EP1831236A1 - Methode servant a preparer 2'-deoxy-2',2'-difluorocytidine - Google Patents

Methode servant a preparer 2'-deoxy-2',2'-difluorocytidine

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Publication number
EP1831236A1
EP1831236A1 EP05823850A EP05823850A EP1831236A1 EP 1831236 A1 EP1831236 A1 EP 1831236A1 EP 05823850 A EP05823850 A EP 05823850A EP 05823850 A EP05823850 A EP 05823850A EP 1831236 A1 EP1831236 A1 EP 1831236A1
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EP
European Patent Office
Prior art keywords
formula
mixture
deoxy
nucleoside
substituted
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.)
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Application number
EP05823850A
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German (de)
English (en)
Other versions
EP1831236A4 (fr
Inventor
Jaeheon Lee
Gha Seung Park
Moonsub Lee
Hyo-Jeong Bang
Jae Chul Lee
Cheol Kyong Sinnamusil Sinmyeong Apt. KIM
Chang-Ju Choi
Han Kyong Kim
Hoe Chul Lee
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 Science Co Ltd
Original Assignee
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Priority claimed from PCT/KR2005/001954 external-priority patent/WO2006070985A1/fr
Application filed by Hanmi Pharmaceutical Co Ltd, Hanmi Pharmaceutical Industries Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Publication of EP1831236A1 publication Critical patent/EP1831236A1/fr
Publication of EP1831236A4 publication Critical patent/EP1831236A4/fr
Withdrawn legal-status Critical Current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

Definitions

  • the present invention relates to a method for stereoselective ⁇ preparing 2 '-deoxy-2 ',2 '-difluorocytidine.
  • 2 '-Deoxy-2 ',2'-difluorocytidine (Gemcitabine) of formula (I) has a cytosine nucleobase stereochemically-oriented to ⁇ -direction at the 1 -position of the ribofuranose backbone, and is effective for treating various cancers such as non-small cell lung (NSCLC) 5 pancreatic, bladder, breast or ovarian cancers.
  • NSCLC non-small cell lung
  • Gemcitabine can be conventionally prepared from a lactol compound as shown in Reaction Scheme 1 via an activated ribofuranose intermediate having a reactive leaving group.
  • Examples of the activated ribofuranose intermediate for glycosylation are 1 -sulfonate ribofuranose such as ⁇ -methanesulfonate ribofuranose and 1-halo ribufuranose.
  • the ⁇ -methanesulfonate ribofuranose may be reacted with a nucleobase to carry out stereoselective glycosylation to obtain the desired ⁇ -nucleosides in a high yield (See US Patent Nos. 5,371,210, 5,401,838, 5,426,183, 5,594,124 and 5,606,048 and EP Patent No. 577303).
  • the 1-halo ribufuranose derivatives may be easily produced under a mild condition (e.g., room temperature) and reacted with an anionic nucleobase to carry out glycosylation (See US Patent No. 5,744,597 and EP Patent No. 577304).
  • a mild condition e.g., room temperature
  • an anionic nucleobase e.g., a 1-halo ribofuranose derivative
  • the glycosylation using a 1-halo ribofuranose derivative is non-stereoselective (i.e., anomerization at 1 -position is occurred), leading to a mixture of ⁇ - and ⁇ -nucleosides and ultimately to a low yield of the desired ⁇ -nucleoside.
  • US Patent No. 5,223,608 discloses a process for selectively isolating the ⁇ -anomer of cytidinenucleoside from a 1 :1 mixture of ⁇ - and ⁇ - cytidinenucleoside anomers by converting the mixture into the hydrochloride form, dissolving the hydrochloride mixture in hot water, adjusting pH of the resulting solution to 8.2, and cooling and filtering the solution.
  • this process also give a low yield of the ⁇ -anomer.
  • the present inventors have endeavored to overcome the problems of the prior arts and found that an anomerization is effectively suppressed by removing the halide compound as it is generated during the glycosylation when 1-halo ribofuranose derivative is used and consequently the stereoselectivity can be markedly enhanced.
  • R is alkyl
  • P 1 is a hydroxy-protecting group
  • P 2 is an amino-protecting group
  • X is halogen
  • FIGs. 1 to 3 high pressure liquid chromatography (HPLC) scans of the compounds prepared in Example 4, Comparative Examples 1 and 2, respectively.
