WO2018023493A1 - Method for manufacturing aryl nitriles - Google Patents

Method for manufacturing aryl nitriles Download PDF

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WO2018023493A1
WO2018023493A1 PCT/CN2016/093064 CN2016093064W WO2018023493A1 WO 2018023493 A1 WO2018023493 A1 WO 2018023493A1 CN 2016093064 W CN2016093064 W CN 2016093064W WO 2018023493 A1 WO2018023493 A1 WO 2018023493A1
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aryl
mmol
ligand
catalyst
organic phase
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PCT/CN2016/093064
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French (fr)
Chinese (zh)
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洪浩
詹姆斯•盖吉
马特约•翰逊
卢江平
刘志清
张恩选
李超
Original Assignee
凯莱英医药集团（天津）股份有限公司
凯莱英生命科学技术(天津)有限公司
天津凯莱英制药有限公司
凯莱英医药化学（阜新）技术有限公司
吉林凯莱英医药化学有限公司
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Priority to PCT/CN2016/093064 priority Critical patent/WO2018023493A1/en
Publication of WO2018023493A1 publication Critical patent/WO2018023493A1/en

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    • 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
    • C07D213/60—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 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3

Definitions

  • the present invention relates to the field of synthesis of cyanide compounds, and in particular to a process for preparing an aryl nitrile compound.
  • Aryl nitriles are not only important structural components such as medicines, pesticides, dyes, functional materials, perfumes and natural products, but also important intermediates in organic synthesis.
  • the aryl nitrile compound can be easily converted into other compounds such as aldehydes, ketones, carboxylic acids, amines, amides and heterocyclic derivatives under certain reaction conditions.
  • the Sandmeyer reaction and the Rosemund-Vonbraun reaction are classical methods for the synthesis of aromatic nitriles.
  • these two methods usually require stoichiometric highly toxic metal cyanides such as zinc cyanide, sodium cyanide, etc., as well as harsh reaction conditions (150-250 ° C). ).
  • Transition metal catalyzed cyanation of halogenated aromatic hydrocarbons has developed rapidly in the last decade, but there are also some problems: sensitive to air and water, expensive catalysts and complex synthesis of phosphine ligands required and low yields
  • the aryl nitrile compound is costly to synthesize, and most of the cyanide source used is highly toxic metal cyanide, which limits its application in industrial production.
  • aryl mesylate substrates can be cyanide under the conditions of Ni or Pd catalysts (J. Org. Chem. 1995, 60, 6895-6903, SynLett. 2014, 25, 2938-2942).
  • Potassium hydride is a cyanide source to achieve a moderate yield of aryl hydrogenation, but the reaction of this type of reaction to the substrate is low, and the substrate mesylate synthesis conditions are harsh, high cost, relatively low activity, need to be Realized at higher temperatures.
  • the main object of the present invention is to provide a process for preparing an aryl nitrile compound to solve the problem of high production cost of the aryl nitrile compound in the prior art.
  • the aryl compound is cyanated with a cyan source to obtain an aryl nitrile compound.
  • the above cyanogenic source is selected from one or both of the group consisting of K 4 Fe(CN) 6 , Zn(CN) 2 , KCN and NaCN.
  • the above catalyst is a non-noble metal salt, and preferably the non-noble metal salt is selected from the group consisting of CuI, CuBr, CuCl, Cu(OAc) 2 , Cu(acac) 2 , Cu(OTf) 2 , CuI 2 , CuCl 2 , CuSO 4 , NiX. 2 , any one or more of the group consisting of Ni(OAc) 2 , NiX 2 (dppf), NiX 2 (dppe), NiX 2 (dppp), Ni(PCy3)X 2 and Ni(Py) 2 Cl 2 , wherein X represents a halogen.
  • the above ligand is an amino ligand or a phosphine ligand, preferably the amino ligand is tetramethylethylenediamine, N-N'dimethylethylenediamine or ethylenediamine, and preferably the phosphine ligand is triphenyl.
  • a solvent preferably a solvent of dimethylformamide, N-methylpyrrolidone, N,N-diethylformamide, dimethyl sulfoxide, toluene, 1,4- Dioxane or acetonitrile preferably has a volume ratio of solvent to aryl compound of from 5 to 10:1.
  • the molar ratio of the cyanide to the aryl compound in the cyanogen source is 1:1 to 1.6:1.
  • the molar ratio of the above catalyst to the aryl compound is from 0.005:1 to 0.2:1, preferably from 0.02:1 to 0.1:1.
  • the molar ratio of the above catalyst to the ligand is from 1:1 to 1:10, preferably from 1:1 to 1:3.
  • the reducing agent is zinc powder
  • the molar ratio of the zinc powder to the aryl compound is 0.05:1 to 1:1, preferably 0.1:1 to 0.5:1.
  • the above preparation method adopts an aryl compound having the general formula II as a substrate, and the preparation of the material is relatively easy with respect to the aryl halide, thereby reducing the cost of preparing the aryl nitrile compound;
  • the activity of the substance is higher than that of the aryl substrate commonly used in the prior art, so the required reaction temperature is lower during the cyanation reaction.
  • the step reduces the energy consumption of the preparation method, and also reduces the synthesis cost from this aspect; in addition, since the activity of the substance is relatively high, the requirement for the catalyst is relatively lowered, making the use of some non-precious metal catalysts possible, thereby further reducing The synthesis cost; further, since the substance has higher activity, the conversion rate is higher, thereby reducing the complexity and complexity of the product separation and recovery process, and further reducing the synthesis cost. Meanwhile, when the aryl group having the general formula II has various aromatic heterocyclic rings, its reactivity is comparable to that of the phenyl group, and therefore it is universal for the synthesis of an aryl nitrile compound. That is, the preparation method of the present application is highly versatile, and a high yield can be obtained for an aryl or heteroaryl substrate containing an electron-rich or electron-deficient substituent.
  • Example 1 shows a 1 H NMR spectrum of a target product obtained in the first step of Example 1 of the present invention
  • Example 2 shows a 13 C NMR spectrum of a target product obtained in the first step of Example 1 of the present invention
  • Figure 3 shows a 1 H NMR spectrum of the product according to Example 2 of the present invention.
  • Figure 4 shows a 1 H NMR spectrum of the product according to Example 8 of the present invention.
  • Figure 5 shows a 13 C NMR spectrum of the product according to Example 8 of the present invention.
  • Figure 6 shows a 1 H NMR spectrum of the product according to Example 9 of the present invention.
  • Figure 7 shows a 13 C NMR spectrum of the product according to Example 9 of the present invention.
  • Figure 8 shows a 1 H NMR spectrum of the product according to Example 21 of the present patent.
  • Figure 9 shows a 1 H NMR spectrum of the product according to Example 22 of the present patent.
  • the preparation method of the aryl nitrile compound in the prior art has a problem of high cost due to various reasons.
  • the present application provides preparation of an aryl nitrile compound.
  • the aryl nitrile compound has the general formula I:
  • the aryl compound is cyanated with a cyan source to obtain an aryl nitrile compound.
  • the above preparation method adopts an aryl compound having the general formula II as a substrate, and the preparation of the substance is relatively easy with respect to the aryl halide, thereby reducing the cost of preparing the aryl nitrile compound; and the activity of the substance is higher than that of the prior art.
  • the commonly used aromatic substrate is high, so the required reaction temperature is lower during the cyanation reaction, further reducing the energy consumption of the preparation method, and also reducing the synthesis cost from this aspect; in addition, due to the activity of the substance Higher, so the requirements for the catalyst are relatively reduced, making the use of some non-precious metal catalysts possible, which in turn further reduces the synthesis cost; further, because of the higher activity of the material, the conversion rate is higher, then the product is reduced.
  • the versatility and complexity of the separation and recovery process can also reduce the cost of synthesis.
  • the preparation method of the present application is highly versatile, and a high yield can be obtained for an aryl or heteroaryl substrate containing an electron-rich or electron-deficient substituent.
  • purification can be carried out by a conventional purification method, and the purification method will not be enumerated here.
  • the cyan source is selected from one or both of the group consisting of K 4 Fe(CN) 6 , Zn(CN) 2 , KCN and NaCN.
  • the use of the above-mentioned low-toxicity salts as a cyanogen source greatly reduces the use amount, and at the same time, greatly reduces the safety risk of the reaction, as well as the risks and costs of the post-treatment reaction and the three-waste treatment.
  • the cost of the above K 4 Fe(CN) 6 is lower than that of other metal cyanides, and the synthesis process is green and environmentally friendly.
  • cyanogenic sources commonly used in the prior art can also be used in the present application without considering safety issues.
  • the catalytic activity requirement of the catalyst can be appropriately lowered, for example, selecting a non-noble metal salt as a catalyst, and preferably the non-precious metal salt is selected from CuI, CuBr, CuCl, Cu(OAc) 2 ( Copper acetate), Cu(acac) 2 (copper acetylacetonate), Cu(OTf) 2 (copper trifluoromethanesulfonate), CuI 2 , CuCl 2 , CuSO 4 , NiX 2 , Ni(OAc) 2 (nickel acetate) Any one or more of the group consisting of NiX 2 (dppf), NiX 2 (dppe), NiX 2 (dppp), Ni(PCy 3 )X 2 and Ni(Py) 2 Cl 2 , wherein X represents a halogen Dppf represents 1,1-bis(diphenylphosphino)ferrocene, dppe represents 1,2-bis(diphen
  • palladium catalysts commonly used in the prior art can also be used, such as PdCl 2 , Pd(OAc) 2 (palladium acetate), Pd(PPh 3 ) 4 (tetrakis(triphenylphosphine)palladium), Pd(dba) 2 (tris(dibenzylideneacetone)dipalladium), Pd(dppf)Cl 2 (1,1-bis(diphenylphosphino)ferrocene palladium dichloride), Pd(acac) 2 (palladium acetylacetonate) .
  • the above catalyst is selected, one skilled in the art can select a suitable ligand according to the prior art knowledge, preferably the above ligand is an amino ligand or a phosphine ligand, and further preferably the amino ligand is tetramethylethylenediamine (TMEDA).
  • TEDA tetramethylethylenediamine
  • the phosphine ligand is triphenylphosphine (PPh 3 ), 1,1-bis(diphenylphosphine) ferrocene Iron (dppf), 1,2-bis(diphenylphosphine)ethane (dppe), 1,3-bis(diphenylphosphino)propane dppp or tricyclohexylphosphine (PCy 3 ).
  • the kind of the above-mentioned catalyst is selected from the above ligands to further improve the catalytic efficiency and activity.
