WO2016141827A1 - 二异丙基胺环境下合成医药中间体菲化合物的方法 - Google Patents

二异丙基胺环境下合成医药中间体菲化合物的方法 Download PDF

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WO2016141827A1
WO2016141827A1 PCT/CN2016/075404 CN2016075404W WO2016141827A1 WO 2016141827 A1 WO2016141827 A1 WO 2016141827A1 CN 2016075404 W CN2016075404 W CN 2016075404W WO 2016141827 A1 WO2016141827 A1 WO 2016141827A1
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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
    • 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
    • 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
    • C07C17/272—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
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    • 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
    • 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
    • C07D213/127—Preparation from compounds containing pyridine rings

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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Abstract

本发明涉及一种二异丙基胺环境下合成式(I)所示菲化合物的方法，所述方法包括：惰性气氛下，在催化剂、有机配体和二异丙基胺存在下，于溶剂中，式(II)化合物与式(III)化合物发生反应，从而得到式(I)化合物，其中，R 1、R 2各自独立地为H、C 1-C 6烷基、C 1-C 6烷氧基或卤素；R 3为C 6-C 10芳基或C 5-C 8杂芳基，所述C 6-C 10芳基或C 5-C 8杂芳基任选被1-3个取代基取代，所述取代基为C 1-C 6烷基或卤素。所述方法通过合适催化剂、有机配体、碱和溶剂的选择而取得了良好的效果，具备广泛的工业应用前景。

Description

二异丙基胺环境下合成医药中间体菲化合物的方法 技术领域
本发明涉及一种稠环化合物的合成方法，更具体地涉及医药中间体菲化合物的合成方法，属于有机合成和医药中间体合成领域。
背景技术
稠环化合物如萘、蒽、菲等化合物由于其普遍存在的生物活性而受到医药研发人员的重视与关注。其中，菲及其衍生物是一类重要的芳香性化合物，已经被广泛地应用于药物设计与合成、材料研发领域。
正是由于菲化合物的如此优秀性能和潜力，因而研究菲及其衍生物的新型合成方法也一直是有机化学合成工作者所十分关切的热点问题。
到目前为止，现有技术中已经存在多种菲化合物的制备工艺，其从多个角度研究了菲化合物所适合的合成方法。例如：