  • the inventive method is characterized that the compound of formula (I) can be efficiently prepared by continuously removing the silyl halide of formula (V) which is produced during the glycosylation.
  • the term "anomer-enriched” used herein means an anomer mixture having a specific anomer content of greater than 50%, including a substantially pure anomer.
  • the term “anomerization” means that a substantially pure anomer or a mixture of ⁇ -anomer and ⁇ -anomer is epimerized at the Crposition of a ribofuranose.
  • carrier used herein means a solvent that is used to remove the silyl halide produced during the glycosylation and the term “heating medium” means a solvent of a high boiling point that can provide a sufficient heat to a reaction system and maintain the reaction mixture at a sufficiently high temperature to enable the continuous removal of the silyl halide by distillation.
  • substituted used herein means substitution alone or in combination by at least one or more of the groups selected from hydrogen, cyano, halo, carboalkoxy, toluoyl, nitro, alkoxy and alkyl.
  • an ⁇ -anomer enriched 1-halo ribofuranose of formula (III) is reacted with a nucleobase of formula (IV) for glycosylation to produce a ⁇ -nucleoside of formula (II) together with a silyl halide of formula (V) which may function as a halide source to bring about the anomerization of ⁇ -anomer.
  • the silyl halide is continuously removed as it is formed by simple distillation or by using an inert gas until the glycosylation reaction is completed.
  • the extent of anomerization is remarkably reduced and highly stereoselective glycosylation occurs in favor of the ⁇ -anomer.
  • the distillation is carried out with simultaneously adding a carrier or a mixture of a carrier and a heating medium which have a high boiling point dropwise to the reaction mixture for glycosylation.
  • the inert gas is passed through a separate tube which is inserted in a reactor to exhaust the silyl halide out of the reaction mixture without affecting the glycosylation reaction.
  • the inert gas is introduced from the tube which is set up within (bubbling) or above (sweeping) the reacting solution for the removal of silyl halide.
  • the ⁇ -anomer enriched 1-halo ribofuranose of formula (III) used as a starting material in the inventive method has a hydroxy-protecting group, and can be prepared by the method described in Korean Patent Application No. 2004-59623.
  • Exemplary hydroxy-protecting groups are formyl, acetyl, substituted acetyl, propionyl, butynyl, pivalamido, benzoyl, biphenylcarbonyl, substituted biphenylcarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, t-butyl, tetrahydropyranyl, allyl, N-phenylcarbamate, N-imidazoyl carbamate, trialkylsilyl, isopropyldialkylsilyl, alkyldiisopropylsilyl, triisopropylsilyl and t-butyldialkylsilyl. Among these, benzoyl, biphenylcarbonyl and substituted biphenylcarbonyl are more preferred.
  • the nucleobase of formula (IV) has an amino-protecting group, and it can be prepared by use of the methods described in US Patent Nos. 5,371,210, 5,401,838, 5,426,183, 5,594,124 and 5,606,048 and EP Patent No. 577303.
  • amino-protecting groups are silyl groups such as trimethylsilyl, triisopropylsilyl, tributylsilyl, t-butyldimethylsilyl and t-butyldiarylsilyl; carbamates such as t-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl; formyl, acetyl, benzoyl and pivaloyl, methoxymethyl, t-butyl, benzyl and tetrahydropyranyl. Among these, trimethylsilyl is most preferred.
  • the nucleobase of formula (IV) is used in an amount ranging from 5 to 50 molar equivalents, preferably 10 to 30 molar equivalents, more preferably 15 to 20 molar equivalents, based on the 1-halo ribofuranose of formula (EI) .
  • the solvents suitable for use in the present glycosylation process are benzene, substituted benzene, toluene, xylene, decalin, diglyme, 2-ethoxyethyl ether, diphenylether, substituted diphenylether, biphenyl, substituted biphenyl, C 6 - M alkane, substituted C ⁇ -u alkane and a mixture thereof. Amone these, toluene, C 7-I4 alkane, diphenylether and a mixture thereof are preferred, and a mixture of diphenylether and heptane is most preferred.
  • the solvent is used in an amount ranging from 5 to 50 ml, preferably 10 to 20 mi based on 1 g of 1-halo ribofuranose of formula (III).
