WO2019237297A1 - Procédés de préparation de composés/intermédiaires utiles dans le traitement d'infections virales - Google Patents

Procédés de préparation de composés/intermédiaires utiles dans le traitement d'infections virales Download PDF

Info

Publication number
WO2019237297A1
WO2019237297A1 PCT/CN2018/091196 CN2018091196W WO2019237297A1 WO 2019237297 A1 WO2019237297 A1 WO 2019237297A1 CN 2018091196 W CN2018091196 W CN 2018091196W WO 2019237297 A1 WO2019237297 A1 WO 2019237297A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
equivalents
employed
iii
Prior art date
Application number
PCT/CN2018/091196
Other languages
English (en)
Inventor
Koen Peeters
Cheng Yi Chen
Ulrich Georg Weigl
Ioannis Nicolaos Houpis
Sébastien Francois Emmanuel Lemaire
Hongjiao ZHANG
Simon Albert WAGSCHAL
Original Assignee
Janssen Pharmaceuticals, Inc.
Johnson & Johnson (China) Investment Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceuticals, Inc., Johnson & Johnson (China) Investment Ltd. filed Critical Janssen Pharmaceuticals, Inc.
Priority to PCT/CN2018/091196 priority Critical patent/WO2019237297A1/fr
Publication of WO2019237297A1 publication Critical patent/WO2019237297A1/fr

Links

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
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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

