CN116041253A - Method for synthesizing diphenyl-2-pyridylmethane derivative - Google Patents
Method for synthesizing diphenyl-2-pyridylmethane derivative Download PDFInfo
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- CN116041253A CN116041253A CN202310178361.4A CN202310178361A CN116041253A CN 116041253 A CN116041253 A CN 116041253A CN 202310178361 A CN202310178361 A CN 202310178361A CN 116041253 A CN116041253 A CN 116041253A
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- pyridylmethane
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- 238000000034 method Methods 0.000 title claims abstract description 22
- MMXYNKLYVRNTCK-UHFFFAOYSA-N diphenyl-2-pyridylmethane Chemical class C1=CC=CC=C1C(C=1N=CC=CC=1)C1=CC=CC=C1 MMXYNKLYVRNTCK-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- 239000003960 organic solvent Substances 0.000 claims abstract description 23
- 239000003446 ligand Substances 0.000 claims abstract description 20
- QPKFVRWIISEVCW-UHFFFAOYSA-N 1-butane boronic acid Chemical compound CCCCB(O)O QPKFVRWIISEVCW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000654 additive Substances 0.000 claims abstract description 7
- 230000000996 additive effect Effects 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 239000007800 oxidant agent Substances 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 64
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical group [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 4
- 229910001923 silver oxide Inorganic materials 0.000 claims description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 239000002585 base Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 10
- 238000010791 quenching Methods 0.000 description 10
- 230000000171 quenching effect Effects 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical group FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 150000001263 acyl chlorides Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- 101150003085 Pdcl gene Proteins 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000006277 sulfonation reaction Methods 0.000 description 4
- 230000004913 activation Effects 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- 230000009471 action Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012649 demethylating agent Substances 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012022 methylating agents Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical group [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 2
- 235000019254 sodium formate Nutrition 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 238000010499 C–H functionalization reaction Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001717 carbocyclic compounds Chemical class 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
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- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
- B01J2231/4211—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group
- B01J2231/4222—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group with R'= alkyl
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Abstract
The invention provides a method for synthesizing diphenyl-2-pyridylmethane derivatives. Mixing and stirring a compound D, butyl boric acid, a catalyst, a ligand, an additive, an oxidant and an organic solvent 1, reacting, and separating and purifying to obtain a diphenyl-2-pyridylmethane derivative E, wherein the chemical reaction formula is as follows:
wherein R is 1 、R 2 Each independently selected from one of hydrogen, alkyl, alkoxy, aryl, heteroaryl. The invention has high selectivity and high yield, high reaction catalysis efficiency, low catalyst consumption, simple post-treatment and no byproduct generation in the system.
Description
Technical Field
The invention relates to the technical field of synthesis of carbocyclic compounds, in particular to a method for synthesizing diphenyl-2-pyridylmethane derivatives.
Background
Chiral compounds are extremely important in fine chemical production as precursors, intermediates or end products of medicines, pesticides, fragrances and functional materials. Research into methods for obtaining single enantiomer compounds remains one of the primary tasks of contemporary chemists. Carbon heteroatom bonds (C-X) are commonly found in biological molecules in nature, are one of the most active parts of the molecular structure of organic compounds, and are also one of the basic framework raw materials for synthesizing the enantiomer products, so the construction of C-X bonds is a hot spot for organic chemists to study.
The C-H bond insertion reaction catalyzed by the transition metal has the characteristics of high efficiency and economy, and provides a simple method for constructing various molecules with complex structures from simple and easily obtained raw materials. Over the past several decades, an increasing number of transition metal catalysts have been developed and successfully applied to the activation of various C-H bonds, providing a new and efficient method for the construction of C-X bonds.
However, there are few effective methods for activating C-H bonds, and the regulation of the activity and selectivity is difficult. Thus, the development of various transition metal catalysts, efficient C-H bond activation, is a significant challenge currently faced. The main obstacle in Pd-catalyzed C-H bond activation reactions is the need for a ligand that binds Pd, controlling its chemical, regional and stereoselectivity of the inserted C-H bond.
Therefore, there is a need to develop a Pd-catalyzed asymmetric C-H activation/C-C coupling reaction with high yields and high selectivity, differentiating chiral C-H bonds by metal insertion.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a method for synthesizing diphenyl-2-pyridylmethane derivatives by palladium-catalyzed hydrocarbon living reaction, which solves the problems of low yield and low selectivity existing in the prior art.
