CN111100165A - Preparation method of compound containing bispyrazole ring and intermediate thereof - Google Patents

Preparation method of compound containing bispyrazole ring and intermediate thereof Download PDF

Info

Publication number
CN111100165A
CN111100165A CN201911409514.1A CN201911409514A CN111100165A CN 111100165 A CN111100165 A CN 111100165A CN 201911409514 A CN201911409514 A CN 201911409514A CN 111100165 A CN111100165 A CN 111100165A
Authority
CN
China
Prior art keywords
formula
solvent
reaction
compound shown
nitrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201911409514.1A
Other languages
Chinese (zh)
Other versions
CN111100165B (en
Inventor
刘秋凤
高中良
魏文蕾
林行军
王海洋
许可
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lianhe Chemical Technology Shanghai Co ltd
Lianhe Chemical Technology Yancheng Co ltd
Lianhua Angjian Zhejiang Pharmaceutical Co ltd
Lianhua Technology Linhai Co ltd
Lianhe Chemical Technology Co Ltd
Hebei University of Technology
Original Assignee
Lianhe Chemical Technology Shanghai Co ltd
Lianhetech Yancheng Co ltd
Lianhua Science & Technology Taizhou Co ltd
Lianhua Technology Linhai Co Ltd
Lianhe Chemical Technology Co Ltd
Hebei University of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lianhe Chemical Technology Shanghai Co ltd, Lianhetech Yancheng Co ltd, Lianhua Science & Technology Taizhou Co ltd, Lianhua Technology Linhai Co Ltd, Lianhe Chemical Technology Co Ltd, Hebei University of Technology filed Critical Lianhe Chemical Technology Shanghai Co ltd
Priority to CN201911409514.1A priority Critical patent/CN111100165B/en
Publication of CN111100165A publication Critical patent/CN111100165A/en
Application granted granted Critical
Publication of CN111100165B publication Critical patent/CN111100165B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
    • B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
    • B01J31/30—Halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention discloses a preparation method of a compound containing a dipyrazole ring and an intermediate thereof. The invention provides a preparation method of a compound containing a dipyrazole ring as shown in a formula I, which comprises the following steps: step (1): adding alkali into a mixture of a double-pyrazole ring compound shown as a formula I-1 and a solvent for a displacement reaction to obtain a mixed system; step (2): adding an organophosphorus compound shown as a formula I-2 into the mixed system in the step (1) to carry out a phosphido reaction shown as the following to obtain a compound containing a dipyrazole ring shown as the formula I; wherein R is1And R2Independently is C1‑C6Alkyl radical, C3‑C8Cycloalkyl and phenyl; r3Is C1～C6Alkyl groups of (a); x is halogen. The prepared compound containing the dipyrazole ring can be used as a ligand, and is suitable for the application range of amide in C-N coupling and the C-C coupling reaction of aryl boric acid and aryl chloride.

