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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
  • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
• • 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
  • C07H19/048—Pyridine radicals
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the invention is directed to the novel difluoronucleoside, 2-deoxy-3,5- dibenzoate-2,2-difluoro-uridine, and to the process for preparation thereof .
• Gemcitabine HCl is the beta isomer of 2'-deoxy-2',2'-difiuorocytidine monohydrochloride, having the following structure
• Gemzar® is a white to off-white solid, marketed under the name Gemzar® as a nucleoside analogue that exhibits antitumor activity.
• Gemcitabine which is the free base of Gemcitabine hydrochloride, exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase), and also blocking the progression of cells through the Gl/S-phase boundary.
• Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides.
• dFdCDP active diphosphate
• dFdCTP triphosphate
• the cytotoxic effect of gemcitabine is attributed to a combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis.
• PCT/ US O S • " "'# • »4-3 E lf i
• Gemcitabine hydrochloride is prepared from Gemcitabine, which is a
• 2',2'-difluoronuclepside derivative that is usually prepared by the attack of a suitable protected base on the 1 -position of a corresponding protected sugar derivative.
• U.S. Patents Nos. 4,965,374 discloses the coupling reaction between l-sulphonyloxy-2-deoxy-2,2,-difluoropentofuranoses and a protected cytidine, to yield the precursor of Gemcitabine as a mixture of ⁇ / ⁇ isomers in a ratio of 1:1.
• U.S. Patents Nos. 5,371,210 discloses the coupling reaction between l-sulphonyloxy-2-deoxy-2,2,-difluoropentofuranoses and a protected cytidine, but the reaction is carried out without any solvent. However, a pre-purification process of thel-sulphonyloxy-2-deoxy-2,2,-difluoropentofuranoses is conducted to obtain an isomerically enriched starting material, that after the coupling reaction leads to the precursor of Gemcitabine having an ⁇ / ⁇ ratio of up to 1 to 1.8.
• U.S. Patents Nos. 5,594,124 discloses the coupling reaction between l-sulphonyloxy-2-deoxy-2,2,-difluoropentofuranoses and a protected cytidine at -78°C, giving the final product with an ⁇ / ⁇ ratio of up to 1 to 2.5.
• U.S. Patents Nos. 5,744,597 discloses the coupling reaction between l-sulphonyloxy-2-deoxy-2,2 5 -difluoropentofuranoses and a protected cytidine, after a pre- purification process, as described in U.S. Patents Nos. 5,371,210.
• the present invention provides a process for the preparation of a
• L is a leaving group selected from the group consisting OfC 1-10 alkyl, C 1-10 haloalkyl, C 1-10 aryl-esters, C 1-10 alkyl and C 1-10 aryl-sulphonates, and halogens;
• R is an alcohol protecting groups selected from the group consisting OfC 1-10 alkyl- and C 1-10 aryl-ester ester, ether, carbamate and acetal;
• P 1 is a C 1-6 trialkyl silyl ether, wherein each alkyl group can be the same or different, and X is either NH and O.
• the present invention provides a process for preparing
• Gemcitabine comprising preparing 2',2'-difluoronucleoside of formula I as described above, and further converting it to Gemcitabine.
• L in the process described above is acetate group
• R is a benzyl group
• P,i is trimethylsilyl group
• the obtained product is 3,5-dibenzoate-2,2- difluoro-uridine of the formula Ia.
• the present invention provides a process for preparing
• Gemcitabine comprising preparing 3,5-dibenzoate-2,2-difluoro-uridine of the formula Ia, as described above, and further converting it to Gemcitabine.
• the present invention provides the novel compound
• the present invention provides 2-deoxy-3,5-dibenzoate-
• 2,2-difluoro-uridine of the formula Ia having ⁇ / ⁇ ratio of about 1:4 to about 1:6, as determined by HPLC.