  • the carrier used to assist the removal of the silyl halide of formula (V) by distillation must be inert under the glycosylation reaction conditions and preferably has a boiling point higher than that of the silyl halide.
  • the carrier may be benzene, substituted benzene, toluene, xylene, C 6 - H alkane, substituted C 6-14 alkane and a mixture thereof. Among these, toluene, heptane, octane and nonane are preferred, and heptane is most preferred.
  • the carrier is used in an amount ranging from 50 to 1000 T ⁇ I, preferably 100 to 300 m£ based on 1 g of the 1-halo ribofuranose of formula (HI).
  • a heating medium having a high boiling point of 200 °C or higher may be further used in the form of a mixture with the carrier, so as to provide a reaction system with sufficient heat and complement the loss solvent due to distillation.
  • the heating medium must be inert under the glycosylation reaction conditions and preferably has a boiling point higher than that of the carrier.
  • the heating medium may be selected from the group consisting of decalin, diphenylether, substituted diphenylether, biphenyl, substituted biphenyl and a mixture thereof. Among these, diphenylether is most preferred.
  • the heating medium is used in an amount ranging from 0.1 to 5 vol%, preferably 0.5 to 3 vol% based on the amount of the carrier.
  • the carrier and the heating medium are continuously added to the reaction mixture in a constant rate until the glycosylation reaction is completed, so as to obtain a uniform stereoselectivity.
  • silyl source such as N,O-bis(trimethylsilyl)acetamide
  • the silyl source may be used in an amount ranging from 0.05 to 1.5 vo 1%, preferably 0.1 to 0.5 vol% based on the amount of the carrier.
  • an inert gas such as nitrogen, helium, neon and argon, preferably nitrogen, may also be used in the removal of the silyl halide of formula (V).
  • the inert gas is preferably introduced at a flow rate of 1 I /min or more based on lOOg of 1-halo ribofuranose compound of formula (III).
  • the inert gas is introduced at a flow rate less than 1 I /min, the ratio of ⁇ -nucleosides to ⁇ -nucleosides becomes not more than 3.
  • the glycosylation according to the present invention is carried out at a temperature ranging from 80 to 300 ° C , preferably 100 to 200 °C, more preferably 130 to 150 ° C for 4 to 24 hours.
  • the progress of the glycosylation may be checked by thin layer chromatography (TLC), 1 H nucleus magnetic resonance ( 1 H -NMR) or high pressure liquid chromatography (HPLC).
  • the deprotection of the ⁇ -anomer enriched nucleoside of formula (II) may be carried out by a conventional method.
  • most silyl protecting groups are easily cleaved by the action of water or an alcohol.
  • the acyl-amino protecting groups such as formyl, acetyl, pivaloyl and benzoyl are removed by hydrolysis with a strong base.
  • bases include alkali metal hydroxides such as sodium or potassium hydroxide; alkali metal alkoxides such as sodium methoxide or potassium t-butoxide; diethylamine, hydroxylamine, ammonia, hydrazine and the like, among these, ammonia is preferred.
  • the acyl protecting groups can be removed using an acid catalyst such as methanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, or an acidic ion exchange resin.
  • ⁇ -Anomer enriched nucleoside of formula (H) may be obtained in a pure form by a separation based on solubility difference from a mixture of ⁇ -anomer enriched nucleoside of formula (II) and the unreacted cytosine as produced after the deprotection.
  • the separation is preferably carried out by using the solvent system consisting of methylene chloride and methanol wherein ⁇ -anomer enriched nucleoside of formula (II) is highly soluble while the unreacted cytosine is sparingly soluble.
  • a ⁇ -enriched nucleoside product having an ⁇ : ⁇ ratio of 1:4 to 1:14 is obtained.
  • the ⁇ -nucleoside of formula (I) can be isolated in the form of hemihydrate or dihydrate in a high purity of 99.8% or more and a yield of 70% or more by a single recrystallization procedure which comprises dissolving the ⁇ / ⁇ anomer mixture in water, heating the mixture to a temperature of 40 to 60 ° C, cooling to 10 to 25 ° C and filtering the solids precipitated during the cooling step. This procedure may be conducted with stirring when the hemihydrate form is derived or without stirring for the dihydrate form.