Definitions

  • the present invention relates to an improved process for preparing certain compounds (and/or intermediates) useful in the treatment of viral infections, e.g. HCV. More particularly, disclosed herein and methods/processes for preparing a phosphoramidate nucleotide analogue, which can be useful in treating diseases/conditions such as viral infections, e.g. HCV.
  • HCV Hepatitis C virus
  • Flaviviridae family of viruses in the hepacivirus genus is the leading cause of chronic liver disease worldwide. Recent estimates report the global hepatitis C prevalence at around 2.4%with up to 170 million people thought to be chronically infected. Although the development of diagnostics and blood screening has considerably reduced the rate of new infections, HCV remains a global health burden due to its chronic nature and its potential for long-term liver damage. It is now known that HCV has the ability to incorporate into the host’s genome.
  • the hepatitis C virus genome is a small positive-sense single stranded RNA enclosed in a nucleocapsid and lipid envelope. It consists of 9.6 kb ribonucleotides, which encodes a large polypeptide of about 3,000 amino acids (Dymock et al. Antiviral Chemistry &Chemotherapy 2000, 11, 79) . Following maturation, this polypeptide is processed into at least ten proteins. NS3/4A serine protease is responsible for the cleavage of the non-structural downstream proteins.
  • NS5A is a zinc-binding proline-rich hydrophilic phosphoprotein which has no apparent enzymatic activity yet has an important function mediating the interaction with other nonstructural viral and cellular proteins.
  • NS5B is an enzyme with polymerase activity that is involved in the synthesis of double-stranded RNA from the single-stranded viral RNA genome, which serves as the template.
  • NS3/4A serine protease, NS5A and NS5B polymerase are essential for viral replication, and inhibitors are important drug candidates for HCV treatment.
  • HCV is mainly transmitted by blood contact. Following initial acute infection, a majority of infected individuals develop chronic hepatitis because HCV replicates preferentially in hepatocytes, but is not directly cytopathic. Over decades, a considerable number of infected persons develop fibrosis, at least 30%develop cirrhosis, 1-4%develop hepatocellular carcinoma, and chronic HCV infection is the leading cause for liver transplantation. HCV is responsible for 50-76%of all liver cancer cases and two thirds of all liver transplants in the developed world. This and the number of patients involved has made HCV the focus of considerable medical research.
  • the main challenges lie in yield and reaction conditions, which can both be improved.
  • the main challenges lie in the selectivity at the phosphorous atom.
  • AL-335 is a single enantiomer with several chiral centres, and indeed the configuration at the phosphorous atom is absolute –the main challenge is the diastereoselectivity at the phosphorous (where it is desired, in order to increase productivity) to obtain as high a diastereoisomeric ratio as possible (so the desired S p : R p ratio is above 90: 10) .
  • 1.3 equivalents of a Grignard reagent were employed in the presence of THF at a temperature of between -10°C and 0°C, using 2 equivalents of the chloro-phosphoramidate side chain component.
  • the above-mentioned route has several disadvantages, for instance the selectivity at the phosphorous is 90: 10, and yield and reliability could also be improved. It is therefore an object of the invention to provide an alternative and/or improved process to preparing AL-355 and intermediates thereto. Manufacturing routes that are suitable for scale-up are particularly desired.
  • each PG independently represents a suitable silyl protecting group, and which process comprises reaction of a compound of formula (II)
  • each PG is as defined above, with a compound of formula (III)
  • a Grignard reagent compared to the compound of formula (II) , at least 1.5 equivalents of a Grignard reagent are employed in the presence of an appropriate solvent (e.g. a polar aprotic solvent, such as THF) at a temperature of between about -35°C to 0°C (e.g. between about -25°C to -5°C) ,
  • an appropriate solvent e.g. a polar aprotic solvent, such as THF
  • the process of the invention may be characterised in that the selectivity at the phosphorous atom of the compound of formula (I) so formed is greater than 90: 10, for instance greater than 95: 5 or about 97: 3 or higher.
  • the selectivity is greater than 20: 1 in favour of the (S) -configuration compared to the (R) -configuration (e.g. the selectivity is greater than 30: 1) at the phosphorous atom.
  • Another advantage is that the compound of formula (III) need not have any specific configuration at the phosphorous atom, and the selectivity in the desired compound of formula (I) can still be achieved.