  • the above ligands of the present application are inexpensive, and can obtain higher system purity and yield, and the catalytic efficiency of the above catalysts in combination with the Pd catalyst can obtain a comparable or higher yield on most substrates.
  • the copper or nickel catalyst described above is more inexpensive, greatly reduces production costs, and is easy to process.
  • the above cyanation reaction is carried out in a solvent, and further preferably the solvent is dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-diethylformamide, dimethyl sulfoxide. (DMSO), toluene, 1,4-dioxane or acetonitrile.
  • the solvent is dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-diethylformamide, dimethyl sulfoxide. (DMSO), toluene, 1,4-dioxane or acetonitrile.
  • the volume ratio of the solvent to the aryl compound is preferably from 5 to 10:1. In order to allow the reaction substrate and the cyanogen source to be sufficiently dispersed in contact, it is ensured that the reaction efficiency is not lowered due to excessive dispersion.
  • the reaction temperature of the above cyanation reaction is lowered, and it is preferred that the above cyanation reaction be carried out in the range of 60 to 100 ° C, preferably 80 ° C.
  • the temperature range is significantly lower than the reaction temperature of more than 100 ° C in the prior art, so the stability of the substrate is required to be low, and the complex functional grouping is performed (for example, the compound structure contains, for example, an ester group, a ketone carbonyl group or an aromatic ring).
  • the substrate of the functional group having a halogen atom has better functional group compatibility, and is favorable for obtaining high separation yield and system purity; at the same time, the requirements for equipment and energy are significantly reduced, and it is more favorable for preparation of the present application.
  • the molar ratio of cyanide to aryl compound in the cyanogen source is from 1:1 to 1.6:1.
  • the molar ratio of the above catalyst to the aryl compound is from 0.005:1 to 0.2:1, preferably from 0.02:1 to 0.1:1.
  • the molar ratio of the catalyst to the ligand is preferably from 1:1 to 1:10, preferably from 1:1 to 1:3, more preferably 1:2.
  • the molar ratio of ligand to catalyst is 2:1 in accordance with the tetradentate coordination requirement of the catalyst. During the catalytic cycle, there is a sufficient amount of coordination and leaving of the ligand, and too much ligand will waste the ligand and increase the cost. .
  • the reducing agent is zinc powder
  • the molar ratio of the zinc powder to the aryl compound is from 0.05:1 to 1:1, preferably from 0.1:1 to 0.5:1.
  • the reducing agent is used to reduce the catalyst to ensure the reaction proceeds; the use of zinc powder as the reducing agent enables the reaction to proceed stably and at a low cost; the amount of the zinc powder is controlled within the above range, preferably 0.1/1.
  • Zinc powder is used to reduce the catalyst into a zero-valent metal, and the zero-valent metal is an active catalyst intermediate during the catalytic cycle.
  • the volume ratio of the solvent to the substrate is from 5:1 to 20:1, preferably 10:1.
  • the substrate in the above embodiments can be taken from the existing products in the prior art, and can also be synthesized at the time of use.
  • the synthesis method can also refer to the prior art, and details are not described herein again.
  • the synthetic route is:
  • 3-Hydroxypyridine (100 g, 1.05 mol) and triethylamine (160 g, 1.58 mol) were added to dichloromethane (500 mL) to form a first mixed system, and at room temperature, a sulfonyl fluoride was introduced into the reaction system. After gas (118g, 1.1equiv.) and stirring for 2 ⁇ 3h, the sample is traced until the disappearance of the raw materials, the reaction system is cooled to 0-5 °C, and 300g of ice water at 0 °C is added to the reaction system for quenching and DCM extraction (300mLDCM each time) After a total of three times, the organic phase was combined and concentrated, and subjected to column chromatography. The volume ratio of petroleum ether to ethyl acetate in the column was 5/1 to obtain an oily liquid of 176 g, and the target product yield was 95%.
  • the target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (1.93 g, 2.8 mmol), ligand PPh 3 (1.46 g, 5.56 mmol), zinc Powder (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the oxygen was controlled.
  • the second mixed system is heated to 80 ° C, and stirred at 80 ° C for 3 h, and then TLC is traced to the completion of the reaction of the starting material to obtain a second product system.
  • MTBE 60 mL
  • 10% ammonia water 130 mL
  • the third mixed system was allowed to stand, and then separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL).
  • the organic phase was again obtained, and the organic phase obtained by the above process was combined, and then the pH of the organic phase was adjusted to 1 to 2 with a concentration of 4 mol/L of HCl, and the liquid phase was obtained by using a mass fraction of 30% NaOH.
  • the pH of the aqueous phase is 7-8, and the precipitate is directly filtered. , Solid dried to give a white solid 5.51g, 94% yield of the product.
  • the target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (0.77 g, 1.13 mmol), ligand dppf (1.28 g, 2.26 mmol), zinc powder. (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (0.19 g, 0.28 mmol), ligand dppf (0.31 g, 0.565 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), a catalyst Ni (dppp)Cl 2 (0.15 g, 0.28 mmol), a ligand dppp (0.23 g, 0.565 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppp)Cl 2 (0.15 g, 0.28 mmol), ligand PPh 3 (0.15 g, 0.565 mmol), zinc Powder (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Pd(PPh 3 ) 4 (1.31 g, 1.13 mmol), ligand PPh 3 (0.592 g, 2.26 mmol), zinc Powder (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), potassium cyanide (5.88 g, 90.4 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 60 ° C, and stirred at 60 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), sodium cyanide sodium cyanide (4.43 g, 90.4 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 100 ° C, and stirred at 100 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Cu(acac) 2 (0.73 g, 2.8 mmol), ligand TMEDA (0.645 g, 5.56 mmol), zinc powder ( 0.367 g, 5.65 mmol), cyanide zinc cyanide (5.28 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second The mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (3.97 g, 33.9 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (3.86 g, 5.6 mmol), ligand dppf (9.39 g, 16.7 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (5.28 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst CuBr (0.40 g, 2.8 mmol), ligand DMEDA (0.49 g, 5.6 mmol), zinc powder (0.367 g, 5.65) were taken. Ment), cyanide zinc cyanide (5.28g, 45.2mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second mixed system was heated to After stirring at 80 ° C for 3 h at 80 ° C, TLC was traced until the reaction of the starting material was completed.
  • the target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), a catalyst CuSO 4 (0.45 g, 2.8 mmol), a ligand PPy 3 (1.56 g, 5.6 mmol), and a zinc powder (0.367 g) were taken. , 5.65 mmol), cyanide zinc cyanide (5.28 g, 45.2 mmol) was added to 50 mL of toluene to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second mixed system was obtained. The temperature was raised to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(OAc) 2 (0.199 g, 1.13 mmol), ligand TMEDA (0.26 g, 2.3 mmol), zinc powder ( 0.367 g, 5.65 mmol), K 4 Fe(CN) 6 (17.93 g, 16.9 mmol) was added to 50 mL of N,N-diethylbenzamide to obtain a second mixed system. After the second mixed system was replaced by nitrogen The oxygen content is controlled to be less than 0.03%, the second mixed system is heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(Py) 2 Cl 2 (0.325 g, 1.13 mmol), ligand DMEDA (0.206 g, 2.3 mmol), zinc Powder (1.84 g, 28.3 mmol), K 4 Fe(CN) 6 (17.93 g, 16.9 mmol) was added to 50 mL of NMP to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the oxygen content was controlled to be less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (7.7 g, 11.3 mmol), ligand dppf (12.8 g, 22.6 mmol), zinc powder were taken. (3.67g, 56.5mmol), cyanide zinc cyanide (4.23g, 45.2mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (0.77 g, 1.13 mmol), ligand dppf (1.28 g, 2.26 mmol), zinc powder. (0.184 g, 2.83 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h.
  • the above preparation method adopts an aryl compound having the general formula II as a substrate, and the preparation of the substance is relatively easy with respect to the aryl halide, thereby reducing the cost of preparing the aryl nitrile compound; and the activity of the substance is higher than that of the prior art.
  • the commonly used aromatic substrate is high, so the required reaction temperature is lower during the cyanation reaction, further reducing the energy consumption of the preparation method, and also reducing the synthesis cost from this aspect; in addition, due to the activity of the substance Higher, so the requirements for the catalyst are relatively reduced, making the use of some non-precious metal catalysts possible, while also reducing the amount of catalyst, thereby further reducing the synthesis cost; further, because of the higher activity of the substance, its conversion rate Higher, then reduces the complexity and complexity of the product separation and recovery process, which in turn can reduce the cost of synthesis.
  • the preparation method of the present application is highly versatile, and a high yield can be obtained for an aryl or heteroaryl substrate containing an electron-rich or electron-deficient substituent.

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Abstract

A method for manufacturing aryl nitriles represented by formula I. The method for manufacturing the compound represented by formula I comprises: using an aryl compound represented by formula II as a starting material; for the compound represented by formula II, n = 0 or 1, and X1, X2, X3, and X4 are independently selected from N, S, O, or C; Y is OSO2F, OTf, or OTs; R1, R2, R3 and R4 are independently selected from any one of H, an alkyl group, an aryl group, or a halide. Nitrilization of the aryl compound is performed using a catalytic effect provided by a catalyst, a reducing agent, and a ligand to obtain the class of aryl nitrile compounds.

Description

芳基腈类化合物的制备方法Method for preparing aryl nitrile compound 技术领域Technical field
本发明涉及氰类化合物的合成领域，具体而言，涉及一种芳基腈类化合物的制备方法。The present invention relates to the field of synthesis of cyanide compounds, and in particular to a process for preparing an aryl nitrile compound.
背景技术Background technique
芳基腈类化合物不但是医药、农药、染料、功能材料、香料和天然产物等重要结构组成部分，而且也是有机合成重要的中间体。在一定的反应条件下芳基腈类化合物可以容易的转化为其他化合物如醛、酮、羧酸、胺、酰胺和杂环衍生物等。Aryl nitriles are not only important structural components such as medicines, pesticides, dyes, functional materials, perfumes and natural products, but also important intermediates in organic synthesis. The aryl nitrile compound can be easily converted into other compounds such as aldehydes, ketones, carboxylic acids, amines, amides and heterocyclic derivatives under certain reaction conditions.
