of WO2007112473A1 publication Critical patent/WO2007112473A1/fr

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • the present invention relates to a process for the selective isolation of a 2,2'- difluoronucleoside as a free base, or as an organic or inorganic addition salt, from a mixture of a- and ⁇ - anomers of the free base nucleoside.
  • 2,2'-Difluoronucleosides are known anti-viral and anti-tumour agents (US 4,808,614 and US 5,464,826).
  • 1-(2-oxo-4-amino-1 H-pyrimidin-1-yl)-2-desoxy-2,2'- difluororibose (commonly known as Gemcitabine)
  • Gemcitabine has been shown to have anti-viral and anti-tumour activity. It has been found that the /? ⁇ anomer of Gemcitabine is the most potent, therefore it is desirable to have a synthetic process that results in simple and relatively high yielding isolation of the ⁇ -anomer of Gemcitabine.
  • Known processes for synthesising 2,2'-difluoronucleosides are generally multi-step processes, (for example, Gemcitabine, US 4,526,988) and the intermediate chiral compounds that are formed during the process are present as a mixture of anomers. It is not until near the end of the process that any attempt is made to isolate one of the anomers.
  • the active /?-anomer is isolated from an approximately 4:1 mixture of a- and /?-Gemcitabine, meaning that the desired ⁇ - Gemcitabine is present as the minor component.
  • the /?-anomer is separated using column chromatography, which is an expensive and arduous process.
  • US 5,223,608 describes a process for the generation of an anomeric mixture of Gemcitabine (ie, a: ⁇ mixture of Gemcitabine) in an about 1 :1 ratio, and the selective isolation of the /?-anomer from that mixture, either as the free base, or as an organic or inorganic acid addition salt.
  • the /?-anomer may be selectively isolated as its hydrochloride or hydrobromide salt (in about 80.0% purity) by dissolving the 1:1 cr. ⁇ anomeric mixture in hot water, adding acetone, cooling the solution to between about -10 0 C and about 50 0 C and collecting the precipitated salt.
  • the product from this recrystallisation is subjected to the above process again.
  • US 5,223,608 also describes (in Example 8) the selective isolation of the hydrochloride salt of the ⁇ -anomer (in about 90% purity) from an approximately 1 :1 cr. ⁇ anomeric mixture of gemcitabine, by dissolving the anomeric mixture in concentrated hydrochloric acid (-38% HCI in water) and isopropanol, cooling the solution and collecting the precipitate.
  • Example 10 of US 5,223,608 describes the selective isolation of the hydrobromide salt of the /?-anomer by a similar process to that described in Example 8.
  • US 5,223,608 describes the selective isolation of free base from an about 1:1 a: ⁇ anomeric mixture of the free base or of the organic or inorganic addition salt thereof by dissolving the cr. ⁇ anomeric mixture in hot water, increasing the pH of the resulting solution to between about 7.0 and 9.0, cooling the solution to a temperature between about -1O 0 C and about 30 0 C and collecting the resulting precipitate of Gemcitabine as its free base.
  • This free base can subsequently be converted into an organic or inorganic addition salt if required.
  • a process for purifying a crude a- or a crude /?-anomer of a 2,2'-difluoronucleoside, or a derivative thereof which process includes:
  • the crude ⁇ -anomer or the crude ⁇ -anomer may contain the ⁇ -anomer or ⁇ - anomer, respectively, as the major component
  • various other compounds may be present in the material as impurities, including, for example, other anomers, enantiomers, salts, intermediates, starting materials, minor reaction products, and the like.
  • the derivative may be of any suitable type known to the person skilled in the art.
  • the derivative may be a salt.
  • An organic or inorganic addition salt is preferred.
  • the organic acid may be selected from the group consisting of but not limited to tartaric acid, citric acid, acetic acid, or salts thereof.
  • the inorganic acid may be selected from a halogenic acid, such as hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid, or salts thereof.
  • the acid is a halogenic acid, such as hydrochloric acid or hydrobromic acid.
  • the acid is hydrochloric acid.
  • the predetermined value that the pH of the resulting solution does not exceed is about 4.0, more preferably 2.0, most preferably 0.5.
  • the precipitate is washed with an alcohol.
  • an alcohol preferably the alcohol is isopropanol.
  • adjusting the pH of the solution to below about 4.0, preferably about 0.5 assists in the purification of the crude a- or crude /?-anomer.
  • adjusting the pH of the solution accelerates the nucleation process during crystallisation, which may result in a more consistent and controlled crystallisation process, an increase in the speed of crystallisation and good quality crystals. It is also postulated that the yield from the crystallisation process is also assisted by the low solubility of the ⁇ -anomer in an acidic environment.
  • the solution of the a- or /?-anomer is obtained by adding the a- or /?-anomer to water that has been heated to an elevated temperature.
  • the water is heated to between about 40 0 C and about 70 0 C and more preferably between about 45 0 C and about 60 0 C.
  • the process of the present invention may further include the step of filtering the solution of the a- or /?-anomer prior to the addition of the acid.
  • the process further includes the step of cooling the solution after the addition of the acid.
  • the temperature to which the mixture of 2,2'-difluoronucleoside and water is cooled is between about -3°C and about 5°C. More preferably, the temperature is between about 0 0 C and about 4 0 C.
