WO2016141826A1 - Procédé de synthèse d'un composé de phénanthrène intermédiaire pharmaceutique dans un environnement tert-butoxyde de potassium - Google Patents

Procédé de synthèse d'un composé de phénanthrène intermédiaire pharmaceutique dans un environnement tert-butoxyde de potassium Download PDF

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WO2016141826A1
WO2016141826A1 PCT/CN2016/075403 CN2016075403W WO2016141826A1 WO 2016141826 A1 WO2016141826 A1 WO 2016141826A1 CN 2016075403 W CN2016075403 W CN 2016075403W WO 2016141826 A1 WO2016141826 A1 WO 2016141826A1
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compound
formula
organic
synthesizing
phenanthrene
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翟学研
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金英花
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/10—Cyclisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
    • C07C17/266—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions of hydrocarbons and halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/272—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by addition reactions
    • C07C17/275—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by addition reactions of hydrocarbons and halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
    • C07C2/02—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by addition between unsaturated hydrocarbons
    • C07C2/42—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by addition between unsaturated hydrocarbons homo- or co-oligomerisation with ring formation, not being a Diels-Alder conversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
    • C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
    • C07C2/861—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon the non-hydrocarbon contains only halogen as hetero-atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/127—Preparation from compounds containing pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/20—Polycyclic condensed hydrocarbons
    • C07C15/27—Polycyclic condensed hydrocarbons containing three rings
    • C07C15/30—Phenanthrenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
    • C07C25/18—Polycyclic aromatic halogenated hydrocarbons
    • C07C25/22—Polycyclic aromatic halogenated hydrocarbons with condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • C07C2531/22—Organic complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring

Definitions

  • the invention relates to a method for synthesizing a fused ring compound, and more particularly to a method for synthesizing a pharmaceutical intermediate phenanthrene compound, and belongs to the field of organic synthesis and pharmaceutical intermediate synthesis.
  • Fused ring compounds such as naphthalene, anthracene, phenanthrene and the like have attracted the attention and attention of pharmaceutical researchers due to their ubiquitous biological activity.
  • phenanthrene and its derivatives are an important class of aromatic compounds, which have been widely used in drug design and synthesis, and material research and development.
  • the present inventors have aimed to provide a novel catalytic synthesis method for phenanthrene compounds through a large number of experimental studies, and achieve the purpose of high yield and rapid reaction, and have a wide range of industrial application prospects.
  • the inventors have developed a synthesis method of a phenanthrene compound which can be used as a pharmaceutical intermediate after intensive research after a lot of creative labor, and completed the present invention.
  • the present invention provides a method for synthesizing a phenanthrene compound represented by the following formula (I),
  • the method comprises: in an inert atmosphere, in the presence of a catalyst, an organic ligand and a base, in a solvent,
  • the compound of the following formula (II) is reacted with a compound of the formula (III) to give a compound of the formula (I);
  • R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen;
  • R 3 is C 6 -C 10 aryl or C 5 -C 8 heteroaryl, the C 6 -C 10 aryl or C 4 -C 8 heteroaryl optionally substituted by 1-3 substituents, for example It may be substituted by 1, 2 or 3 substituents which are C 1 -C 6 alkyl or halogen.
  • C 1 -C 6 alkyl means an alkyl group having 1 to 6 carbon atoms, and may be, for example, methyl, ethyl, n-propyl, isopropyl or n-butyl. , sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl and the like.
  • the C 1 -C 6 alkoxy group means a group in which the "C 1 -C 6 alkyl group" defined above is bonded to an O atom.
  • the halogen may be, for example, fluorine, chlorine, bromine or iodine.
  • the C 6 -C 10 aryl group means an aryl group having 6 to 10 carbon atoms, and may be, for example, a phenyl group or a naphthyl group.
  • the C 4 -C 8 heteroaryl group means a heteroaryl group having 4 to 8 carbon atoms, and may be, for example, a pyridyl group, a furthiyl group or a thienyl group.
  • the catalyst is a mixture of an organic palladium compound and an organic copper compound in a molar ratio of 1:2-4, for example, 1:2, 1:3 or 1:4. .
  • the organic palladium compound is exemplified by palladium acetate (Pd(OAc) 2 ), palladium chloride (PdCl 2 ), palladium acetylacetonate (Pd(acac) 2 ), (1,5-cyclooctadiene).
  • the organic copper compound is copper hexafluorophosphate ([(CH 3 CN) 4 Cu]PF 6 ), copper triflate (Cu(OTf) 2 ), copper acetylacetonate (Cu(acac)) 2 ) Any one or more of copper acetate, most preferably copper hexafluorophosphate tetraacetonitrile ([(CH 3 CN) 4 Cu]PF 6 )).
  • the organic ligand is a nitrogen-containing bidentate ligand, and may be, for example, a substituted or unsubstituted bipyridine, a substituted or unsubstituted phenanthroline or the like, and for example, may be as follows L1-L4:
  • the base is Na 2 CO 3 , K 2 CO 3 , NaOH, KOH, K 3 PO 4 , Na 3 PO 4 , NaHCO 3 , KHCO 3 , sodium acetate, sodium ethoxide, Any one or a mixture of any of a plurality of potassium t-butoxide, diisopropylamine, diisopropylethanolamine, etc.; most preferably diisopropylethanolamine.
  • the solvent is a mixture of PEG-400 and 1-allyl-3-methylimidazolium tetrafluoroborate, and the volume ratio of the two is 1:0.1-0.3, for example, It is 1:0.1, 1:0.2 or 1:0.3.
  • the inert atmosphere may be, for example, a nitrogen atmosphere or an argon atmosphere.
  • the molar ratio of the compound of the formula (II) to the compound of the formula (III) is 1:2-4, and may be, for example, 1:2, 1:3 or 1:4.
  • the molar ratio of the compound of the formula (II) to the catalyst is 1:0.08-0.15, that is, the molar amount of the compound of the formula (II) and the two components constituting the catalyst.
  • the ratio of the sum of the molar amounts is from 1:0.08 to 0.15, for example, it may be 1:0.08, 1:0.1, 1:0.12, 1:0.14 or 1:0.15.
  • the molar ratio of the compound of the formula (II) to the organic ligand is from 1:0.1 to 0.2, for example, it may be 1:0.1, 1:0.15 or 1:0.2.
  • the molar ratio of the compound of the formula (II) to the base is 1:2-3, and may be, for example, 1:2, 1:2.5 or 1:3.
  • the amount of the solvent is not strictly limited, and those skilled in the art can appropriately select the amount thereof, for example, according to making the post-treatment easy to carry out, and the reaction can be carried out smoothly.
  • the reaction temperature is 60 to 80 ° C, for example, 60 ° C, 70 ° C or 80 ° C.
  • the reaction time is 8 to 12 hours, for example, 8 hours, 10 hours or 12 hours.
  • the post-treatment after the completion of the reaction is specifically as follows: after the reaction is completed, deionized water is added to the reaction system, thoroughly shaken, washed, and the organic layer is separated and washed again with deionized water. The organic layer was concentrated, and the organic layer was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with a solvent mixture of n-hexanol and chloroform in a volume ratio of 1:2-4 as elution solvent. The same fractions were combined and the elution solvent was removed to give the title compound.
  • the present invention provides a method for synthesizing a phenanthrene compound for use as a pharmaceutical intermediate, which obtains a desired product in high yield by selection/combination/coordination of a suitable catalyst, organic compound, base and solvent. It has great benefits for the actual production of pharmaceuticals, chemicals and other intermediates, and has broad industrial application prospects.
  • the ligand L1 used is a ligand represented by the above formula L1 unless otherwise specified.
  • a suitable solvent consisting of PEG-400 and 1-allyl-3-methylimidazolium tetrafluoroborate (1:0.1 by volume) was added to the reactor, and then replaced with nitrogen twice.
  • the inside of the reactor was a nitrogen atmosphere; then 100 mmol of the compound of the formula (II), 2-bromo-4'-chlorobiphenyl, 200 mmol of the compound of the above formula (III), styrene, 3 mmol of PdCl 2 (dppf) and 6 mmol of hexafluorophosphate tetraacetonitrile were added.
  • a composite catalyst composed of copper, 10 mmol of ligand L1 and 200 mmol of diisopropylethanolamine were heated to 60 ° C with stirring, and reacted at this temperature for 12 hours.