Sandmeyer反应和Rosemund-Vonbraun反应是合成芳腈的经典方法，然而这两种方法通常需要化学计量的剧毒金属氰化物如氰化锌、***等，以及苛刻的反应条件(150～250℃)。过渡金属催化卤代芳烃的氰基化反应在最近十几年里得到了快速发展，但也存在一些问题：对空气和水敏感、催化剂价格昂贵且所需膦配体的合成复杂且收率低导致芳基腈类化合物合成成本较高，采用的氰源大多数是剧毒金属氰化物，限制了其在工业生产中的应用。The Sandmeyer reaction and the Rosemund-Vonbraun reaction are classical methods for the synthesis of aromatic nitriles. However, these two methods usually require stoichiometric highly toxic metal cyanides such as zinc cyanide, sodium cyanide, etc., as well as harsh reaction conditions (150-250 ° C). ). Transition metal catalyzed cyanation of halogenated aromatic hydrocarbons has developed rapidly in the last decade, but there are also some problems: sensitive to air and water, expensive catalysts and complex synthesis of phosphine ligands required and low yields The aryl nitrile compound is costly to synthesize, and most of the cyanide source used is highly toxic metal cyanide, which limits its application in industrial production.
最近文献报道了使用低毒的黄血盐(亚铁***)为氰化试剂，钯或铜催化的芳环氰基化反应获得较为理想的收率(如申请号为200610048481.9的中国专利申请，Catal.Commun.2009.10 768–771,J.Am.Chem.Soc.2003,125,2890-2891,Eur.J.Org.Chem.2007,2401–2404，Tetrahedron Lett.2005,46 2585–2588)；也有文献报道使用剧毒的金属氰化物为氰源，使用铜催化实现芳基的氰化反应，且这一类反应中均加入添加剂KI，但是反应温度仍然大于100℃，且收率中等。另外相关文献专利报道使用叠氮化钠在钯或铜催化剂条件下(申请号为200910088860和201510194625的中国专利申请)对各种取代芳基实现芳基氰基化，虽然这一类反应避免使用剧毒氰化物，但使用易***的叠氮化钠和高成本的金属钯催化剂，不易于工艺规模化生产。Recently, it has been reported in the literature that the use of low-toxic yellow blood salt (potassium ferrocyanide) as cyanide reagent, palladium or copper-catalyzed aromatic ring cyanation reaction to obtain a better yield (such as Chinese patent application No. 200610048481.9) , Catal.Commun.2009.10 768–771, J. Am. Chem. Soc. 2003, 125, 2890-2891, Eur. J. Org. Chem. 2007, 2401–2404, Tetrahedron Lett. 2005, 46 2585–2588) It has also been reported in the literature that the highly toxic metal cyanide is used as a cyanogen source, and copper is used to catalyze the acylation of aryl groups. In this type of reaction, the additive KI is added, but the reaction temperature is still greater than 100 ° C, and the yield is moderate. In addition, the related literature reports on the use of sodium azide in the palladium or copper catalyst conditions (Chinese Patent Application No. 200910088860 and 201510194625) to achieve aryl cyanation of various substituted aryl groups, although this type of reaction avoids the use of drama Poisonous cyanide, but using explosive sodium azide and high-cost metal palladium catalysts, is not easy to process scale production.
最近，有文献报道了芳基甲磺酸酯底物能在Ni或Pd催化剂条件下(J.Org.Chem.1995,60,6895-6903，SynLett.2014,25,2938–2942)，以***为氰源实现中等收率的芳基氢化反应，但该类反应对底物的普适性较低，且底物甲磺酸酯合成条件苛刻、成本高、活性相对较低，需要在较高温度下实现。Recently, it has been reported in the literature that aryl mesylate substrates can be cyanide under the conditions of Ni or Pd catalysts (J. Org. Chem. 1995, 60, 6895-6903, SynLett. 2014, 25, 2938-2942). Potassium hydride is a cyanide source to achieve a moderate yield of aryl hydrogenation, but the reaction of this type of reaction to the substrate is low, and the substrate mesylate synthesis conditions are harsh, high cost, relatively low activity, need to be Realized at higher temperatures.
发明内容Summary of the invention
本发明的主要目的在于提供一种芳基腈类化合物的制备方法，以解决现有技术中的芳基腈类化合物的制备成本较高的问题。 The main object of the present invention is to provide a process for preparing an aryl nitrile compound to solve the problem of high production cost of the aryl nitrile compound in the prior art.
为了实现上述目的，根据本发明的一个方面，提供了一种芳基腈类化合物的制备方法，上述芳基腈类化合物具有通式I：
Figure PCTCN2016093064-appb-000001
通式I，制备方法包括：以具有通式II的芳基化合物为底物，
Figure PCTCN2016093064-appb-000002
通式II，其中，n＝0～1，X1、X2、X3和X4中在化学可接受的结构中各自独立地选自N、S、O和C中的任意一种；Y为OSO2F、OTf或OTs；R1、R2、R3和R4各自独立地选自H、烷基、芳基和卤素中的任意一种，在催化剂、还原剂和配体的催化作用下使芳基化合物与氰源进行氰基化反应，得到芳基腈类化合物。In order to achieve the above object, according to one aspect of the present invention, there is provided a process for producing an aryl nitrile compound having the formula I:
Figure PCTCN2016093064-appb-000001
Formula I, the preparation method comprises: using an aryl compound having the general formula II as a substrate,
Figure PCTCN2016093064-appb-000002
Formula II, wherein n = 0 to 1, X 1 , X 2 , X 3 and X 4 are each independently selected from any one of N, S, O and C in a chemically acceptable structure; Is OSO 2 F, OTf or OTs; R 1 , R 2 , R 3 and R 4 are each independently selected from any of H, alkyl, aryl and halogen, catalyzed by a catalyst, a reducing agent and a ligand The aryl compound is cyanated with a cyan source to obtain an aryl nitrile compound.
进一步地，上述氰源选自K4Fe(CN)6、Zn(CN)2、KCN和NaCN组成的组中的一种或两种。Further, the above cyanogenic source is selected from one or both of the group consisting of K 4 Fe(CN) 6 , Zn(CN) 2 , KCN and NaCN.
进一步地，上述催化剂为非贵金属盐，优选非贵金属盐选自CuI、CuBr、CuCl、Cu(OAc)2、Cu(acac)2、Cu(OTf)2、CuI2、CuCl2、CuSO4、NiX2、Ni(OAc)2、NiX2(dppf)、NiX2(dppe)、NiX2(dppp)、Ni(PCy3)X2和Ni(Py)2Cl2组成的组中的任意一种或多种，其中X表示卤素。Further, the above catalyst is a non-noble metal salt, and preferably the non-noble metal salt is selected from the group consisting of CuI, CuBr, CuCl, Cu(OAc) 2 , Cu(acac) 2 , Cu(OTf) 2 , CuI 2 , CuCl 2 , CuSO 4 , NiX. 2 , any one or more of the group consisting of Ni(OAc) 2 , NiX 2 (dppf), NiX 2 (dppe), NiX 2 (dppp), Ni(PCy3)X 2 and Ni(Py) 2 Cl 2 , wherein X represents a halogen.
进一步地，上述配体为氨基配体或膦配体，优选氨基配体为四甲基乙二胺、N-N’二甲基乙二胺或乙二胺，优选膦配体为三苯基膦、1,1-双(二苯基膦)二茂铁、1,2-双(二苯膦)乙烷、1,3-双(二苯膦)丙烷或三环己基膦。Further, the above ligand is an amino ligand or a phosphine ligand, preferably the amino ligand is tetramethylethylenediamine, N-N'dimethylethylenediamine or ethylenediamine, and preferably the phosphine ligand is triphenyl. Phosphine, 1,1-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane or tricyclohexylphosphine.
进一步地，上述氰基化反应在溶剂中进行，优选溶剂为二甲基甲酰胺、N-甲基吡咯烷酮、N,N-二乙基甲酰胺、二甲基亚砜、甲苯、1，4-二氧六烷或乙腈，优选溶剂与芳基化合物的体积比为5～10：1。Further, the above cyanation reaction is carried out in a solvent, preferably a solvent of dimethylformamide, N-methylpyrrolidone, N,N-diethylformamide, dimethyl sulfoxide, toluene, 1,4- Dioxane or acetonitrile preferably has a volume ratio of solvent to aryl compound of from 5 to 10:1.
进一步地，上述氰基化反应在60～100℃范围内进行。Further, the above cyanation reaction is carried out in the range of 60 to 100 °C.
进一步地，上述氰源中的氰根与芳基化合物的摩尔比1：1～1.6：1。Further, the molar ratio of the cyanide to the aryl compound in the cyanogen source is 1:1 to 1.6:1.
进一步地，上述催化剂与芳基化合物的摩尔比为0.005：1～0.2：1，优选为0.02：1～0.1：1。Further, the molar ratio of the above catalyst to the aryl compound is from 0.005:1 to 0.2:1, preferably from 0.02:1 to 0.1:1.
进一步地，上述催化剂与配体的摩尔比为1:1～1:10，优选为1:1～1:3。Further, the molar ratio of the above catalyst to the ligand is from 1:1 to 1:10, preferably from 1:1 to 1:3.
进一步地，上述还原剂为锌粉，锌粉与芳基化合物的摩尔比为0.05：1～1：1，优选为0.1：1～0.5:1。Further, the reducing agent is zinc powder, and the molar ratio of the zinc powder to the aryl compound is 0.05:1 to 1:1, preferably 0.1:1 to 0.5:1.
应用本发明的技术方案，上述制备方法采用具有通式II的芳基化合物为底物，该物质相对于芳基卤代物的制备较为容易，因此可以降低制备芳基腈类化合物的成本；且该物质的活性比现有技术中常用的芳基底物高，因此在氰基化反应过程中，所需的反应温度较低，进一 步降低了制备方法对能量的消耗，也从该方面降低了合成成本；另外，由于该物质活性较高，因此对催化剂的要求相对降低，使得一些非贵金属催化剂的使用成为可能，进而又进一步降低合成成本；进一步地，由于该物质活性较高，因此其转化率较高，那么降低了产物的分离和回收工艺的操作繁复性和复杂程度，进而还可以降低合成成本。同时，具有通式II的芳基化合物中芳基为各种芳杂环时，其反应活性与苯基时的反应活性相当，因此对于合成芳基腈类化合物具有普适性。即使得本申请的制备方法通用性强，对于含有富电子或缺电子取代基的芳基或杂芳基底物，均能获得较高的收率。According to the technical solution of the present invention, the above preparation method adopts an aryl compound having the general formula II as a substrate, and the preparation of the material is relatively easy with respect to the aryl halide, thereby reducing the cost of preparing the aryl nitrile compound; The activity of the substance is higher than that of the aryl substrate commonly used in the prior art, so the required reaction temperature is lower during the cyanation reaction. The step reduces the energy consumption of the preparation method, and also reduces the synthesis cost from this aspect; in addition, since the activity of the substance is relatively high, the requirement for the catalyst is relatively lowered, making the use of some non-precious metal catalysts possible, thereby further reducing The synthesis cost; further, since the substance has higher activity, the conversion rate is higher, thereby reducing the complexity and complexity of the product separation and recovery process, and further reducing the synthesis cost. Meanwhile, when the aryl group having the general formula II has various aromatic heterocyclic rings, its reactivity is comparable to that of the phenyl group, and therefore it is universal for the synthesis of an aryl nitrile compound. That is, the preparation method of the present application is highly versatile, and a high yield can be obtained for an aryl or heteroaryl substrate containing an electron-rich or electron-deficient substituent.
