WO2016110761A1 - Procédé de production de 1-β-d-arabinofuranosylcytosine et de 2,2'-o-cyclocytidine - Google Patents

Procédé de production de 1-β-d-arabinofuranosylcytosine et de 2,2'-o-cyclocytidine Download PDF

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Publication number
WO2016110761A1
WO2016110761A1 PCT/IB2015/059809 IB2015059809W WO2016110761A1 WO 2016110761 A1 WO2016110761 A1 WO 2016110761A1 IB 2015059809 W IB2015059809 W IB 2015059809W WO 2016110761 A1 WO2016110761 A1 WO 2016110761A1
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compound
group
hydroxide
pharmaceutically acceptable
process defined
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Khashayar Karimian
Ahmad YARI
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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
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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 refers to a synthetic process for the preparation of 2,2'-anhydro-l-P- D-arabinofuranosylcytosine hydrochloride as well as ⁇ - ⁇ -D-arabinofuranosylcytosine or cytarabine or Ara-C starting from cytidine, which is obtained in two steps.
  • Cytarabine which is also chemically known as 4-amino-l-[(2R,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrim- idin-2- one and cytosine arabinoside, is a chemotherapy agent used mainly in the treatment of cancers of white blood cells such as acute myeloid leukemia (AML) and non-Hodgkin lymphoma. It kills cancer cells by interfering with DNA synthesis. Cytarabine has the following chemical structure:
  • Hoffer U.S. Pat. No. 3.721.664 explains a process for the preparation of cytosine nucleoside by a glycolysation reaction between silylated cytosine and acylated sugar halide. The synthesis is accomplished at a temperature of about 120-170 °C and utilizing at least 2 moles of the silylated cytosine in which process two different isomers ( ⁇ + ⁇ ) of Ara- C are formed.
  • Beranek et al Nucleic Acid Chemistry, Vol. 1, 249, Edited by Townsend and Tipson, Wiley, N.Y. teach the production of cytarabine from cytidine. Specifically, cytidine is reacted with incremental amounts of diphenyl carbonate in the presence of DMF and water at 120 °C.
  • Roberts et al (J. Org. Chem. 32, 816 (1967)) teach the production of cytarabine from cytidine (or from 2'(3')-cytidylic acid). Specifically, cytidine is reacted with phosphoric acid at 80 °C for a period of 30 hours to produce a 2,2'-0-cyclocytidine analogue intermediate. This intermediate is then hydrolyzed at a pH of 9 utilizing lithium hydroxide to produce the 3',5'-diphosphate of cytarabine.
  • the diphosphate is then treated with magnesium chloride, ammonium chloride and concentrated ammonium hydroxide, and thereafter purified by column chromatography to yield pure cytarabine.
  • the overall yield is 53% based on the uncovered portion of starting cytidine.
  • Kanai et al (U.S. Pat. No. 3.755.296) describe preparation of arabinofuranosylcytosine.
  • the process comprises of reacting cytidine with a Vilsmeier-Haack reagent formed from an acid chloride such as thionyl chloride, phosphorus oxychloride or phosgene in the presence of DMF. Sulfurous acid was removed and then the pH was basified to 9 with ammonia. The solution was then acidified to pH 2 with hydrochloric acid. After treating with active charcoal and washing with water and elution with 50 percent ethanol containing 2 percent ammonia, the eluent was concentrated to dryness and treated with a column of ion exchange resin. In the end, the crystals of ⁇ - ⁇ -D-arabinofuranosylcytosine were obtained from ethanol to yield 70% of the titled compound. Inventors use a complicate, thionyl chloride, phosphorus oxychloride or
  • Cytidine hydrochloride is reacted with ethylene carbonate in the presence incremental amounts of ethylene carbonate at 150 °C for a period of 50 minutes. The resulting mixture was then dissolved in water and then the solution was passed through a column packed with active charcoal. Thereafter, the eluate was evaporated to dryness and the residue was recrystallized from water: ethanol mixture to obtain 2,2'-0-cyclocytidine hydrochloride. Thereafter, sodium hydroxide is added to an aqueous solution of 2,2'-0-cyclocytidine hydrochloride and followed by extraction with methanol and crystallization from water to obtain cytosine nucleoside with the overall yield of 35%.
  • Use of a column packed with active charcoal to purify the product, as well as large quantity of water used as eluent (which is difficult to evaporate) are cumbersome, expensive and difficult to carry out on commercial scale.
  • Sowa et al (Bull. Chem. Soc. Jap., 48, 505-507 (1975) teach the production of cytarabine from 2,2'-0-cyclocytidine. Specifically, sodium hydroxide is added to an aqueous solution of 2,2'-0-cyclocytidine hydrochloride thereby raising the pH of the solution to 10. Thereafter, the solution is run through an acid ionic exchange resin followed by recrystallization of pure cytarabine from ethanol.
  • Inoue et al (U.S. Pat. No. 3.950.325) explains a process for producing cytarabine.
  • the process comprises reacting cytidine with a functional derivative of silicon such as silicon tetrachloride in acetic acid under reflux condition. After the reaction is complete, the mixture is concentrated under reduced pressure and the reside is dissolved in ice-water and pH raised to 12.5 utilizing aqueous sodium hydroxide. Thereafter, the solution passed through a column of an acidic ion exchange and eluted with aqueous ammonia. Finally, the eluate is concentrated under reduced pressure and the residue is crystallized from 50% ethanol to obtain cytarabine with the yield of 55%.
  • Meglio (E.P. Pat. No. 0.757.056 Al) teaches a process for the preparation of cytarabine from arabinofuranosyluracil.
