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WO2016112746A1 - Procédé de préparation de dérivés de phosphate de ribofuranose - Google Patents

Procédé de préparation de dérivés de phosphate de ribofuranose Download PDF

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Publication number
WO2016112746A1
WO2016112746A1 PCT/CN2015/095524 CN2015095524W WO2016112746A1 WO 2016112746 A1 WO2016112746 A1 WO 2016112746A1 CN 2015095524 W CN2015095524 W CN 2015095524W WO 2016112746 A1 WO2016112746 A1 WO 2016112746A1
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Prior art keywords
reaction
preparation
formula
action
under
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PCT/CN2015/095524
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English (en)
Chinese (zh)
Inventor
李泽标
丁海明
严军
戴宇
顾文超
张兆国
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Nantong Changyoo Pharmatech Co Ltd
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Nantong Changyoo Pharmatech Co Ltd
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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
    • C07H1/02—Phosphorylation
    • 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
    • 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
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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 relates to a preparation method of a furan ribose phosphate derivative, and belongs to the field of medicinal chemical synthesis.
  • Hepatitis C virus (referred to as hepatitis C, hepatitis C) is a viral hepatitis caused by hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • the global hepatitis C infection rate is about 3%, about 180 million people are infected with HCV, and about 35,000 new cases of hepatitis C are reported each year.
  • Hepatitis C is globally prevalent and can cause chronic inflammation, necrosis and fibrosis in the liver. 1% to 5% of 100 patients can develop cirrhosis or even hepatocellular carcinoma (HCC) and die.
  • HCC hepatocellular carcinoma
  • Peg-IFN peginterferon
  • RBV ribavirin
  • DAAs direct antiviral drugs
  • Sofosbuvir is a prodrug of a fluorine-containing nucleotide analogue and has a strong inhibitory effect on hepatitis C virus (HCV) NS5B polymerase. It can be used as a component in the treatment of chronic hepatitis C (CHC) antiviral combination therapy.
  • HCV genotype 2 GT2
  • HCV genotype 3 GT3
  • sofosbuvir only needs to be combined with RBV, becoming the world's first all-oral treatment without the use of interferon (IFN). Infected patients with HCV genotypes 1 and 4 must be associated with RBV and Peg-IFN is used in combination.
  • Sofosbuvir is a ribofuran phosphate derivative
  • the English name is Sofosbuvir
  • the Chinese name is N-[(S)-2-(S)-(2R,3R,4R,5R)-5-(2,4-two Oxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoramido Isopropyl propionate
  • the structural formula is N-[(S)-2-(S)-(2R,3R,4R,5R)-5-(2,4-two Oxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoramido Isopropyl propionate
  • sofosbuvir At present, most of the preparation methods of sofosbuvir have the following disadvantages: the yield of the side chain fragment of the main chain is low, the product is not easy to be purified, and the quality of the subsequent reaction is affected; the process route is long and the operation is cumbersome; the solvent of the material used is large and difficult to recycle; The yield of the finished product of sofosbuvir is low, the content of isomer is too large, and the purity is not easy to control.
  • a preparation method of a furan ribose phosphate derivative wherein the preparation steps include:
  • the intermediate formula 2-2 and the benzoylcytosine derivative are subjected to a docking reaction under the action of a condensing agent;
  • the intermediate formula 2-5 is docked with the formula 1 under the action of a format reagent to obtain Sofosbuvir.
  • the substituted phenol is one of 4-chlorophenol, 4-bromophenol, 4-nitrophenol or perfluorophenol;
  • the base is in DIPEA, triethylamine or piperidine One;
  • the reaction temperature is -78 to 0 ° C;
  • the reaction solvent is dichloromethane, tetrahydrofuran, toluene or diethyl ether.
  • step a the crude intermediate formula 1 obtained after the docking reaction is subjected to a purification step to obtain a fine product
  • the solvent used in the purification step is one or more of methyl tert-butyl ether, n-hexane, ethyl acetate or isopropyl ether.
  • the solvent used in the purification step is one or more of methyl tert-butyl ether, n-hexane, ethyl acetate or isopropyl ether.
  • the solvent used in the purification step is one or more of methyl tert-butyl ether, n-hexane, ethyl acetate or isopropyl ether.
  • the solvent used in the purification step is one or more of methyl tert-butyl ether, n-hexane, ethyl acetate or isopropyl ether.
  • the solvent used in the purification step is one or more of
  • the strong reducing agent is lithium tri-tert-butoxyaluminum hydride, RED-AL toluene solution or DIBAL-H solution; the reaction temperature is -30 to 30 ° C; the ether solvent is Tetrahydrofuran or diethyl ether.
  • the base is triethylamine, DIPEA or DMAP; the reaction temperature is -10 to 30 ° C; and the reaction solvent is dichloromethane, toluene or isopropyl ether.
  • step d hexamethyldisilazane or N,O-bis(trimethylsilyl)acetamide is added as a hydroxy protecting agent;
  • the condensing agent is tin tetrachloride or trifluoromethanesulfonic acid Trimethylsilyl ester;
  • the reaction temperature is -10 to 100 ° C;
  • the reaction solvent is dichloromethane or acetonitrile.
  • the organic acid is glacial acetic acid or glacial acetic acid; and the reaction temperature is 30 to 120 °C.
  • the alkali reagent is sodium methoxide or ammonia methanol; the reaction temperature is 0 to 30 ° C; the reaction solvent is methanol;
  • the format reagent is t-butyl magnesium chloride; the reaction temperature is -50 to 30 ° C; and the reaction solvent is tetrahydrofuran, toluene, DMF or DMSO.
  • the invention has the advantages of starting from the easily available (2R)-2-deoxy-2-fluoro-2-methyl-D-erythro-olithionic acid GAMMA-lactone 3,5-dibenzoate
  • the raw materials are synthesized in six steps, and the route is short; the purity of each intermediate is easy to control, which is beneficial to control the impurity content; the yield of the raw materials and the intermediate formula 1 is high, and the excessive loss of materials is avoided;
  • the operation is simple, the solvent can be recycled and used, and the pollution is small; the prepared sofosbuvir has high purity, the impurities are easy to control, and the process is suitable for industrial production.
  • Figure 1 is a process road diagram of the present invention.