附图说明DRAWINGS
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：The accompanying drawings, which are incorporated in the claims of the claims In the drawing:
图1示出了根据本发明实施例1的步骤一得到的目标产物的1H NMR谱图；1 shows a 1 H NMR spectrum of a target product obtained in the first step of Example 1 of the present invention;
图2示出了根据本发明实施例1的步骤一得到的目标产物13C NMR谱图；2 shows a 13 C NMR spectrum of a target product obtained in the first step of Example 1 of the present invention;
图3示出了根据本发明实施例2的产物的1H NMR谱图；Figure 3 shows a 1 H NMR spectrum of the product according to Example 2 of the present invention;
图4示出了根据本发明实施例8的产物的1H NMR谱图；Figure 4 shows a 1 H NMR spectrum of the product according to Example 8 of the present invention;
图5示出了根据本发明实施例8的产物的13C NMR谱图；Figure 5 shows a 13 C NMR spectrum of the product according to Example 8 of the present invention;
图6示出了根据本发明实施例9的产物的1H NMR谱图；Figure 6 shows a 1 H NMR spectrum of the product according to Example 9 of the present invention;
图7示出了根据本发明实施例9的产物的13C NMR谱图；Figure 7 shows a 13 C NMR spectrum of the product according to Example 9 of the present invention;
图8示出了根据本专利实施例21的产物的1H NMR谱图；以及Figure 8 shows a 1 H NMR spectrum of the product according to Example 21 of the present patent;
图9示出了根据本专利实施例22的产物的1H NMR谱图。Figure 9 shows a 1 H NMR spectrum of the product according to Example 22 of the present patent.
具体实施方式detailed description
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。It should be noted that the embodiments in the present application and the features in the embodiments may be combined with each other without conflict. The invention will be described in detail below with reference to the drawings in conjunction with the embodiments.
如背景技术所记载的，现有技术中芳基腈类化合物的制备方法存在由于各种原因导致的成本较高的问题，为了解决该问题，本申请提供了一种芳基腈类化合物的制备方法，芳基腈类化合物具有通式I：
Figure PCTCN2016093064-appb-000003
通式I，该制备方法包括：以具有通式II的芳基化 合物为底物，
Figure PCTCN2016093064-appb-000004
通式II，其中，n＝0～1，X1、X2、X3和X4中在化学可接受的结构中各自独立地选自N、S、O和C中的任意一种；Y为OSO2F、OTf或OTs；R1、R2、R3和R4各自独立地选自H、烷基、芳基和卤素中的任意一种，在催化剂、还原剂和配体的催化作用下使芳基化合物与氰源进行氰基化反应，得到芳基腈类化合物。As described in the background art, the preparation method of the aryl nitrile compound in the prior art has a problem of high cost due to various reasons. To solve the problem, the present application provides preparation of an aryl nitrile compound. Method, the aryl nitrile compound has the general formula I:
Figure PCTCN2016093064-appb-000003
Formula I, the preparation method comprises: using an aryl compound having the general formula II as a substrate,
Figure PCTCN2016093064-appb-000004
Formula II, wherein n = 0 to 1, X 1 , X 2 , X 3 and X 4 are each independently selected from any one of N, S, O and C in a chemically acceptable structure; Is OSO 2 F, OTf or OTs; R 1 , R 2 , R 3 and R 4 are each independently selected from any of H, alkyl, aryl and halogen, catalyzed by a catalyst, a reducing agent and a ligand The aryl compound is cyanated with a cyan source to obtain an aryl nitrile compound.
上述制备方法采用具有通式II的芳基化合物为底物，该物质相对于芳基卤代物的制备较为容易，因此可以降低制备芳基腈类化合物的成本；且该物质的活性比现有技术中常用的芳基底物高，因此在氰基化反应过程中，所需的反应温度较低，进一步降低了制备方法对能量的消耗，也从该方面降低了合成成本；另外，由于该物质活性较高，因此对催化剂的要求相对降低，使得一些非贵金属催化剂的使用成为可能，进而又进一步降低合成成本；进一步地，由于该物质活性较高，因此其转化率较高，那么降低了产物的分离和回收工艺的操作繁复性和复杂程度，进而还可以降低合成成本。The above preparation method adopts an aryl compound having the general formula II as a substrate, and the preparation of the substance is relatively easy with respect to the aryl halide, thereby reducing the cost of preparing the aryl nitrile compound; and the activity of the substance is higher than that of the prior art. The commonly used aromatic substrate is high, so the required reaction temperature is lower during the cyanation reaction, further reducing the energy consumption of the preparation method, and also reducing the synthesis cost from this aspect; in addition, due to the activity of the substance Higher, so the requirements for the catalyst are relatively reduced, making the use of some non-precious metal catalysts possible, which in turn further reduces the synthesis cost; further, because of the higher activity of the material, the conversion rate is higher, then the product is reduced. The versatility and complexity of the separation and recovery process can also reduce the cost of synthesis.
同时，具有通式II的芳基化合物中芳基为各种芳杂环时，其反应活性与苯基时的反应活性相当，因此对于合成芳基腈类化合物具有普适性。即使得本申请的制备方法通用性强，对于含有富电子或缺电子取代基的芳基或杂芳基底物，均能获得较高的收率。Meanwhile, when the aryl group having the general formula II has various aromatic heterocyclic rings, its reactivity is comparable to that of the phenyl group, and therefore it is universal for the synthesis of an aryl nitrile compound. That is, the preparation method of the present application is highly versatile, and a high yield can be obtained for an aryl or heteroaryl substrate containing an electron-rich or electron-deficient substituent.
在经过上述合成后，采用现有常规的提纯方法进行提纯即可，在此不再一一列举提纯方法。After the above synthesis, purification can be carried out by a conventional purification method, and the purification method will not be enumerated here.
在本申请一种优选的实施例中，上述氰源选自K4Fe(CN)6、Zn(CN)2、KCN和NaCN组成的组中的一种或两种。采用上述低毒性的盐类作为氰源，其使用量大大降低，同时大大降低了反应安全风险，以及后处理反应及三废处理的风险和成本。而且上述K4Fe(CN)6的成本比其他金属氰化物成本更加低廉，合成工艺绿色环保，环境无污染。当然，如果不考虑安全问题，现有技术中常用的氰源也可以用于本申请。In a preferred embodiment of the present application, the cyan source is selected from one or both of the group consisting of K 4 Fe(CN) 6 , Zn(CN) 2 , KCN and NaCN. The use of the above-mentioned low-toxicity salts as a cyanogen source greatly reduces the use amount, and at the same time, greatly reduces the safety risk of the reaction, as well as the risks and costs of the post-treatment reaction and the three-waste treatment. Moreover, the cost of the above K 4 Fe(CN) 6 is lower than that of other metal cyanides, and the synthesis process is green and environmentally friendly. Of course, cyanogenic sources commonly used in the prior art can also be used in the present application without considering safety issues.
如前所描述的，由于底物的反应活性提高，因此对催化剂催化活性要求可以适当降低，比如选择非贵金属盐作为催化剂，优选非贵金属盐选自CuI、CuBr、CuCl、Cu(OAc)2(醋酸铜)、Cu(acac)2(乙酰丙酮铜)、Cu(OTf)2(三氟甲烷磺酸铜)、CuI2、CuCl2、CuSO4、NiX2、Ni(OAc)2(醋酸镍)、NiX2(dppf)、NiX2(dppe)、NiX2(dppp)、Ni(PCy3)X2和Ni(Py)2Cl2组成的组中的任意一种或多种，其中X表示卤素，dppf表示1,1-双(二苯基膦)二茂铁，dppe表示1,2-双(二苯膦)乙烷，dppp表示1,3-双(二苯膦)丙烷，PCy3表示三环己基膦，Py表示吡啶。上述各非贵金属盐的成本较低，因此可以进一步降低芳基腈类化合物的合成成本。当然，现有技术中常用的钯催化剂也可以使用，比如PdCl2、Pd(OAc)2(醋酸钯)、Pd(PPh3)4(四(三苯基膦)钯)、Pd(dba)2(三(二亚苄基丙酮)二钯)、Pd(dppf)Cl2(1,1-双(二苯基膦)二茂铁二氯化钯)、Pd(acac)2(乙酰丙酮钯)。 As described above, since the reactivity of the substrate is increased, the catalytic activity requirement of the catalyst can be appropriately lowered, for example, selecting a non-noble metal salt as a catalyst, and preferably the non-precious metal salt is selected from CuI, CuBr, CuCl, Cu(OAc) 2 ( Copper acetate), Cu(acac) 2 (copper acetylacetonate), Cu(OTf) 2 (copper trifluoromethanesulfonate), CuI 2 , CuCl 2 , CuSO 4 , NiX 2 , Ni(OAc) 2 (nickel acetate) Any one or more of the group consisting of NiX 2 (dppf), NiX 2 (dppe), NiX 2 (dppp), Ni(PCy 3 )X 2 and Ni(Py) 2 Cl 2 , wherein X represents a halogen Dppf represents 1,1-bis(diphenylphosphino)ferrocene, dppe represents 1,2-bis(diphenylphosphino)ethane, dppp represents 1,3-bis(diphenylphosphino)propane, and PCy 3 represents Tricyclohexylphosphine, Py represents pyridine. The cost of each of the above non-precious metal salts is low, so that the synthesis cost of the aryl nitrile compound can be further reduced. Of course, palladium catalysts commonly used in the prior art can also be used, such as PdCl 2 , Pd(OAc) 2 (palladium acetate), Pd(PPh 3 ) 4 (tetrakis(triphenylphosphine)palladium), Pd(dba) 2 (tris(dibenzylideneacetone)dipalladium), Pd(dppf)Cl 2 (1,1-bis(diphenylphosphino)ferrocene palladium dichloride), Pd(acac) 2 (palladium acetylacetonate) .