  • each protecting group (represented by “PG” in the compounds of formula (I) and (II) ) may be any suitable silyl protecting group that can be attached to the hydroxy moieties of the relevant compound (s) .
  • PG Protective Groups in Organic Synthesis
  • Wiley-Interscience New York, 1999, by T.W. Green and P.G.M. Wuts, Carey and Sundberg, Chapter 13.1
  • each protecting group independently and together with the hydroxy moiety together may form a:
  • a silyl ether e.g. where PG represents -Si (R t1 ) (R t2 ) R t3 , wherein each of R t1 , R t2 and R t3 are independently selected from alkyl (e.g. C 1-6 alkyl) and aryl (e.g. phenyl) so forming for instance tri-alkyl silyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl ether or the like.
  • alkyl e.g. C 1-6 alkyl
  • aryl e.g. phenyl
  • each PG independently (together with the relevant hydroxy moiety) forms a silyl ether.
  • PG represents, in an embodiment, -Si (R t1 ) (R t2 ) R t3 , in which it is preferred that each of R t1 , R t2 and R t3 is as defined above and preferably independently represents alkyl, e.g. C 1-6 alkyl, and in a preferred embodiments each of these represents ethyl, so forming a -Si (ethyl) 3 group.
  • each PG in the compound of formula (II) (and hence in the compound of formula (II) so prepared) is the same (for instance, in an embodiment, both PG groups in each of formula (II) and (I) represent a -Si (ethyl) 3 group.
  • LG in the compound of formula (III) may represent any suitable leaving group, for instance halo.
  • the halo group is chloro.
  • At least one equivalent of compound of formula (III) is employed, compared to (or relative to) compound (II) .
  • at least 1.8 equivalents such as, in an embodiment, at least 2 equivalents (e.g. between 2 and 3 equivalents) are employed.
  • equivalents are referred to herein, it is meant molar equivalents.
  • Grignard agents that may be employed in the process of the invention include any suitable agent, for instance any suitable alkyl, vinyl or aryl-magnesium halide, where: the halide may be bromo, fluoro or chloro, and in an embodiment in this aspect of the invention, it is preferred that it is chloro; and in a preferred embodiment it is alkyl-magnesium halide in which the alkyl moiety is preferably C 1-6 alkyl (such as a branched C 3-6 alkyl group, e.g. isopropyl) .
  • the alkyl moiety is preferably C 1-6 alkyl (such as a branched C 3-6 alkyl group, e.g. isopropyl) .
  • At least 1.5 equivalents of Grignard reagent are employed. In an embodiment, between about 1.5 and 3 equivalents (e.g. between about 1.7 and 2.7 equivalents) of Grignard reagent are employed and in a further embodiment about 2.3 equivalents or about 2.65 equivalents are employed.
  • the process of the invention may be conducted in a suitable solvent.
  • the solvent is a polar aprotic solvent (such as an ether, for example tetrahydrofuran) .
  • the compound of formula (II) is first added to the solvent and then the Grignard reagent is added to it.
  • the Grignard reagent is added to such mixture over a period of time (e.g. over at least 10 minutes, for instance over at least 30 mins and can be added over about one hour or at least one hour, for instance on a large scale it can be added over a period of about 12 hours) .
  • the compound of formula (III) can then be added to the reaction mixture, for instance, in an embodiment, it can be added dropwise over a period of time.
  • such addition may be at the lower temperature of the range (e.g. -35°C or -25°C) and the reaction mixture so formed may be stirred for a period of time (e.g. over a period of at least one hour, for instance at least three hours (e.g. between three and ten hours or between three and six hours) , and in an embodiment might be over a period of about five hours) .
  • the reaction mixture is warmed up or allowed to warm (e.g.
  • the reaction can be warmed, quenched and the desired product separated (although it need not be isolated for use in the next step) .
  • the solvent employed in the process of the reaction may be removed and/or switched (e.g. to acetonitrile) , and may be used in that form directly in the next step.
  • the addition of reagents may also be changed without significantly impacting yield or selectivity.
  • a compound of formula (I) as prepared by (any of the embodiments of) the process of the invention to AL-335, which may involve removal of the protecting groups defined by PG.
  • silyl protecting groups may be removed using suitable acid conditions (e.g. using HCl) , for instance as described hereinafter.
  • suitable acid conditions e.g. using HCl
  • a process for preparing a pharmaceutical formulation comprising the preparation of AL-335 prepared as defined herein, followed by conversion to a suitable formulation (e.g. by bringing that product into contact with a suitable carrier, excipient and/or diluent, etc) .