  • the highly pure hemihydrate or dihydrate of ⁇ -nucleosides can be directly used without further purification to prepare a pharmaceutically acceptable hydrochloride salt of the purity range described in pp 892-894 of U.S. Pharmacopoeia (2004).
  • the present invention also provides a method for preparing 2'-deoxy-2',2'-difluorocytidine hydrochloride comprising reacting 2'-deoxy-2',2'-difluorocytidine of formula (I) or a hemihydrate or dihydrate thereof with hydrochloric acid in an organic solvent.
  • each product obtained was analyzed by HPLC under two conditions : (1) Zorbax RX-C8 column (4.5x250 mm, 5 ⁇ m), NaH 2 PO 4 -H 2 O 13.8 g/H 2 PO 4 (pH 2.4-2.6) 2.5 ml dissolved in 1 I of water for the compound of formula (I); and (2) YMC hydrosphere Cl 8 column (4.6x150 mm, 5 ⁇ m), a mixture of 760 ml of methanol and 240 ml Of NaH 2 PO 4 -H 2 O 13.8 g/H 2 PO 4 (pH 2.4-2.6) 2.5 ml dissolved in U of water for the compound of formula (II).
  • Step 1 Preparation of 2 f -deoxy-2 r ,2 f -difluoro-D-ribofuranosyl-5-benzoyl- 3 -(4-phenyl s )benzoate
  • the aqueous layer was extracted with 220 mi of ether, combined with the pre-separated teterahydrofuran layer, washed successively with 220 mi portion of water, saturated sodium bicarbonate and brine, dried over magnesium sulfate and filtered.
  • the solvent was removed under a reduced pressure and the residue was purified by silica gel column chromatography to obtain 18.3 g of the title compound (yield : 91%) as a light yellow syrup.
  • Step 2 Preparation of 2'-deoxy-2 ⁇ 2'-difluoro-D-ribofuranosyl-5-benzoyl-3- ( 4-phenyl)benzoate- 1 ⁇ -diphenvf ⁇ hosphate
  • the ether extract was combined with the pre-separated toluene layer and washed successively with water, saturated sodium bicarbonate and brine.
  • the organic layer was separated, dried over magnesium sulfate and filtered.
  • the solvent was removed under a reduced pressure to obtain a mixture of ⁇ - and ⁇ -phosphate as a solid.
  • the mixture was examined by 1 H -NMR analysis to find that the ⁇ - ⁇ hosphate : ⁇ -phosphate ratio was 1 :10.6.
  • the ⁇ -phosphate was selectively recrystallized from a 3:1 (v/v) mixture of isopropanol and water, to obtain 26.5 g (yield: 87%) of the title compound as a white solid.
  • Step 3 Preparation of l- ⁇ -bromo-2'-deo ⁇ y-2 ⁇ 2'-difluoro-D-ribofuranosyl-5- benzoyl-3-(4-phenyl)benzoate
  • the filtrate was concentrated under a reduced pressure to obtain a mixture of ⁇ - and ⁇ -isomers as a solid.
  • the mixture was examined by 1 H -NMR analysis to find that the ⁇ -bromo : ⁇ -bromo ratio was 10.7:1.
  • the ⁇ -bromo compound was selectively recrystallized from isopropanol to obtain 17.0 g (yield: 82%) of the title compound as a white solid.
  • Step 1 Preparation of 2'-deoxy-2 ⁇ 2'-difluoro-D-ribofuranosyl-3,5-di-(4- phenvDbenzoate
  • the aqueous layer was extracted with 150 ml of ether, combined with the pre-separated organic layer, washed successively with 220 ml of water, saturated sodium bicarbonate and brine, dried over magnesium sulfate and filtered. The solvent was removed under a reduced pressure and the resulting solid was recrystallized from toluene to obtain 13.4 g of the title compound (yield : 89%) as a white solid.
  • Step 2 Preparation of 2'-deoxy-2 ⁇ 2'-difluoro-D- ribofuranosyl-3,5-di-(4- phenvDbenzoyl- 1 ⁇ -diphenyrphosphate
  • the organic layer was separated, washed successively with water, saturated sodium bicarbonate and brine, dried over magnesium sulfate and filtered.