  • the process may additionally involve the step of further readjusting the pH of the solution after the cooling step, such that the pH does not exceed the predetermined value.
  • the 2,2'-difluoronucleoside is 1-(2-oxo-4-amino-1 H-pyrimidin-1-yl)-2-desoxy- 2,2'-difluororibose.
  • the crude a- or crude /?-anomer of a 2,2'-difluoronucleoside or derivative thereof may be produced by any suitable method.
  • the crude a- or crude /?-anomer is isolated from an aqueous solution of a mixture of a- and /?-anomers of the 2,2'-difluoronucleoside, or a derivative thereof, by adding an alcohol to the aqueous solution, collecting the resulting precipitate and optionally subjecting the precipitate to one or more washing steps.
  • the aqueous solvent is water.
  • Dissolution of the a- and ⁇ - anomers of the 2,2'-difluoronucleoside, or derivative thereof, in an aqueous solvent may be performed by any suitable means.
  • dissolution may occur with the assistance of stirring or heating of the mixture.
  • the solution is both heated and stirred.
  • the aqueous solvent may be heated before the mixture of a- and ⁇ - anomers of the 2,2'-difluoronucleoside is added.
  • the aqueous solvent When the aqueous solvent is heated, it may be heated to any suitable temperature, but preferably it is heated to between about 40 0 C and about 70 0 C, more preferably, between about 45°C and about
  • the alcohol is a short chain alcohol. More preferably the alcohol is a Ci -4 alcohol, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, f-butanol, and the like.
  • the optional washing step may be performed using any suitable solvent.
  • the solvent is an alcohol, preferably isopropanol.
  • the alcohol added to the aqueous solution is the same alcohol used in the optional washing of the precipitate.
  • the selective isolation process may include the further step of filtering the aqueous solution prior to the addition of the alcohol to the filtrate produced.
  • the selective isolation process further includes the step of cooling the aqueous solution or allowing the aqueous solution to cool after the addition of the alcohol.
  • the aqueous solution may be cooled to between about 5 0 C and about 35°C, more preferably between about 1O 0 C and about 30 0 C, most preferably between about 15°C and about 25 0 C.
  • the precipitate is collected by filtration.
  • the 2,2'-difluoronucleoside is 1-(2-oxo-4-amino-1 H-pyrimidin-1-yl)-2-desoxy- 2,2'-difluororibose (Gemcitabine).
  • the mixture of a- and ⁇ - anomers of Gemcitabine may be prepared by processes well known to those skilled in the art.
  • the /?-anomer is selectively isolated.
  • a process for the production of an organic or inorganic acid addition salt of a 2,2'-difluoronucleoside According to this aspect, the free base is used as a starting material and the pH adjustment has the added effect of forming the acid addition salt of the 2,2'-difluoronucleoside.
  • the process includes: providing
  • an a- or a ⁇ -2,7!- difluoronucleoside, or a derivative thereof prepared by a process as described above.
  • an organic or inorganic acid addition salt of a 2,2'-dif!uoronucleoside prepared from the free base 2,2- difluoronucleoside as described above.
  • the 2'-deoxy-2',2'-difluoronuc!eosides are useful antiviral or oncolytic agents.
  • the active component may be included in a pharmaceutical composition.
  • the pharmaceutical composition may include standard ingredients, including suitable solvents, fillers, colourants and the like.
  • the active component may be used alone, or in combination with other actives.
  • Figure 1 is a reaction sequence in relation to a process according to one preferred embodiment of the present invention.
  • Figure 2 is a flow-chart depicting sequential steps in a resolution process according to the preferred embodiment of the invention described in Figure 1.
  • Figure 3 is a flow-chart depicting sequential steps in a purification process according to the invention.
  • Purified water 25 L was discharged into a 500 L reactor and heated to 55 ⁇ 5 0 C for 30 minutes.
  • the reactor was charged with ⁇ //M-(2-oxo-4-amino-1H-pyrimidin-1-yl)-2- desoxy-2,2 -difluororibose hydrochloride (3.57 kg) and the mixture was stirred to ensure dissolution.
  • the mixture was then filtered, lsopropanol (250 L) was added to the filtrate. The mixture was stirred for 2 hours and allowed to cool to about 25°C.
  • the solution was then filtered and the solid washed.
  • the precipitate was then placed on a tray and covered with a cloth.
  • the tray was placed into a vacuum dryer for at least 6 hours at a temperature of 40 ⁇ 5 0 C at a vacuum of about ⁇ 0.07 MPa resulting in /?-1- (2-oxo-4-amino-1H-pyrimidin-1-yl)-2-desoxy-2,2 f -difluororibose hydrochloride (1 b) being obtained as-a white powder (1.035 kg, 98% purity as determined by HPLC).
  • Purified water (42 L) was discharged into a 100 L reactor and heated to 55 ⁇ 5°C. The reactor is then charged with crude /M-(2-oxo-4-amino-1 H-pyrimidin-1-yl)-2-desoxy-2,2'- difluororibose hydrochloride (4.14 kg) prepared according to the above example. The solution was then stirred for approximately 30 minutes and then filtered using a Buchner funnel. The pH of the filtrate was adjusted to ⁇ 0.5 with concentrated hydrochloric acid (approximately 500 mL). The solution was stirred and cooled to about 0 0 C for 1 hour.
  • the resulting precipitate was collected on a 250 mm Buchner funnel, and washed with isopropanol (3 x 3 L). The precipitate was then placed on a tray and covered with a cloth. The tray was placed into a vacuum oven for at least 6 hours at a temperature of 40 ⁇ 5 0 C at a vacuum of about ⁇ 0.07 MPa resulting in /?-1-(2-oxo-4-amino-1 H-pyrimidin- 1-y!)-2-desoxy-2,2'-difluororibose hydrochloride being obtained as a white powder (3.6 kg, 99.8% purity as determined by HPLC).