  • the process comprises the reaction of ⁇ - ⁇ -D- arabinofuranosyluracil (Ara-U) under a pressure comprised between 8-18 bar and a temperature 130-140°C with hexamethyldisilazane and a C1-C3 acylamide, subsequently dry evaporating the resulting mixture and then treating the oily residue with methyl alcohol and aqueous ammonia, further dry evaporating and purifying said residual by percolating on an acidic resin, washing with water and subsequently eluting with ammonia, finally after evaporating a large volume of diluted ammonia, the oily product is made crystalline with methanol to obtained the titled compound with 77% yield. Even though the product is obtained in good yield, the process suffers from reduction of a large volume of water, utilizing
  • Kanai et al (U.S. Patent No. 3.595.853) teach the production of arabinofuranosylcytosine wherein cytidine is reacted with fuming nitric acid at -20 °C in the presence of phosphorous
  • 2,2' -O-cyclocytidine hydrochloride is obtained by reacting cytidine hydrochloride with ethylene carbonate at 130°C by precipitation of the pure product from the resulting mixture from a highly polar solvent such as alcohol, DMF, etc. at 0-20°C via a simple and inexpensive isolation technique with an acceptable yield.
  • Resulting 2,2' -O-cyclocytidine hydrochloride was converted to cytarabine utilizing lithium hydroxide in a protic solvent such as water, methanol, ethanol and a mixture of water and at least one other solvent miscible therewith and preferably methanol.
  • the crude cytarabine was purified using methanol to obtain pharmaceutical grade product.
  • the present invention provides a process for preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof:
  • Ri is selected from the group comprising hydrogen, trityl, methoxytrityl, dimethoxytrityl, acetyl, a C 2 -C 6 alkylacyl group, a C 6 -C9 arylacyl group, allyl, 2,2,2- trichloroethyl, phosphates and salts thereof, tosyl and mesyl and the like;
  • W is selected from the group comprising -NH-CO- and -NH-C(NH 2 ) -;
  • Z is selected from the group comprising hydrogen, methyl and halide; and
  • Y is selected from the group comprising - N(H)- or O.
  • the process for producing a compound of Formula III can be used to produce 2,2'-0-cycloribonucleosides such as 2,2'-0-cyclocytidine, 2,2'-0-cyclouridine, 2,2'-0- cyclothymidine, or pharmaceutically acceptable salts thereof.
  • 2,2'-0- cycloribonucleosides may be prepared by reacting the appropriate nucleoside with ethylene carbonate. More preferably, this process is used to produce 2,2'-0-cyclocytidine by reacting cytidine and its salts thereof with at least 5 eq moles of ethylene carbonate.
  • the above-noted reaction can be conducted at a temperature comprised between 110 to 140°C and preferably at 130°C.
  • the most preferred starting material of Formula III for the process of producing a compound of Formula I is 2,2'-0-cyclocytidine in which Ri of Formula III is hydrogen.
  • the product of Formula I is cytarabine. It will of course be understood that the manner in which starting compound of Formula III is made is not particularly restricted as regards the process of making Formula I.
  • the base suitable for use in the process of producing a compound of Formula I is selected from the group comprising lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide and barium hydroxide.
  • the crude 2,2'-0-cyclonucleoside precursor product preferably, 2,2'-0-cyclocytidine, as well as the crude final products, preferably, Cytarabine and its analogues or pharmaceutically acceptable salts thereof, may be separated from the reaction mixture and purified using conventional techniques within the purview of a person skilled in the art.
  • crude 2,2'-0-cyclonueleoside may be suspended in a suitable polar solvent.
  • suitable polar solvents include alcohols, ketones and amides.
  • the most preferred solvent is selected from amides and preferably dimethy If oramide .
  • the process of producing a compound of Formula I is conducted in the presence of a protic solvent.
  • suitable protic solvents include water, methanol, ethanol and a mixture of water and at least one other solvent miscible therewith.
  • the most preferred solvent for use in this process is methanol.
  • the resulting final cytarabine solid may be suspended and agitated in a suitable medium to produce a purified product.
  • suitable medium include alcohol and mixtures containing alcohol and water.
  • the preferred alcohol for use is methanol.
  • a 500 ml three-necked flask was equipped with a mechanical stirrer and condenser and then charged with 157,52 g (1.79 mol) of ethylene carbonate and heated to 130°C with slow stirring.
  • 100 g (0.358 mol) cytidine hydrochloride was added into the flask in a period of 50 minutes.
  • the resulting suspension was stirred at 130°C for four hours and then the mixture was cooled to room temperature.
  • 250 ml dimethylformamide was cooled to 10°C and added to the resulting brown gummy precipitate and the resulting mixture was stirred at 10°C for two hours.
  • 2,2'-0-cyclocytidine hydrochloride 50 g, 0.191 mol was suspended in 500 ml methanol and stirred a reflux temperature. Then, 8.026 g (0.191 mol) lithium hydroxide monohydrate was added to the resulting suspension. Thereafter, the resulting yellow solution was stirred at reflux for 75 minutes. Then the reaction mixture was adjusted to pH 7-8 using concentrated hydrochloric acid. The resulting solution treated with active charcoal and the yellow filtrate was evaporated under reduced pressure to about 250 ml. Thereafter, the resulting solution was stirred at room temperature for an hour and then the precipitate was filtered and dried to yield 37 g of crude cytarabine (79% yield).

