WO2020140559A1 - Dérivé du 5-désoxy-d-ribose - Google Patents

Dérivé du 5-désoxy-d-ribose Download PDF

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Publication number
WO2020140559A1
WO2020140559A1 PCT/CN2019/112065 CN2019112065W WO2020140559A1 WO 2020140559 A1 WO2020140559 A1 WO 2020140559A1 CN 2019112065 W CN2019112065 W CN 2019112065W WO 2020140559 A1 WO2020140559 A1 WO 2020140559A1
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WIPO (PCT)
Prior art keywords
deoxy
reaction
ribose
derivative
chloroform
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Application number
PCT/CN2019/112065
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English (en)
Chinese (zh)
Inventor
张贵民
白文钦
郑艺
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山东新时代药业有限公司
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Publication of WO2020140559A1 publication Critical patent/WO2020140559A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
    • 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
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/08—Deoxysugars; Unsaturated sugars; Osones
    • 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 present invention belongs to the field of pharmaceutical synthesis, and specifically relates to a 5-deoxy-D-ribose derivative and its preparation method and use.
  • capecitabine (capecitabine)
  • the chemical name is 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl] cytidine
  • the structural formula is shown in formula I:
  • Capecitabine is a new 5-fluorocytosine prodrug developed by Roche, is an oral cytotoxic agent with selective activity on tumor cells; it is not cytotoxic in itself, through a unique three Step enzymatic reaction, converted into 5-fluorouracil (5-Fu) in tumor cells to play a highly selective anti-tumor effect, has obvious cell targeting and simulated pharmacokinetic characteristics of continuous 5-Fu intravenous drip, It has strong activity on many solid tumors. It was approved by the US FDA in September 1998 and is clinically used to treat advanced primary or metastatic breast cancer that is ineffective against drugs such as paclitaxel and doxorubicin. It was launched in Japan in April 2003 with the same indications. In 2001, the FDA approved this product for the treatment of metastatic colorectal cancer. Capecitabine can also be used in combination with a variety of drugs, which has a good effect.
  • the synthetic route of capecitabine mainly includes the following: [0007] Route One; [Nobou Shimma etal, Bioorganic & Medicinacal Chemistry, 2000
  • CN102977169A discloses using anhydrous sodium carbonate or anhydrous potassium carbonate as a base, quaternary ammonium salt as a phase transfer catalyst, 4-substituted pyridine as a catalyst, 2 / 3 / -di-0-acetyl V-deoxy-5 -The amidation reaction between fluorocytidine and n-pentyl chloroformate gives 2 / 3 / -di-0-acetyl-5 / -deoxy-5-fluoro-N4-(pentyloxycarbonyl) cytidine.
  • CN104744537A also improves the synthesis of intermediate 2 catalyzed by dimethylaminopyridine using potassium carbonate or sodium carbonate as the acid binding agent. This method does not explain much about the three-dimensional configuration of the product.
  • the method uses compound 3 as a starting material, protected by a hydroxyl group to form a compound of formula 4, and then sulfonylated to generate a compound of formula 5, compound 5 is iodinated and then deiodinated with hypophosphorous acid or hypophosphite to obtain compound 2.
  • Compound 2 is then deisopropylated and acetylated to obtain compound 6, compound 6 is glycosylated, acylated at the N4-position and deprotected to obtain capecitabine. This route avoids the use of metal catalysts and reduces pollution.
  • This route takes 5'-deoxy-5-fluorocytidine as the starting material, protects two hydroxyl groups at the 2, 3 position with an acetyl group, and then reacts with n-pentyl chloroformate, followed by a methanol solution of sodium hydroxide Remove the protection in the middle to get the target product capecitabine.
  • the separation of intermediates in this route mostly uses column chromatography, which is not suitable for industrial production.
  • CN102241721A discloses the use of 1-0-acetyl-2,3,5-tri-benzoyl> 0-ribose and [(n-pentyloxy)carbonyl] 5-fluorocytosine for the reaction, the sugar 2,
  • the phenyl acyl group at the 3, 5 position, especially the introduction of the large group at the 5 position can effectively avoid the generation of the oc isomer, but in the subsequent reaction deoxygenation of the sugar at the 5 position is required, and the yield is very low in actual production , The cost is very high, not suitable for industrial production.
  • the present invention overcomes the shortcomings of the prior art, and provides a 5-deoxy-D-ribose derivative (m) and a preparation method thereof.
  • m 5-deoxy-D-ribose derivative
  • the content ratio of P: a is greatly improved compared with the existing technology, and the yield and purity are improved, which is suitable for industrial production. Solution to the problem
  • the present invention provides a 5-deoxy-D-ribose derivative (m), the derivative structural formula is as follows:
  • the compound can be used as a starting material to synthesize capecitabine, and at the same time discloses the preparation method of the 5-deoxy-D-ribose derivative (m).
  • the preparation method includes the following steps:
  • the catalyst is one of concentrated sulfuric acid, p-toluenesulfonic acid, acetic acid, preferably concentrated sulfuric acid; the molar ratio of the intermediate n and the catalyst is 1: 0.2 ⁇ 1: 0.4; dropping catalyst and maintaining the reaction Temperature -20°C ⁇ 10 oc