  • the solvent was removed under a reduced pressure to obtain a mixture of ⁇ - and ⁇ -phosphate as a solid.
  • the mixture was examined by 1 H -NMR analysis to find that the ⁇ -phosphate : ⁇ -phosphate ratio was 1 :10.8.
  • the ⁇ -phosphate was selectively recrystallized from isopropanol to obtain 15 g (yield: 83%) of the title compound as a white solid.
  • Step 3 Preparation of l- ⁇ -bromo-2'-deox ⁇ -2 ⁇ 2'-difluoro-D-ribofuranosyl-3.,5- di-(4-phenyl)benzoate
  • the solid containing the nucleoside mixture and unreacted cytosine was added to a mixture of methylene chloride (200 mi) and methanol (40 mi), refluxed for 1 hour and filtered to remove cytosine.
  • the filtrate was distilled under a reduced pressure, isopropylether was added to the residue, filtered and the filtrate was dried with warm wind to obtain 10.8 g (yield: 98%) of the title compound as a white solid.
  • the resulting mixture was reacted for 10 hours while adding dropwise a diphenylether (10 m#)/heptane (1 i ) mixture thereto and at the same time carrying out distillation with maintaining the reaction temperature at 140 to 150 ° C .
  • This procedure allowed continuous removal of trimethylsilyl bromide from the reaction mixture during the course of the reaction.
  • 50 mi of heptane was added to the reaction mixture.
  • the solution was cooled to 80 to 100 ° C, carefully added dropwise 12 mi of water and the mixture was stirred at room temperature for 1 hour.
  • the solid formed was filtered and washed with heptane to obtain a mixture of ⁇ - and ⁇ -nucleoside isomers including unreacted cytosine in the form of a white solid.
  • the nucleoside mixture was examined by HPLC analysis to find that the ⁇ -nucleoside : ⁇ -nucleoside ratio was 1:5.6.
  • the solid containing the nucleoside mixture and unreacted cytosine was added to a mixture of methylene chloride (70 mi) and methanol (15 mi), refluxed for 1 hour and filtered to remove cytosine.
  • the resulting mixture was reacted for 6 hours while adding N,O-bis(trimethylsilyl)acetamide (2 mi)/heptane (200 mi) mixture dropwise and at the same time carrying out distillation with maintaining the reaction temperature at 125 to 140 ° C .
  • This procedure allowed continuous removal of trimethylsilyl bromide from the reaction mixture during the course of the reaction.
  • the solution was cooled to 80 0 C , carefully added dropwise 1 mi of water and the mixture was stirred at room temperature for 1 hour.
  • the solid formed was filtered and washed with heptane to obtain a mixture of ⁇ - and ⁇ -nucleoside isomers including unreacted cytosine in the form of a white solid.
  • the nucleoside mixture was examined by HPLC analysis to find that the ⁇ -nucleoside : ⁇ -nucleoside ratio was 1 :14.
  • the resulting mixture was reacted for 12 hours while inserting a separate tube in the reactor and introducing nitrogen at a flow of 1.0 to 1.3 i /min by sweeping thereto with maintaining the reaction temperature at 140 to 143 °C .
  • This procedure allowed continuous removal of trimethylsilyl bromide from the reaction mixture during the course of the reaction.
  • the solution was cooled to 80 0 C and 100 ml of water was carefully added thereto dropwise. The mixture was stirred at room temperature for 1 hour.
  • the solid formed was filtered and washed with heptane to obtain a mixture of ⁇ - and ⁇ -nucleoside isomers including unreacted cytosine in the form of a white solid.
  • the nucleoside mixture was examined by HPLC analysis to find that the ⁇ -nucleoside : ⁇ -nucleoside ratio was 1:4.9.
  • Example 1-4 The procedure of Example 1-4 was repeated except that nitrogen was introduced into the tube at a flow rate of 3.0 to 3.5 -6 /min, to obtain a mixture of ⁇ - and ⁇ -nucleoside isomers including unreacted cytosine in the form of a white solid.
  • the nucleoside mixture was examined by HPLC analysis to find that the ⁇ -nucleoside : ⁇ -nucleoside ratio was 1:6.1.