• the present invention provides the novel ⁇ isomer of 2-deoxy-
• Figure 1 illustrates the 1 H-NMR spectrum for a compound of formula Ia
• Figure 2 illustrates the 1 H-NMR spectrum for a compound of formula ⁇ a- ⁇ .
• the present invention provides a process to obtain Gemcitabine, by a stereoselective coupling reaction, which is done under mild condition, leading to the ⁇ enriched precursor of Gemcitabine, hence, avoiding purification steps such as, chromatography.
• the process of the present invention can be adapted to an industrial scale.
• the present invention provides a process for the preparation of a
• L is a leaving group selected from the group consisting OfC 1-10 alkyl, C 1-10 haloalkyl, C 1-10 aryl-esters, C 1-10 alkyl and C 1-10 aryl-sulphonates, and halogens
• R is an alcohol-protecting group selected from the group consisting OfC 1-10 alkyl, C 1-10 aryl ester, ether, carbamate and acetal
• P 1 is a C 1-6 trialkyl silyl ether, wherein each alkyl group can be the same or different
• X is either NH and O.
• the process of the invention may be used for the synthesis of
• R is either C 1-10 alkyl- or C 1-10 aryl-ester, more preferably, C 1-10 aryl-ester and most preferably, benzoyl ester.
• a more preferred P 1 is C 1-3 alkyl and most preferably, trimethylsilyl
• L is either C 1-10 alkyl, or C 1- I 0 aryl-esters, more preferably, C 1-10 alkyl ester, and most preferably, methylester.
• the present invention further provides a process for preparing Gemcitabine comprising preparing 2',2'-difluoronucleoside of formula I as described above, and further converting it to Gemcitabine.
• the present invention also provides the process described above wherein, L is methyl ester and R is benzoyl ester, hence, the fluorinated protected sugar derivatives of formula II corresponds to l-acetyl-2-deoxy-3,5-dibenzoate-2,2-difluoro-ribofuranose of the formula II-a,
• the l-acetyl-2-deoxy-3,5-dibenzoate-2,2-difluoro-ribofuranose of formula Ha may be prepared as, exemplified in example 2. According to the process exemplified in example 3, the compound of formula IV,
• the water immiscible organic solvent is selected from the group consisting OfC 1-4 halogenated hydrocarbon, more preferably, either dichloroethane or dichloromethane, most preferably, dichloroethane.
• the organic base in the coupling step is commercial.
• the organic base in the coupling step is selected from the group consisting of pyrimidine and purine derivatives.
• the pyrimidine derivative is cytosine, uracil or thymine.
• a preferred purine derivative is either guanine or adenine.
• the base is a protected base in which each oxygen atom is protected with a protecting group.
• the base is a protected base in which each oxygen atom is protected with a protecting group.
• the protected base is selected from the group consisting of 2-O-trimethylsilylcytosine, 2-O-trimethyl-N- trimethylsilylacetylcytosine, 2,4-bis-O-trimethylsilyluracil, 2,4-bis-O-trimethylsilylthymine, and 6-O-trimethylsilylguanine.
• the protected base is 2,4-bis-O-trimethylsilyluracil.
• the Lewis acid is TiCl 4 , AlCl 3 , BF 3 , ZnCl 2 , SnCl 2 or SnCl 4 , more preferably, SnCl 4 .
• the Lewis acid is used in an amount of 1.5 mole equivalent to 6 mole equivalent per mole equivalent of the compound of formula FV.
• the mixture is heated to a temperature of about 6O 0 C to about
• the reaction is maintained at a temperature of about 6O 0 C to about
• the isomeric ratio is fixed, and the reaction can be stopped by quenching.
• the observed ec. ⁇ ratio in 3,5-dibenzoate-2,2-difluoro-uridine of the formula Ia is not determined by the initial ratio of anomers in the starting sugar, but is driven by the nature of the catalyst and by the reaction solvent.
• the conversion is preferably measured by HPLC.
• the mixture is cooled to a temperature of about 25°C to about 2O 0 C, prior to recovering of the product.