Description

Preparation method of compound containing bispyrazole ring and intermediate thereof
Technical Field
The invention relates to a preparation method of a compound containing a dipyrazole ring and an intermediate thereof.
Background
The coupling reaction is an effective synthesis means for forming C-C, C-N, C-S, C-B and other bonds in organic synthesis, and mainly comprises Heck reaction, Suzuki reaction, Stille reaction, Negishi reaction, Buchwald-Hartwig reaction and the like. These coupling reactions have a very wide range of applications in the synthesis of natural products, polymers, functional materials, liquid crystals, drug molecules and biologically active compounds. Among the early methods for constructing C-N are the Jourdan method, Ullmann method and Goldberg method, which suffer from the disadvantages of high reaction temperature, strong base participation, large nucleophilic reagent excess and large amount of copper powder participation. Copper belongs to the three wastes generated by heavy metals in industrial production and is difficult to treat, and palladium can be recycled in industrial production.
Pd-catalyzed cross-coupling has wide application in organic synthesis, wherein the coupling of C-N, C-C is the most common in various coupling reactions, and the reaction speed depends on the strength of a C-X bond and M-X (M ═ Pd). The order of chemical activity of the oxidative addition of the R-X bond is I > Br > Cl.
The Pd-catalyzed C-N cross coupling reaction mainly comprises the reaction of amine or amide with bromide and iodide, and has poor coupling effect on chloralkane or chloroarene which is easy to synthesize and low in price, so that a novel phosphine ligand needs to be designed to improve the activity of the chloroalkane or chloroalkane in C-N and C-C coupling.
In 2008, Singer synthesizes a ligand BippyPhos (G.J.Withbroe, R.A.Singer, J.E.Sieser, org.Process Res.Dev.2008,12, 480-ion 489) and has better effect of combining Pd to catalyze C-N coupling involving chlorinated aromatic hydrocarbon, but the ligand is mainly applied to amination reaction of aromatic amine and chlorinated aromatic hydrocarbon; no report is available about the application of BippyPhos to aryl boronic acids for C-C coupling reaction. The art is still lacking ligands for C-C and C-N coupling reactions of amide or arylboronic acids with chloroalkanes.
Figure BDA0002349582330000011
Disclosure of Invention
The technical problem to be solved by the invention is to solve the problem of insufficient ligand applied to C-C and C-N coupling reaction of amide or arylboronic acid and chloralkane in the prior art; and provides a preparation method of a compound containing a dipyrazole ring and an intermediate thereof. The compound containing the dipyrazole ring prepared by the preparation method provided by the invention can be used as a ligand, has high selectivity, and is suitable for the application range of amide in C-N coupling and C-C coupling reaction of aryl boric acid and aryl chloride, especially the coupling with chlorinated aromatic hydrocarbon.
The present invention solves the above-mentioned problems by the following technical means.
The invention provides a compound containing a dipyrazole ring as shown in a formula I,
Figure BDA0002349582330000021
wherein R is1And R2Independently is C1-C6Alkyl radical, C3-C8Cycloalkyl and phenyl;
R3is C1～C6Alkyl group of (1).
In the invention, certain substituents in the compound containing the dipyrazole ring shown in the formula I can be defined as follows, and the definition of the substituent which is not mentioned is described in any scheme.
In a preferred embodiment of the invention, R1And R2Independently is C1-C6In the alkyl radical, said C1-C6Alkyl is independently C1-C4Alkyl radicals, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl radical, for example tert-butyl.
In a preferred embodiment of the invention, R1And R2Independently is C3-C8In the cycloalkyl radical, said C3-C8Cycloalkyl is independently C3-C6Alkyl radicals, such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radical, for example the cyclohexyl radical.
In a preferred embodiment of the invention, R3Is C1～C6In the alkyl group of (A), said C1-C6Alkyl is independently C1-C4An alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; also for example methyl or isopropyl.
In a preferred embodiment of the invention, R1And R2Independently is C1-C6Alkyl or C3-C8A cycloalkyl group.
In a preferred embodiment of the invention, R1And R2Identical or different, for example identical.
In a preferred embodiment of the invention, the compound containing a dipyrazole ring shown in formula I is selected from the following compounds:
Figure BDA0002349582330000022
the invention also provides a catalyst composition which comprises the compound containing the dipyrazole ring shown in the formula I and a transition metal catalyst.
In a preferred embodiment of the present invention, the catalyst composition comprises the compound containing a dipyrazole ring represented by formula I and the transition metal catalyst.
In a preferred embodiment of the present invention, all or part of the compound containing a dipyrazole ring represented by the formula I and all or part of the transition metal catalyst are present in the form of a complex.
In a preferred embodiment of the present invention, the transition metal catalyst may be a transition metal catalyst that is conventional in the art; such as a transition metal halide (e.g., palladium chloride, PdCl)2Or nickel chloride), transition metal carboxylates [ e.g. palladium acetate Pd (OAc) ]2Or palladium trifluoroacetate) or a transition metal ligand complex (e.g., (1, 5-cyclooctadiene) palladium dichloride, (polyimide-cinnamoyl) palladium (II) chloride dimer (also known as palladium (pi-cinnamyl) chloride dimer, [ Pd (cinnamyl) Cl]2) (1, 5-cyclooctadiene) chlororhodium (I) dimer, 1, 5-cyclooctadiene iridium chloride dimer, triphenylphosphine palladium, allyl palladium, bis-dibenzylideneacetone palladium (Pd (dba))2) One or more of tris (dibenzylideneacetone) dipalladium and bis- (1, 5-cyclooctadiene) nickel)](ii) a The transition metal catalyst is preferably Pd (dba)2、Pd(OAc)2And palladium chloride.
In a preferred embodiment of the present invention, the molar ratio of the compound containing a dipyrazole ring represented by formula I and the transition metal catalyst in the catalyst composition is 1:1 to 10:1 (e.g., 1:1 to 2: 1).
The invention also provides application of the compound containing the dipyrazole ring shown in the formula I or the catalyst composition in coupling reaction. In the application, the compound containing the dipyrazole ring shown in the formula I can be used as a ligand. In the application, the coupling reaction can be a coupling reaction (such as a C-N coupling reaction or a C-C coupling reaction) which is conventional in the art; also for example a Heck reaction, a Suzuki reaction, a Stille reaction, a Negishi reaction or a Buchwald-Hartwig reaction.
In a preferred embodiment of the present invention, the application may be any of the following:
in a solvent, in the presence of a compound containing a dipyrazole ring shown in a formula I, a transition metal catalyst and alkali, carrying out C-N coupling reaction shown in the specification on an amide compound containing a structural fragment shown in a formula VI and halogenated aromatic hydrocarbon or halogenated heteroarene containing a structural fragment shown in a formula VII to obtain the amide compound containing the structural fragment shown in the formula VIII;
Figure BDA0002349582330000031
in a solvent, in the presence of a compound containing a dipyrazole ring shown in a formula I, a transition metal catalyst and alkali, carrying out C-C coupling reaction shown in the specification on an aryl or heteroaryl boron reagent containing a structural fragment shown in a formula IX and halogenated aromatic hydrocarbon or halogenated heteroaromatic hydrocarbon containing a structural fragment shown in a formula X to obtain a compound containing a structural fragment shown in a formula XI;
Figure BDA0002349582330000032
wherein, X1And X2Independently is halogen;
Figure BDA0002349582330000033
independently represents an unsaturated bond on an aromatic ring in an aryl group or a heteroaromatic ring in a heteroaryl group.
In the first scheme, the reaction conditions and operation of the C-N coupling reaction can be those conventional in the art. For example:
in scheme one, the C-N coupling reaction can be carried out under the protective gas conventional in the reaction in the field; such as nitrogen or argon.
In the first embodiment, the solvent may be a solvent conventional in the art, such as one or more of a sulfoxide solvent (e.g., Dimethylsulfoxide (DMSO)), an amide solvent (e.g., N-methylpyrrolidone (NMP) and/or N, N-Dimethylformamide (DMF)), an aromatic solvent (e.g., toluene), an alcohol solvent (e.g., tert-amyl alcohol and/or tert-butyl alcohol) free of α -H, and an ether solvent (e.g., dioxane), preferably an alcohol solvent (e.g., ethanol) free of α -H, more preferably tert-butyl alcohol or tert-amyl alcohol.
In scheme one, the base may be a base conventional in the art such as an alkali metal phosphate (e.g., potassium phosphate K)3PO4) Alkali metal alkoxides (e.g. sodium tert-butoxide NaOtBu), alkali metal carbonates (e.g. potassium carbonate K)2CO3Sodium carbonate and cesium carbonate Cs2CO3One or more of) and one or more of an alkali metal carboxylate (e.g., sodium pivalate); the present invention is preferably an alkali metal phosphate and/or an alkali metal carbonate; more preferably potassium carbonate.
In the first embodiment, the transition metal catalyst may be a transition metal catalyst conventional in the art, such as the transition metal catalyst described in the catalyst composition; the present invention is preferably bis (dibenzylideneacetone) palladium.
In scheme one, the molar ratio of the compound containing a dipyrazole ring represented by formula I and the transition metal catalyst can be a molar ratio conventionally used in reactions of this type in the art, such as 1:1 to 10:1 (e.g., 1:1 to 2: 1).
In the first embodiment, the molar ratio of the compound containing a dipyrazole ring as shown in formula I to the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment as shown in formula VII may be a molar ratio conventionally used in the reaction of this kind, for example, 0.05:1 to 0.5:1 (e.g., 0.05:1 to 0.01: 1).
In the first scheme, the molar ratio of the amide compound containing the structural fragment shown in the formula VI to the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment shown in the formula VII can be the molar ratio which is conventional in the reaction in the field, such as (0.5-2):1 (and also such as (1-1.2): 1).
In the first scheme, the dosage of the solvent is not limited, so that the reaction is not influenced; for example, the mass ratio of the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment represented by the formula VII to the solvent can be (0.02-0.5):1 (for example, (0.1-0.2): 1).
In scheme one, the molar ratio of the base to the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment of formula VII may be a molar ratio conventional in the art for such reactions, such as (1-2):1 (and, for example, (1.5-1.8): 1).
In the first embodiment, the temperature of the C-N coupling reaction may be a temperature conventional in the art, such as room temperature to 150 ℃, and in the present invention, preferably 95 ℃ to 110 ℃ (such as 95 ℃, 100 ℃, 110 ℃).
In scheme one, the progress of the C-N coupling reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and generally the reaction endpoint is the disappearance or no longer reaction of the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment shown in formula VII. The reaction time may be from 1 to 24 hours, for example from 3 to 18 hours.
In the second scheme, the reaction conditions and operation of the C-C coupling reaction can be those conventional in the art. For example:
in scheme two, the C-C coupling reaction can be carried out under the protective gas conventional in the reaction in the field; such as nitrogen or argon.
In scheme two, the solvent may be a solvent conventional in the art for such reactions, for example, one or more of an ethereal solvent (e.g., one or more of methyl tert-butyl ether MTBE, cyclopentyl methyl ether CPME, tetrahydrofuran THF, and dioxane), a sulfoxide solvent (e.g., dimethyl sulfoxide DMSO), and an alcoholic solvent (e.g., tert-amyl alcohol and/or tert-butyl alcohol). The present invention is preferably an ether solvent, more preferably tetrahydrofuran.
In scheme two, the base may be a base conventional to such reactions in the art, such as one or more of an alkali metal hydroxide (e.g., sodium hydroxide and/or potassium hydroxide), an alkali metal phosphate (e.g., potassium phosphate), an alkali metal alkoxide (e.g., sodium tert-butoxide), an alkali metal carbonate (e.g., one or more of potassium carbonate, sodium carbonate, and cesium carbonate), and an alkali metal carboxylate (e.g., sodium pivalate); the present invention is preferably an alkali metal phosphate and/or an alkali metal carbonate; more preferably potassium carbonate.
In scheme two, the transition metal catalyst may be a transition metal catalyst conventional in the art for such reactions, such as the transition metal catalyst described in the catalyst composition described above; the present invention is preferably palladium chloride.
In the second scheme, the molar ratio of the compound containing a dipyrazole ring represented by formula I and the transition metal catalyst can be a molar ratio conventionally used in the reaction of this type in the art, such as 1:1 to 10:1 (e.g., 1:1 to 2: 1).
In the second scheme, the molar ratio of the compound containing the dipyrazole ring shown in formula I to the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment shown in formula X can be a molar ratio conventionally used in the reaction in the art, for example, 0.05:1-0.5:1 (e.g., 0.05:1-0.01: 1).
In scheme two, the molar ratio of the aryl or heteroaryl boron reagent comprising the structural fragment of formula IX to the halogenated arene or halogenated heteroarene comprising the structural fragment of formula X may be a molar ratio conventional in the art for such reactions, e.g., (0.5-2):1 (and, e.g., (1-1.2): 1).
In the second scheme, the dosage of the solvent is not limited, so that the reaction is not influenced; for example, the molar volume ratio of the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment shown in the formula X to the solvent can be 0.1mol/L-0.5mol/L (for example, 0.25mol/L-0.3 mol/L).
In scheme two, the molar ratio of the base to the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment represented by formula X can be a molar ratio conventional in the art such as (1-2):1 (and also such as (1.5-1.8): 1).
In scheme two, the temperature of the C-C coupling reaction can be a temperature conventional in the art, such as room temperature to 150 ℃, and preferably 80 ℃ to 90 ℃ in the present invention.
In scheme two, the progress of the C-C coupling reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and generally the reaction end point is determined as the disappearance or no longer reaction of the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment shown in formula X. The reaction time may be from 1 to 24 hours, for example from 3 to 4 hours.
In a preferred embodiment of the present invention, said X is1And X2Independently halogen, and the halogen is independently Cl, Br or I.
In a preferred embodiment of the invention, in the first embodiment, the amide compound containing the structural fragment shown in formula VI is shown in formula VI'; the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment shown in the formula VII is shown in a formula VII'; the corresponding amide compound containing the structural fragment shown in the formula VIII is prepared and obtained and is shown in the formula VIII';
Figure BDA0002349582330000051
wherein R is1Is C1-C6By one or more R1-1Substituted C1-C6Alkyl of (C)6-C12Aryl radicals, substituted by one or more R1-2Substituted C6-C12Aryl, 5-10 membered heteroaryl, or substituted with one or more R1-3Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by one or more R1-3In the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, O and S, and the number of the heteroatom is 1-4; when the substituents are plural, the same or different;