在选用上述催化剂时，本领域技术人员可以根据现有技术知识选择合适的配体，优选上述配体为氨基配体或膦配体，进一步优选氨基配体为四甲基乙二胺(TMEDA)、N-N’二甲基乙二胺(DMEDA)或乙二胺(EDA)，进一步优选膦配体为三苯基膦(PPh3)、1,1-双(二苯基膦)二茂铁(dppf)、1,2-双(二苯膦)乙烷(dppe)、1,3-双(二苯膦)丙烷dppp或三环己基膦(PCy3)。从上述配体中选择与上述催化剂相适用的种类，以进一步提高催化效率和活性。When the above catalyst is selected, one skilled in the art can select a suitable ligand according to the prior art knowledge, preferably the above ligand is an amino ligand or a phosphine ligand, and further preferably the amino ligand is tetramethylethylenediamine (TMEDA). , N-N' dimethylethylenediamine (DMEDA) or ethylenediamine (EDA), further preferably the phosphine ligand is triphenylphosphine (PPh 3 ), 1,1-bis(diphenylphosphine) ferrocene Iron (dppf), 1,2-bis(diphenylphosphine)ethane (dppe), 1,3-bis(diphenylphosphino)propane dppp or tricyclohexylphosphine (PCy 3 ). The kind of the above-mentioned catalyst is selected from the above ligands to further improve the catalytic efficiency and activity.
本申请上述各配体价格低廉，且能够获得较高的体系纯度和收率，其上述催化剂配合使用后的催化效率与Pd催化剂相比，在大多数底物上获得相当或更高的收率，而上述的铜或镍催化剂价格更加低廉，大大降低生产成本，易于工艺化生产。The above ligands of the present application are inexpensive, and can obtain higher system purity and yield, and the catalytic efficiency of the above catalysts in combination with the Pd catalyst can obtain a comparable or higher yield on most substrates. The copper or nickel catalyst described above is more inexpensive, greatly reduces production costs, and is easy to process.
此外，优选上述氰基化反应在溶剂中进行，进一步优选溶剂为二甲基甲酰胺(DMF)、N-甲基吡咯烷酮(NMP)、N,N-二乙基甲酰胺、二甲基亚砜(DMSO)、甲苯、1，4-二氧六烷或乙腈。上述各溶剂为本领域的常用溶剂，其使用较为安全且成本较低。为了进一步提高反应速率，优选溶剂与芳基化合物的体积比5～10:1。以使反应底物和氰源既能充分分散接触，又能保证不至于因为分散度过大导致反应效率下降。Further, it is preferred that the above cyanation reaction is carried out in a solvent, and further preferably the solvent is dimethylformamide (DMF), N-methylpyrrolidone (NMP), N,N-diethylformamide, dimethyl sulfoxide. (DMSO), toluene, 1,4-dioxane or acetonitrile. Each of the above solvents is a commonly used solvent in the art, and is safe to use and low in cost. In order to further increase the reaction rate, the volume ratio of the solvent to the aryl compound is preferably from 5 to 10:1. In order to allow the reaction substrate and the cyanogen source to be sufficiently dispersed in contact, it is ensured that the reaction efficiency is not lowered due to excessive dispersion.
在本申请的底物具有较高反应活性的基础上，上述氰基化反应的反应温度得到降低，优选上述氰基化反应在60～100℃范围内进行，优选为80℃。该温度范围相对于现有技术中大于100℃的反应温度明显降低，因此对底物的稳定性要求较低，且对复杂官能团化(比如化合物结构中含有比如酯基、酮羰基或者芳环上具有卤素原子的官能团)的底物具有较好的官能团兼容性，有利于获得较高的分离收率和体系纯度；同时，其对设备和能源的要求均有明显下降，且更利于本申请制备方法在工业中的推广应用。In the case where the substrate of the present application has a high reactivity, the reaction temperature of the above cyanation reaction is lowered, and it is preferred that the above cyanation reaction be carried out in the range of 60 to 100 ° C, preferably 80 ° C. The temperature range is significantly lower than the reaction temperature of more than 100 ° C in the prior art, so the stability of the substrate is required to be low, and the complex functional grouping is performed (for example, the compound structure contains, for example, an ester group, a ketone carbonyl group or an aromatic ring). The substrate of the functional group having a halogen atom has better functional group compatibility, and is favorable for obtaining high separation yield and system purity; at the same time, the requirements for equipment and energy are significantly reduced, and it is more favorable for preparation of the present application. The application of the method in industry.
在本申请一种优选的实施例中，上述氰源中的氰根与芳基化合物的摩尔比为1：1～1.6：1。In a preferred embodiment of the present application, the molar ratio of cyanide to aryl compound in the cyanogen source is from 1:1 to 1.6:1.
此外，为了在保证催化效率的前提下，尽可能减少催化剂使用量以降低成本，优选上述催化剂与芳基化合物的摩尔比为0.005：1～0.2：1，优选为0.02:1～0.1:1。Further, in order to reduce the amount of catalyst used to reduce the cost while ensuring catalytic efficiency, it is preferred that the molar ratio of the above catalyst to the aryl compound is from 0.005:1 to 0.2:1, preferably from 0.02:1 to 0.1:1.
进一步地，优选催化剂与配体的摩尔比为1:1～1:10，优选为1：1～1：3，更优选为1：2。配体与催化剂摩尔比为2：1符合催化剂的四齿配位要求，在催化循环过程中，有足够量的配体的配位和离去，而配体过多会浪费配体，增加成本。Further, the molar ratio of the catalyst to the ligand is preferably from 1:1 to 1:10, preferably from 1:1 to 1:3, more preferably 1:2. The molar ratio of ligand to catalyst is 2:1 in accordance with the tetradentate coordination requirement of the catalyst. During the catalytic cycle, there is a sufficient amount of coordination and leaving of the ligand, and too much ligand will waste the ligand and increase the cost. .
此外，优选还原剂为锌粉，锌粉与芳基化合物的摩尔比为0.05：1～1：1，优选为0.1：1～0.5:1。利用还原剂去还原催化剂，保证反应进行；利用锌粉作为还原剂能够使反应稳定进行且成本较低；锌粉的用量控制在上述范围内，优选为0.1/1。锌粉是用来还原催化剂成零价金属，在催化循环过程中是零价金属为活性催化剂中间体。Further, it is preferred that the reducing agent is zinc powder, and the molar ratio of the zinc powder to the aryl compound is from 0.05:1 to 1:1, preferably from 0.1:1 to 0.5:1. The reducing agent is used to reduce the catalyst to ensure the reaction proceeds; the use of zinc powder as the reducing agent enables the reaction to proceed stably and at a low cost; the amount of the zinc powder is controlled within the above range, preferably 0.1/1. Zinc powder is used to reduce the catalyst into a zero-valent metal, and the zero-valent metal is an active catalyst intermediate during the catalytic cycle.
此外，为保证降低溶剂的使用成本，优选溶剂与底物的体积比为5：1～20：1，优先为10：1。Further, in order to ensure a reduction in the use cost of the solvent, it is preferred that the volume ratio of the solvent to the substrate is from 5:1 to 20:1, preferably 10:1.
上述各实施例中的底物可以取自现有技术中的已有产品，也可以在使用时进行合成，其合成方法也可以参考现有技术，在此不再赘述。 The substrate in the above embodiments can be taken from the existing products in the prior art, and can also be synthesized at the time of use. The synthesis method can also refer to the prior art, and details are not described herein again.
以下将结合实施例和对比例进一步说明本申请的有益效果。Advantageous effects of the present application will be further described below in conjunction with the examples and comparative examples.
实施例1Example 1
合成路线为：The synthetic route is:
Figure PCTCN2016093064-appb-000005
Figure PCTCN2016093064-appb-000005
步骤一：step one:
将3-羟基吡啶(100g，1.05mol)和三乙胺(160g，1.58mol)加入到二氯甲烷(500mL)中形成第一混合体系，在室温下，向该反应体系中通入磺酰氟气体(118g，1.1equiv.)并持续搅拌2～3h后，取样跟踪至原料消失后，反应体系降温到0-5℃，向反应体系加入0℃冰水300g淬灭，DCM萃取(每次300mLDCM，共三次)后，有机相合并浓缩，进行柱层析，所用层析柱中石油醚和乙酸乙酯体积比为5/1，得到油状液体176g，目标产物收率95％。3-Hydroxypyridine (100 g, 1.05 mol) and triethylamine (160 g, 1.58 mol) were added to dichloromethane (500 mL) to form a first mixed system, and at room temperature, a sulfonyl fluoride was introduced into the reaction system. After gas (118g, 1.1equiv.) and stirring for 2~3h, the sample is traced until the disappearance of the raw materials, the reaction system is cooled to 0-5 °C, and 300g of ice water at 0 °C is added to the reaction system for quenching and DCM extraction (300mLDCM each time) After a total of three times, the organic phase was combined and concentrated, and subjected to column chromatography. The volume ratio of petroleum ether to ethyl acetate in the column was 5/1 to obtain an oily liquid of 176 g, and the target product yield was 95%.
产物验证：1H NMR(400MHz,CDCl3)δ8.61(s,2H),7.69–7.60(m,1H),7.38(dd,J＝8.5,4.8Hz,1H).；13C NMR(100MHz,CDCl3)δ149.92,147.16,142.68,128.69,124.89,Product validation: 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (s, 2H), 7.69 - 7.60 (m, 1H), 7.38 (dd, J = 8.5, 4.8 Hz, 1H).; 13 C NMR (100 MHz , CDCl 3 ) δ149.92, 147.16, 142.68, 128.69, 124.89,
步骤二Step two
将步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppf)Cl2(1.93g，2.8mmol)，配体dppf(3.13g，5.56mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(4.23g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后得到第二产物体系，将第二产物体系降温到室温后，加入MTBE(60mL)和10％氨水(130mL)并混合形成第三混合体系，第三混合体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，然后用浓度为4mol/L的HCl调节有机相的pH到1～2后，分液，所得水相用质量分数为30％NaOH调节pH到7～8搅拌1～2小时后，测试水相pH为7～8，则直接过滤析出的固体，固体烘干得5.0g白色固体，产物收率95％。Using the target product obtained in the first step as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder (0.367 g, 5.65mmol), cyanide zinc cyanide (4.23g, 45.2mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the oxygen content was controlled to be less than 0.03%, and the second mixed system was heated. After stirring to 80 ° C and stirring at 80 ° C for 3 h, TLC was traced to completion of the reaction of the starting material to obtain a second product system. After the second product system was cooled to room temperature, MTBE (60 mL) and 10% aqueous ammonia (130 mL) were added and mixed. The third mixed system, the third mixed system is left to stand, and the obtained aqueous phase is again extracted with MTBE (45 mL*2), and the obtained organic phase is added to 10% aqueous ammonia (20 mL), and the organic phase is separated again to obtain the organic phase. The obtained organic phases were combined, and then the pH of the organic phase was adjusted to 1-2 with a concentration of 4 mol/L HCl, and the liquid phase was separated, and the obtained aqueous phase was adjusted to pH 7-8 with a mass fraction of 30% NaOH for 1 to 2 hours. After the test, the pH of the aqueous phase is 7-8, and the precipitated solid is directly filtered, and the solid is dried to obtain 5.0 g of a white solid. Yield was 95%.