  • a process to prepare a compound of formula (III) (e.g. in which LG represents chloro) as specified above (which process may be employed as a first step preceding the process described above to prepare the compound of formula (I) ) , which process comprises reaction of a compound of formula (IV)
  • reaction is performed at a temperature of -40°C or higher (for instance up to 20°C; but in an embodiment up to 10°C) , in the presence of a suitable base (for instance, at least 1.5 equivalents of an amine base) ,
  • this aspect of the process of the invention is conducted in the in the presence of a non-halogenated solvent (e.g. a polar aprotic solvent such as THF, MeTHF) .
  • a non-halogenated solvent e.g. a polar aprotic solvent such as THF, MeTHF
  • cyclohexane or the like is employed as a solvent.
  • base which is preferably an amine base (in an embodiment, a tertiary amine) such as triethylamine or diispropylamine/DIPEA (which base may be used in the number of equivalent specified hereinafter) .
  • amine base in an embodiment, a tertiary amine
  • the number of equivalents of base may be at least 1.5 equivalents (compared to the Compound of formula (IV) ) , for instance, in an embodiment, between 1.5 and 2.5 equivalents of base may be employed.
  • the base for instance the tertiary amine, e.g.
  • DIPEA may be added together or, in an embodiment, over a period of time e.g. at least 1 minute or longer, e.g. dropwise addition over 1 hour (addition, e.g. dropwise, over a period of more than 10 minutes, e.g. more than 30 minutes, are preferred embodiments) or longer, for instance, the addition time may be key to control the removal of the base.
  • HCl e.g. tertiary amine: HCl salt, which specifically may be triethylamine. HCl salt or DIPEA. HCl salt
  • HCl salt e.g. tertiary amine: HCl salt, which specifically may be triethylamine. HCl salt or DIPEA. HCl salt
  • This aspect of the process of the invention may be carried out in the presence of any suitable solvent or mixture of solvents.
  • the solvent may be a polar aprotic solvent (e.g. THF or MeTHF or the like) dichloromethane and/or a cycloalkane or a mixture of different cycloalkanes (e.g. cyclohexane) or any mixtures thereof.
  • the amount of solvent employed may be between 5V and 50V (although any suitable amount will suffice) , for instance between 10V and 30V, e.g. about 20V) .
  • the solvent may be a mixture of THF (e.g. about 10V) and cyclohexane (e.g. about 10V) .
  • the solvent that may be employed in this aspect of the invention may be added in portions, for example the compound of formula (IV) may first be dissolved in one portion of solvent (e.g. 10V THF) , the compound of formula (V) may be added, the base (e.g. tertiary amine base, such as triethylamine/DIPEA may then added, for instance over a period of time; see above) and after stirring for a period of time such as between 10 mins and 4 hours (e.g.
  • the second portion of solvent e.g. 10V cyclohexane
  • the reaction mixture stirred for a further period of time, e.g. between 10 mins and 4 hours (e.g. about 30 mins) .
  • This aspect of the process of the invention should also be carried out at a suitable temperature, within the range specified (-40°C or higher) , for instance, between -40°C and -20°C, e.g. between -40°C and -10°C, and in an embodiment between -20°C and 0°C (and in a very specific embodiment, at a temperature of about -10°C including -8°C; in this instance, the solvent employed in the process of the reaction may be added in stages/portions as indicated above and, for instance in an embodiment, this aspect of the process of the invention need not be carried out at the same temperature (although the range (s) mentioned herein will still apply) , for instance in the embodiment mentioned above where the solvent is added in portions/phases, during the first phase (e.g.
  • this part of the reaction may be carried out at a range between -20°C to 0°C, such as between -15°C to -5°C, e.g. about -10°C, then after the second portion of solvent (e.g. 10V cyclohexane) is added, the second phase may be carried out at a temperature range between -10°C to 10°C, such as between -5°C to 5°C, e.g. about 0°C.
  • solvent e.g. 10V cyclohexane
  • reaction time of this aspect of the process of the invention may be at least one hour, for instance between 1 and 5 (e.g. between 1 and 3 hours) .
  • each reaction phase may be between 15 mins and 2 hours, for instance about 30 mins.
  • the compound of formula (III) may be derivatized in order to prepare a compound, for which the yield may be measured.
  • the compound of formula (III) so formed may be brought into contact (e.g. the corresponding compound in which LG represents chloro) with an amine (e.g. a primary amine, such as n-propylamine) so forming for example an amine (e.g. an n-propylamine) adduct of a compound of formula (III) .
  • an amine e.g. a primary amine, such as n-propylamine