R2is C6-C12Aryl radicals, substituted by one or more R2-1Substituted C6-C12Aryl, 5-10 membered heteroaryl, or substituted with one or more R2-2Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by one or more R2-2In the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, O and S, and the number of the heteroatom is 1-4; when the substituents are plural, the same or different;
R1-1、R1-2、R1-3、R2-1and R2-2Independently CN, C1-C6Alkyl, C substituted by one or more halogens1-C6Alkyl of (C)1-C6alkyl-O-or phenyl of (a); when the substituent is plural, the same or different.
In a preferred embodiment of the present invention, in scheme one, R is as defined in scheme I1Is C1-C6Or by one or more R1-1Substituted C1-C6C in alkyl of (A)1-C6The alkyl group (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) of (A) may be C1～C4Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), for example methyl.
In a preferred embodiment of the invention, in scheme one, R1Is C6-C12Aryl radicals or by one or more R1-2Substituted C6-C12C in aryl6-C12Aryl is phenyl.
In a preferred embodiment of the invention, in scheme one, R1Is 5-10 membered heteroaryl or substituted by one or more R2-2The 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is a pyridyl group (e.g.
Figure BDA0002349582330000061
)。
In a preferred embodiment of the invention, in scheme one, R2Is C6-C12Aryl radicals or by one or more R2-1Substituted C6-C12C in aryl6-C12Aryl is phenyl.
In a preferred embodiment of the invention, in scheme one, R2Is 5-10 membered heteroaryl or substituted by one or more R2-2The 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is a pyridyl group (e.g.
Figure BDA0002349582330000062
)。
In a preferred embodiment of the invention, in scheme one, R1-1、R1-2、R1-3、R2-1And R2-2Independently of each otherIs C1-C6Alkyl, C substituted by one or more halogens1-C6Alkyl or C1-C6C in alkyl-O-of1-C6The alkyl group (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) of (A) may be C1～C4Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), for example methyl.
In a preferred embodiment of the invention, in scheme one, R1-1、R1-2、R1-3、R2-1And R2-2Independently C substituted by one or more halogens1-C6The halogen in the alkyl group of (a) is independently F, Cl, Br or I.
In a preferred embodiment of the invention, in scheme one, R1-1、R1-2、R1-3、R2-1And R2-2Independently C substituted by one or more halogens1-C6One or more of said alkyl groups in (b) may be 1, 2 or 3. Said C substituted by one or more halogens1-C6The alkyl group of (A) may be-CF3。
In a preferred embodiment of the invention, in scheme one, when R is2Is represented by one or more R2-1Substituted C6-C12When aryl is used, the substituted position may be ortho, meta or para.
In a preferred embodiment of the invention, in scheme one, when R is2Is represented by one or more R2-2Substituted 5-10 membered heteroaryl, the substituted position may be ortho or meta.
In a preferred embodiment of the present invention, in the first embodiment, the amide compound containing the structural fragment shown in formula VI, the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment shown in formula VII, and the corresponding amide compound containing the structural fragment shown in formula VIII are selected from any one of the following groups:
Figure BDA0002349582330000063
Figure BDA0002349582330000071
in a preferred embodiment of the invention, in scheme two, the aryl or heteroaryl boron reagent comprising a structural fragment as shown in formula IX is as shown in formula IX-1 or IX-2; the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment shown in the formula X is shown in a formula X'; preparing a corresponding compound containing a structural fragment shown in a formula XI and shown in a formula XI';
Figure BDA0002349582330000081
wherein R is3Is C6-C12Aryl radicals, substituted by one or more R3-1Substituted C6-C12Aryl, 5-10 membered heteroaryl, or substituted with one or more R3-2Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by one or more R3-2In the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, O and S, and the number of the heteroatom is 1-4; when the substituents are plural, the same or different;
R4is C6-C12Aryl radicals, substituted by one or more R4-1Substituted C6-C12Aryl, 5-10 membered heteroaryl, or substituted with one or more R4-2Substituted 5-10 membered heteroaryl; said 5-to 10-membered heteroaryl group being substituted by one or more R4-2In the 5-10 membered heteroaryl in the substituted 5-10 membered heteroaryl, the heteroatom is selected from one or more of N, O and S, and the number of the heteroatom is 1-4; when the substituents are plural, the same or different;
R3-1、R3-2、R4-1and R4-2Independently is NO2Halogen, C1-C6Alkyl, C substituted by one or more halogens1-C6Alkyl groups of (a); when the substituents are plural, the same or different;
R5and R6Independently is hydrogen or C1-C6An alkyl group;
or, R5And R6Is connected with
Figure BDA0002349582330000082
Together form an unsubstituted or substituted 5-to 6-membered heterocycloalkyl; said substitution means substitution with one or more of the following substituents: c1～C6Alkyl or phenyl; when the substituent is plural, the substituents may be the same or different.
In a preferred embodiment of the invention, in scheme two, R3Is C6-C12Aryl radicals or by one or more R3-1Substituted C6-C12C in aryl6-C12Aryl is phenyl.
In a preferred embodiment of the invention, in scheme two, R3Is 5-10 membered heteroaryl or substituted by one or more R3-2The 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is a pyridyl group.
In a preferred embodiment of the invention, in scheme two, R4Is C6-C12Aryl radicals or by one or more R4-1Substituted C6-C12C in aryl6-C12Aryl is phenyl.
In a preferred embodiment of the invention, in scheme two, R4Is 5-10 membered heteroaryl or substituted by one or more R4-2The 5-10 membered heteroaryl group in the substituted 5-10 membered heteroaryl group is a pyridyl group.
In a preferred embodiment of the invention, in scheme two, R3-1、R3-2、R4-1And R4-2Independently is C1-C6Alkyl or C substituted by one or more halogens1-C6C in alkyl of (A)1-C6The alkyl group (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) of (A) may be C1～C4Alkyl radicals (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), and also, for example, methyl。
In a preferred embodiment of the invention, in scheme two, R3-1、R3-2、R4-1And R4-2Independently halogen or C substituted by one or more halogens1-C6The halogen in the alkyl group of (a) is independently F, Cl, Br or I.
In a preferred embodiment of the invention, in scheme two, R3-1、R3-2、R4-1And R4-2Independently C substituted by one or more halogens1-C6In the alkyl group of (a), one or more of them may be 1, 2 or 3. Said C substituted by one or more halogens1-C6The alkyl group of (A) may be-CF3。
In a preferred embodiment of the present invention, in scheme II, R is5And R6Independently is C1-C6C in alkyl of (A)1-C6The alkyl group (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) of (A) may be C1～C4Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), for example methyl.
In a preferred embodiment of the invention, in scheme two, when R3And R4Is connected with
Figure BDA0002349582330000091
Together form an unsubstituted or substituted 5-to 6-membered heterocycloalkyl, said substituents being C1-C6When there is an alkyl group, said C1-C6The alkyl group (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) of (A) may be C1～C4Alkyl groups (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), for example methyl.
In a preferred embodiment of the invention, in scheme two, when R3And R4Is connected with
Figure BDA0002349582330000092
Together shareWhen unsubstituted or substituted 5-to 6-membered heterocycloalkyl is formed, the 5-to 6-membered heterocycloalkyl may be
Figure BDA0002349582330000093
In a preferred embodiment of the invention, in scheme two, when R4Is represented by one or more R4-1Substituted C6-C12When aryl is used, the substituted position may be ortho, meta or para.
In a preferred embodiment of the invention, in scheme two, when R4Is represented by one or more R4-2Substituted 5-10 membered heteroaryl, the substituted position may be ortho or meta.
In a preferred embodiment of the present invention, in scheme two, the aryl or heteroaryl boron reagent containing the structural fragment represented by formula IX, the halogenated aromatic hydrocarbon or halogenated heteroarene containing the structural fragment represented by formula X, and the corresponding compound containing the structural fragment represented by formula XI are selected from any one of the following groups:
Figure BDA0002349582330000094
the invention also provides a preparation method of the compound containing the dipyrazole ring as shown in the formula I, which comprises the following steps:
step (1): adding alkali into a mixture of a double-pyrazole ring compound shown as a formula I-1 and a solvent for a displacement reaction to obtain a mixed system;
step (2): adding an organophosphorus compound shown as a formula I-2 into the mixed system in the step (1) to carry out a phosphido reaction shown as the following to obtain a compound containing a dipyrazole ring shown as the formula I,
Figure BDA0002349582330000095
wherein R is1、R2And R3The definitions of (A) and (B) are the same as described above; x is halogen.
In a preferred embodiment of the invention, X is fluorine, chlorine, bromine or iodine, for example chlorine.
The preparation method can be carried out under the protective gas conventional in the reaction in the field; such as nitrogen or argon.
In the preparation method, the solvent can be a solvent conventional in the reaction in the field, such as an ether solvent (for example, one or more of tetrahydrofuran, methyltetrahydrofuran and dimethyl ether); tetrahydrofuran is preferred in the present invention.
In the preparation method, the base can be a base which is conventional in the reaction in the field, such as an alkyl lithium reagent (for example, a solution of an alkane solvent of alkyl lithium); the present invention is preferably a 2.5M n-butyllithium solution in n-hexane.
In the preparation method, the dosage of the solvent is not limited so as not to influence the reaction; for example, the volume-to-mass ratio of the solvent to the bis-pyrazole ring compound shown in formula I-1 can be the volume-to-mass ratio conventional in the reaction in the field, such as 5ml/g to 20ml/g, and the volume-to-mass ratio is preferably 10ml/g to 15 ml/g.
In the preparation method, the molar ratio of the base to the double-pyrazole ring compound shown in the formula I-1 can be a molar ratio which is conventional in the reaction in the field, such as 1:1-3:1, and the invention is preferably 1.2:1-1.5: 1.
In the preparation method, the molar ratio of the organophosphorus compound shown in the formula I-2 to the dipyrazolyl ring compound shown in the formula I-1 can be a molar ratio which is conventional in the reaction in the field, such as 1:1-2:1, and the invention is preferably 1.2:1-1.5: 1.
In the step (1), the base is preferably added dropwise to the double-pyrazole ring compound shown in the formula I-1 and the solvent. The temperature of adding the base to the mixture of the double pyrazole ring compound shown in the formula I-1 and the solvent is preferably-20 ℃ to-10 ℃.
The temperature of the metathesis reaction is preferably from-20 ℃ to-10 ℃.
And (2) preferably dropwise adding the organophosphorus compound shown in the formula I-2 into the mixed system in the step (1). The temperature of the organic phosphorus compound shown in the formula I-2 added into the mixed system in the step (1) is preferably-20 ℃ to-10 ℃.
The temperature of the phosphido reaction is preferably from-20 ℃ to 30 ℃.
The progress of the phosphido reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the end point of the reaction is generally determined as the disappearance or no longer reaction of the bispyrazole ring compound shown in formula I-1. The reaction time may be from 1 to 48 hours, for example from 8 to 24 hours.
In the preparation method, the method can further comprise post-treatment, and the post-treatment operation can be the operation of the conventional post-treatment in the preparation method in the field; for example, it comprises the following steps: after the phosphine generation reaction is finished, quenching reaction, extracting, washing, drying, concentrating and purifying. The reagent used for quenching the reaction may be water. The extraction reagent may be an ethereal solvent (e.g., methyl tert-butyl ether and/or isopropyl ether). The washing reagent may be a saturated saline solution. The reagent used for drying can be anhydrous sodium sulfate. The purification mode can be pulping washing, column chromatography (preferably column chromatography under the protection of nitrogen) or crystallization. In the purification mode, the reagent used in the pulping washing can be an alkane solvent (such as n-heptane). The reagents used for the column chromatography may be petroleum ether and ethyl acetate (10: 1 by volume is preferred). The diameter-height ratio of the column used for column chromatography can be 3: 10. The dissolving solvent for the crystallization may be a cyclic ether-based solvent (e.g., tetrahydrofuran), and the anti-solvent may be an alkane-based solvent (e.g., n-heptane).
The preparation method of the compound containing the dipyrazole ring shown in the formula I can further comprise the following steps: in a solvent, in the presence of acid, performing cyclization reaction on phenylhydrazine (shown as a formula I-4) and the compound shown as a formula I-3 to obtain the compound shown as a formula I-1;
Figure BDA0002349582330000111
wherein R is3The definition of (A) is as described above.
In the cyclization reaction, the solvent may be a solvent conventional in the art such as an amide-based solvent (again, for example, N-dimethylformamide DMF and/or N-methylpyrrolidone NMP).
In the cyclization reaction, the dosage of the solvent is not limited so as not to influence the reaction; for example, the volume-to-mass ratio of the solvent to the phenylhydrazine can be a volume-to-mass ratio conventional in such reactions in the art, such as 1ml/g to 10 ml/g; preferably 4ml/g to 6ml/g (again e.g. 4.8ml/g, 5.5ml/g, 5.6 ml/g).
In the cyclization reaction, the acid may be an acid conventional in such reactions in the art, such as acetic acid.
In the ring formation reaction, the volume mol ratio of the acid to the phenylhydrazine can be a volume mol ratio conventional in such reactions in the art, such as 0.1L/mol to 1.0L/mol (again, for example, 0.3L/mol to 0.45L/mol).
In the cyclization reaction, the phenylhydrazine can be in a form which is conventional in the reactions in the field, such as an alcoholic solution; the present invention is preferably a methanol solution of phenylhydrazine, and the mass-to-volume ratio of the phenylhydrazine in the methanol solution can be a mass-to-volume ratio conventional in such reactions in the art, such as 0.1g/mL to 0.5g/mL (e.g., 0.12g/mL, 0.145g/mL, 0.21 g/mL).
The temperature of the cyclization reaction may be a temperature conventional in such reactions in the art, for example room temperature to 60 ℃; preferably from 40 ℃ to 50 ℃ (e.g., 45 ℃ and 48 ℃).
The progress of the cyclization reaction can be monitored by a monitoring method (e.g., TLC, HPLC or NMR) which is conventional in the art, and the end point of the reaction is generally determined by the disappearance or no longer reaction of the compound represented by the formula I-3. The reaction time may be from 1 to 48 hours, for example from 12 to 20 hours.
In the cyclization reaction of the preparation method, the preparation method can further comprise post-treatment, and the operation of the post-treatment can be the operation of the conventional post-treatment in the preparation method in the field; for example, it comprises the following steps: after the cyclization reaction is finished, adding water to separate out a solid, filtering, washing and purifying. The reagents used for washing can be water, methanol and n-heptane in sequence. And carrying out column chromatography or crystallization on the purified product. The dissolving solvent for the crystallization may be an aromatic hydrocarbon solvent (e.g., toluene), and the anti-solvent may be an alkane solvent (e.g., n-heptane).
The preparation method of the compound containing the dipyrazole ring shown in the formula I can further comprise the following steps:
carrying out substitution reaction shown as the following on a compound shown as a formula I-6 and a compound shown as a formula I-5 in a solvent to obtain a compound shown as a formula I-3;
Figure BDA0002349582330000112
wherein R is3The definition of (A) is as described above.
The substitution reaction can be carried out under a protective gas which is conventional in the reaction in the field; such as nitrogen or argon.
In the substitution reaction, the solvent may be a solvent conventional in the art, such as an amide-based solvent (again, for example, N-dimethylformamide DMF and/or N-methylpyrrolidone NMP).
In the substitution reaction, the dosage of the solvent is not limited, so that the reaction is not influenced; for example, the volume to mass ratio of the solvent to the compound of formula I-6 can be a volume to mass ratio conventional in such reactions in the art, such as from 1ml/g to 10ml/g (again, for example, from 2.5ml/g to 3 ml/g).
In the substitution reaction, the molar ratio of the compound shown in the formula I-6 to the compound shown in the formula I-5 can be a molar ratio which is conventional in the reactions in the field, such as 3:1-4:1 (for example, 3.3:1-3.5: 1).
In the substitution reaction, the compound represented by the formula I-6 is preferably added dropwise to the compound represented by the formula I-5 and the solvent.
In the substitution reaction, the temperature of the substitution reaction can be a temperature conventional in the reactions of this type in the art, for example, room temperature to 60 ℃; preferably from 40 ℃ to 50 ℃ (e.g., 45 ℃ and 48 ℃).
In the substitution reaction, the progress of the substitution reaction can be detected by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and the end point of the reaction is generally determined by disappearance or no longer reaction of the compound represented by the formula I-5. The reaction time may be from 1 to 48 hours, for example from 6 to 18 hours.
In the substitution reaction, preferably, the compound shown as the formula I-1 is prepared by directly using the compound in the cyclization reaction without post-treatment after the substitution reaction is finished.
The preparation method of the compound containing the dipyrazole ring shown in the formula I can further comprise the following steps: in a solvent, carrying out a halogenation reaction on a compound shown in a formula I-7 and a bromine reagent as shown in the specification to obtain the compound shown in the formula I-5,
Figure BDA0002349582330000121
the reaction conditions and procedures for the halogenation reaction may be those conventional in such reactions in the art. For example:
in the halogenation reaction, the solvent may be a solvent conventional in the art, such as an amide-based solvent (again, for example, N-dimethylformamide DMF and/or N-methylpyrrolidone NMP).
In the halogenation reaction, the dosage of the solvent is not limited so as not to influence the reaction; for example, the volume-to-mass ratio of the solvent to the compound represented by formula I-7 can be the volume-to-mass ratio conventionally used in such reactions in the art, such as 1ml/g to 10ml/g, and the present invention is preferably 3ml/g to 4 ml/g.
In the halogenation reaction, the bromine reagent may be a solvent conventional in such reactions in the art, such as bromine and/or N-bromosuccinimide NBS.
The molar ratio of the bromine reagent to the compound of formula I-7 in the halogenation reaction can be any ratio conventionally used in such reactions, such as from 1:1 to 2:1 (again, for example, (1.1 to 1.22): 1).
The temperature of the halogenation reaction may be a reaction temperature conventional in such reactions in the art, and room temperature is particularly preferred in the present invention.
The progress of the halogenation can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC or NMR), and is generally determined as the end point of the reaction when the compound of formula I-7 disappears or ceases to react. The reaction time may be 5 to 60 minutes.
Preferably, the compound shown in the formula I-3 is prepared by directly using the compound in the substitution reaction without post-treatment after the halogenation reaction is finished.
The invention also provides a compound shown as the following formula I-1 and a compound shown as the formula I-3;
Figure BDA0002349582330000131
wherein R is3The definition of (A) is as described above.
In a preferred embodiment of the present invention, the compound represented by the formula I-1 may be
Figure BDA0002349582330000132
In a preferred embodiment of the present invention, the compound represented by the formula I-3 may be
Figure BDA0002349582330000133
The invention also provides a preparation method of the compound shown in the formula I-1, which comprises the following steps: in a solvent, in the presence of acid, performing cyclization reaction on phenylhydrazine (shown as a formula I-4) and the compound shown as a formula I-3 to obtain the compound shown as a formula I-1;
Figure BDA0002349582330000134
wherein R is3The definition of (A) is as described above.
The reaction conditions and operations in the preparation method are as described above.
The invention also provides a preparation method of the compound shown in the formula I-3, which comprises the following steps: carrying out substitution reaction shown as the following on a compound shown as a formula I-6 and a compound shown as a formula I-5 in a solvent to obtain a compound shown as a formula I-3;
Figure BDA0002349582330000141
wherein R is3The definition of (A) is as described above.
The reaction conditions and operations in the preparation method are as described above.
The invention also provides a crystal form of the compound shown as the formula IV' shown as the specification;
Figure BDA0002349582330000142
the crystal is an orthogonal crystal, the space group is Pccn, and the unit cell parameters are as follows:
Figure BDA0002349582330000143
α＝90°，
Figure BDA0002349582330000144
β＝90°，
Figure BDA0002349582330000145
γ 90 °, Z4, unit cell volume
Figure BDA0002349582330000146
。
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds. When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left.
Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. E.g. C1-C6Alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4,5, or 6 carbon atoms. The total number of carbon atoms in the shorthand notation excludes carbons that may be present in a substituent of the group.
Numerical ranges defined in the substituents herein, such as 0 to 4, 1-4, 1 to 3, etc., indicate integers within the range, such as 1-6 being 1, 2, 3, 4,5, 6.
In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.
The term "comprising" is open-ended, i.e. comprising what is specified in the invention, but does not exclude other aspects.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including deuterium and hydrogen variants, so long as the valency of the particular atom is normal and the substituted compound is stable.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1～C6Alkyl "or" C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group; "C1-4Alkyl refers specifically to independently disclosed methyl, ethyl, C3Alkyl (i.e. propyl, including n-propyl and isopropyl), C4Alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
In this application, the term "alkyl" as a group or part of another group (e.g., as used in halo-substituted alkyl and the like groups) is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms. As in "C1～C6Alkyl is defined to include groups having 1, 2, 3, 4,5, or 6 carbon atoms in a straight or branched chain configuration.
Wherein propyl is C3Alkyl (including isomers such as n-propyl or isopropyl); butyl being C4Alkyl (including isomers such as n-butyl, sec-butyl, isobutyl, or tert-butyl); pentyl is C5Alkyl (including isomers, e.g. n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3)-methyl-1-butyl, isoamyl, tert-amyl or neopentyl); hexyl is C6Alkyl (including isomers such as n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl).
In this application, as a group or part of another group, unless otherwise specified, the term "cycloalkyl" means a saturated monocyclic, polycyclic or bridged carbocyclic substituent consisting only of carbon and hydrogen atoms, and which may be attached to the remainder of the molecule by a single bond via any suitable carbon atom; when polycyclic, there may be a fused ring system, bridged ring system or spiro ring system in which the fused, bridged or spiro ring is linked (i.e., two geminal hydrogens on a carbon atom are replaced with an alkylene group). The cycloalkyl substituents may be attached to the central molecule via any suitable carbon atom. In some embodiments, C3～C6Cycloalkyl groups of (C) include cyclopropyl (C)3) Cyclobutyl (C)4) Cyclopentyl (C)5) And cyclohexyl (C)6). In some embodiments, C3～C10Examples of the cycloalkyl group of (1) include the above-mentioned C3～C6Cycloalkyl groups together with cycloheptyl (C)7) Cyclooctyl (C)8) Cyclononyl (C)9) And cyclodecyl (C)10)。
In this application, the term "aryl" as a group or part of another group refers to a group having 6-12 ring atoms (preferably 6-10 ring atoms) and zero heteroatoms provided in an aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n +2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) ("C)6-C12Aryl radical ", preferably" C6-C10Aryl "). Examples of the above aryl unit include phenyl, naphthyl, phenanthryl, or anthryl.
In this application, the term "heteroaryl" as a group or part of another group refers to a group ("5-10 membered heteroaryl") having a carbon atom and a 5-10 membered monocyclic or bicyclic 4n +2 aromatic ring system (e.g., having 6 or 10 shared p electrons in a cyclic array) of 1-4 heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits. In some embodiments, the heteroaryl is a 5-membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S. In some embodiments, the heteroaryl is one or more selected from N, O and S, and is a monocyclic or bicyclic 6-to 10-membered heteroaryl with 1-4 heteroatoms, preferably 6-membered heteroaryl or 8-to 10-membered bicyclic heteroaryl.
Exemplary 5-membered heteroaryl groups include, but are not limited to: pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, furazanyl, oxatriazolyl or tetrazolyl. Exemplary 6-membered heteroaryl groups include, but are not limited to: pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl or tetrazinyl. Exemplary 5, 6-bicyclic heteroaryl groups (9-membered heteroaryl groups) include, but are not limited to: indolyl, isoindolyl, benzothienyl, isobenzothienyl, benzofuryl, isobenzofuryl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, indazolyl, isoindolyl, benzotriazolyl, benzooxadiazolyl, benzothiadiazolyl, indolizinyl, pyrrolopyridyl, pyridooxazolyl, pyridothiazolyl, imidazopyridazinyl, imidazopyrazinyl, pyridoimidazolyl, triazolopyridazinyl, triazolopyrazinyl, triazolopyrimidinyl, triazolopyridinyl, pyridothiazolyl, tetrazolopyridinyl, or purinyl. Exemplary 6, 6-bicyclic heteroaryl groups (10-membered heteroaryl groups) include, but are not limited to: quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, naphthyridinyl, pyridopyrimidine, pyrazinopyridazine or pteridinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to: carbazolyl, dibenzofuranyl, carbolinyl, acridinyl, phenanthridinyl, diazaphenanthrenyl, phenazinyl, bipyridyl, or bistritenyl.
The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.
When no atom is indicated in the listed substituents for connecting to a compound included in the general chemical structure but not specifically mentioned, such substituent may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
In some specific structures, when an alkyl group is expressly indicated as a linking group, then the alkyl group represents a linked alkylene group, e.g., the group "halo-C1～C6C in alkyl1-C6Alkyl is understood to mean C1～C6An alkylene group.
It should be understood that as used herein, singular forms, such as "a", "an", include plural references unless the context clearly dictates otherwise. Furthermore, the term "comprising" is open-ended, i.e. including what is specified in the invention, but not excluding other aspects.
The present invention employs conventional methods of mass spectrometry, elemental analysis, and the various steps and conditions can be referred to those conventional in the art unless otherwise indicated.
In addition, it should be noted that, unless otherwise explicitly indicated, the description of "… independently" as used herein is to be understood in a broad sense to mean that each individual entity so described is independent of the other and may be independently the same or different specific groups. In more detail, the description "… is independently" can mean that the specific options expressed between the same symbols do not affect each other in different groups; it can also be said that in the same group, the specific options expressed between the same symbols do not affect each other.
It will be understood by those skilled in the art that, in accordance with the convention used in the art, the structural formulae used in the radicals described herein
Figure BDA0002349582330000161
Means that the corresponding group is linked to other fragments, groups in the compound through this site.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the compound containing the dipyrazole ring provided by the invention can be used as a ligand, has high selectivity, and is suitable for the application range of amide in C-N coupling and C-C coupling reaction of aryl boric acid and aryl chloride, especially the coupling with chlorinated aromatic hydrocarbon.
Drawings
FIG. 1 is a structural diagram of X-ray diffraction of a single crystal of the compound represented by the formula IV' obtained in example 37.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, HPLC analysis methods: a chromatographic column: agilent, XDB-C18150 cm X4.6 mm,5 μm, column temperature 40 ℃, detection wavelength 230 nm. Mobile phase A: 0.1 percent ofH3PO4Aqueous solution) mobile phase B: acetonitrile (chromatographically pure); the flow rate was 1.0 ml/min.
Time(min) A(％) B(％)
0 90 10
15 10 90
20 10 90
EXAMPLE 1 preparation of intermediate a
Figure BDA0002349582330000171
5g (0.023mol) of 1, 3-diphenyl-propanedione and 20mL (4mL/g) of N-methylpyrrolidone (NMP) were charged into a 250mL four-necked round-bottomed flask, and 4.30g (0.027mol,1.2eq) of bromine was added dropwise at room temperature over 5 minutes to give a yield of 97% (the yield was obtained by HPLC area normalization, the same applies hereinafter). Directly heating to 45 ℃, dropwise adding 6.43g (0.078mol,3.5eq) of 3-methylpyrazole at the temperature, keeping the temperature for 12h after finishing dropwise adding for 5 minutes, and obtaining the yield of 83%; without post-treatment, 15mL (3mL/g) of acetic acid was added directly, 30mL (6mL/g ratio of solution volume to 1, 3-diphenyl-propanedione volume) of a methanol solution containing 3.6g (0.033mol,1.5eq) of phenylhydrazine was added, and after completion of dropwise addition for 10 minutes, the reaction was carried out at 45 ℃ for 12 hours with a yield of 80%. After the reaction is finished, 20mL of water is added, the product is separated out from the solvent, filtered, washed by 20mL of water, washed by 5mL of methanol and washed by 5mL of n-heptane, thus obtaining 7.01g of a crude light yellow solid with the purity of 76%, the crude product is dissolved in 10mL of hot toluene (65-75 ℃) and added with n-heptane until the solid just appears, the temperature is kept for 10 minutes and is reduced to 0 ℃, filtered, washed by a small amount of n-heptane and dried, thus obtaining a white product I-1a, the purity of the high performance liquid chromatography is 98%, the total yield is 65%, the mass is 5.09g, and the melting point: 135.2-135.7 ℃.
1H NMR(400MHz,DMSO)δ7.73(s,1H),7.62–7.23(m,11H),7.17(d,J＝6.4Hz,3H),6.18(s,1H),3.54(s,3H),2.20(s,3H).13C NMR(101MHz,dmso)δ149.52(s),147.27(d,J＝2.1Hz),141.24(s),139.71(s),135.11(d,J＝7.3Hz),131.29(d,J＝5.1Hz),129.70(t,J＝8.9Hz),129.00(d,J＝13.2Hz),128.62(d,J＝3.1Hz),127.74(d,J＝2.4Hz),126.63(d,J＝6.8Hz),125.72(d,J＝9.0Hz),121.47(s),107.04(s),13.88(s).。
Example 2