Xiao Tiebo等(“Phenanthrene Synthesis by Eosin Y-Catalyzed,Visible Light-Induced[4+2]Benzannulation of Biaryldiazonium Salts with Alkynes”，Adv.Synth.Catal.,2012,354,3195-3199)报道了一种无金属催化的、可见光诱导的二芳基偶氮盐的[4+2]苯并环化反应。其方程式如下：
Figure PCTCN2016075404-appb-000001
Ye Fei等(“Expeditious Synthesis of Phenanthrenes via CuBr2-Catalyzed Coupling of Terminal Alkynes and N-Tosylhydrazones Derived from O-Fo rmyl Biphenyls”,Organic Letters,2011,13,5020-5023)公开了一种苄CuBr2催化的偶联/环化反应，其衍生于邻甲酰基联苯的N-对甲苯磺酰腙为原料，反应式如下所示：
Figure PCTCN2016075404-appb-000002
Kwon Yongseok等(“Expedient Synthesis of Phenanthrenes via In(III)-C atalyzed 6-Exo-DigCycloisomerization”,Organic Letters,2013,15,920-923)报道了一种In(III)催化的制备菲化合物的反应，其具有反应高效、底物适用范围广的优点，其反应式如下：
Figure PCTCN2016075404-appb-000003
如上所述，尽管现有技术中已经公开了各种类型的菲化合物的制备方法，但这些方法仍然不能满足医药、化工合成领域的生产需求，这是由于其固有的生产效率低、原料不能充分利用等诸多问题。
有鉴于此，本发明人通过大量的实验研究而旨在提供了一种菲化合物的新型催化合成方法，达到了收率高、反应迅速的目的，具有十分广泛的工业应用前景。
发明内容
针对上述存在的诸多缺陷，本发明人在付出了大量的创造性劳动后，经过深入研究，而开发了一种可用作药物中间体的菲化合物的合成方法，进而完成了本发明。
具体而言，本发明提供了一种下式(I)所示菲化合物的合成方法，
Figure PCTCN2016075404-appb-000004
所述方法包括：惰性气氛下，在催化剂、有机配体和碱存在下，于溶剂中， 下式(II)化合物与式(III)化合物发生反应，从而得到式(I)化合物；
Figure PCTCN2016075404-appb-000005
其中，R1、R2各自独立地为H、C1-C6烷基、C1-C6烷氧基或卤素；
R3为C6-C10芳基或C5-C8杂芳基，所述C6-C10芳基或C4-C8杂芳基任选被1-3个取代基取代，例如可被1个、2个或3个取代基所取代，所述取代基为C1-C6烷基或卤素。
在本发明的所述合成方法中，C1-C6烷基是指具有1-6个碳原子的烷基，例如可为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、正己基等。
在本发明的所述合成方法中，C1-C6烷氧基是指上述定义的“C1-C6烷基”与O原子相连后的基团。
在本发明的所述合成方法中，所述卤素例如可为氟、氯、溴或碘。
在本发明的所述合成方法中，所述C6-C10芳基是指具有6-10个碳原子的芳基，例如可为苯基或萘基。
在本发明的所述合成方法中，所述C4-C8杂芳基是指具有4-8个碳原子的杂芳基，例如可为吡啶基、呋噻基或噻吩基等。
在本发明的所述合成方法中，所述催化剂为有机钯化合物与有机铜化合物的混合物，两者的摩尔比为1:2-4，例如可为1:2、1:3或1:4。
其中，所述有机钯化合物例为乙酸钯(Pd(OAc)2)、氯化钯(PdCl2)、乙酰丙酮钯(Pd(acac)2)、(1,5-环辛二烯)氯化钯(PdCl2(cod))、三氟乙酸钯(Pd(TFA)2)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(PdCl2(dppf))、二(三苯基膦)氯化钯(PdCl2(PPh3)2)中的任何一种或任何多种的混合物，最优选为PdCl2(dppf)。