The invention provides a method for synthesizing diphenyl-2-pyridylmethane derivatives, which comprises the steps of mixing and stirring a compound D, butyl boric acid, a catalyst, a ligand, an additive, an oxidant and an organic solvent 1, reacting, separating and purifying to obtain the diphenyl-2-pyridylmethane derivatives E, wherein the chemical reaction formula is as follows:
wherein R is 1 、R 2 Each independently selected from one of hydrogen, alkyl, alkoxy, aryl, heteroaryl.
Further, the catalyst is Pd (OAc) 2 The ligand is
Wherein R is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
Further, the oxidant is terephthalquinone, and the additive is silver oxide.
Further, the organic solvent 1 is tetrahydrofuran.
Further, the molar ratio of the compound D, the butyl boric acid, the catalyst, the ligand and the oxidant to the additive is 1:1:0.1:0.2:0.5:1.0.
Further, the reaction temperature is 50-60 ℃ and the reaction time is 20-24h.
Further, the preparation method of the ligand comprises the following steps: in the presence of an organic solvent 2, an acylating agent, a catalyst and an organic base, a 7-carboxyl-1, 1' -spiroindane compound shown in a formula B reacts with a compound shown in a formula C to prepare a compound shown in a formula A, wherein the reaction formula is as follows:
wherein R is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
Further, the acylating agent is oxalyl chloride, the catalyst is N, N-dimethylformamide, the organic base is triethylamine, and the organic solvent 2 is dichloromethane.
Further, the molar ratio of the 7-carboxyl-1, 1' -spiroindane compound shown in the formula B to the compound shown in the formula C to the acylating agent to the organic base is 0.9-1:1-1.1:1.3-1.5:3;
the 7-carboxyl-1, 1' -spiroindane compound shown in the formula A and the catalyst are 1:0.01 in mol/L.
Further, the reaction time is 5-7 hours, and the reaction temperature is 0-room temperature.
In one embodiment of the invention, the preparation method of the 7-carboxyl-1, 1' -spiroindane compound shown in the formula B comprises the following steps:
1,1 '-spiroindan-7, 7' -diol is used as an initiator, and is obtained through methylation reaction, first sulfonation reaction, first substitution reaction, demethylation reaction, second sulfonation reaction, second substitution reaction and hydrolysis reaction; the reaction process is as follows:
the method specifically comprises the following steps: (1) Adding 1,1 '-spiroindan-7, 7' -diol into an organic solvent 1, and generating a compound 2 under the action of a methylating reagent and a first base;
(2) Mixing the compound 2 with an organic solvent 2, and adding a first sulfonating reagent and a second base to generate a compound 3;
(3) Adding the compound 3 into an organic solvent 3, and adding a first catalyst, a first reaction substrate and a third base in the presence of CO to perform a first substitution reaction to generate a compound 4;
(4) Adding an organic solvent 4 into the compound 4, and carrying out a demethylation reaction under the action of a demethylating reagent to generate a compound 5;
(5) Adding an organic solvent 5 into the compound 5, and adding a second sulfonation reagent and a fourth base to generate a compound 6;
(6) Adding the compound 6 into an organic solvent 6, adding a second catalyst and a second reaction substrate in the presence of nitrogen, and performing a second substitution reaction to generate a compound 7;
(7) And adding an organic solvent 7 into the compound 7, and hydrolyzing in the presence of a fifth base to obtain the 7-carboxyl-1, 1' -spiroindane compound shown in the formula B.
Preferably, in the step (1), the organic solvent 1 is tetrahydrofuran, the methylating agent is methyl iodide, and the first base is sodium hydride; the reaction temperature is 0-10 ℃ and the reaction time is 6-12h;
in the step (2), the organic solvent 2 is methylene dichloride, the first sulfonating agent is trifluoro methanesulfonic anhydride, and the second base is pyridine; the reaction temperature is 0-10 ℃ and the reaction time is 6-12h;
in the step (3), the organic solvent 3 is acetonitrile and methanol; the third base is triethylamine; the first catalyst is PdCl 2 (dppf); the first reaction substrate is methanol; the reaction temperature is 80 ℃ and the reaction time is 16-24 hours;
in the step (4), the organic solvent 4 is DCM, and the demethylating agent is BBr 3 The reaction temperature is between 20 ℃ below zero and 10 ℃ below zero, and the reaction time is between 6 and 8 hours;
in the step (5), the organic solvent 5 is dichloromethane, the second sulfonation reagent is trifluoromethanesulfonic anhydride, the fourth base is pyridine, the reaction temperature is-0-10 ℃, and the reaction time is 6-12h;
in the step (6), the organic solvent 6 is methanol; the second catalyst is PdCl 2 (dppf); the second reaction substrate is HCOONa;
in the step (7), the organic solvent 7 is DMSO; the fifth alkali is potassium hydroxide; the reaction temperature is 150 ℃ and the reaction time is 16-24 hours.