15g (0.067mol) of 1, 3-diphenyl-propanedione and 60mL (4mL/g) of N-methylpyrrolidone were placed in a 250mL four-necked round-bottomed flask, and 13.12g (0.082mol,1.22eq) of bromine was added dropwise at room temperature over 20 minutes, resulting in a yield of 98%. Directly heating to 45 ℃, dropwise adding 19.28g (0.23mol,3.5eq) of 3-methylpyrazole at the temperature, keeping the temperature for 18h after dropwise adding is finished for 10 min, and obtaining the yield of 85%; without any post-treatment, 45mL (3mL/g) of acetic acid was added directly, 60mL (4mL/g) of a methanol solution containing 10.86g (0.10mol,1.5eq) of phenylhydrazine was added, and after dropping for 20 minutes, the reaction was carried out at 45 ℃ for 20 hours with a yield of 83%. Adding 80mL of water after the reaction is finished, separating out a product from a solvent, filtering, washing with 30mL of water, washing with 15mL of methanol and washing with 15mL of n-heptane to obtain a crude product, analyzing the purity of the crude product by High Performance Liquid Chromatography (HPLC) to obtain 21.3g of a light yellow solid with 81%, dissolving the crude product in 60mL of hot toluene (55 ℃), adding n-heptane when the crude product is hot until the solid just appears, preserving the temperature for 10 minutes, cooling to 0 ℃, filtering, washing with a small amount of n-heptane, and drying to obtain a white product I-1a, wherein the HPLC analysis purity is 98.6%, the yield is 68%, the mass is 16.45 g: 135.2-135.7 ℃.
Example 3
40g (0.178mol) of 1, 3-diphenyl-propanedione and 120mL (3mL/g) of N-methylpyrrolidone were placed in a 500mL four-necked round-bottomed flask, and 32.50g (0.20mol,1.1eq) of bromine was added dropwise at room temperature over 20 minutes, giving a yield of 98%. Directly heating to 48 ℃, dropwise adding 48.06g (0.0.58mol,3.3eq) of 3-methylpyrazole at the temperature, keeping the temperature for 6-10h after the dropwise adding is finished within 10 minutes, and obtaining the yield of 86%; without any post-treatment, 70mL (1.8mL/g) of acetic acid was added, 120mL (3mL/g) of a methanol solution containing 25.18g (0.232mol,1.3eq) of phenylhydrazine was added, and after dropping for 20 minutes, the reaction was carried out at 40 ℃ for 15 hours with a yield of 83%. After the reaction is finished, 100mL of water is added, the product is separated out from the solvent, filtered, washed by 50mL of water, washed by 30mL of methanol and washed by 20mL of n-heptane, thus obtaining 56.9g of crude product with HPLC purity of 76% light yellow solid, the crude product is dissolved in 80mL of hot toluene (70 ℃) and added with n-heptane while the crude product is hot until the solid just appears, the temperature is kept for 10 minutes and reduced to 0 ℃, filtered, washed by a small amount of n-heptane, and dried to obtain a white product I-1a, the HPLC analysis purity is 98.4%, the yield is 70%, the mass is 42.6g, and the melting point: 135.2-135.7 ℃.
EXAMPLE 4 preparation of ligand [ IV ]
Figure BDA0002349582330000181
Under nitrogen atmosphere, 1.03g (2.82mmol) of the intermediate a is added into a 100ml three-neck round-bottom flask, dissolved by 15ml (15ml/g) of tetrahydrofuran, 1.7ml (1.5eq) of a 2.5M n-butyllithium solution of n-hexane is dropwise added at-30 ℃ for 5 minutes, the temperature is kept for 1.5 hours, 0.81g (1.5eq) of 95 percent di-tert-butylphosphonium chloride is dropwise added for 5 minutes, the temperature is naturally raised to 0 ℃ and kept for 1 hour, the temperature is naturally raised to room temperature, and the mixture is stirred overnight. Quenching the reaction solution with water, adding methyl tert-butyl ether to extract the product into an organic phase (the effect of isopropyl ether treatment is the same as that of methyl tert-butyl ether treatment, the same is applied below), washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, spin-drying the organic phase, heating the solid to 45 ℃, adding tetrahydrofuran solution, adding n-heptane until solid appears, keeping the temperature for five minutes, cooling to 0 ℃, filtering, washing with a small amount of n-heptane to obtain a white solid [ IV ], wherein the HPLC purity is 94.8%, and the yield is: 74%, mass 0.98g, melting point: 157.2-158.1 ℃.
1H NMR(400MHz,CDCl3)δ7.49(s,2H),7.39(s,2H),7.36–7.18(m,8H),7.15(s,3H),6.38(s,1H),2.51(s,3H),0.70(d,J＝11.9Hz,9H),0.57(d,J＝11.9Hz,9H).13C NMR(101MHz,cdcl3)δ149.71(s),148.64(d,J＝1.7Hz),144.00(s),143.75(s),141.23(s),140.22(s),132.18(s),129.93(s),128.95–128.46(m),128.24(s),128.02(s),127.50(d,J＝15.3Hz),125.51(s),120.98(s),113.40(d,J＝4.4Hz),77.39(s),77.07(s),76.76(s),31.85(dd,J＝18.2,3.2Hz),29.68(dd,J＝29.7,14.7Hz),13.83(s).
Example 5
5.0g (13.3mmol) of the intermediate a was charged into a 250ml three-necked round-bottomed flask under nitrogen atmosphere, dissolved in 50ml (10ml/g) of tetrahydrofuran, 6.5ml (1.2eq) of a 2.5M n-butyllithium solution in n-hexane was dropped at-20 ℃ for 15 minutes, after dropping, the temperature was maintained for 1 hour, 3.0g (1.2eq) of 95% di-tert-butylphosphonium chloride was dropped for 10 minutes, after dropping, the temperature was maintained for 1 hour, the mixture was allowed to spontaneously warm to room temperature, and the mixture was stirred for 1 hour. Quenching the reaction liquid with water, adding isopropyl ether to extract a product into an organic phase, washing the organic phase with saturated saline, drying the organic phase with anhydrous sodium sulfate, spin-drying the organic phase, adding n-heptane, heating to dissolve, cooling to 0 ℃, filtering, washing with a small amount of n-heptane to obtain a white solid, analyzing the purity by HPLC (high performance liquid chromatography) to obtain the yield of 96 percent: 75%, mass 4.89g, melting point: 157.2-158.1 ℃.
EXAMPLE 6 preparation of ligand [ V ]
Figure BDA0002349582330000191
1.03g (2.73mmol) of the intermediate a is added into a 100ml three-neck round-bottom flask under nitrogen atmosphere, dissolved by 15ml (15ml/g) of tetrahydrofuran, 1.64ml (1.5eq) of a 2.5M n-butyllithium solution of n-hexane is added dropwise at-40 ℃ after 10 minutes of dropwise addition, the temperature is kept for 1.5 hours, 1.02g (1.5eq) of 93 percent dicyclohexyl phosphorus chloride is added dropwise after 5 minutes of dropwise addition, the temperature is kept for 1 hour, the temperature is naturally raised to room temperature, and the mixture is stirred overnight. Quenching the reaction liquid with water, adding methyl tert-butyl ether to extract the product into an organic phase, washing the organic phase with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, analyzing that 7.0% of raw materials are not reacted completely, 25.4% of oxidation products and 52.9% of products, obtaining a white solid [ V ] through column chromatography, and analyzing the purity by high performance liquid chromatography to 93% and the yield by using a high performance liquid chromatography: 34%, mass 0.56g, melting point: 181.0 to 181.7 ℃. (the column chromatography has a height of 10cm and a diameter of 3cm, and the ratio of petroleum ether to ethyl acetate is 10: 1).
1H NMR(400MHz,CDCl3)δ7.48(d,J＝5.2Hz,2H),7.42(d,J＝6.1Hz,2H),7.37–6.95(m,11H),6.15(s,1H),2.48(s,3H),1.34(dd,J＝19.7,13.1Hz,10H),1.16(d,J＝10.9Hz,1H),0.81(d,J＝49.8Hz,7H),0.54(d,J＝9.7Hz,1H),0.43(s,2H),0.24(d,J＝10.0Hz,1H).13C NMR(101MHz,cdcl3)δ149.52–149.20(m),143.78(d,J＝18.6Hz),141.31(d,J＝0.9Hz),140.13(s),131.70(s),129.55(s),128.84(s),128.32(dd,J＝21.8,3.9Hz),127.99(s),127.37(d,J＝13.9Hz),125.28(s),120.99(s),112.09(d,J＝4.1Hz),77.34(d,J＝11.1Hz),77.08(s),76.76(s),33.30(dd,J＝9.2,3.6Hz),29.46(d,J＝15.1Hz),28.65(d,J＝8.4Hz),28.28(d,J＝9.3Hz),27.41–26.63(m),26.03(s),13.85(s).
Example 7
10g (0.027mol) of the intermediate a was added to a 500ml three-neck round-bottom flask under nitrogen atmosphere, dissolved in 100ml (10ml/g) of tetrahydrofuran, 16ml (1.2eq) of a 2.5M n-butyllithium solution in n-hexane was added dropwise at-30 ℃ over 25 minutes, the mixture was kept warm for 1.5 hours, 9.57g (1.2eq) of 96% dicyclohexylphosphonium chloride was added dropwise over 20 minutes, the mixture was kept warm for 1 hour, and the mixture was allowed to warm to room temperature naturally and stirred overnight. Quenching the reaction liquid with water, adding isopropyl ether to extract a product into an organic phase, washing the organic phase with saturated sodium chloride, drying the organic phase with anhydrous sodium sulfate, analyzing to obtain 10% of unreacted raw materials, 5% of oxidation products and 80% of products, spin-drying the organic phase, adding n-heptane for removing oxygen, pulping, cooling to 0 ℃, filtering the solid, performing column chromatography on the solid to obtain a white solid, analyzing the purity by HPLC (high performance liquid chromatography) to obtain the yield of 95%: 33%, mass 5.18g, melting point: 181.0 to 181.7 ℃. (the column chromatography has a height of 10cm and a diameter of 3cm, and the ratio of petroleum ether to ethyl acetate is 10: 1).
Example 8
Preparation of intermediate 1b
Figure BDA0002349582330000201
5g (0.023mol) of 1, 3-diphenyl-propanedione and 20mL (4mL/g) of N-methylpyrrolidone (NMP) were charged into a 250mL four-necked round-bottomed flask, and 4.30g (0.027mol,1.2eq) of bromine was added dropwise at room temperature over 5 minutes, yielding 97%. Directly heating to 45 ℃, dropwise adding 8.9g (0.078mol,3.5eq) of 3-isopropyl pyrazole at the temperature, keeping the temperature for 14h after finishing dropwise adding for 5 minutes, and obtaining the yield of 78%; without post-treatment, 15mL (3mL/g) of acetic acid was added directly, 30mL (6mL/g) of a methanol solution containing 3.6g (0.033mol,1.5eq) of phenylhydrazine was added, and after completion of dropwise addition for 10 minutes, the reaction was carried out at 45 ℃ for 15 hours with a yield of 76%. After the reaction is finished, 20mL of water is added, the product is separated out from the solvent, filtered, washed by 20mL of water, washed by 5mL of methanol and washed by 5mL of n-heptane, 7.89g of a light yellow solid with the crude product purity of 72% is obtained, the crude product is dissolved in 10mL of hot toluene (65-75 ℃) and added with n-heptane until the solid just appears, the temperature is kept for 10 minutes and is reduced to 0 ℃, filtered, washed by a small amount of n-heptane and dried, and a white product 1b is obtained, the purity is 98% by high performance liquid chromatography, the yield is 52% and the mass is 4.8 g.
Preparation of ligand [ III ]
Figure BDA0002349582330000202
Under nitrogen atmosphere, 2.0g (4.94mmol) of the intermediate 1b is added into a 100ml three-neck round-bottom flask, dissolved by 15ml (15ml/g) of tetrahydrofuran, 3.0ml (1.5eq) of a 2.5M n-butyllithium solution of n-hexane is added dropwise at-30 ℃ for 5 minutes, the temperature is kept for 1.5 hours, 1.42g (1.5eq) of 95 percent di-tert-butylphosphonium chloride is added dropwise for 5 minutes, the temperature is naturally raised to 0 ℃ and kept for 1 hour, the temperature is naturally raised to room temperature, and the mixture is stirred overnight. Quenching the reaction liquid with water, adding methyl tert-butyl ether to extract the product into an organic phase, washing the organic phase with saturated saline, drying with anhydrous sodium sulfate, spin-drying the organic phase, heating the solid to 45 ℃, adding tetrahydrofuran to dissolve the solid, adding n-heptane until the solid appears, preserving the temperature for five minutes, cooling to 0 ℃, filtering, washing with a small amount of n-heptane to obtain a white solid [ III ], wherein the HPLC purity is 94%, and the yield is as follows: 57% by mass, 1.64 g.
Example 9
C-N coupling reaction
Firstly, the method comprises the following steps: screening for bases
Figure BDA0002349582330000203
Under the protection of nitrogen, 1 mol% Pd (dba)2(12.77mg), 2 mol% ligand [ IV ]](25.66mg) was charged into a 25mL branched reaction tube, acetamide (0.15g,1.1 eq) and base (1.5 eq; see Table 1 below) were added, air was replaced three times with nitrogen, tert-amyl alcohol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, chlorobenzene (0.25g,1.0 eq) was added, replaced three times with nitrogen, the temperature was raised to 100 ℃ and the reaction was monitored in the gas phase. (1H NMR(400MHz,cdcl3)δ7.65(s,1H),7.50(d,J＝7.4Hz,2H),7.29(t,J＝6.6Hz,2H),7.09(t,J＝6.6Hz,1H),2.15(s,3H).)
TABLE 1 screening of bases
Figure BDA0002349582330000211
II, secondly: screening of solvents
Figure BDA0002349582330000212
Under the protection of nitrogen, 1 mol% Pd (dba)2(12.77mg), 2 mol% ligand [ IV ]](25.66mg) was charged into a 25mL branched reaction tube, acetamide (0.15g,1.1 eq) and potassium carbonate (0.46g,1.5 eq) were added, air was replaced three times with nitrogen, a solvent deoxygenated by ultrasound (2.5 g; shown in Table 2 below) was added and replaced with nitrogen, chlorobenzene (0.25g,1.0 eq) was added, nitrogen was replaced three times, the temperature was raised to a certain temperature, and the reaction was monitored in the gas phase. Wherein, the temperature of toluene, DMSO, DMF and NMP is raised to 110 ℃, the temperature of tertiary amyl alcohol is raised to 100 ℃, and the temperature of tertiary butyl alcohol is raised to 95 ℃.
TABLE 2 screening of solvents
Figure BDA0002349582330000213
From the above data, t-butanol is the most suitable solvent, t-amyl alcohol.
Thirdly, the method comprises the following steps: screening of the catalyst
Under nitrogen, 1 mol% of a palladium source (shown in Table 3 below), 2 mol% of a ligand [ IV ] (25.66mg) were charged into a 25mL branched reaction tube, acetamide (0.15g,1.1 equiv) and potassium carbonate (0.46g,1.5 equiv) were added, air was replaced three times with nitrogen, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, chlorobenzene (0.25g,1.0 equiv) was added, nitrogen was replaced three times, the temperature was raised to 95 ℃ and the reaction was monitored in the gas phase.
TABLE 3 screening of catalysts
Figure BDA0002349582330000221
Example 10
Figure BDA0002349582330000222
Under the protection of nitrogen, 1 mol% Pd (dba)2(12.77mg), 2 mol% ligand [ IV ]](25.66mg) was charged into a 25mL branched reaction tube, benzamide (0.32g,1.2 equiv.) and potassium carbonate (0.46g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, chlorobenzene (0.25g,1.0 equiv.) was added, nitrogen was replaced three times, the temperature was raised to 95 ℃ for 5 hours, and the conversion was 99.6% by gas phase detection. (1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.86(d,J＝7.3Hz,2H),7.64(d,J＝7.7Hz,2H),7.54(t,J＝6.9Hz,1H),7.46(t,J＝7.3Hz,2H),7.36(t,J＝7.6Hz,2H),7.15(t,J＝7.2Hz,1H).)。
Example 11
Figure BDA0002349582330000223
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.08mg)，2 mol% of ligand [ IV](20.22mg) was charged into a 25mL branched reaction tube, benzamide (0.25g,1.2 equiv.) and potassium carbonate (0.36g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, m-chloroanisole (0.25g,1.0 equiv.) was added, nitrogen was replaced three times, the temperature was raised to 95 ℃ for 4 hours, and the conversion was 98.8% by gas phase detection. (1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.84(d,J＝7.4Hz,2H),7.51(t,J＝7.0Hz,1H),7.41(d,J＝7.9Hz,3H),7.22(t,J＝8.1Hz,1H),7.12(d,J＝7.7Hz,1H),6.69(d,J＝7.6Hz,1H),3.78(s,3H).)。
Example 12
Figure BDA0002349582330000231
Under the protection of nitrogen, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ IV ]](16.00mg) was charged into a 25mL branched reaction tube, benzamide (0.20g,1.2 equiv.) and potassium carbonate (0.28g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, p-chlorotrifluoromethylene (0.25g,1.0 equiv.) was added and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 3 hours, and the reaction was carried out by gas phase detection with a conversion of 99.7%. (1H NMR(400MHz,CDCl3)δ7.95(s,1H),7.88(d,J＝6.9Hz,2H),7.78(d,J＝7.9Hz,2H),7.63(d,J＝8.0Hz,2H),7.58(d,J＝6.9Hz,1H),7.52(d,J＝7.1Hz,2H).)。
Example 13
Figure BDA0002349582330000232
Under the protection of nitrogen, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ IV ]](16.00mg) was charged into a 25mL branched reaction tube, benzamide (0.32g,1.2 equiv.) and potassium carbonate (0.28g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, 2-chloropyridine (0.25g,1.0 equiv.) was added again and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 18 hours, and the conversion was 55.4% by gas phase detection.(1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.40(d,J＝7.9Hz,1H),8.15(s,1H),7.92(d,J＝6.7Hz,2H),7.72(d,J＝7.4Hz,1H),7.53(d,J＝6.2Hz,1H),7.47(d,J＝6.4Hz,2H),7.02(s,1H).)。
Example 14
Figure BDA0002349582330000233