  • a composite catalyst composed of copper tetraacetonitrile phosphate, 15 mmol of ligand L1 and 250 mmol of diisopropylethanolamine were heated to 70 ° C with stirring, and reacted at this temperature for 10 hours.
  • a suitable solvent consisting of PEG-400 and 1-allyl-3-methylimidazolium tetrafluoroborate (1:0.3 by volume) was added to the reactor, and then replaced with nitrogen twice.
  • the inside of the reactor was a nitrogen atmosphere; then 100 mmol of the compound of the above formula (II) 2-bromobiphenyl, 400 mmol of the compound of the above formula (III) 1-vinylnaphthalene, 3 mmol of PdCl 2 (dppf) and 12 mmol of copper hexafluorophosphate tetraacetonitrile were added.
  • the composite catalyst, 20 mmol of ligand L1 and 300 mmol of diisopropylethanolamine were heated to 80 ° C with stirring and reacted at this temperature for 8 hours.
  • Example 5 was carried out in the same manner as in Example 1-4 except that PdCl 2 (dppf) was replaced with palladium acetate (Pd(OAc) 2 ), respectively. -8.
  • Examples 9 to 12 Examples 9 to 12 were carried out in the same manner as in Example 1-4 except that PdCl 2 (dppf) was replaced with palladium chloride (PdCl 2 ), respectively.
  • Examples 13 to 16 Examples were carried out in the same manner as in Example 1-4, except that PdCl 2 (dppf) therein was replaced with palladium acetylacetonate (Pd(acac) 2 ), respectively. 13-16.
  • Examples 17-20 except that PdCl 2 (dppf) was replaced with (1,5-cyclooctadiene) palladium chloride (PdCl 2 (cod)), respectively, the other operations were unchanged, and the examples were Examples 17-20 were carried out in the same manner as 1-4.
  • Examples 21 to 24 Other operations were carried out except that PdCl 2 (dppf) was replaced with palladium trifluoroacetate (Pd(TFA) 2 ), and the same was carried out in the same manner as in Example 1-4.
  • Examples 25-28 Except that PdCl 2 (dppf) was replaced with bis(triphenylphosphine)palladium chloride (PdCl 2 (PPh 3 ) 2 ), respectively, the other operations were unchanged, and Examples 1-4 Examples 25-28 were carried out in the same manner.
  • Examples 29-32 The operation was the same except that copper hexafluorophosphate tetraacetonitrile was replaced with copper triflate (Cu(OTf) 2 ), respectively, in the same manner as in Example 1-4. Examples 29-32 were implemented.
  • Examples 33-36 The operation was carried out except that copper hexafluorophosphate tetraacetonitrile was replaced with copper acetylacetonate (Cu(acac) 2 ), and the same operation as in Example 1-4 was carried out.
  • Example 33-36 The operation was carried out except that copper hexafluorophosphate tetraacetonitrile was replaced with copper acetylacetonate (Cu(acac) 2 ), and the same operation as in Example 1-4 was carried out.
  • Example 33-36 The operation was carried out except that copper hexafluorophosphate tetraacetonitrile was replaced with copper acetylacetonate (Cu(acac) 2 ), and the same operation as in Example 1-4 was carried out.
  • Example 33-36 The operation was carried out except that copper hexafluorophosphate tetraacetonitrile was replaced with copper acetylacetonate (Cu(acac) 2 ), and
  • Examples 37 to 40 Examples 37 to 40 were carried out in the same manner as in Example 1-4 except that copper hexafluorophosphate tetraacetonitrile was replaced with copper acetate, respectively.
  • Examples 41-44 Examples 41-44 were carried out in the same manner as in Examples 1-4 except that the organic ligands therein were replaced by L1 to L2, respectively.
  • Examples 45-48 were carried out in the same manner as in Examples 1-4 except that the organic ligands therein were replaced by L1 to L3, respectively.
  • Examples 49-52 Examples 49-52 were carried out in the same manner as in Examples 1-4 except that the organic ligands therein were replaced by L1 to L4, respectively.
  • L1 has the best reaction effect, and even L2 which is very similar to the L1 structure has a considerable decrease in the yield.
  • Examples 53-64 were carried out in the same manner as in Examples 1-4, except that the base was replaced with diisopropylethanolamine to other bases.
  • the bases used, the corresponding relationships, and the product yields are shown. Table 4 below:
  • Examples 65-68 The mixed solvents of Examples 1-4 were replaced with PEG-400, respectively, and the others were unchanged, and Examples 65-68 were obtained.
  • Examples 69-72 The mixed solvents of Examples 1-4 were replaced with 1-allyl-3-methylimidazolium tetrafluoroborate, respectively, and the others were unchanged, and Examples 69-72 were obtained.
  • Example 73-76 Examples 1-4, respectively, of the total amount of replacement composite catalyst (dppf), i.e. the amount of PdCl 2 (dppf) PdCl 2 in the same amount as the original two components, the embodiment is obtained Examples 73-76.
  • Examples 77-80 The composite catalysts of Examples 1-4 were replaced with the same amount of copper hexafluorophosphate tetraacetonitrile, that is, the amount of copper hexafluorophosphate tetraacetonitrile was the total amount of the original two components. Examples 77-80.
  • the present invention provides a method for synthesizing a pharmaceutical intermediate phenanthrene compound, in which a high yield is obtained by comprehensive selection and/or synergy of a catalyst, an organic ligand, a base and a solvent.
  • the product when changed in any one of the components or omitted, resulted in a significant decrease in product yield. It can be seen that the method of the invention has good and wide industrial application potential and can be applied to the field of synthesis of pharmaceutical intermediates.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé de synthèse d'un composé de phénanthrène tel que représenté dans la formule (I) dans un environnement tert-butoxyde de potassium, le procédé consistant à : faire réagir le composé de formule (II) avec le composé de formule (III) dans une atmosphère inerte, en présence d'un catalyseur, de ligands organiques et de tert-butoxyde de potassium, et dans un solvant, ce qui permet d'obtenir le composé de formule (I), dans laquelle R1 et R2 sont chacun indépendamment H, un groupe alkyle en C1-C6, un groupe alcoxy en C1-C6 ou un halogène, R3 est un groupe aryle en C6-C10 ou un groupe hétéroaryle en C5-C8, le groupe aryle en C6-C10 ou le groupe hétéroaryle en C5-C8 étant facultativement substitué par 1 à 3 substituants, les substituants étant des groupes alkyle en C1-C6 ou des halogènes. Le procédé permet d'obtenir un bon effet via la sélection d'un catalyseur, de ligands organiques, d'une base et d'un solvant appropriés, et présente de larges perspectives pour une application industrielle.
PCT/CN2016/075403 2015-03-06 2016-03-03 Procédé de synthèse d'un composé de phénanthrène intermédiaire pharmaceutique dans un environnement tert-butoxyde de potassium WO2016141826A1 (fr)