  • Example 2 l-(2 -Deoxy-2',2'-difluoro-3,5-di-(4-phenyI) benzoyl-D- ribofuranosyl-4-aminopyrimidin-2-one
  • the resulting mixture was allowed to react for 9 hours while adding dropwise 4 I of heptane thereto and at the same time carrying out distillation with maintaining the reaction temperature at 130 to 140 °C .
  • This procedure allowed continuous removal of trimethylsilyl bromide from the reaction mixture during the course of the reaction.
  • 160 mi of heptane was added to the reaction mixture.
  • the solution was cooled to 100 ° C and 8 mi of water was carefully added dropwise thereto.
  • the solution was stirred at room temperature and filtered.
  • the solid formed was washed with heptane to obtain a mixture of ⁇ - and ⁇ -nucleoside isomers including unreacted cytosine in the form of a white solid.
  • the nucleoside mixture was examined by HPLC analysis to find that the ⁇ -nucleoside : ⁇ -nucleoside ratio was 1 :5.4.
  • the solid containing nucleoside mixture and the unreacted cytosine was added to a mixture of methylene chloride (200 mi) and methanol (40 mi), refluxed for 1 hour and filtered to remove cytosine.
  • the filtrate was distilled under a reduced pressure to obtain 4 g (yield: 64%) of the title compound as a white solid.
  • Example 3-1 2'-Deoxy-2 ⁇ 2'-difluorocytidine hemihydrate
  • Example 3-1 The procedure of Example 3-1 was repeated except that the solution was cooled without stirring during the precipitation of solid, to obtain 4.22 g (yield: 81.3%) of the title compound in the form of pure white dihydrate.
  • the resulting mixture was allowed to react for 10 hours while adding dropwise 1.5 I of heptane thereto and at the same time carrying out distillation with maintaining the reaction temperature at 135 to 140 °C .
  • This procedure allowed continuous removal of trimethylsilyl bromide from the reaction mixture during the course of the reaction.
  • 240 mi of heptane was added to the resulting solution and 11.6 ml of water was slowly added thereto.
  • the solid formed was stirred, filtered, washed with heptane and dried at room temperature, to obtain a mixture of ⁇ - and ⁇ -nucleoside isomers including unreacted cytosine in the form of a white solid.
  • the nucleoside mixture was examined by HPLC analysis to find that the ⁇ -nucleoside : ⁇ -nucleoside ratio was 1:6.1 (See Fig. 1).
  • the solid was suspended in 300 mi of methylene chloride and 60 mi of methanol solution, and refluxed for 2 hours.
  • the resulting mixture was filtered, the filtered solid was washed with a mixture of methylene chloride (150 mi) and methanol (30 mi) and distilled under a reduced pressure, to obtain an ⁇ / ⁇ mixture of l-(2'-deoxy-2',2'-difluoro-5-benzoyl-3-(4-phenyl)benzoyl-D- ribofuranosyl-4-aminopyrimidin-2-one.
  • the residue solid was added with 200 mi of methanol and 83 mi of 7N-ammonia/methanol solution, and stirred at room temperature overnight. After completing the reaction, the solvent was removed under a reduced pressure, and 80 mi of ethyl acetate and 90 mi of water were added to the residue. The aqueous layer was separated and the ethyl acetate layer was extracted with 40 mi of water. The aqueous layers were combined and washed with 40 ml of ether (x2). The water was distilled off under a reduced pressure until water was left in the amount of 5 times based on the theoretical weight of the desired product, and the residue was heated to 50 to 55 ° C and cooled to room temperature with stirring for 2 hours to induce the precipitation of a solid. The precipitated solid was filtered, washed with water and acetone and dried with warm wind overnight, to obtain 3.69 g (yield: 72.6%) of the title compound in the form of a pure white crystal.
  • the nucleoside mixture was examined by HPLC analysis to find that the ⁇ -nucleoside : ⁇ -nucleoside ratio was 1 :4.8.
  • the nulceoside mixture was suspended in 108 ml of methanol and 45 ml of 7N ammonia/methanol solution, the solvent was removed under a reduced pressure, and 50 ml of ethyl acetate and 60 ml of water were added to the residue. The aqueous layer was separated and the ethyl acetate layer was extracted with 20 ml of water. The aqueous layers were combined and washed with 40 ml of ether (x2).