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例2Example 2
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppf)Cl2(1.93g，2.8mmol)，配体PPh3(1.46g，5.56mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(4.23g，45.2mmol)加入到50mL DMF中，得到第二混合体系，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后得到第二产物体系，将第二产物体系降温到室温后， 加入MTBE(60mL)和10％氨水(130mL)并混合形成第三混合体系，第三混合体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，然后用浓度为4mol/L的HCl调节有机相的pH到1～2后，分液，所得水相用质量分数为30％NaOH调节pH到7～8搅拌1～2小时后，测试水相pH为7～8，则直接过滤析出的固体，固体烘干得5.51g白色固体，产物收率94％。The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (1.93 g, 2.8 mmol), ligand PPh 3 (1.46 g, 5.56 mmol), zinc Powder (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the oxygen was controlled. The content is less than 0.03%, the second mixed system is heated to 80 ° C, and stirred at 80 ° C for 3 h, and then TLC is traced to the completion of the reaction of the starting material to obtain a second product system. After the second product system is cooled to room temperature, MTBE (60 mL) is added. And 10% ammonia water (130 mL) and mixed to form a third mixed system, the third mixed system was allowed to stand, and then separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL). After the liquid separation, the organic phase was again obtained, and the organic phase obtained by the above process was combined, and then the pH of the organic phase was adjusted to 1 to 2 with a concentration of 4 mol/L of HCl, and the liquid phase was obtained by using a mass fraction of 30% NaOH. After adjusting the pH to 7-8, stirring for 1 to 2 hours, the pH of the aqueous phase is 7-8, and the precipitate is directly filtered. , Solid dried to give a white solid 5.51g, 94% yield of the product.
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例3Example 3
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppf)Cl2(0.77g，1.13mmol)，配体dppf(1.28g，2.26mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(4.23g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.57g，收率95％。The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (0.77 g, 1.13 mmol), ligand dppf (1.28 g, 2.26 mmol), zinc powder. (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The combined phases were concentrated and purified by column chromatography eluting with petroleum ether / ethyl acetate = 10/1 (volume ratio) to give an oily liquid 5.57 g, yield 95%.
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例4Example 4
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppf)Cl2(0.19g，0.28mmol)，配体dppf(0.31g，0.565mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(4.23g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.16，收率88％。The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (0.19 g, 0.28 mmol), ligand dppf (0.31 g, 0.565 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The phases were combined and concentrated, and then purified, mjjjjjjj
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例5Example 5
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppp)Cl2(0.15g，0.28mmol)，配体dppp(0.23g，0.565mmol)，锌粉(0.367g，5.65mmol)，氰 源氰化锌(4.23g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.57g，收率95％。The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), a catalyst Ni (dppp)Cl 2 (0.15 g, 0.28 mmol), a ligand dppp (0.23 g, 0.565 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The combined phases were concentrated and purified by column chromatography eluting with petroleum ether / ethyl acetate = 10/1 (volume ratio) to give an oily liquid 5.57 g, yield 95%.
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例6Example 6
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppp)Cl2(0.15g，0.28mmol)，配体PPh3(0.15g，0.565mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(4.23g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.2g，收率88％。The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppp)Cl 2 (0.15 g, 0.28 mmol), ligand PPh 3 (0.15 g, 0.565 mmol), zinc Powder (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then placed in a system of MTBE (60 mL) and 10% ammonia (130 mL). After the liquid separation, the obtained aqueous phase was again extracted with MTBE (45 mL*2), the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the above process. The organic phase was combined and concentrated, and then purified tolulululululululululululu
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例7Example 7
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Pd(PPh3)4(1.31g，1.13mmol)，配体PPh3(0.592g，2.26mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(4.23g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.28g，收率90％。The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Pd(PPh 3 ) 4 (1.31 g, 1.13 mmol), ligand PPh 3 (0.592 g, 2.26 mmol), zinc Powder (0.367 g, 5.65 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then placed in a system of MTBE (60 mL) and 10% ammonia (130 mL). After the liquid separation, the obtained aqueous phase was again extracted with MTBE (45 mL*2), the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the above process. The organic phase was combined and concentrated, and then purified tolulululululululululululululu
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例8 Example 8
将4-苯甲酰基硫酰氟作为底物，取10g(35.7mmol)，催化剂Ni(dppf)Cl2(0.488g，0.714mmol)，配体dppf(0.792g，1.43mmol)，锌粉(0.232g，3.57mmol)，氰源氰化锌(3.35g，28.56mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到白色固体6.6g，收率89％。Using 4-benzoylsulfuryl fluoride as a substrate, 10 g (35.7 mmol), catalyst Ni(dppf)Cl 2 (0.488 g, 0.714 mmol), ligand dppf (0.792 g, 1.43 mmol), zinc powder (0.232) g, 3.57 mmol), cyanide zinc cyanide (3.35 g, 28.56 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second mixture was mixed. The system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the starting material, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand for separation. The obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to combine the organic phases obtained in the above process. After concentration and column chromatography, the eluent petroleum ether / ethyl acetate = 10/1 (volume ratio) afforded 6.6 g of white solid.
1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.88(s,1H),7.81(m,2H),7.79(m,2H),7.67-7.63(m,1H),7.54(m,2H).13C NMR(100MHz,CDCl3)δ195.17,141.39,136.50,133.48,132.33,130.39,130.22,128.80,118.17,115.82.ESI-MS Calcd for C14H10NO[M+H]+:208.1；found for208.1 1 H NMR (400MHz, CDCl 3 ) δ7.89 (s, 1H), 7.88 (s, 1H), 7.81 (m, 2H), 7.79 (m, 2H), 7.67-7.63 (m, 1H), 7.54 ( m,2H). 13 C NMR (100MHz, CDCl 3 ) δ 195.17, 141.39, 136.50, 133.48, 132.33, 130.39, 130.22, 128.80, 118.17, 115.82. ESI-MS Calcd for C 14 H 10 NO[M+H] + :208.1;found for208.1
实施例9Example 9
将8-氟磺酰酯基喹啉作为底物，取10g(44.1mmol)，催化剂Ni(dppf)Cl2(0.60g，0.88mmol)，配体dppf(0.98g，1.76mmol)，锌粉(0.287g，4.41mmol)，氰源氰化锌(4.13g，35.3mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，体系降温到15～25℃后，加入MTBE(60mL)和10％氨水(130mL)淬灭体系，静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝3/1(体积比)，得到白色固体6.2g收率91％。Using 8-fluorosulfonyl quinolate as a substrate, 10 g (44.1 mmol), catalyst Ni(dppf)Cl 2 (0.60 g, 0.88 mmol), ligand dppf (0.98 g, 1.76 mmol), zinc powder ( 0.287g, 4.41mmol), cyanide zinc cyanide (4.13g, 35.3mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second The mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the starting material, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to quench the system and allowed to stand. After the liquid separation, the obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined and concentrated, and then subjected to column chromatography. The eluent petroleum ether / ethyl acetate = 3 / 1 (volume ratio) gave a white solid 6.2 g yield 91%.
1H NMR(400MHz,CDCl3)δ9.09(dd,J＝4.2,1.4Hz,1H),8.25(dd,J＝8.3,1.5Hz,1H),8.12(dd,J＝7.2,0.7Hz,1H),8.08(d,J＝8.3Hz,1H),7.62(t,J＝7.7Hz,1H),7.56(dd,J＝8.3,4.3Hz,1H).13C NMR(100MHz,CDCl3)δ152.67,147.65,136.66,135.69,133.08,128.30,126.04,122.95,117.41,113.29；ESI-MS Calcd for C10H7N2[M+H]+:155.1；found for 155.1。 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (dd, J = 4.2, 1.4 Hz, 1H), 8.25 (dd, J = 8.3, 1.5 Hz, 1H), 8.12 (dd, J = 7.2, 0.7 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.56 (dd, J = 8.3, 4.3 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.67, 147.65, 136.66, 135.69, 133.08, 128.30, 126.04, 122.95, 117.41, 113.29; ESI-MS Calcd for C 10 H 7 N 2 [M+H] + : 155.1; found for 155.1.
实施例10Example 10
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppf)Cl2(1.93g，2.8mmol)，配体dppf(3.13g，5.56mmol)，锌粉(0.367g，5.65mmol)，氰源***(5.88g，90.4mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到60℃，并在60℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.22g，收率89％。 The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), potassium cyanide (5.88 g, 90.4 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 60 ° C, and stirred at 60 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The phases were combined and concentrated, and then purified and evaporated to ethyl ether.
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例11Example 11
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppf)Cl2(1.93g，2.8mmol)，配体dppf(3.13g，5.56mmol)，锌粉(0.367g，5.65mmol)，氰源***(4.43g，90.4mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到100℃，并在100℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.34g，收率91％。The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), sodium cyanide sodium cyanide (4.43 g, 90.4 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 100 ° C, and stirred at 100 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The phases were combined and concentrated, and then purified, mjjjjjjjj
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例12Example 12
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Cu(acac)2(0.73g，2.8mmol)，配体TMEDA(0.645g，5.56mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(5.28g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.16g，收率88％。The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Cu(acac) 2 (0.73 g, 2.8 mmol), ligand TMEDA (0.645 g, 5.56 mmol), zinc powder ( 0.367 g, 5.65 mmol), cyanide zinc cyanide (5.28 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second The mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The obtained aqueous phase was extracted again with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic phase obtained by the above process. After combined concentration and column chromatography, eluent petroleum ether / ethyl acetate = 10/1 (volume ratio) afforded 5.16 g of oily liquid.