  • the reaction solvent in this step is one or two of dichloromethane and chloroform; the feeding molar ratio of intermediate n and acetic anhydride is 1: 1.2 to 1: 1.6, preferably 1: 1.3 to 1: 1.4 .
  • the preparation method of the intermediate II includes the following steps:
  • Step a 5-deoxy-D-ribose is dissolved in anhydrous methanol solution, under the action of strong acid methanol solution, to generate intermediate I;
  • Step b Under basic conditions, Intermediate I is dissolved in a solvent and reacts with the Fmoc-Cl solution to produce protected products of the 2 and 3 hydroxyl groups, namely Intermediate n;
  • the reaction route is as follows:
  • the reaction temperature is room temperature, and the reaction time is 0.5 ⁇ 2 hours;
  • the strong acid is one of HC1 and sulfuric acid; preferably HC1;
  • the mass fraction of the strong acid in the strong acid methanol solution added dropwise is 1 ⁇ 1.2%;
  • the mass-volume ratio of the 5-deoxy-D-ribose and anhydrous methanol is 1: 8 ⁇ 1: 15, g/ml; preferably 1: 1 0 ⁇ 1: 12, g/ml.
  • the feed molar ratio of intermediate I and base is 1: 2.4 ⁇ 1: 2.6; the feed molar ratio of intermediate I and Fmoc-Cl is 1: 2.2 ⁇ 1: 2.4.
  • the reaction solvent is one or two of dichloromethane and chloroform; the organic base providing alkaline conditions is pyridine, DMAP, TMEDA, triethylamine, DIPEA one or Two kinds.
  • the temperature of the dropwise addition of Fmoc-Cl is -15°C ⁇ 10°C; the reaction temperature is room temperature.
  • step a of the present invention After the detection reaction is completed, add anhydrous pyridine to neutralize the excess acid; concentration under reduced pressure to remove the solvent to obtain intermediate I.
  • Step b After the reaction is completed, the reaction solution is poured into a mixture of ice and water, quickly stirred, allowed to stand, and the liquid is separated. The organic layer is washed with 5% hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated saline solution, respectively. 2. Dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure; to obtain the double-protected product at the 2 and 3 hydroxyl groups as intermediate n.
  • the intermediate n reacts with acetic anhydride to form a 5-deoxy-D-ribose derivative (m), during post-treatment: after detecting the completion of the reaction, the reaction solution Pour into a mixture of ice and water, then add chloroform or dichloromethane to extract, the extract is washed with saturated sodium bicarbonate solution until neutral, and then washed with saturated brine; dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, the remaining Under rapid stirring, add water dropwise, stir and crystallize, filter, wash with ether, and dry under reduced pressure to obtain an off-white solid as a derivative of 5-deoxy-D-ribose (m).
  • the temperature when adding water dropwise is 0°C ⁇ 5°C; the volumetric mass ratio of adding water dropwise and intermediate n is 10: 1-12: 1
  • the 5-deoxy-D-ribose derivative (m) can be used to synthesize capecitabine:
  • a method for preparing a 5-deoxy-D-ribose derivative (m) is provided.
  • the method is simple to operate, has high product yield, good purity, does not require special equipment, and is suitable for industrial production.
  • Liquid chromatograph Waters e2695 high performance liquid chromatograph
  • Chromatography column Ajer Venusil XBP-C18 column (4.6 250mm, 5
  • Test solution Take an appropriate amount of 5-deoxy-D-ribose derivative (m), place it in a 25ml measuring flask, use 80% acetonitrile water as the mobile phase, add an appropriate amount, dissolve and dilute to the mark with ultrasound, shake well , Filtered, you get it.
  • test solution 20ol Precisely measure the test solution 20ol, inject it into the liquid chromatograph, and record the chromatogram to the main peak m-2 peak retention time 3.0 times.
  • the main peak of the chromatogram of the test solution is calculated according to the normalization method.
  • the fat was quickly poured into 6L of ice water, extracted with chloroform, and allowed to stand for liquid separation; the organic phase was neutralized with a saturated aqueous solution of NaHCO 3 to neutrality, and the organic phase was washed with saturated brine, anhydrous Na 2 S0 4 Dry the organic phase, evaporate the solvent under reduced pressure, and cool the residue to 0°C ⁇ 5°C. Under rapid stirring, add 10670ml of purified water dropwise and stir for 5 hours.
  • the desiccant was removed by filtration, and the solvent was concentrated under reduced pressure to obtain a white solid as 5'-deoxy-2', 3'-diacetyl-5-fluorocytosine.
  • the yield was 78.0%
  • the HPLC purity was 9 6.1%
  • the a isomer was 2%
  • the N-isomerization impurity was 0.13%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne un dérivé du 5-désoxy-D-ribose (III), qui, lors de l'utilisation de ce dérivé (III) pour préparer de la capécitabine, permet une bonne stéréosélectivité et un rendement élevé. L'invention concerne en outre un procédé de préparation du dérivé, le procédé de préparation comprenant : une étape a, consistant à réaliser une oxyméthylation du groupe 1-hydroxyl du 5-désoxy-D-ribose ; une étape b, consistant à protéger les groupes 2-, 3-hydroxyl avec du Fmoc- ; et enfin une étape consistant à protéger le groupe 1 par acétylation. Le procédé est simple et pratique à utiliser, ne nécessite pas d'équipement spécial, et est approprié pour une production industrielle.
PCT/CN2019/112065 2018-12-30 2019-10-19 Dérivé du 5-désoxy-d-ribose WO2020140559A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811648376.8A CN111377981B (zh) 2018-12-30 2018-12-30 一种5-脱氧-d-核糖衍生物
CN201811648376.8 2018-12-30