Under the protection of nitrogen, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ IV ]](16.00mg) was charged into a 25mL branched reaction tube, phenylacetamide (0.36g,1.2 equivalents) and potassium carbonate (0.46g,1.5 equivalents) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, chlorobenzene (0.25g,1.0 equivalent) was added, nitrogen was replaced three times, the temperature was raised to 95 ℃ and the reaction was carried out for 5 hours, and the conversion was 99.3% by gas phase detection. (1H NMR(400MHz,CDCl3)δ7.40(t,J＝8.5Hz,4H),7.34(s,3H),7.28(d,J＝7.5Hz,2H),7.19(s,1H),7.08(t,J＝7.1Hz,1H),3.73(s,2H).)。
Example 15
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.08mg), 2 mol% ligand [ IV ]](20.22mg) was charged into a 25mL branched reaction tube, phenylacetamide (0.28g,1.2 equivalents) and potassium carbonate (0.36g,1.5 equivalents) were added, air was replaced with nitrogen gas three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen gas, m-chloroanisole (0.25g,1.0 equivalent) was added, nitrogen gas was replaced three times, the temperature was raised to 95 ℃ for 4 hours, and the conversion was 99.2% by gas phase detection. (1H NMR(400MHz,CDCl3)δ7.54–7.20(m,7H),7.16(t,J＝8.1Hz,1H),6.86(d,J＝7.7Hz,1H),6.64(d,J＝7.7Hz,1H),3.76(s,3H),3.71(s,2H).)
Example 16
Figure BDA0002349582330000241
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.45mg), 2 mol% ligand [ IV ]](21.00mg) was charged into a 25mL branched reaction tube, phenylacetamide (0.29g,1.2 equiv.) and potassium carbonate (0.38g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, p-chlorobenzonitrile (0.25g,1.0 equiv.) was added and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 3 hours, and the conversion was 99.3% by gas phase detection. (1H NMR(400MHz,CDCl3)δ7.56(s,4H),7.49–7.29(m,6H),3.76(s,2H).)。
Example 17
Figure BDA0002349582330000242
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.45mg), 2 mol% ligand [ IV ]](21.00mg) was charged into a 25mL branched reaction tube, phenylacetamide (0.36g,1.2 equiv.) and potassium carbonate (0.38g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, 2-chloropyridine (0.25g,1.0 equiv.) was added again and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 3 hours, and the conversion was 53.3% by gas phase detection. (1H NMR(400MHz,CDCl3)δ8.22(d,J＝8.1Hz,2H),8.11(s,1H),7.68(t,J＝7.7Hz,1H),7.42–7.35(m,2H),7.32(d,J＝6.7Hz,3H),7.07–6.90(m,1H),3.75(s,2H).)。
Example 18
Figure BDA0002349582330000243
Under the protection of nitrogen, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ IV ]](16.00mg) was charged into a 25mL branched reaction tube, nicotinamide (0.20g,1.2 equivalents) and potassium carbonate (0.28g,1.5 equivalents) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, p-chlorotrifluoromethylene (0.25g,1.0 equivalent) was added and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 5 hours, and the conversion was 99.4% by gas phase detection. (1H NMR(400MHz,CDCl3)δ9.10(s,1H),8.77(s,1H),8.38(s,1H),8.22(d,J＝6.1Hz,1H),7.79(d,J＝6.9Hz,2H),7.63(d,J＝7.3Hz,2H),7.45(s,1H).)。
Example 19
Figure BDA0002349582330000251
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.45mg), 2 mol% ligand [ IV ]](21.00mg) was charged into a 25mL branched reaction tube, nicotinamide (0.27g,1.2 equivalents) and potassium carbonate (0.38g,1.5 equivalents) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, p-chlorobenzonitrile (0.25g,1.0 equivalent) was added and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 3 hours, and the conversion was 99.4% by gas phase detection. (1H NMR(400MHz,CDCl3)δ9.11(s,1H),8.81(s,1H),8.22(d,J＝6.5Hz,1H),8.16(s,1H),7.82(d,J＝7.0Hz,2H),7.69(d,J＝7.2Hz,2H),7.48(s,1H).)。
Example 20
Figure BDA0002349582330000252
Under the protection of nitrogen, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ V ]](16.00mg) was charged into a 25mL branched reaction tube, benzamide (0.20g,1.2 equiv.) and potassium carbonate (0.28g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-amyl alcohol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, m-chlorotrifluoromethylene (0.25g,1.0 equiv.) was added and replaced with nitrogen three times, the temperature was raised to 110 ℃ for 18h, gas phase detection was performed, and the conversion was 59.7%. (1HNMR(400MHz,CDCl3)δ8.18(s,1H),7.94(s,1H),7.86(s,3H),7.55(t,J＝7.2Hz,1H),7.45(t,J＝7.6Hz,3H),7.39(d,J＝7.5Hz,1H).)。
Example 21
Figure BDA0002349582330000253
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.45mg), 2 mol% ligand [ V ]](21.00mg) was charged into a 25mL branched reaction tube, phenylacetamide (0.23g,1.2 equiv.) and potassium carbonate (0.38g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-amyl alcohol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, p-chlorotrifluoromethylene (0.25g,1.0 equiv.) was added and replaced with nitrogen three times, the temperature was raised to 110 ℃ for 18 hours, and the conversion was 59.3% by gas phase detection. (1HNMR(400MHz,CDCl3)δ7.53(s,4H),7.48–7.27(m,6H),3.76(s,2H).)。
Example 22
Figure BDA0002349582330000254
Under the protection of nitrogen, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ IV ]](16.00mg) was charged into a 25mL branched reaction tube, nicotinamide (0.33g,1.2 equiv.) and potassium carbonate (0.46g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, chlorobenzene (0.25g,1.0 equiv.) was added, nitrogen was replaced three times, the temperature was raised to 95 ℃ and the reaction was carried out for 5 hours, and the conversion was 60.7% by gas phase detection. (1H NMR(400MHz,CDCl3)δ9.07(s,1H),8.72(s,1H),8.35(s,1H),8.19(d,J＝6.5Hz,1H),7.63(d,J＝6.5Hz,2H),7.37(d,J＝6.7Hz,3H),7.17(d,J＝5.9Hz,1H).)。
Example 23
Figure BDA0002349582330000261
Under the protection of nitrogen, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ IV ]](16.00mg) was charged into a 25mL branched reaction tube, acetamide (0.10g,1.2 equiv.) and potassium carbonate (0.46g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, p-chlorotrifluoromethylene (0.25g,1.0 equiv.) was added, nitrogen was replaced three times, the temperature was raised to 95 ℃ for 5 hours, and the conversion was 99.3% by gas phase detection. (1H NMR(400MHz,dmso)δ10.26(s,1H),7.76(d,J＝7.5Hz,2H),7.62(d,J＝7.8Hz,2H),2.06(s,3H).)。
Example 24
Figure BDA0002349582330000262
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.08mg), 2 mol% ligand [ IV ]](20.22mg) was charged into a 25mL branched reaction tube, benzamide (0.26g,1.2 equiv.) and potassium carbonate (0.36g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, p-chlorobenzonitrile (0.25g,1.0 equiv.) was added and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 4 hours, and the conversion was 99.0% by gas phase detection. (1H NMR(400MHz,cdcl3)δ8.16(s,1H),7.86(s,2H),7.80(d,J＝8.2Hz,2H),7.63(d,J＝8.2Hz,2H),7.57(d,J＝6.9Hz,1H),7.49(t,J＝7.1Hz,2H).)
Example 25
Figure BDA0002349582330000263
Under the protection of nitrogen, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ IV ]](16.00mg) was charged into a 25mL branched reaction tube, benzamide (0.32g,1.2 equiv.) and potassium carbonate (0.28g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, 3-chloropyridine (0.25g,1.0 equiv.) was added again and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 18 hours, and the conversion was 32.4% by gas phase detection.
Example 26
Figure BDA0002349582330000264
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.08mg), 2 mol% ligand [ IV ]](20.22mg) was charged into a 25mL reaction tube with a branch tube, benzamide (0.25g,1.2 equiv.) and potassium carbonate (0.36g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, o-chloroanisole (0.25g,1.0 equiv.) was added) Nitrogen is substituted for three times, the temperature is raised to 95 ℃, the reaction lasts for 4 hours, and the conversion rate is 60.2 percent through gas phase detection.1H NMR(400MHz,cdcl3)δ8.54(d,J＝8.1Hz,2H),7.90(d,J＝7.0Hz,2H),7.61–7.44(m,3H),7.06(dt,J＝25.3,7.3Hz,2H),6.92(d,J＝7.8Hz,1H),3.93(s,3H).
Example 27
Figure BDA0002349582330000271
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.08mg), 2 mol% ligand [ IV ]](20.22mg) was charged into a 25mL branched reaction tube, phenylacetamide (0.28g,1.2 equivalents) and potassium carbonate (0.36g,1.5 equivalents) were added, air was replaced with nitrogen gas three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen gas, o-chloroanisole (0.25g,1.0 equivalent) was added again and replaced with nitrogen gas three times, the temperature was raised to 95 ℃ for 4 hours, and the conversion was 38.0% by gas phase detection.
Example 28
Figure BDA0002349582330000272
Under the protection of nitrogen, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ IV ]](16.00mg) was charged into a 25mL branched reaction tube, phenylacetamide (0.23g,1.2 equiv.) and potassium carbonate (0.28g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, m-chlorotrifluoromethylene (0.25g,1.0 equiv.) was added and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 5 hours, and the reaction was carried out by gas phase detection with a conversion of 99.2%. (1H NMR(400MHz,cdcl3)δ7.71(s,1H),7.63(d,J＝7.4Hz,1H),7.51(s,1H),7.37(dd,J＝17.6,8.6Hz,7H),3.73(s,2H).)
Example 29
Figure BDA0002349582330000273
Under the protection of nitrogen, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ IV ]](16.00mg) was added to a 25mL branched reaction tube, phenylacetamide (0.23g,1.2 equivalents) and potassium carbonate (0.28g,1.5 equivalents) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, p-chlorotrifluoromethylene (0.25g,1.0 equivalent) was added, nitrogen was replaced three times, the temperature was raised to 95 ℃ for 5 hours, and the conversion was 99.4% by gas phase detection. (1H NMR(400MHz,cdcl3)δ7.53(s,
4H),7.49–7.27(m,6H),3.76(s,2H).)。
Example 30
Figure BDA0002349582330000274
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.45mg), 2 mol% ligand [ IV ]](21.00mg) was charged into a 25mL branched reaction tube, phenylacetamide (0.36g,1.2 equivalents) and potassium carbonate (0.38g,1.5 equivalents) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, 3-chloropyridine (0.25g,1.0 equivalent) was added, nitrogen was replaced three times, the temperature was raised to 95 ℃ for 3 hours, and the conversion was 40.3% by gas phase detection.
Example 31
Figure BDA0002349582330000281
Under the protection of nitrogen, 1 mol% Pd (dba)2(10.08mg), 2 mol% ligand [ IV ]](20.22mg) was charged into a 25mL branched reaction tube, phenylacetamide (0.22g,1.2 equivalents) and potassium carbonate (0.36g,1.5 equivalents) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen three times, m-bromoanisole (0.25g,1.0 equivalent) was added and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 4 hours, and the conversion was 98.4% by gas phase detection.
Example 32
Figure BDA0002349582330000282
Under nitrogenUnder protection, 1 mol% Pd (dba)2(7.96mg), 2 mol% ligand [ IV ]](16.00mg) was charged into a 25mL branched reaction tube, phenylacetamide (0.23g,1.2 equiv.) and potassium carbonate (0.28g,1.5 equiv.) were added, air was replaced with nitrogen three times, tert-butanol (2.5g) deoxygenated by ultrasound was added and replaced with nitrogen, p-bromotrifluorotoluene (0.25g,1.0 equiv.) was added again and replaced with nitrogen three times, the temperature was raised to 95 ℃ for 5 hours, and the conversion was 99.1% by gas phase detection.
Example 33: Suzuki-Miyaura cross-coupling reaction applied to aryl boric acid
Firstly, the method comprises the following steps: screening of solvents and bases
Figure BDA0002349582330000283
Under the protection of nitrogen, palladium chloride (0.05 mol%) and ligand [ V ] are added into a high-pressure reaction kettle](0.05 mol%), o-nitrochlorobenzene (1.0mmol), 4-chlorobenzeneboronic acid (1.2mmol), base (see Table 4 below) (1.5mmol) and 4mL of solvent (see Table 4 below). The reaction mixture was allowed to proceed at 80-90 ℃ for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and 20mL of water was added. The mixture was diluted with ethyl acetate and then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The product is purified by silica gel column chromatography. The yield was determined by gas chromatography. (1H NMR(400MHz,CDCl3):δ7.85(dd,J＝8.1,1.2Hz,Ar-H,1H),7.60(td,J＝7.6,1.3Hz,Ar-H,1H),7.48(td,J＝7.8,1.4Hz,Ar-H,1H),7.40-7.34(m,Ar-H,3H),7.25-7.21(m,Ar-H,2H).13CNMR(101MHz,CDCl3):δ148.9,135.8,135.0,134.3,132.4,131.7,129.2,128.8,128.5,124.1.)。
TABLE 4 screening of solvents and bases
Figure BDA0002349582330000284
Figure BDA0002349582330000291
II, secondly: screening of the catalyst
Figure BDA0002349582330000292
Under the protection of nitrogen, a palladium source (0.05 mol%; see Table 5 below), a ligand [ V ] (0.05 mol%), o-nitrochlorobenzene (1.0mmol), 4-chlorobenzeneboronic acid (1.2mmol), potassium carbonate (1.5mmol), and 6mL of a solvent were added to an autoclave. The reaction mixture was allowed to proceed at 80-90 ℃ for 4 h. The conversion was determined by gas chromatography and the results are given in the table below.
Entry (Serial number) Palladium source Yield%)
1 Pd(dba)2 78
2 [Pd(cinnamyl)Cl]2 50
3 Pd(OAc)2 88
4 PdCl2 98
Example 34
Figure BDA0002349582330000293
Under the protection of nitrogen, palladium chloride (0.05 mol%) and ligand [ IV ] are added into a high-pressure reaction kettle](0.05 mol%), o-nitrochlorobenzene (1.0mmol), 4-chlorobenzeneboronic acid (1.2mmol), K2CO3(1.5mmol) and 4mL of tetrahydrofuran. The reaction mixture was allowed to proceed at 80-90 ℃ for 4 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and 20mL of water was added. The mixture was diluted with ethyl acetate and then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The product is purified by silica gel column chromatography. The conversion was 96%.
Example 35
Figure BDA0002349582330000294
Under the protection of nitrogen, palladium chloride (0.05 mol%) and ligand [ V ] are added into a high-pressure reaction kettle](0.05 mol%), 2-chloro-p-xylene (1.2mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) fluorobenzene (1.0mmol), K2CO3(1.5mmol) and 6mL of tetrahydrofuran. The reaction mixture was allowed to proceed at 80-90 ℃ for 8 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and 20mL of water was added. The mixture was diluted with ethyl acetate and then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The product is purified by silica gel column chromatography. The conversion was 92%. (1HNMR(400MHz,CDCl3)δ＝7.30(dd,J＝8.7,5.4Hz,2H),7.18(d,J＝7.7Hz,1H),7.11(app t,J＝8.7Hz,3H),7.05(d,J＝1.9Hz,1H),2.37(s,3H),2.24(s,3H))。
Example 36
Figure BDA0002349582330000301
Under the protection of nitrogen, palladium chloride (0.05 mol%) and ligand [ IV ] are added into a high-pressure reaction kettle](0.05 mol%), 2-chloro-p-xylene (1.2mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxanBorane-2-yl) fluorobenzene (1.0mmol), K2CO3(1.5mmol) and 6mL of tetrahydrofuran. The reaction mixture was allowed to proceed at 80-90 ℃ for 8 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and 20mL of water was added. The mixture was diluted with ethyl acetate and then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The product is purified by silica gel column chromatography. The conversion was 89%.
Some examples of the present application are compared with some examples of the prior art (BippyPhos: A Single Ligand and Un-phenyl introduced Scope in the Buchwald-Hartwig amplification of (Hetero) arylChlorides; DOI: 10.1002/chem.201302453, p.7) reported for the application of BippyPhos to C-N coupling of amides, with the results shown in the following table:
Figure BDA0002349582330000302
from the above, in the catalytic system of the present application, the amount of the catalyst and the ligand is less than that in the literature, and the yield of part of the substrate is high; it can be seen that the ligands of the present application achieve beneficial technical effects in the application of coupling reactions.
EXAMPLE 37 Single Crystal of ligand [ IV' ]
And (3) culturing of the single crystal: putting a small amount of sample IV into three chromatographic sample bottles, respectively dropwise adding slightly-heated methanol, acetone and ethanol until the mixture is just dissolved, pricking a small hole on a sample bottle cover by using a needle, putting the sample bottle cover into a glass drier, replacing the system with nitrogen for three times to enable the solvent to be naturally volatilized, putting the drier into a stable environment, and growing crystals from the sample dissolved in the acetone in about 5-7 days, wherein the crystals are not grown from the rest samples. The obtained crystal is a solvate of two molecules of ligand [ IV ] and one molecule of acetone, and is a compound shown as a formula IV'.
Figure BDA0002349582330000311
Subjecting the crystal to X-ray diffraction detection, such as the structure shown in FIG. 1, in accordance with the target structure.
Figure BDA0002349582330000312