  • the number of equivalents of base may be modified, although at least 1.5 equivalents (compared to Compound 1) should be used, for instance between 1.5 and 2.5 equivalents of base may be employed
  • the base e.g. triethylamine
  • the base e.g. triethylamine
  • the base may be added together or, in an embodiment, over a period of time e.g. at least 1 minute or longer, e.g. dropwise addition over 1 hour (addition, e.g. dropwise, over a period of more than 10 minutes, e.g. more than 30 minutes, are preferred embodiments)
  • the amount of THF and cyclohexane can be varied (although 10V of each is preferred)
  • DCM dichloromethane
  • MeTHF Methyl ether
  • the temperature may be varied, although it should remain -40°C or higher, for instance, between about -20°C and 20°C
  • reaction time may be, in an embodiment, at least one hour, for instance between 1 and 3 hours
  • Compound 3 may be converted to the n-propylamine adduct in order to determine the yield.
  • IPC In Process Control
  • HPLC High Performance Liquid Chromatography
  • Compound 4 may be prepared in accordance with the procedures described in international patent application WO 2015/200216.
  • Compound 4 (1.0 equiv) was then dissolved in THF (10 L/kg) and cooled down to -25°C.
  • iPrMgCl (2M in THF) was added slowly over one hour and the resulting mixture was stirred for one hour.
  • the Compound 3 solution previously made (see above) was then added dropwise at -25°C and the mixture was stirred for 5h at that temperature before being warmed to -5°C and stirred for 10 additional hours at that temperature.
  • the reaction was warmed up to 5°C and an aqueous solution of NH 4 Cl (5L/kg -9 w/w%) was added slowly over 30 minutes.
  • At least one 1.5 equivalents of Compound 3 are employed, for instance at least 1.8 equivalents, such as, in an embodiment, at least 2 equivalents (e.g. between 2 and 3 equivalents)
  • any suitable Grignard reagent may be employed, such as iPrMgCl
  • At least 1.5 equivalents of Grignard agent is employed, e.g. between about 1.5 and 3 equivalents (e.g. between about 1.7 and 2.7 equivalents) ; in an embodiment about 2.3 equivalents or about 2.65 equivalents is employed
  • the temperature may be varied
  • Compound 5 250 mg was weighed and transferred (e.g. in a portion of acetonitrile) to a 50 ml volumetric flask. The sample was dissolved and diluted to volume with the diluent (acetonitrile) and mixed well. If needed, it may be sonicated to dissolve.
  • HPLC High Performance Liquid Chromatography
  • a similar HPLC technique may also be used to determine the diastereoselectivity of Compound 4 (although Compound 4 need not have any particular configuration at the phosphorous in the process of the invention) .
  • Compound 5 prepared above is essentially a compound of formula (I) as defined herein.
  • the relevant protecting group e.g. tri-alkyl-silyl group
  • may be cleaved off under appropriate conditions e.g. using acid conditions, e.g. HCl conditions, e.g. in between 2 to 2.6 equivalents
  • AL-335 also known as adafosbuvir:
  • Various conditions may also be used to crystallise the final product (for instance, crystallisation in a mix of solvents such as acetone/heptane.
  • Similar methods to those described herein may be used herein for the preparation of AL-335.
  • a process for preparing a product (AL-335) , which included one of more of the earlier steps of the processes of the invention as described herein, followed by conversion to AL-335 (e.g. by removing the protecting groups, e.g. the silyl protecting groups may be cleaved off, for isntance with acid under known reaction conditions) .
  • Such AL-335 may also be prepared in a form that is crystalline and hence there is further provided the step of converting AL-335 to a suitable form, e.g. by crystallising it (e.g. in a mixture of solvents as described herein) .
  • a process for preparing a pharmaceutical formulation which comprises a process for preparing AL-335 (or a form, e.g. a crystalline form of AL-335) as descibed herein (e.g. by using one or more of the process steps described herein, followed by conversion to AL-335) by bringing that product into contact with a pharmaceutically acceptable carrrier, excipient and/or diluent.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Virology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé amélioré de préparation du composé (I) : qui peut être utilisé dans la synthèse de AL-335 par ex. ; AL-355 est un inhibiteur nucléosidique de la polymérase NS3B, qui joue un rôle important dans la réplication du virus de l'hépatite C.
PCT/CN2018/091196 2018-06-14 2018-06-14 Procédés de préparation de composés/intermédiaires utiles dans le traitement d'infections virales WO2019237297A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2018/091196 WO2019237297A1 (fr) 2018-06-14 2018-06-14 Procédés de préparation de composés/intermédiaires utiles dans le traitement d'infections virales