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CN201510100568.5 2015-03-06
CN201510100568.5A CN104692986B (zh) 2015-03-06 2015-03-06 一种医药中间体菲类化合物的合成方法

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PCT/CN2016/075435 WO2016141835A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène faisant appel à un trifluométhanesulfonate de cuivre
PCT/CN2016/075416 WO2016141831A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires pharmaceutiques, à l'aide d'acétylacétonate de palladium
PCT/CN2016/075417 WO2016141832A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, à l'aide de pdcl2(cod)
PCT/CN2016/075418 WO2016141833A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, à l'aide de trifluoroacétate de palladium
PCT/CN2016/075437 WO2016141837A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène faisant appel à l'acétate de cuivre
PCT/CN2016/075446 WO2016141840A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un composé intermédiaire pharmaceutique de phénanthrène dans un environnement d'hydroxyde de sodium
PCT/CN2016/075415 WO2016141830A1 (fr) 2015-03-06 2016-03-03 Procédé d'application de chlorure de palladium pour synthétiser un composé de phénanthrène interméaire pharmaceutique
PCT/CN2016/075452 WO2016141842A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un composé de phénanthrène intermédiaire pharmaceutique dans un environnement de phosphate de potassium
PCT/CN2016/075402 WO2016141825A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, dans un environnement d'acétate de sodium
PCT/CN2016/075449 WO2016141841A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène dans un environnement d'hydroxyde de potassium
PCT/CN2016/075404 WO2016141827A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène en présence de diisopropylamine
PCT/CN2016/075439 WO2016141839A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène dans un environnement de carbonate de potassium
PCT/CN2016/075436 WO2016141836A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène faisant appel à un acétylacétonate de cuivre
PCT/CN2016/075414 WO2016141829A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, à l'aide d'acétate de palladium
PCT/CN2016/075413 WO2016141828A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux
PCT/CN2016/075454 WO2016141844A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène dans un environnement de bicarbonate de sodium
PCT/CN2016/075403 WO2016141826A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un composé de phénanthrène intermédiaire pharmaceutique dans un environnement tert-butoxyde de potassium
PCT/CN2016/075453 WO2016141843A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène dans un environnement de phosphate de sodium
PCT/CN2016/075434 WO2016141834A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un composé phénanthrène, intermédiaire pharmaceutique, à l'aide de pdcl2(pph3)2
PCT/CN2016/075401 WO2016141824A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, dans un environnement d'acétate de sodium
PCT/CN2016/075400 WO2016141823A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, dans un environnement de bicarbonate de potassium
PCT/CN2016/075438 WO2016141838A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène dans un environnement de carbonate de sodium