Claims (10)

1. A preparation method of a compound containing a dipyrazole ring shown as a formula I is characterized by comprising the following steps:
step (1): adding alkali into a mixture of a double-pyrazole ring compound shown as a formula I-1 and a solvent for a displacement reaction to obtain a mixed system;
step (2): adding an organophosphorus compound shown as a formula I-2 into the mixed system in the step (1) to carry out a phosphido reaction shown as the following to obtain a compound containing a dipyrazole ring shown as the formula I;
Figure FDA0002349582320000011
wherein R is1And R2Independently is C1-C6Alkyl radical, C3-C8Cycloalkyl and phenyl;
R3is C1～C6Alkyl groups of (a); x is halogen.
2. The method of claim 1, wherein the method is performed under a protective gas; the protective gas can be nitrogen or argon;
and/or the solvent is an ether solvent; the ether solvent can be one or more of tetrahydrofuran, methyltetrahydrofuran and dimethyl ether; preferably tetrahydrofuran;
and/or, the base is an alkyl lithium reagent; the alkyllithium reagent can be a solution of alkyllithium in an alkane solvent; a solution of n-butyllithium, preferably 2.5M n-hexane;
and/or the volume-mass ratio of the solvent to the double-pyrazole ring compound shown in the formula I-1 is 5ml/g-20 ml/g; preferably 10ml/g to 15 ml/g;
and/or the molar ratio of the base to the double-pyrazole ring compound shown in the formula I-1 is 1:1-3: 1; preferably 1.2:1 to 1.5: 1;
and/or the molar ratio of the organophosphorus compound shown as the formula I-2 to the double-pyrazole ring compound shown as the formula I-1 is 1:1-2: 1; preferably 1.2:1 to 1.5: 1;
and/or, in the step (1), the base is dropwise added into the double-pyrazole ring compound shown in the formula I-1 and the solvent; the temperature of adding the base into the mixture of the double-pyrazole ring compound shown in the formula I-1 and the solvent is preferably-20 ℃ to-10 ℃;
and/or the temperature of the displacement reaction is-20 ℃ to-10 ℃;
and/or step (2), dripping the organic phosphorus compound shown in the formula I-2 into the mixed system in the step (1); the temperature of the organic phosphorus compound shown as the formula I-2 added into the mixed system in the step (1) is preferably-20 ℃ to-10 ℃;
and/or, the temperature of the phosphitylation reaction is preferably-20 ℃ to 30 ℃;
and/or, in the preparation method, the method further comprises post-treatment; the post-processing operation comprises the following steps: after the phosphine generation reaction is finished, quenching reaction, extracting, washing, drying, concentrating and purifying; the reagent used for quenching reaction can be water; the reagent used for extraction can be an ether solvent; the reagent used for washing can be saturated saline; the reagent used for drying can be anhydrous sodium sulfate; the purification mode can be pulping washing, column chromatography or crystallization; preferably, in the purification mode, the reagent used in the beating washing can be an alkane solvent, and the alkane solvent is preferably n-heptane; the reagents used for the column chromatography can be petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is preferably 10: 1; the diameter-height ratio of the column used for column chromatography can be 3: 10; the dissolubility solvent of the crystallization can be a cyclic ether solvent, the anti-solvent can be an alkane solvent, the cyclic ether solvent is preferably tetrahydrofuran, and the alkane solvent is preferably n-heptane.
3. The method of claim 1, wherein X is fluorine, chlorine, bromine, or iodine; preferably chlorine;
and/or, R1And R2Independently is C1-C6In the alkyl radical, said C1-C6Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl;
and/or, R1And R2Independently is C3-C8In the cycloalkyl radical, said C3-C8Cycloalkyl is independently C3-C6Alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
and/or, R3Is C1～C6In the alkyl group of (A), said C1-C6Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl;
and/or, R1And R2Independently is C1-C6Alkyl or C3-C8A cycloalkyl group;
and/or, R1And R2The same or different.
4. The process according to claim 3, wherein the compound containing a bispyrazole ring, represented by formula I, is selected from the following compounds:
Figure FDA0002349582320000021
5. the method of any one of claims 1 to 4, further comprising the steps of: in a solvent, in the presence of acid, performing cyclization reaction on phenylhydrazine and the compound shown as the formula I-3 to obtain the compound shown as the formula I-1;
Figure FDA0002349582320000022
wherein R is3As defined in any one of claims 1 and 3 to 4.
6. The process according to claim 5, wherein the solvent used in the cyclization is an amide-based solvent; the amide solvent can be N, N-dimethylformamide DMF and/or N-methylpyrrolidone NMP;
and/or in the cyclization reaction, the volume mass ratio of the solvent to the phenylhydrazine is 1ml/g-10 ml/g; preferably 4ml/g to 6 ml/g;
and/or, in the cyclization reaction, the acid is acetic acid;
and/or, in the ring-forming reaction, the volume mol ratio of the acid to the phenylhydrazine is 0.1L/mol to 1.0L/mol; preferably 0.3L/mol to 0.45L/mol;
and/or, in the cyclization reaction, the phenylhydrazine is in the form of an alcoholic solution; preferably phenylhydrazine in methanol; more preferably, the mass-volume ratio of the phenylhydrazine in the methanol solution is 0.1g/mL-0.5 g/mL;
and/or the temperature of the cyclization reaction is between room temperature and 60 ℃; preferably 40 ℃ to 50 ℃;
and/or, in the ring-forming reaction of the preparation method, the preparation method further comprises post-treatment, and the post-treatment comprises the following steps: after the cyclization reaction is finished, adding water to separate out a solid, filtering, washing and purifying; the reagents used for washing can be water, methanol and n-heptane in sequence; the purification column chromatography or crystallization; preferably, the soluble solvent of the crystallization is an aromatic hydrocarbon solvent, the anti-solvent can be an alkane solvent, the aromatic hydrocarbon solvent can be toluene, and the anti-solvent can be n-heptane.
7. The method of any one of claim 5, further comprising the steps of:
carrying out substitution reaction shown as the following on a compound shown as a formula I-6 and a compound shown as a formula I-5 in a solvent to obtain a compound shown as a formula I-3;
Figure FDA0002349582320000031
wherein R is3Is defined as in claim 5.
8. The process according to claim 7, wherein the substitution reaction is carried out under a protective gas; the protective gas can be nitrogen or argon;
and/or, in the substitution reaction, the solvent is an amide solvent; the amide solvent can be N, N-dimethylformamide DMF and/or N-methylpyrrolidone NMP;
and/or in the substitution reaction, the volume-mass ratio of the solvent to the compound shown in the formula I-6 is 1ml/g-10 ml/g; preferably 2.5ml/g to 3 ml/g;
and/or in the substitution reaction, the molar ratio of the compound shown as the formula I-6 to the compound shown as the formula I-5 is 3:1-4: 1; preferably 3.3:1 to 3.5: 1;
and/or dripping the compound shown in the formula I-6 into the compound shown in the formula I-5 and the solvent;
and/or the temperature of the substitution reaction is between room temperature and 60 ℃; preferably 40 ℃ to 50 ℃;
and/or directly using the substituted compound in the cyclization reaction without post-treatment after the substitution reaction is finished to prepare the compound shown in the formula I-1.
9. A preparation method of a compound shown in a formula I-1 is characterized in that the preparation method of the compound shown in the formula I-1 comprises the following steps: in a solvent, in the presence of acid, performing cyclization reaction on phenylhydrazine and the compound shown as the formula I-3 to obtain the compound shown as the formula I-1;
Figure FDA0002349582320000041
wherein R is3As defined in any one of claims 1,3 to 4;
the reaction conditions and operation of the cyclization reaction are as described in any one of claims 5 to 8.
10. A preparation method of a compound shown in a formula I-3 is characterized by comprising the following steps: carrying out substitution reaction shown as the following on a compound shown as a formula I-6 and a compound shown as a formula I-5 in a solvent to obtain a compound shown as a formula I-3;
Figure FDA0002349582320000042
wherein R is3As defined in any one of claims 1,3 to 4;
the reaction conditions and operation of the substitution reaction are as defined in claim 7 or 8.
CN201911409514.1A 2019-12-31 2019-12-31 Preparation method of compound containing bipyrazole ring and intermediate thereof Active CN111100165B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201911409514.1A CN111100165B (en) 2019-12-31 2019-12-31 Preparation method of compound containing bipyrazole ring and intermediate thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911409514.1A CN111100165B (en) 2019-12-31 2019-12-31 Preparation method of compound containing bipyrazole ring and intermediate thereof