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Publication Number Publication Date
WO2020140559A1 true WO2020140559A1 (fr) 2020-07-09

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CN (1) CN111377981B (fr)
WO (1) WO2020140559A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008145403A1 (fr) * 2007-06-01 2008-12-04 Synthon B.V. Procédés se rapportant à la fabrication de la capécitabine
WO2009086687A1 (fr) * 2008-01-03 2009-07-16 Nanjing Zhongshi Chemical Co., Ltd. Procédé de synthèse de la décitabine
CN102070679A (zh) * 2010-12-24 2011-05-25 齐鲁制药有限公司 1-乙酰氧基-2-脱氧-3，5-二-o-芴甲氧羰酰基-d-呋喃核糖及应用
CN103288905A (zh) * 2012-02-22 2013-09-11 北京博时安泰科技发展有限公司 一种合成卡培他滨的新工艺
CN103739636A (zh) * 2014-01-09 2014-04-23 山东新时代药业有限公司 一种地西他滨中间体的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008145403A1 (fr) * 2007-06-01 2008-12-04 Synthon B.V. Procédés se rapportant à la fabrication de la capécitabine
WO2009086687A1 (fr) * 2008-01-03 2009-07-16 Nanjing Zhongshi Chemical Co., Ltd. Procédé de synthèse de la décitabine
CN102070679A (zh) * 2010-12-24 2011-05-25 齐鲁制药有限公司 1-乙酰氧基-2-脱氧-3，5-二-o-芴甲氧羰酰基-d-呋喃核糖及应用
CN103288905A (zh) * 2012-02-22 2013-09-11 北京博时安泰科技发展有限公司 一种合成卡培他滨的新工艺
CN103739636A (zh) * 2014-01-09 2014-04-23 山东新时代药业有限公司 一种地西他滨中间体的制备方法

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CN111377981A (zh) 2020-07-07
CN111377981B (zh) 2023-03-17

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