其中，所述有机铜化合物为六氟磷酸四乙腈铜([(CH3CN)4Cu]PF6)、三氟甲磺酸铜(Cu(OTf)2)、乙酰丙酮铜(Cu(acac)2)、乙酸铜中的任意一种或多种，最优选为六氟磷酸四乙腈铜([(CH3CN)4Cu]PF6)。
在本发明的所述合成方法中，所述有机配体为含氮双齿配体，例如可为取代或未取代的联吡啶、取代或未取代的邻菲罗啉等，例如可为如下的L1-L4：
Figure PCTCN2016075404-appb-000006
最优选为L1。
在本发明的所述合成方法中，所述碱为Na2CO3、K2CO3、NaOH、KOH、K3PO4、Na3PO4、NaHCO3、KHCO3、乙酸钠、乙醇钠、叔丁醇钾、二异丙基胺、二异丙基乙醇胺等中的任何一种或任何多种的混合物；最优选为二异丙基乙醇胺。
在本发明的所述合成方法中，所述溶剂为PEG-400与1-烯丙基-3-甲基咪唑四氟硼酸盐的混合物，两者体积比为1:0.1-0.3，例如可为1:0.1、1:0.2或1:0.3。
在本发明的所述合成方法中，所述惰性氛围例如可为氮气氛围或氩气氛围。
在本发明的所述合成方法中，所述式(II)化合物与式(III)化合物的摩尔比为1:2-4，例如可为1:2、1:3或1:4。
在本发明的所述合成方法中，所述式(II)化合物与催化剂的摩尔比为1:0.08-0.15，即所述式(II)化合物的摩尔用量与构成所述催化剂的两种组分的摩尔用量之和的比为1:0.08-0.15，例如可为1:0.08、1:0.1、1:0.12、1:0.14或1:0.15。
在本发明的所述合成方法中，所述式(II)化合物与有机配体的摩尔比为1:0.1-0.2，例如可为1:0.1、1:0.15或1:0.2。
在本发明的所述合成方法中，所述式(II)化合物与碱的摩尔比为1:2-3，例如可为1:2、1:2.5或1:3。
在本发明的所述合成方法中，所述溶剂的用量并没有严格的限定，本领域技术人员可对其用量进行合适的选择，例如可根据使得后处理易于进行、足以反应顺利进行即可。
在本发明的所述合成方法中，反应温度为60-80℃，例如可为60℃、70℃或80℃。
在本发明的所述合成方法中，反应时间为8-12小时，例如可为8小时、10小时或12小时。
在本发明的所述合成方法中，反应结束后的后处理具体如下：反应结束后，向反应体系中加入去离子水，充分振荡、洗涤，分出有机层，再次用去离子水洗涤，分出有机层；将有机层减压浓缩，除去，所得残留物上硅胶柱色谱，以体积比为1:2-4的正己醇与氯仿的混合溶剂作为洗脱溶剂进行洗脱，经TLC检测，合并相同组分，除去洗脱溶剂，得到目标化合物。
如上所述，本发明提供了一种用作医药中间体的菲化合物的合成方法，所述方法通过合适催化剂、有机配、碱和溶剂的选择/组合/协同，从而以高产率得到了目的产物，对医药、化工等中间体的实际生产大有裨益，具有广泛的工业应用前景。
具体实施方式
下面通过具体的实施例对本发明进行详细说明，但这些例举性实施方式的用途和目的仅用来例举本发明，并非对本发明的实际保护范围构成任何形式的任何限定，更非将本发明的保护范围局限于此。
其中，在所有实施例中，除非另有规定，所使用的配体L1均为上式L1所指代的配体。
实施例1
Figure PCTCN2016075404-appb-000007
向反应器中加入适量由PEG-400与1-烯丙基-3-甲基咪唑四氟硼酸盐组成的混合溶剂(两者体积比为1:0.1)，然后用氮气置换两次，使得反应器内为氮气氛围；然后加入100mmol上式(II)化合物2-溴-4’-氯联苯、200mmol上式(III)化合物苯乙烯、由3mmolPdCl2(dppf)和6mmol六氟磷酸四乙腈铜组成的复合催化剂、10mmol配体L1和200mmol二异丙基乙醇胺，搅拌下升温至60℃，并在该温度下反应12小时。