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2018/091196 WO2019237297A1 (fr) 2018-06-14 2018-06-14 Procédés de préparation de composés/intermédiaires utiles dans le traitement d'infections virales

Publications (1)

Publication Number Publication Date
WO2019237297A1 true WO2019237297A1 (fr) 2019-12-19

Family

ID=68842494

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/091196 WO2019237297A1 (fr) 2018-06-14 2018-06-14 Procédés de préparation de composés/intermédiaires utiles dans le traitement d'infections virales

Country Status (1)

Country Link
WO (1) WO2019237297A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102459299A (zh) * 2009-05-20 2012-05-16 法莫赛特股份有限公司 N-[(2′r)-2′-脱氧-2′-氟-2′-甲基-p-苯基-5′-尿苷酰基]-l-丙氨酸1-甲基乙基酯及其制备方法
WO2014209979A1 (fr) * 2013-06-26 2014-12-31 Alios Biopharma, Inc. Nucléosides, nucléotides substitués et leurs analogues
CN105073766A (zh) * 2012-12-21 2015-11-18 艾丽奥斯生物制药有限公司 取代的核苷、核苷酸及其类似物
CN105829333A (zh) * 2013-10-11 2016-08-03 艾丽奥斯生物制药有限公司 取代的核苷、核苷酸及其类似物
CN106661076A (zh) * 2014-06-24 2017-05-10 艾丽奥斯生物制药有限公司 制备取代的核苷酸类似物的方法
CN105348320B (zh) * 2015-12-24 2018-01-02 江苏阿尔法药业有限公司 一种索非布韦中间体及其制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102459299A (zh) * 2009-05-20 2012-05-16 法莫赛特股份有限公司 N-[(2′r)-2′-脱氧-2′-氟-2′-甲基-p-苯基-5′-尿苷酰基]-l-丙氨酸1-甲基乙基酯及其制备方法
CN105073766A (zh) * 2012-12-21 2015-11-18 艾丽奥斯生物制药有限公司 取代的核苷、核苷酸及其类似物
WO2014209979A1 (fr) * 2013-06-26 2014-12-31 Alios Biopharma, Inc. Nucléosides, nucléotides substitués et leurs analogues
CN105829333A (zh) * 2013-10-11 2016-08-03 艾丽奥斯生物制药有限公司 取代的核苷、核苷酸及其类似物
CN106661076A (zh) * 2014-06-24 2017-05-10 艾丽奥斯生物制药有限公司 制备取代的核苷酸类似物的方法
CN105348320B (zh) * 2015-12-24 2018-01-02 江苏阿尔法药业有限公司 一种索非布韦中间体及其制备方法

Similar Documents

Publication Publication Date Title
CN104151352B (zh) 一种索非布韦的中间体的制备方法
CN110330540A (zh) 核苷盐及其制备方法
CN104672288B (zh) 一种氘代索菲布韦及其用途
NO342965B1 (no) Antiviralt bisfuran-derivat som HIV-protease-inhibitorer og mellomprodukter derav
CN103804446A (zh) 一种3,5-二苯甲酰基-2-去氧-2-氟-2甲基-D-核糖-γ-内酯的制备方法
TW201022276A (en) Process for the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate
CN110964057B (zh) 一种利用微流体反应装置制备索非布韦中间体的方法
CN105294795B (zh) 核苷氨基磷酸酯衍生物及其应用
WO2019237297A1 (fr) Procédés de préparation de composés/intermédiaires utiles dans le traitement d'infections virales
CN103476260A (zh) 用于制备丙型肝炎病毒抑制剂的方法
WO2016184361A1 (fr) Composé nucléosidique anti-virus de l'hépatite c et son utilisation
TW426654B (en) Regiospecific process to make cis-1-amino-2-alkanol form epoxide
JPWO2004022514A1 (ja) スピロフルオレノールの製造方法
CN111777638B (zh) 喹啉类化合物、其制备方法、药物组合物和用途
CN106977543A (zh) 改进的索非布韦中间体的制备工艺
CN105461774B (zh) 索非布韦的制备方法
CN107868105A (zh) 一种索非布韦关键中间体的制备方法
WO2016202232A1 (fr) Procédé de synthèse dun sel d'amine de (4s)-n-boc-4-méthoxy méthyl-l-proline
EP3405463A1 (fr) Procédé pour la préparation de sofosbuvir
CN109422790B (zh) 一种索非布韦的制备新工艺
CN108290844B (zh) 一种取代的萘环化合物及药物组合物及其应用
CN101128469B (zh) 蛋白酶抑制剂前体的合成
WO1999019327A1 (fr) Procede de synthese d'intermediaires de la chloropurine
CN106496208A (zh) 恩曲他滨的制备方法
CN106478618A (zh) 恩曲他滨氢卤酸盐的制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18922428

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18922428

Country of ref document: EP

Kind code of ref document: A1