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例13Example 13
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppf)Cl2(1.93g，2.8mmol)，配体dppf(3.13g，5.56mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(3.97g，33.9mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有 机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.4g，收率92％。The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (1.93 g, 2.8 mmol), ligand dppf (3.13 g, 5.56 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (3.97 g, 33.9 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The combined phases were concentrated and purified by column chromatography eluting with EtOAc EtOAc EtOAc
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例14Example 14
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppf)Cl2(3.86g，5.6mmol)，配体dppf(9.39g，16.7mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(5.28g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.2g，收率89％。The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (3.86 g, 5.6 mmol), ligand dppf (9.39 g, 16.7 mmol), zinc powder were taken. (0.367 g, 5.65 mmol), cyanide zinc cyanide (5.28 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The phases were combined and concentrated, and then purified tolulululululululululululululu
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例15Example 15
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂CuBr(0.40g，2.8mmol)，配体DMEDA(0.49g，5.6mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(5.28g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体4.93g，收率84％。The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst CuBr (0.40 g, 2.8 mmol), ligand DMEDA (0.49 g, 5.6 mmol), zinc powder (0.367 g, 5.65) were taken. Ment), cyanide zinc cyanide (5.28g, 45.2mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second mixed system was heated to After stirring at 80 ° C for 3 h at 80 ° C, TLC was traced until the reaction of the starting material was completed. After the system was cooled to 15-25 ° C, MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand for separation. The phase was extracted again with MTBE (45 mL*2), the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again. The organic phase obtained by the above process was combined, and the organic phase obtained by the above process was combined and concentrated. Chromatography, eluent petroleum ether / ethyl acetate = 10/1 (volume ratio) afforded 4.93 g of oily liquid, yield 84%.
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例16Example 16
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂CuSO4(0.45g，2.8mmol)，配体PPy3(1.56g，5.6mmol)，锌粉(0.367g，5.65mmol)，氰源氰化锌(5.28g，45.2mmol)加入到50mL甲苯中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL) 洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体4.75g，收率81％。The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), a catalyst CuSO 4 (0.45 g, 2.8 mmol), a ligand PPy 3 (1.56 g, 5.6 mmol), and a zinc powder (0.367 g) were taken. , 5.65 mmol), cyanide zinc cyanide (5.28 g, 45.2 mmol) was added to 50 mL of toluene to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%, and the second mixed system was obtained. The temperature was raised to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the starting material, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand for separation. The obtained aqueous phase was extracted again with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again. The organic phase obtained by the above process was combined, and the organic phase obtained by the above process was combined and concentrated. After column chromatography, the eluent petroleum ether / ethyl acetate = 10/1 (volume ratio) afforded 4.75 g of oily liquid, yield 81%.
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例17Example 17
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(OAc)2(0.199g，1.13mmol)，配体TMEDA(0.26g，2.3mmol)，锌粉(0.367g，5.65mmol)，K4Fe(CN)6(17.93g，16.9mmol)加入到50mL N,N-二乙基苯甲酰胺中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.0g，收率86％。The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(OAc) 2 (0.199 g, 1.13 mmol), ligand TMEDA (0.26 g, 2.3 mmol), zinc powder ( 0.367 g, 5.65 mmol), K 4 Fe(CN) 6 (17.93 g, 16.9 mmol) was added to 50 mL of N,N-diethylbenzamide to obtain a second mixed system. After the second mixed system was replaced by nitrogen The oxygen content is controlled to be less than 0.03%, the second mixed system is heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC is traced to the completion of the reaction of the raw materials, the system is cooled to 15-25 ° C, and MTBE (60 mL) is added. After 10% ammonia (130 mL) system was allowed to stand, the liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% ammonia water (20 mL), and the organic phase was separated again to obtain the organic phase. The organic phase was combined, and the organic phase obtained by the above procedure was combined and concentrated, and then subjected to column chromatography, eluent petroleum ether / ethyl acetate = 10/1 (volume ratio) to obtain an oily liquid 5.0 g, yield 86%.
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例18Example 18
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(Py)2Cl2(0.325g，1.13mmol)，配体DMEDA(0.206g，2.3mmol)，锌粉(1.84g，28.3mmol)，K4Fe(CN)6(17.93g，16.9mmol)加入到50mL NMP中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体4.7g，收率80％。The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(Py) 2 Cl 2 (0.325 g, 1.13 mmol), ligand DMEDA (0.206 g, 2.3 mmol), zinc Powder (1.84 g, 28.3 mmol), K 4 Fe(CN) 6 (17.93 g, 16.9 mmol) was added to 50 mL of NMP to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the oxygen content was controlled to be less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added. After standing, the liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined. The obtained organic phases were combined and concentrated, and then purified, mjjjjjjj
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例19Example 19
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppf)Cl2(7.7g，11.3mmol)，配体dppf(12.8g，22.6mmol)，锌粉(3.67g，56.5mmol)，氰源氰化锌(4.23g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130 mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.45g，收率93％。The target product obtained in the first step of Example 1 was used as a substrate, and 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (7.7 g, 11.3 mmol), ligand dppf (12.8 g, 22.6 mmol), zinc powder were taken. (3.67g, 56.5mmol), cyanide zinc cyanide (4.23g, 45.2mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. After the liquid separation, the obtained aqueous phase was again extracted with MTBE (45 mL*2), the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the above process. The organic phase was combined and concentrated, and then purified, mjjjjjjj
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例20Example 20
将实施例1的步骤一得到的目标产物作为底物，取10g(56.5mmol)，催化剂Ni(dppf)Cl2(0.77g，1.13mmol)，配体dppf(1.28g，2.26mmol)，锌粉(0.184g，2.83mmol)，氰源氰化锌(4.23g，45.2mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，将体系降温到15-25℃后，加入MTBE(60mL)和10％氨水(130mL)体系静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝10/1(体积比)，得到油状液体5.34g，收率91％。The target product obtained in the first step of Example 1 was used as a substrate, 10 g (56.5 mmol), catalyst Ni(dppf)Cl 2 (0.77 g, 1.13 mmol), ligand dppf (1.28 g, 2.26 mmol), zinc powder. (0.184 g, 2.83 mmol), cyanide zinc cyanide (4.23 g, 45.2 mmol) was added to 50 mL of DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the raw materials, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to stand. The liquid phase was separated, and the obtained aqueous phase was again extracted with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined to obtain the organic obtained by the above process. The phases were combined and concentrated, and then purified, mjjjjjjjj
产物验证：1H NMR(500MHz,CDCl3)δ8.68,8.68,7.85,7.83,7.82,7.69,7.67,7.53,7.52,7.51,7.51,7.50.ESI-MS Calcd for C6H5N2[M+H]+:105.1；found for 105.1。Product validation: 1 H NMR (500 MHz, CDCl 3 ) δ 8.68, 8.68, 7.85, 7.83, 7.82, 7.69, 7.67, 7.53, 7.52, 7.51, 7.51, 7.50. ESI-MS Calcd for C 6 H 5 N 2 [ M+H] + : 105.1; found for 105.1.
实施例21Example 21
2-乙酰-5-磺酰氟噻吩为底物，取9.9g(44.1mmol)，催化剂Ni(dppf)Cl2(0.60g，0.88mmol)，配体dppf(0.98g，1.76mmol)，锌粉(0.287g，4.41mmol)，氰源氰化锌(4.13g，35.3mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应完毕后，体系降温到15～25℃后，加入MTBE(60mL)和10％氨水(130mL)淬灭体系，静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝3/1(体积比)，得到白色固体6.1g收率92％。2-Acetyl-5-sulfonylfluorothiophene as a substrate, 9.9 g (44.1 mmol), catalyst Ni(dppf)Cl 2 (0.60 g, 0.88 mmol), ligand dppf (0.98 g, 1.76 mmol), zinc powder (0.287g, 4.41mmol), cyanide zinc cyanide (4.13g, 35.3mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The two mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the starting material, the system was cooled to 15-25 ° C, and then MTBE (60 mL) and 10% ammonia water (130 mL) were added to quench the system. After the liquid separation, the obtained aqueous phase was again extracted with MTBE (45 mL*2), and the obtained organic phase was washed with 10% aqueous ammonia (20 mL), and then the organic phase was separated, and the organic phase obtained by the above process was combined and concentrated. Eluent petroleum ether / ethyl acetate = 3 / 1 (volume ratio) gave a white solid 6.1 g yield of 92%.
1H NMR(500MHz；CDCl3):δ7.63(d,J＝4.0Hz,1H),7.61(d,J＝4.0Hz,1H),2.60(s,3H)；13C NMR(125MHz；CDCl3):δ189.9,149.9,137.8,131.3,116.4,113.4,27.2 1 H NMR (500MHz; CDCl3) : δ7.63 (d, J = 4.0Hz, 1H), 7.61 (d, J = 4.0Hz, 1H), 2.60 (s, 3H); 13 C NMR (125MHz; CDCl3) : δ189.9, 149.9, 137.8, 131.3, 116.4, 113.4, 27.2
实施例22Example 22
7-磺酰氟-4-甲基香豆素为底物，取11.38g(44.1mmol)，催化剂Ni(dppf)Cl2(0.60g，0.88mmol)，配体dppf(0.98g，1.76mmol)，锌粉(0.287g，4.41mmol)，氰源氰化锌(4.13g，35.3mmol)加入到50mL DMF中，得到第二混合体系，该第二混合体系氮气置换后，控制氧含量小于0.03％，将第二混合体系升温到80℃，并在80℃下搅拌3h后TLC跟踪至原料反应 完毕后，体系降温到15～25℃后，加入MTBE(60mL)和10％氨水(130mL)淬灭体系，静置后分液，所得水相再次用MTBE(45mL*2)萃取，所得有机相加入10％氨水(20mL)洗涤后分液再次得到有机相，将上述过程得到的有机相合并浓缩后柱层析，洗脱剂石油醚/乙酸乙酯＝3/1(体积比)，得到白色固体7.58g收率93％。7-sulfonyl fluoride-4-methylcoumarin as a substrate, 11.38 g (44.1 mmol), catalyst Ni(dppf)Cl 2 (0.60 g, 0.88 mmol), ligand dppf (0.98 g, 1.76 mmol) Zinc powder (0.287g, 4.41mmol), cyanide zinc cyanide (4.13g, 35.3mmol) was added to 50mL DMF to obtain a second mixed system. After the second mixed system was replaced by nitrogen, the controlled oxygen content was less than 0.03%. The second mixed system was heated to 80 ° C, and stirred at 80 ° C for 3 h. After TLC was traced to the completion of the reaction of the starting material, the system was cooled to 15-25 ° C, and then quenched by adding MTBE (60 mL) and 10% ammonia water (130 mL). The system was separated, and the liquid phase was separated, and the obtained aqueous phase was extracted again with MTBE (45 mL*2). The obtained organic phase was washed with 10% aqueous ammonia (20 mL), and the organic phase was separated again, and the organic phase obtained by the above process was combined and concentrated. Column chromatography, eluent petroleum ether / ethyl acetate = 3 / 1 (volume ratio) afforded a white solid 7.58 g yield 93%.