Publications (2)

Publication Number Publication Date
CN111100165A true CN111100165A (en) 2020-05-05
CN111100165B CN111100165B (en) 2023-05-12

Family

ID=70425019

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911409514.1A Active CN111100165B (en) 2019-12-31 2019-12-31 Preparation method of compound containing bipyrazole ring and intermediate thereof

Country Status (1)

Country Link
CN (1) CN111100165B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115466960A (en) * 2022-09-15 2022-12-13 河北工业大学 Preparation method and application of benzothiazole group-containing modified polyaspartic acid fluorescent corrosion inhibitor

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GREGORY J. WITHBROE等: ""Streamlined Synthesis of the Bippyphos Family of Ligands and Cross-Coupling Applications"", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 *
ROBERT A. SINGER等: ""Development of nonproprietary phosphine ligands for the Pd-catalyzed amination reaction"", 《TETRAHEDRON LETTERS》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115466960A (en) * 2022-09-15 2022-12-13 河北工业大学 Preparation method and application of benzothiazole group-containing modified polyaspartic acid fluorescent corrosion inhibitor
CN115466960B (en) * 2022-09-15 2023-05-26 河北工业大学 Preparation method and application of benzothiazole group-containing modified polyaspartic acid fluorescent corrosion inhibitor

Also Published As

Publication number Publication date
CN111100165B (en) 2023-05-12

Similar Documents

Publication Publication Date Title
Wang et al. PhI (OAc) 2-mediated synthesis of 6-(trifluoromethyl) phenanthridines by oxidative cyclization of 2-isocyanobiphenyls with CF3SiMe3 under metal-free conditions
RU2725888C2 (en) Method of producing cenicriviroc and related analogues
Chelucci et al. Enantiomerically pure pyridine and 2, 2′-bipyridine thioethers: new N–S chiral ligands for asymmetric catalysis. Palladium-catalyzed allylic alkylation
CN110862354B (en) Bifunctional 1,2, 3-triazole derivative intermediate, preparation method and application
CN111100165B (en) Preparation method of compound containing bipyrazole ring and intermediate thereof
JP2806483B2 (en) Method for producing pyridine-2-carboxamide
KR20180120730A (en) Method for producing fluorine-containing compound
Harikrishnan et al. The cooperative effect of Lewis pairs in the Friedel–Crafts hydroxyalkylation reaction: a simple and effective route for the synthesis of (±)-carbinoxamine
CN111072721B (en) Compound containing bipyrazole ring, intermediate and application thereof
CN110627772A (en) Pinene-fused chiral terpyridine bidentate compound and preparation method thereof
CN114956924A (en) Method for synthesizing polyfluoro biaryl through series/coupling reaction
CN111807977B (en) 9-aniline fluorene-9-carboxylic ester compound and preparation method thereof
WO2020118597A1 (en) Process for making 1- [ (3r, 4s) -4-cyanotetrahydropyran-3-yl] -3- [ (2-fluoro-6-methoxy-4-pyridyl) amino] pyrazole-4-carboxamide
CN108659028B (en) (Z) -type fluoroalkyl alkenyl borate and preparation method and application thereof
CN110563551B (en) Method for synthesizing trans-2-alkene-4-alkyne-1-alcohol compound
KR102325919B1 (en) Monoarylation of aromatic amines
CN113121432A (en) Synthesis method of aliphatic alkene with guide group
CN113227077A (en) Method for preparing 1- [ (3R,4S) -4-cyano tetrahydropyran-3-yl ] -3- [ (2-fluoro-6-methoxy-4-pyridyl) amino ] pyrazole-4-formamide
CN111943874A (en) Aryl naproxen derivative high-valence iodine compound and preparation method and application thereof
CN101891569B (en) Preparation method of alpha-aromatic ketone compound
JP2017132738A (en) Manufacturing method of bipyridyl compound
CN110003062B (en) N-phenyl-N-p-toluenesulfonyl difluoroacetamide and application thereof
CN109265325B (en) 1, 2-dibromo olefin compound and preparation method and application thereof
CN107382642B (en) α -diphenyl-1-aryl propenone compound preparation method
CN110015946B (en) Preparation method of 1, 5-diaryl-4-pentene-1-alcohol compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CP03 Change of name, title or address

Address after: 300130 No. 8, glorious road, Hongqiao District, Tianjin

Patentee after: Hebei University of Technology

Country or region after: China

Patentee after: LIANHE CHEMICAL TECHNOLOGY (SHANGHAI) Co.,Ltd.

Patentee after: LIANHE CHEMICAL TECHNOLOGY (YANCHENG) Co.,Ltd.

Patentee after: Lianhua Angjian (Zhejiang) Pharmaceutical Co.,Ltd.

Patentee after: Lianhua Technology (Linhai) Co.,Ltd.

Patentee after: LIANHE CHEMICAL TECHNOLOGY Co.,Ltd.

Address before: 300130 No. 8, glorious road, Hongqiao District, Tianjin

Patentee before: Hebei University of Technology

Country or region before: China

Patentee before: LIANHE CHEMICAL TECHNOLOGY (SHANGHAI) Co.,Ltd.

Patentee before: LIANHE CHEMICAL TECHNOLOGY (YANCHENG) Co.,Ltd.

Patentee before: LIANHE CHEMICAL TECHNOLOGY (TAIZHOU) Co.,Ltd.

Patentee before: Lianhua Technology (Linhai) Co.,Ltd.

Patentee before: LIANHE CHEMICAL TECHNOLOGY Co.,Ltd.

CP03 Change of name, title or address