反应结束后，向反应体系中加入去离子水，充分振荡、洗涤，分出有机层，再次用去离子水洗涤，分出有机层；将有机层减压浓缩，除去，所得残留物上硅胶柱色谱，以体积比为1:2的正己醇与氯仿的混合溶剂作为洗脱溶剂进行洗脱，经TLC检测，合并相同组分，除去洗脱溶剂，得到目标化合物2-氯-10-苯基菲，产率为95.3％。
1H-NMR(300MHz，CDCl3)δ:8.63(d，J＝8.9Hz，1H)，8.49-8.44(m，2H)，7.84(d，J＝2.2Hz，1H)，7.71(d，J＝8.1Hz，1H)，7.63(s，1H)，7.52(dd，J＝8.9，2.3Hz，1H)，7.51-7.41(m，6H)。
实施例2
Figure PCTCN2016075404-appb-000008
向反应器中加入适量由PEG-400与1-烯丙基-3-甲基咪唑四氟硼酸盐组成的混合溶剂(两者体积比为1:0.2)，然后用氮气置换两次，使得反应器内为氮气氛围；然后加入100mmol上式(II)化合物2-溴联苯、300mmol上式(III)化合物1-甲基-3-乙烯基苯、由3mmolPdCl2(dppf)和9mmol六氟磷酸四乙腈铜组成的复合催化剂、15mmol配体L1和250mmol二异丙基乙醇胺，搅拌下升温至70℃，并在该温度下反应10小时。
反应结束后，向反应体系中加入去离子水，充分振荡、洗涤，分出有机层，再次用去离子水洗涤，分出有机层；将有机层减压浓缩，除去，所得残留物上硅胶柱色谱，以体积比为1:3的正己醇与氯仿的混合溶剂作为洗脱溶剂进行洗脱，经TLC检测，合并相同组分，除去洗脱溶剂，得到目标化合物9-间甲苯基菲，产率为94.7％。
1H-NMR(300MHz，CDCl3，)δ:8.72(dd，J＝8.3，1.2Hz，1H)，8.51(d，J＝1.6Hz，1H)，7.96(dd，J＝8.3，1.4Hz，1H)，7.83(d，J＝8.0Hz，1H)，7.68-7.61(m，2H)，7.52(ddd，J＝8.2，6.9，1.3Hz，1H)，7.45-7.31(m，4H)，7.27-7.22(m，2H)，2.63(s，3H)。
实施例3
Figure PCTCN2016075404-appb-000009
向反应器中加入适量由PEG-400与1-烯丙基-3-甲基咪唑四氟硼酸盐组成的混合溶剂(两者体积比为1:0.3)，然后用氮气置换两次，使得反应器内为氮气氛围；然后加入100mmol上式(II)化合物2-溴联苯、400mmol上式(III)化合物1-乙烯基萘、由3mmolPdCl2(dppf)和12mmol六氟磷酸四乙腈铜组成的复合催化剂、20mmol配体L1和300mmol二异丙基乙醇胺，搅拌下升温至80℃，并在该温度下反应8小时。
反应结束后，向反应体系中加入去离子水，充分振荡、洗涤，分出有机层，再次用去离子水洗涤，分出有机层；将有机层减压浓缩，除去，所得残留物上硅胶柱色谱，以体积比为1:4的正己醇与氯仿的混合溶剂作为洗脱溶剂进行洗脱，经TLC检测，合并相同组分，除去洗脱溶剂，得到目标化合物9-(萘-1-基)菲，产率为95.7％。
1H-NMR(300MHz，CDCl3)δ:8.82(d，J＝8.2Hz，2H)，8.61(s，1H)，8.02-7.95(m，2H)，7.83(d，J＝8.0Hz，1H)，7.74(s，1H)，7.65-7.31(m，9H)。
实施例4
Figure PCTCN2016075404-appb-000010
向反应器中加入适量由PEG-400与1-烯丙基-3-甲基咪唑四氟硼酸盐组成的混合溶剂(两者体积比为1:0.2)，然后用氮气置换两次，使得反应器内为氮气氛围；然后加入100mmol上式(II)化合物2-溴联苯、300mmol上式(III)化合物2-乙烯基吡啶、由2mmolPdCl2(dppf)和6mmol六氟磷酸四乙腈铜组成的复合催化剂、20mmol配体L1和200mmol二异丙基乙醇胺，搅拌下升温至70℃，并在该温度下反应12小时。