• quenching is done using a saturated aqueous solution of potassium or sodium bicarbonate, more preferably, potassium bicarbonate.
• the 2-deoxy-3,5-dibenzoate-2,2-difluoro-uridine,of the formula Ia may be recovered from the reaction mixture by filtering the suspension obtained after quenching, followed by washing the filtrate with a saturated sodium bicarbonate solution and concentrating under reduced pressure.
• the present invention provides a process for preparing Gemcitabine comprising preparing 3,5-dibenzoate-2,2-difluoro-uridine of the formula Ia, as described above, and further converting it to Gemcitabine, for example, according to processes known in the art, such as the ones described in J. Chem. Soc. Perkin Trans. 1, 1982, 1171, J. Org. ii> C T - ⁇ ⁇ ' Lu H Cl 1 K / H-H- ; 51& ie J
• the present invention further provides the novel compound, 2-deoxy-3,5- dibenzoate-2,2-difluoro-uridine of the formula Ia.
• the present invention also provides 2-deoxy-3,5-dibenzoate-2,2-difluoro- uridine of the formula Ia having ⁇ / ⁇ ratio of about 1 :4 to about 1 :6, as determined by HPLC.
• the 2-deoxy-3,5-dibenzoate-2,2-difluoro-uridine of the formula Ia of the present invention is characterized by an 1 H-NMR spectrum having peaks at about 4.85-4.55, 4.85, 5.25, 5.77, 5.95-5.80, 6.37, 6.60, 7.75-7.42, 7.90, 7.95-8.10 and 11.65 ppm.
• the 1 H-NMR spectrum for this compound is illustrated in Figure 1.
• the present invention provides the novel ⁇ isomer of 2-deoxy-3,5-dibenzoate-
• Ia- ⁇ of the present invention is characterized by an 1 H-NMR spectrum having peaks at about 4.92-4.85, 5.77, 5.95-5.85, 6.37, 7.80-7.42, 7.90, 8.10 and 11.65 ppm.
• the 1 H-NMR spectrum of this compound is illustrated in Figure 2.
• the difluoro sugar derivative was dissolved in 20 to 30 volumes of solvent, then 1.5 to 4.5 equivalents of 2,4-bis-O-trimethylsilyluracil and 2 to 4.5 equivalents of Sn (II) or (IV) salts were added at room temperature.
• the mixture was heated at temperatures between 20°C and 105°C, and the reaction was monitored by HPLC. When the desired conversion was observed, the mixture was cooled to room temperature, and then a saturated sodium bicarbonate solution was added. The mixture was filtered, and the filtrate was concentrated to dryness.
• the crude mixture of stereoisomers was triturated in heptane/ethyl acetate and filtered to yield pure beta anomer as a white solid.
• the suspension was filtered over a pad of Celite eluting with 100 ml of dichloromethane.
• the filtrate was washed with 20 ml of saturated sodium bicarbonate solution, dried over Na 2 SO 4 , and filtered and concentrated under reduced pressure to obtain an off-white foam.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Biochemistry (AREA)
• Health & Medical Sciences (AREA)
• Molecular Biology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biotechnology (AREA)
• Genetics & Genomics (AREA)
• Saccharide Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (1)

Family

ID=36147231

Family Applications (1)

Country Status (10)

Cited By (5)

Families Citing this family (1)

Citations (2)

Family Cites Families (10)

• 2005
  • 2005-12-08 KR KR1020077012245A patent/KR20070073958A/ko not_active Ceased
  • 2005-12-08 WO PCT/US2005/044369 patent/WO2006063105A1/en not_active Ceased
  • 2005-12-08 MX MX2007006837A patent/MX2007006837A/es unknown
  • 2005-12-08 CA CA002586687A patent/CA2586687A1/en not_active Abandoned
  • 2005-12-08 TW TW094143372A patent/TW200634022A/zh unknown
  • 2005-12-08 JP JP2006552382A patent/JP2007522151A/ja active Pending
  • 2005-12-08 US US11/298,359 patent/US20060173174A1/en not_active Abandoned
  • 2005-12-08 EP EP05853313A patent/EP1819718A1/en not_active Withdrawn
  • 2005-12-08 CN CNA2005800423787A patent/CN101076535A/zh active Pending
• 2007
  • 2007-06-05 IL IL183702A patent/IL183702A0/en unknown

Patent Citations (2)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events