  • Example 3-1 was dissolved in 35 ml of acetone and 1.2 ml • of concentrated hydrochloric acid was added dropwise thereto. The resulting mixture was stirred at room temperature for 2 hours. The solid formed was filtered, washed with acetone and dried with warm wind to obtain 3.52 g (yield: 91.9%) of the title compound in the form of a pure white crystal.
  • Example 3-2 3.5g of 2'-Deoxy-2',2'-difluorocytidine dihydrate (moisture content : 11.5%) obtained in Example 3-2 was dissolved in 35 mi of acetone and 1.2 mi of concentrated hydrochloric acid was added drop wise thereto. The resulting mixture was stirred at room temperature for 2 hours. The solid formed was filtered, washed with acetone and dried with warm wind to obtain 3.23 g (yield: 91.5%) of the title compound in the form of a pure white crystal.
  • the solid formed was stirred, filtered, washed with heptane and dried at room temperature, to obtain a mixture of ⁇ - and ⁇ -nucleoside isomers including unreacted cytosine in the form of a white solid.
  • the nucleoside mixture was examined by HPLC analysis to find that the ⁇ -nucleoside : ⁇ -nucleoside ratio was 1:1.4 (See Fig. 2).
  • the solid was suspended in 300 ml of methylene chloride and 60 ml of methanol solution, and refluxed for 2 hours.
  • the solvent was removed under a reduced pressure, and 80 ml of ethyl acetate and 90 ml of water were added to the residue.
  • the aqueous layer was separated and the ethyl acetate layer was extracted with 40 ml of water.
  • the aqueous layers were combined and washed with 40 ml of ether (x2).
  • the water was distilled off under a reduced pressure until water was left in the amount of 5 times based on the theoretical weight of the desired product, and the residue was heated to 50 to 55 "C and cooled to room temperature with stirring for 2 hours to induce the precipitation of a solid.
  • the precipitated solid was filtered, washed with water and acetone and dried with warn wind overnight, to obtain 1.80 g (yield: 35.5%) of the title compound in the form of a pure white crystal.
  • the solid formed was stirred, filtered, washed with heptane and dried at room temperature, to obtain a mixture of ⁇ - and ⁇ -nucleoside isomers including unreacted cytosine in the form of a white solid.
  • the nucleoside mixture was examined by HPLC analysis to find that the ⁇ -nucleoside : ⁇ -nucleoside ratio was 1 : 1.3 (See Fig. 3).
  • the solid was suspended in 300 mi of methylene chloride and 60 mi of methanol, and refluxed for 2 hours.
  • the aqueous layer was separated and the ethyl acetate layer was extracted with 40 mi of water.
  • the aqueous layers were combined and washed with 40 mi of ether (x2).
  • the water was distilled off under a reduced pressure until water was left in the amount of 5 times based on the theoretical weight of the desired product, and the residue was heated to 50 to 55 °C and cooled to room temperature with stirring for

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Abstract

Méthode améliorée de préparation stéréosélective de 2'-deoxy-2',2'-difluorocytidine représentée par la formule (I) et consistant à effectuer la réaction d'un composé de 1-halo-ribofuranose représenté par la formule (III) avec une nucléobase représentée par la formule (IV) dans un solvant afin d'obtenir un nucléoside représenté par la formule (II) et à extraire l'halogénure de silyle représenté par la formule (V) produit pendant la réaction, puis à déprotéger le nucléoside (formule II), de manière à obtenir 2-'deoxy-2'2' difluorocytidine (formule I).