反应结束后，向反应体系中加入去离子水，充分振荡、洗涤，分出有机层，再次用去离子水洗涤，分出有机层；将有机层减压浓缩，除去，所得残留物上硅胶柱色谱，以体积比为1:3的正己醇与氯仿的混合溶剂作为洗脱溶剂进行洗脱，经TLC检测，合并相同组分，除去洗脱溶剂，得到目标化合物9-(吡啶-2-基)菲，产率为94.9％。
1H-NMR(300MHz，CDCl3)δ:8.83(d，J＝4.9Hz，1H)，8.76(dd，J＝8.3，1.3Hz，1H)，8.57-8.51(m，1H)，8.07(dd，J＝8.2，1.4Hz，1H)，7.89-7.83(m，3H)，7.71-7.62(m，2H)，7.58-7.52(m，1H)，7.45(dd，J＝8.1Hz，1.6Hz，1H)，7.41-7.35(m，2H)。
实施例5-28：催化剂钯化合物组分的考察
实施例5-8：除分别将其中的PdCl2(dppf)替换为乙酸钯(Pd(OAc)2)外，其它操作均不变，以与实施例1-4的相同方式实施了实施例5-8。
实施例9-12：除分别将其中的PdCl2(dppf)替换为氯化钯(PdCl2)外，其它操作均不变，以与实施例1-4的相同方式实施了实施例9-12。
实施例13-16：除分别将其中的PdCl2(dppf)替换为乙酰丙酮钯(Pd(acac)2)外，其它操作均不变，以与实施例1-4的相同方式实施了实施例13-16。
实施例17-20：除分别将其中的PdCl2(dppf)替换为(1,5-环辛二烯)氯化钯(PdCl2(cod))外，其它操作均不变，以与实施例1-4的相同方式实施了实施例17-20。
实施例21-24：除分别将其中的PdCl2(dppf)替换为三氟乙酸钯(Pd(TFA)2)外，其它操作均不变，以与实施例1-4的相同方式实施了实施例21-24。
实施例25-28：除分别将其中的PdCl2(dppf)替换为二(三苯基膦)氯化钯(PdCl2(PPh3)2)外，其它操作均不变，以与实施例1-4的相同方式实施了实施例25-28。
所得产物的产率如下表1所示：
表1：钯化合物组分的考察
Figure PCTCN2016075404-appb-000011
由此可见，当将复合催化剂中的PdCl2(dppf)替换为其它钯化合物时，均导致产率有大幅度降低，这证明了PdCl2(dppf)可与六氟磷酸四乙腈铜一起具有最好的催化效果。
实施例29-40：催化剂铜化合物组分的考察
实施例29-32：除分别将其中的六氟磷酸四乙腈铜替换为三氟甲磺酸铜(Cu(OTf)2)外，其它操作均不变，以与实施例1-4的相同方式实施了实施例29-32。
实施例33-36：除分别将其中的六氟磷酸四乙腈铜替换为乙酰丙酮铜(Cu(acac)2)外，其它操作均不变，以与实施例1-4的相同方式实施了实施例33-36。
实施例37-40：除分别将其中的六氟磷酸四乙腈铜替换为乙酸铜外，其它操作均不变，以与实施例1-4的相同方式实施了实施例37-40。
所得产物的产率如下表2所示：
表2：铜化合物组分的考察
Figure PCTCN2016075404-appb-000012
由此可见，当将复合催化剂中的六氟磷酸四乙腈铜替换为其它铜化合物时，均导致产率有大幅度降低，这证明了六氟磷酸四乙腈铜可与PdCl2(dppf)一起发挥最好的催化效果。
实施例41-52：有机配体的考察
实施例41-44：除分别将其中的有机配体由L1替换为L2外，其它操作均不变，以与实施例1-4的相同方式实施了实施例41-44。
实施例45-48：除分别将其中的有机配体由L1替换为L3外，其它操作均不变，以与实施例1-4的相同方式实施了实施例45-48。
实施例49-52：除分别将其中的有机配体由L1替换为L4外，其它操作均不变，以与实施例1-4的相同方式实施了实施例49-52。
所得产物的产率如下表3所示：
表3：有机配体的考察
Figure PCTCN2016075404-appb-000013