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de dérivés de phosphate de ribofuranose, les étapes de préparation de celui-ci consistant à : coupler des produits de départ de chlorhydrate d'isopropyl-L-alanine, de dichlorophosphate de phénol et de phénol substitué sous l'action d'un alcali ; réduire un groupe carbonyle en groupe hydroxyle alcoolique en traitant de l'acide (2R)-2-désoxy-2-fluoro-2-méthyl-D-érythropentonique-gamma lactone-3,5-dibenzoate avec un agent de réduction fort dans le solvant de dichlorométhane ou des éthers ; faire réagir l'intermédiaire de formule 2-1 avec du chlorure de p-toluènesulfonyle sous l'action d'un alcali pour obtenir du p-toluènesulfonate ; coupler l'intermédiaire de formule 2-2 avec un dérivé de benzoylcytosine sous l'action d'un agent de condensation ; convertir la cytosine de l'intermédiaire de formule 2-3 en uracile sous l'action d'un acide organique ; éliminer le benzoyle, agissant comme groupe protecteur, de l'intermédiaire de formule 2-4 sous l'action d'un réactif alcalin ; et coupler l'intermédiaire de formule 2-5 avec la formule 1 sous l'action d'un réactif de Grignard afin d'obtenir le sofosbuvir.
PCT/CN2015/095524 2015-01-16 2015-11-25 Procédé de préparation de dérivés de phosphate de ribofuranose Ceased WO2016112746A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510022269.4A CN104610404B (zh) 2015-01-16 2015-01-16 一种呋喃核糖磷酸酯衍生物的制备方法
CN201510022269.4 2015-01-16

Publications (1)

Publication Number Publication Date
WO2016112746A1 true WO2016112746A1 (fr) 2016-07-21

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WO (1) WO2016112746A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113105329A (zh) * 2021-04-22 2021-07-13 成都道合尔医药技术有限公司 一种(e)-甲酯3-(3,5-二氟-4-甲酰基苯基)丙烯酸的合成方法
WO2022088161A1 (fr) * 2020-11-02 2022-05-05 南京正大天晴制药有限公司 PROCÉDÉ DE PRÉPARATION D'UN COMPOSÉ β-GLYCOSIDE À HAUTE STEREOSÉLECTIVITÉ
CN115433194A (zh) * 2022-09-13 2022-12-06 上海毕得医药科技股份有限公司 一种六氢-3aH-呋喃[2,3-c]吡咯-3a-羧酸甲酯类衍生物的合成方法
CN115724889A (zh) * 2022-11-17 2023-03-03 中国药科大学 一类核苷衍生物及其制备方法与用途
CN116554237A (zh) * 2023-04-20 2023-08-08 安徽大学 一种氟代核糖中间体的制备方法与应用

Families Citing this family (15)