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PCT/CN2016/075435 WO2016141835A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène faisant appel à un trifluométhanesulfonate de cuivre
PCT/CN2016/075416 WO2016141831A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires pharmaceutiques, à l'aide d'acétylacétonate de palladium
PCT/CN2016/075417 WO2016141832A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, à l'aide de pdcl2(cod)
PCT/CN2016/075418 WO2016141833A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, à l'aide de trifluoroacétate de palladium
PCT/CN2016/075437 WO2016141837A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène faisant appel à l'acétate de cuivre
PCT/CN2016/075446 WO2016141840A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un composé intermédiaire pharmaceutique de phénanthrène dans un environnement d'hydroxyde de sodium
PCT/CN2016/075415 WO2016141830A1 (fr) 2015-03-06 2016-03-03 Procédé d'application de chlorure de palladium pour synthétiser un composé de phénanthrène interméaire pharmaceutique
PCT/CN2016/075452 WO2016141842A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un composé de phénanthrène intermédiaire pharmaceutique dans un environnement de phosphate de potassium
PCT/CN2016/075402 WO2016141825A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, dans un environnement d'acétate de sodium
PCT/CN2016/075449 WO2016141841A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène dans un environnement d'hydroxyde de potassium
PCT/CN2016/075404 WO2016141827A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène en présence de diisopropylamine
PCT/CN2016/075439 WO2016141839A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène dans un environnement de carbonate de potassium
PCT/CN2016/075436 WO2016141836A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène faisant appel à un acétylacétonate de cuivre
PCT/CN2016/075414 WO2016141829A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, à l'aide d'acétate de palladium
PCT/CN2016/075413 WO2016141828A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux
PCT/CN2016/075454 WO2016141844A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène dans un environnement de bicarbonate de sodium

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PCT/CN2016/075434 WO2016141834A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un composé phénanthrène, intermédiaire pharmaceutique, à l'aide de pdcl2(pph3)2
PCT/CN2016/075401 WO2016141824A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, dans un environnement d'acétate de sodium
PCT/CN2016/075400 WO2016141823A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse de composés phénanthrène, intermédiaires médicaux, dans un environnement de bicarbonate de potassium
PCT/CN2016/075438 WO2016141838A1 (fr) 2015-03-06 2016-03-03 Procédé de synthèse d'un intermédiaire pharmaceutique de type composé de phénanthrène dans un environnement de carbonate de sodium

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WO2016141831A1 (fr) 2016-09-15
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CN105801336A (zh) 2016-07-27
CN105801338B (zh) 2018-08-14
WO2016141830A1 (fr) 2016-09-15
WO2016141829A1 (fr) 2016-09-15
WO2016141837A1 (fr) 2016-09-15
WO2016141834A1 (fr) 2016-09-15
WO2016141838A1 (fr) 2016-09-15
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CN105801338A (zh) 2016-07-27
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WO2016141843A1 (fr) 2016-09-15
WO2016141833A1 (fr) 2016-09-15
CN104692986A (zh) 2015-06-10
WO2016141827A1 (fr) 2016-09-15
WO2016141825A1 (fr) 2016-09-15
WO2016141823A1 (fr) 2016-09-15
WO2016141836A1 (fr) 2016-09-15
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