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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)

Abstract

Cette invention concerne un procédé simple et efficace de production de 1-β-D-arabinofuranosylcytosine ou de cytarabine, qui consiste à convertir un chlorhydrate de cytidine en chlorhydrate de 2,2'-anhydro-1-β-D-arabinofuranosylcytosine correspondant par réaction avec un carbonate d'éthylène. Le composé de chlorhydrate de 2,2'-O-cyclocytidine est hydrolysé en arabinofuranosylcytosine dans une condition basique pour obtenir la cytarabine qui est un agent antinéoplastique et antiviral connu.
PCT/IB2015/059809 2015-01-05 2015-12-20 Procédé de production de 1-β-d-arabinofuranosylcytosine et de 2,2'-o-cyclocytidine Ceased WO2016110761A1 (fr)

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IR13933011086 2015-01-05
IR139350140003011086 2015-01-05

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112552361A (zh) * 2020-12-30 2021-03-26 瀚晖制药有限公司 阿糖胞苷晶体、阿糖胞苷冻干粉剂及冻干方法
CN114736258A (zh) * 2022-04-18 2022-07-12 北京斯利安药业有限公司 盐酸阿糖胞苷的晶型及其制备方法和应用
CN117164646A (zh) * 2023-11-03 2023-12-05 广州市桐晖药业有限公司 一种阿糖胞苷的合成方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3856777A (en) * 1971-12-14 1974-12-24 Ajinomoto Kk Method of producing pyrimidine nucleoside derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3856777A (en) * 1971-12-14 1974-12-24 Ajinomoto Kk Method of producing pyrimidine nucleoside derivatives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112552361A (zh) * 2020-12-30 2021-03-26 瀚晖制药有限公司 阿糖胞苷晶体、阿糖胞苷冻干粉剂及冻干方法
CN114736258A (zh) * 2022-04-18 2022-07-12 北京斯利安药业有限公司 盐酸阿糖胞苷的晶型及其制备方法和应用
CN117164646A (zh) * 2023-11-03 2023-12-05 广州市桐晖药业有限公司 一种阿糖胞苷的合成方法

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