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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)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de purification d'un anomère α brut ou d'un anomère β brut d'un 2,2'-difluoronucléoside ou d'un dérivé de ceux-ci. Ce procédé consiste à disposer d'un acide organique ou inorganique, d'une certaine quantité d'anomère α brut ou d'anomère β brut d'un 2,2'-difluoronucléoside ou de dérivé de ceux-ci et d'eau, à produire une solution aqueuse d'anomère α brut ou d'anomère β brut dans l'eau, à ajouter une quantité suffisante d'acide à la solution aqueuse, de manière que le pH de la solution résultante ne dépasse pas une valeur prédéfinie, à collecter un précipité, puis à soumettre éventuellement le précipité à une ou plusieurs étapes de lavage.
PCT/AU2006/000430 2006-03-31 2006-03-31 Purification d'un anomère de difluoronucléoside au moyen d'une solution acide aqueuse WO2007112473A1 (fr)

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PCT/AU2006/000430 WO2007112473A1 (fr) 2006-03-31 2006-03-31 Purification d'un anomère de difluoronucléoside au moyen d'une solution acide aqueuse

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PCT/AU2006/000430 WO2007112473A1 (fr) 2006-03-31 2006-03-31 Purification d'un anomère de difluoronucléoside au moyen d'une solution acide aqueuse

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100105887A1 (en) * 2008-10-23 2010-04-29 Prime European Therapeuticals S.P.A. Process for the preparation of gemcitabine hydrochloride
CN103864871A (zh) * 2014-03-10 2014-06-18 洪军 一种盐酸吉西他滨化合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223608A (en) * 1987-08-28 1993-06-29 Eli Lilly And Company Process for and intermediates of 2',2'-difluoronucleosides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223608A (en) * 1987-08-28 1993-06-29 Eli Lilly And Company Process for and intermediates of 2',2'-difluoronucleosides

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100105887A1 (en) * 2008-10-23 2010-04-29 Prime European Therapeuticals S.P.A. Process for the preparation of gemcitabine hydrochloride
US8299239B2 (en) * 2008-10-23 2012-10-30 Prime European Therapeucials S.p.A. Process for the preparation of gemcitabine hydrochloride
CN103864871A (zh) * 2014-03-10 2014-06-18 洪军 一种盐酸吉西他滨化合物
CN103864871B (zh) * 2014-03-10 2016-03-02 洪军 一种盐酸吉西他滨化合物

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