由此可见，在所有的配体中，L1具有最好的反应效果，即便是与L1结构非常类似的L2，其产率也有相当的降低。
实施例53-64：碱的考察
除将其中的碱由二异丙基乙醇胺替换为其它碱外，其它均不变而与实施例1-4的相同方式实施了实施例53-64，所使用碱、对应关系和产物产率见下表4：
表4：碱的考察
Figure PCTCN2016075404-appb-000014
由此可见，当使用其它碱时，均导致产率有大幅度降低，即便是与实施例1-4中所使用二异丙基乙醇胺非常类似的二异丙基胺，其产率也有显著降低。
实施例65-72：溶剂的考察
实施例65-68：分别将实施例1-4中的混合溶剂替换为PEG-400，其它均不变，而得到了实施例65-68。
实施例69-72：分别将实施例1-4中的混合溶剂替换为1-烯丙基-3-甲基咪唑四氟硼酸盐，其它均不变，而得到了实施例69-72。
所得产物的产率如下表5所示：
表5：溶剂的考察
Figure PCTCN2016075404-appb-000015
由此可见，当使用单一组分的溶剂时，产率有相当的降低，只有使用两者的组合物时，才能取得本发明的优异效果。
实施例73-80：单一催化剂组分的考察
实施例73-76：分别将实施例1-4中的复合催化剂替换为相同用量的 PdCl2(dppf)，即PdCl2(dppf)的用量为原来两种组分的总用量，而得到了实施例73-76。
实施例77-80：分别将实施例1-4中的复合催化剂替换为相同用量的六氟磷酸四乙腈铜，即六氟磷酸四乙腈铜的用量为原来两种组分的总用量，而得到了实施例77-80。
所得产物的产率如下表6所示：
表6：单一催化剂组分的考察
Figure PCTCN2016075404-appb-000016
由此可见，当使用单一组分催化剂时，产率有相当的降低，只有使用两者混合物时，相互之间发挥了独特的协同作用，从而取得了本发明的优异催化效果，这是非显而易见的。
综上所述，本发明提供了一种医药中间体菲化合物的合成方法，在该方法中，通过催化剂、有机配体、碱和溶剂的综合选择和/或协同，从而以高产率得到了目的产物，而当改变任何一种组分或者予以省略时，均导致产物产率有显著降低。由此可见，本发明的方法具有良好的、广泛的工业应用潜力，可应用于医药中间体的合成领域。
应当理解，这些实施例的用途仅用于说明本发明而非意欲限制本发明的保护范围。此外，也应理解，在阅读了本发明的技术内容之后，本领域技术人员可以对本发明作各种改动、修改和/或变型，所有的这些等价形式同样落于本申请所附权利要求书所限定的保护范围之内。

Claims (14)

  1. 一种二异丙基胺环境下合成下式(I)所示菲化合物的方法，
    Figure PCTCN2016075404-appb-100001
    所述方法包括：惰性气氛下，在催化剂、有机配体和碱存在下，于溶剂中，下式(II)化合物与式(III)化合物发生反应，从而得到式(I)化合物；
    Figure PCTCN2016075404-appb-100002
    其中，R1、R2各自独立地为H、C1-C6烷基、C1-C6烷氧基或卤素；
    R3为C6-C10芳基或C5-C8杂芳基，所述C6-C10芳基或C4-C8杂芳基任选被1-3个取代基取代，所述取代基为C1-C6烷基或卤素；
    所述催化剂为有机钯化合物与有机铜化合物的混合物，两者的摩尔比为1:2-4，其中，所述有机钯化合物为PdCl2(dppf)，所述有机铜化合物为六氟磷酸四乙腈铜；
    所述有机配体为如下的L1-L4中的一种：
    Figure PCTCN2016075404-appb-100003
    所述碱为二异丙基胺；
    所述溶剂为PEG-400与1-烯丙基-3-甲基咪唑四氟硼酸盐的混合物，两者体积比为1:0.1-0.3。
  2. 根据权利要求1所述的合成所述菲化合物的方法，其中，所述有机配体为L1。
  3. 根据权利要求1所述的合成所述菲化合物的方法，其中，所述式(II)化合物与式(III)化合物的摩尔比为1:2-4。