EP05823850.2A 2004-12-30 2005-12-29 Methode servant a preparer 2'-deoxy-2',2'-difluorocytidine Withdrawn EP1831236A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR20040116316 2004-12-30
PCT/KR2005/001954 WO2006070985A1 (fr) 2004-12-30 2005-06-23 Méthode de synthèse de la 2’-désoxy-2’,2’-difluorocytidine
PCT/KR2005/004633 WO2006071090A1 (fr) 2004-12-30 2005-12-29 Methode servant a preparer 2'-deoxy-2',2'-difluorocytidine

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Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE602005019626D1 (de) * 2005-03-04 2010-04-08 Fresenius Kabi Oncology Ltd Zwischenprodukt und verfahren zur herstellung von an beta-anomeren angereicherten 2'-desoxy,2',2'-difluor-d-ribufuranosylnukleosiden
CN100475832C (zh) 2007-05-31 2009-04-08 南京卡文迪许生物工程技术有限公司 一种新颖的高立体选择性合成吉西他滨工艺及中间体
CN101381387B (zh) * 2007-09-06 2011-08-31 上海希迪制药有限公司 制备2'-脱氧-2',2'-二氟-β-胞苷盐酸盐的方法
KR20100102107A (ko) * 2007-11-06 2010-09-20 파마이센시아 코퍼레이션 β-뉴클레오시드의 새로운 합성 방법
CA2727813A1 (fr) * 2008-06-12 2009-12-17 Scinopharm Taiwan, Ltd. Polymorphes cristallins de la base gemcitabine
WO2010029574A2 (fr) * 2008-08-18 2010-03-18 Vishwanath Kannan Procédé amélioré de préparation de gemcitabine et de ses intermédiaires au moyen de nouveaux groupes de protection et de résines échangeuses d'ions
CN102617484B (zh) * 2011-06-30 2014-05-14 江苏豪森药业股份有限公司 盐酸吉西他滨制备过程中胞嘧啶的回收处理方法
CN102617483B (zh) * 2011-06-30 2013-04-24 江苏豪森药业股份有限公司 盐酸吉西他滨制备过程中胞嘧啶的回收处理方法
CN102432654A (zh) * 2011-09-26 2012-05-02 宋云龙 吉西他滨酰胺衍生物及其制备方法和用途
CN103224541B (zh) * 2013-04-27 2015-07-01 江苏豪森药业股份有限公司 吉西他滨α-异构体转化回收工艺
CN106317147B (zh) * 2015-07-06 2018-11-27 扬州硒瑞恩生物医药科技有限公司 核苷类化合物及其制备方法
CN109305992A (zh) * 2017-07-28 2019-02-05 江苏先声药业有限公司 一种阿扎胞苷的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1442420A (zh) * 2003-04-08 2003-09-17 深圳市汉德森技术有限公司 以1，6－脱水－β－D－葡萄糖为原料制备2'－脱氧－2'，2'－二氟－β－核胞苷或其药用盐的方法

Family Cites Families (5)

* 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
CA2098874C (fr) * 1992-06-22 2004-04-20 Ta-Sen Chou Methode de glycosylation anionique stereoselective
US5371210A (en) * 1992-06-22 1994-12-06 Eli Lilly And Company Stereoselective fusion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
US5606048A (en) * 1992-06-22 1997-02-25 Eli Lilly And Company Stereoselective glycosylation process for preparing 2'-Deoxy-2', 2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
US5401861A (en) * 1992-06-22 1995-03-28 Eli Lilly And Company Low temperature process for preparing alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl sulfonates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1442420A (zh) * 2003-04-08 2003-09-17 深圳市汉德森技术有限公司 以1，6－脱水－β－D－葡萄糖为原料制备2'－脱氧－2'，2'－二氟－β－核胞苷或其药用盐的方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BARDOS, THOMAS J. ET AL: "Stereoselective synthesis of the anomeric 5-mercapto-2'-deoxyuridines and of some other anomeric 2-deoxy-D-erythropentonucleosides", TETRAHEDRON LETTERS, vol. 16, 1966, pages 1759-1764, XP002713325, ISSN: 0040-4039 *
KOTICK, MICHAEL P. ET AL: "Synthesis of 5-s-substituted 2'-deoxyuridines. Study of the factors influencing the stereoselectivity of the silyl modification of the Hilbert-Johnson reaction", JOURNAL OF ORGANIC CHEMISTRY, vol. 34, no. 12, 1969, pages 3806-3813, XP002713326, ISSN: 0022-3263 *
See also references of WO2006071090A1 *
VORBRUEGGEN, HELMUT ET AL: "Synthesis of nucleosides", ORGANIC REACTIONS, 2000, XP002713324, (HOBOKEN, NJ, UNITED STATES) *

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NO20070865L (no) 2007-04-24
EP1831236A4 (fr) 2013-11-20
CN101010329A (zh) 2007-08-01
AU2005320374B2 (en) 2009-01-08
CN101010329B (zh) 2011-06-08
BRPI0514718A (pt) 2008-07-01
WO2006071090A1 (fr) 2006-07-06

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