1H NMR(500MHz；CDCl3):δ7.71(d,J＝8.2Hz,1H),7.61(d,J＝1.6Hz,1H),7.57(dd,J＝8.1,1.6Hz,1H),6.43(q,J＝1.4Hz,1H),2.47(d,J＝1.3Hz,3H)；13C NMR(125MHz；CDCl3):δ159.2,153.2,151.0,127.5,125.8,123.7,120.9,117.9,117.5,115.0,18.8 1 H NMR (500MHz; CDCl3) : δ7.71 (d, J = 8.2Hz, 1H), 7.61 (d, J = 1.6Hz, 1H), 7.57 (dd, J = 8.1,1.6Hz, 1H), 6.43 (q, J = 1.4 Hz, 1H), 2.47 (d, J = 1.3 Hz, 3H); 13 C NMR (125 MHz; CDCl3): δ 159.2, 153.2, 151.0, 127.5, 125.8, 123.7, 120.9, 117.9, 117.5, 115.0, 18.8
经过上述各实施例的合成过程及结果可以看出，在反应温度较低的情况下，仍然能够取得较高的转化率；且所采用的催化剂为非贵金属催化剂且用量较少时，也能取得理想的催化效果，同时得到较高转化率；进一步地，由于转化率较高，那么本申请采用上述常规的提纯方法，也能取得80％以上的收率。Through the synthesis process and the results of the above various examples, it can be seen that at a lower reaction temperature, a higher conversion rate can still be obtained; and the catalyst used is a non-precious metal catalyst and can be obtained when the amount is small. The ideal catalytic effect, at the same time, a higher conversion rate; further, since the conversion rate is high, the present application can achieve a yield of 80% or more by the above conventional purification method.
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
上述制备方法采用具有通式II的芳基化合物为底物，该物质相对于芳基卤代物的制备较为容易，因此可以降低制备芳基腈类化合物的成本；且该物质的活性比现有技术中常用的芳基底物高，因此在氰基化反应过程中，所需的反应温度较低，进一步降低了制备方法对能量的消耗，也从该方面降低了合成成本；另外，由于该物质活性较高，因此对催化剂的要求相对降低，使得一些非贵金属催化剂的使用成为可能，同时也可以减少催化剂的用量，进而又进一步降低合成成本；进一步地，由于该物质活性较高，因此其转化率较高，那么降低了产物的分离和回收工艺的操作繁复性和复杂程度，进而还可以降低合成成本。The above preparation method adopts an aryl compound having the general formula II as a substrate, and the preparation of the substance is relatively easy with respect to the aryl halide, thereby reducing the cost of preparing the aryl nitrile compound; and the activity of the substance is higher than that of the prior art. The commonly used aromatic substrate is high, so the required reaction temperature is lower during the cyanation reaction, further reducing the energy consumption of the preparation method, and also reducing the synthesis cost from this aspect; in addition, due to the activity of the substance Higher, so the requirements for the catalyst are relatively reduced, making the use of some non-precious metal catalysts possible, while also reducing the amount of catalyst, thereby further reducing the synthesis cost; further, because of the higher activity of the substance, its conversion rate Higher, then reduces the complexity and complexity of the product separation and recovery process, which in turn can reduce the cost of synthesis.
同时，具有通式II的芳基化合物中芳基为各种芳杂环时，其反应活性与苯基时的反应活性相当，因此对于合成芳基腈类化合物具有普适性。即使得本申请的制备方法通用性强，对于含有富电子或缺电子取代基的芳基或杂芳基底物，均能获得较高的收率。Meanwhile, when the aryl group having the general formula II has various aromatic heterocyclic rings, its reactivity is comparable to that of the phenyl group, and therefore it is universal for the synthesis of an aryl nitrile compound. That is, the preparation method of the present application is highly versatile, and a high yield can be obtained for an aryl or heteroaryl substrate containing an electron-rich or electron-deficient substituent.
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。 The above description is only the preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes can be made to the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and scope of the present invention are intended to be included within the scope of the present invention.

Claims (10)

  1. 一种芳基腈类化合物的制备方法，其特征在于，所述芳基腈类化合物具有通式I：A method for producing an aryl nitrile compound, characterized in that the aryl nitrile compound has the formula I:
    Figure PCTCN2016093064-appb-100001
    所述制备方法包括：
    Figure PCTCN2016093064-appb-100001
    The preparation method comprises:
    以具有通式II的芳基化合物为底物，Taking an aryl compound having the general formula II as a substrate,
    Figure PCTCN2016093064-appb-100002
    Figure PCTCN2016093064-appb-100002
    其中，n＝0～1，X1、X2、X3和X4中在化学可接受的结构中各自独立地选自N、S、O和C中的任意一种；Y为OSO2F、OTf或OTs；R1、R2、R3和R4各自独立地选自H、烷基、芳基和卤素中的任意一种，Wherein n = 0 to 1, X 1 , X 2 , X 3 and X 4 are each independently selected from any one of N, S, O and C in a chemically acceptable structure; Y is OSO 2 F , OTf or OTs; R 1 , R 2 , R 3 and R 4 are each independently selected from any one of H, an alkyl group, an aryl group and a halogen.
    在催化剂、还原剂和配体的催化作用下使所述芳基化合物与氰源进行氰基化反应，得到所述芳基腈类化合物。The aryl compound is cyanated with a cyanogen source under the catalytic action of a catalyst, a reducing agent and a ligand to obtain the aryl nitrile compound.
  2. 根据权利要求1所述的制备方法，其特征在于，所述氰源选自K4Fe(CN)6、Zn(CN)2、KCN和NaCN组成的组中的一种或两种。The method according to claim 1, wherein the cyanogen source is one or more selected from the group consisting of K 4 Fe(CN) 6 , Zn(CN) 2 , KCN and NaCN.
  3. 根据权利要求1所述的制备方法，其特征在于，所述催化剂为非贵金属盐，优选所述非贵金属盐选自CuI、CuBr、CuCl、Cu(OAc)2、Cu(acac)2、Cu(OTf)2、CuI2、CuCl2、CuSO4、NiX2、Ni(OAc)2、NiX2(dppf)、NiX2(dppe)、NiX2(dppp)、Ni(PCy3)X2和Ni(Py)2Cl2组成的组中的任意一种或多种，其中X表示卤素。The preparation method according to claim 1, wherein the catalyst is a non-noble metal salt, and preferably the non-noble metal salt is selected from the group consisting of CuI, CuBr, CuCl, Cu(OAc) 2 , Cu(acac) 2 , Cu ( OTf) 2 , CuI 2 , CuCl 2 , CuSO 4 , NiX 2 , Ni(OAc) 2 , NiX 2 (dppf), NiX 2 (dppe), NiX 2 (dppp), Ni(PCy3)X 2 and Ni (Py Any one or more of the group consisting of 2 Cl 2 wherein X represents a halogen.
  4. 根据权利要求1所述的制备方法，其特征在于，所述配体为氨基配体或膦配体，优选所述氨基配体为四甲基乙二胺、N-N’二甲基乙二胺或乙二胺，优选所述膦配体为三苯基膦、1,1-双(二苯基膦)二茂铁、1,2-双(二苯膦)乙烷、1,3-双(二苯膦)丙烷或三环己基膦。The preparation method according to claim 1, wherein the ligand is an amino ligand or a phosphine ligand, and preferably the amino ligand is tetramethylethylenediamine or N-N'dimethylethylene. An amine or an ethylenediamine, preferably the phosphine ligand is triphenylphosphine, 1,1-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane, 1,3- Bis(diphenylphosphino)propane or tricyclohexylphosphine.
  5. 根据权利要求1所述的制备方法，其特征在于，所述氰基化反应在溶剂中进行，优选所述溶剂为二甲基甲酰胺、N-甲基吡咯烷酮、N,N-二乙基甲酰胺、二甲基亚砜、甲苯、1，4-二氧六烷或乙腈，优选所述溶剂与所述芳基化合物的体积比为5～10：1。The process according to claim 1, wherein the cyanation reaction is carried out in a solvent, preferably the solvent is dimethylformamide, N-methylpyrrolidone, N,N-diethyl The amide, dimethyl sulfoxide, toluene, 1,4-dioxane or acetonitrile preferably has a volume ratio of the solvent to the aryl compound of from 5 to 10:1.
  6. 根据权利要求1所述的制备方法，其特征在于，所述氰基化反应在60～100℃范围内进行。The process according to claim 1, wherein the cyanation reaction is carried out in the range of from 60 to 100 °C.
  7. 根据权利要求1或2所述的制备方法，其特征在于，所述氰源中的氰根与所述芳基化合物的摩尔比1：1～1.6：1。 The preparation method according to claim 1 or 2, wherein a molar ratio of cyanogen to the aryl compound in the cyanogen source is 1:1 to 1.6:1.
  8. 根据权利要求1或3所述的制备方法，其特征在于，所述催化剂与所述芳基化合物的摩尔比为0.005：1～0.2：1，优选为0.02：1～0.1：1。The process according to claim 1 or 3, wherein the molar ratio of the catalyst to the aryl compound is from 0.005:1 to 0.2:1, preferably from 0.02:1 to 0.1:1.
  9. 根据权利要求1或4所述的制备方法，其特征在于，所述催化剂与所述配体的摩尔比为1:1～1:10，优选为1:1～1:3。The production method according to claim 1 or 4, wherein the molar ratio of the catalyst to the ligand is from 1:1 to 1:10, preferably from 1:1 to 1:3.
  10. 根据权利要求1所述的制备方法，其特征在于，所述还原剂为锌粉，所述锌粉与所述芳基化合物的摩尔比为0.05：1～1：1，优选为0.1：1～0.5:1。 The preparation method according to claim 1, wherein the reducing agent is zinc powder, and the molar ratio of the zinc powder to the aryl compound is 0.05:1 to 1:1, preferably 0.1:1. 0.5:1.
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