  4. 根据权利要求1所述的合成所述菲化合物的方法，其中，所述式(II)化合物与催化剂的摩尔比为1:0.08-0.15。
  5. 根据权利要求1所述的合成所述菲化合物的方法，其中，所述式(II)化合物与有机配体的摩尔比为1:0.1-0.2。
  6. 根据权利要求1所述的合成所述菲化合物的方法，其中，所述式(II)化合物与碱的摩尔比为1:2-3。
  7. 根据权利要求1所述的合成所述菲化合物的方法，其中，反应温度为60-80℃；反应时间为8-12小时。
  8. 根据权利要求2所述的合成所述菲化合物的方法，其中，所述式(II)化合物与式(III)化合物的摩尔比为1:2-4。
  9. 根据权利要求2所述的合成所述菲化合物的方法，其中，所述式(II)化合物与催化剂的摩尔比为1:0.08-0.15。
  10. 根据权利要求2所述的合成所述菲化合物的方法，其中，所述式(II)化合物与有机配体的摩尔比为1:0.1-0.2。
  11. 根据权利要求2所述的合成所述菲化合物的方法，其中，所述式(II)化合物与碱的摩尔比为1:2-3。
  12. 根据权利要求2所述的合成所述菲化合物的方法，其中，反应温度为60-80℃；反应时间为8-12小时。
  13. 一种二异丙基胺环境下合成下式(I)所示菲化合物的方法，
    Figure PCTCN2016075404-appb-100004
    所述方法包括：惰性气氛下，在催化剂、有机配体和碱存在下，于溶剂中，下式(II)化合物与式(III)化合物发生反应，从而得到式(I)化合物；
    Figure PCTCN2016075404-appb-100005
    其中，R1、R2各自独立地为H、C1-C6烷基、C1-C6烷氧基或卤素；
    R3为C6-C10芳基或C5-C8杂芳基，所述C6-C10芳基或C4-C8杂芳基任选被1-3个取代基取代，所述取代基为C1-C6烷基或卤素；
    所述催化剂为有机钯化合物与有机铜化合物的混合物，两者的摩尔比为1:2-4，其中，所述有机钯化合物为PdCl2(dppf)，所述有机铜化合物为六氟磷酸四乙腈铜；
    所述有机配体为如下的L1-L4中的一种：
    Figure PCTCN2016075404-appb-100006
    所述碱为二异丙基胺；
    所述溶剂为PEG-400与1-烯丙基-3-甲基咪唑四氟硼酸盐的混合物，两者体积比为1:0.1-0.3，所述式(II)化合物与式(III)化合物的摩尔比为1:2-4。
  14. 一种二异丙基胺环境下合成下式(I)所示菲化合物的方法，
    Figure PCTCN2016075404-appb-100007
    所述方法包括：惰性气氛下，在催化剂、有机配体和碱存在下，于溶剂中，下式(II)化合物与式(III)化合物发生反应，从而得到式(I)化合物；
    Figure PCTCN2016075404-appb-100008
    其中，R1、R2各自独立地为H、C1-C6烷基、C1-C6烷氧基或卤素；
    R3为C6-C10芳基或C5-C8杂芳基，所述C6-C10芳基或C4-C8杂芳基任选被1-3个取代基取代，所述取代基为C1-C6烷基或卤素；
    所述催化剂为有机钯化合物与有机铜化合物的混合物，两者的摩尔比为1:2-4，其中，所述有机钯化合物为PdCl2(dppf)，所述有机铜化合物为六氟磷酸四乙腈铜；
    所述有机配体为如下的L1-L4中的一种：
    Figure PCTCN2016075404-appb-100009
    所述碱为二异丙基胺；
    所述溶剂为PEG-400与1-烯丙基-3-甲基咪唑四氟硼酸盐的混合物，两者体积比为1:0.1-0.3，所述式(II)化合物与催化剂的摩尔比为1:0.08-0.15。
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