* Cited by examiner, † Cited by third party
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CN104610404B (zh) * 2015-01-16 2016-04-06 南通常佑药业科技有限公司 一种呋喃核糖磷酸酯衍生物的制备方法
CN106146588A (zh) * 2015-03-26 2016-11-23 常州制药厂有限公司 一种索非布韦的制备方法
CN104829672B (zh) * 2015-05-19 2018-03-13 江苏福瑞生物医药有限公司 一种药物中间体的合成方法
CN105061535A (zh) * 2015-09-02 2015-11-18 江苏科本医药化学有限公司 一种索非布韦中间体的合成方法
CN106565805B (zh) * 2015-10-10 2020-04-14 常州市勇毅生物药业有限公司 一种索氟布韦的制备方法
CN105503983B (zh) * 2015-12-17 2019-06-28 江苏阿尔法药业有限公司 索菲布韦中间体及其衍生物的制备方法
CN105461775B (zh) * 2015-12-24 2018-03-13 江苏阿尔法药业有限公司 一种索非布韦的制备方法
CN105566422B (zh) * 2015-12-29 2019-06-25 江苏阿尔法药业有限公司 索菲布韦中间体或其衍生物的制备方法
CN105503787A (zh) * 2015-12-31 2016-04-20 阜阳欣奕华材料科技有限公司 一种索非布韦中间体的纯化方法
CN105646626B (zh) * 2016-02-24 2018-04-24 贵州理工学院 一种高收率索氟布韦的合成方法
CN105859811A (zh) * 2016-05-05 2016-08-17 精华制药集团南通有限公司 一种(2’r)-2’-脱氧-2’-氟-2’-甲基脲苷的制备方法
CN105906673A (zh) * 2016-05-05 2016-08-31 精华制药集团南通有限公司 一种索非布韦中间体的合成方法
CN106083961B (zh) * 2016-07-13 2019-02-22 南通常佑药业科技有限公司 一种(2’r)-2’-脱氧-2’-氟-2’-甲基脲苷的制备方法
CN106810515A (zh) * 2017-02-06 2017-06-09 抚州市星辰药业有限公司 一种合成索非布韦的中间体化合物及其合成方法
CN107880089B (zh) * 2017-11-29 2021-02-12 昆明科麦德科技有限公司 一种糖类化合物的三甲基硅烷化方法

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CN104829672A (zh) * 2015-05-19 2015-08-12 江苏福瑞生物医药有限公司 一种药物中间体的合成方法

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MX355708B (es) * 2012-05-22 2018-04-27 Idenix Pharmaceuticals Llc Compuestos de d-aminoacidos para enfermedades del higado.
CN103848876B (zh) * 2013-03-25 2016-05-11 安徽贝克联合制药有限公司 一种核苷磷酰胺前药及其制备方法和其应用

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WO2008045419A1 (fr) * 2006-10-10 2008-04-17 Pharmasset, Inc. Préparation de nucléosides de ribofuranosylpyrimidines
WO2010135569A1 (fr) * 2009-05-20 2010-11-25 Pharmasset, Inc. Ester de n-[(2 ' r) -2' -désoxy-2' -fluoro-2' -méthyl-p-phényl-5' -uridylyl]-l-alanine 1-méthyléthyle et son procédé de production
CN104610404A (zh) * 2015-01-16 2015-05-13 南通常佑药业科技有限公司 一种呋喃核糖磷酸酯衍生物的制备方法
CN104829672A (zh) * 2015-05-19 2015-08-12 江苏福瑞生物医药有限公司 一种药物中间体的合成方法

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022088161A1 (fr) * 2020-11-02 2022-05-05 南京正大天晴制药有限公司 PROCÉDÉ DE PRÉPARATION D'UN COMPOSÉ β-GLYCOSIDE À HAUTE STEREOSÉLECTIVITÉ
CN113105329A (zh) * 2021-04-22 2021-07-13 成都道合尔医药技术有限公司 一种(e)-甲酯3-(3,5-二氟-4-甲酰基苯基)丙烯酸的合成方法
CN113105329B (zh) * 2021-04-22 2023-10-03 成都道合尔医药技术有限公司 一种(e)-甲酯3-(3,5-二氟-4-甲酰基苯基)丙烯酸的合成方法
CN115433194A (zh) * 2022-09-13 2022-12-06 上海毕得医药科技股份有限公司 一种六氢-3aH-呋喃[2,3-c]吡咯-3a-羧酸甲酯类衍生物的合成方法
CN115433194B (zh) * 2022-09-13 2023-06-23 上海毕得医药科技股份有限公司 一种六氢-3aH-呋喃[2,3-c]吡咯-3a-羧酸甲酯类衍生物的合成方法
CN115724889A (zh) * 2022-11-17 2023-03-03 中国药科大学 一类核苷衍生物及其制备方法与用途
CN116554237A (zh) * 2023-04-20 2023-08-08 安徽大学 一种氟代核糖中间体的制备方法与应用

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