Preferably, in step (1), 1 '-spiroindan-7, 7' -diol in molar ratio: methylating agent: first base = 2:1:1;
in the step (2), the first sulfonating agent is compound 2, and the second base=10:13:15;
in the step (3), the compound 3 comprises a first catalyst, a first reaction substrate and a third base=10:0.5:100:30 in terms of mole ratio;
in step (4), compound 4: first demethylating agent = 1:3 in molar ratio;
in the step (5), the compound 5 comprises a second sulfonating agent and a fourth base=10:13:15 according to the mole ratio;
in the step (6), the compound 6 is a second catalyst and a second reaction substrate=10:0.5:30 in terms of molar ratio;
in step (7), compound 7: fifth base=1:10 in terms of molar ratio.
Compared with the prior art, the invention has the following beneficial effects:
1. according to the invention, palladium acetate and chiral spiro ligand are used as catalysts for the first time, and a series of diphenyl-2-pyridylmethane derivatives are synthesized through the C-C bond coupling reaction of the substituted diphenyl-2-pyridylmethane and butyl boric acid with excellent enantioselectivity and high yield, so that more choices are provided for the development of organic synthesis and biological medicine;
2. the chiral spiro ligand synthesized for the first time has the advantages of high reaction catalysis efficiency, low catalyst consumption, simple post-treatment and no byproduct generation in the system.
3. The method is simple and convenient to operate, mild in reaction conditions and suitable for large-scale industrial production.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
EXAMPLE 1 Synthesis of ligands
Compound B1 (10 mmol), N-dimethylformamide (DMF, 100. Mu.L) and dichloromethane (DCM, 10 mL) were added to the reaction flask under nitrogen protection, oxalyl chloride (15 mmol) was added dropwise to the reaction system, and the temperature was controlled between 0℃and 10℃during the addition. After the dripping is finished, the mixture is restored to room temperature, stirred and reacted for 2 to 3 hours, concentrated to dryness to obtain the acyl chloride of B1, and 10mL of dichloromethane is added for standby. Another reaction flask was charged with C1 (11 mmol), triethylamine (Et) 3 N,30 mmol) and dichloromethane (30 mL), slowly dropwise adding the acyl chloride solution of B1 obtained in the previous step into C1 and triethylamine, stirring at room temperature for 3-4 hours, and carrying out quenching column chromatography to obtain a product A1 with a yield of 95%;
the preparation method of the compound B1 comprises the following steps:
compound 1 (10 mmol) and tetrahydrofuran (200 mL) were added to the reaction flask under nitrogen protection, naH (5 mmol) was added to the reaction system, and the temperature was controlled between 0℃and 10℃during the addition. Then, THF solution (5mmol MeI in 60mL THF) of methyl iodide is added into the system dropwise, the temperature is controlled to be 0-10 ℃, the reaction is carried out for 6-12 hours after the completion of the addition, and the reaction liquid is subjected to quenching column chromatography to obtain a product 2, wherein the yield is 77%.
Compound 2 (10 mmol) and methylene chloride (100 mL) were added to a reaction flask under nitrogen protection, and pyridine (15 mmol) was added to the reaction system. Subsequently, a methylene chloride solution of trifluoromethanesulfonic anhydride (13 mmol Tf) was added dropwise to the system 2 O in 60mL DCM), controlling the temperature to be 0-10 ℃, and reacting for 6-12 hours after dripping, wherein the reaction liquid is subjected to quenching column chromatography to obtain the product 3 with the yield of 91%.
Compound 3 (10 mmol) and methanol (100 mmol), acetonitrile (100 mL), triethylamine (30 mmol) were added to the reaction flask under nitrogen. Subsequently add PdCl to the system 2 (dppf) (0.5 mmol), CO was replaced three times after the addition, the reaction was carried out under pressure of 2.5MPa at 80℃for 16-24 hours, and the reaction mixture was subjected to quenching column chromatography to give product 4 in 80% yield.
Compound 4 (10 mmol) and DCM (500 mL) were added to the reaction flask under nitrogen. Subsequently, BBr is added into the system in a dropwise manner 3 (30 mmol) and controlling the temperature to-20-10 ℃. After the addition, the reaction is carried out for 6 to 8 hours, and the reaction liquid is subjected to quenching column chromatography to obtain the compound 5 with the yield of 65 percent.
Compound 5 (10 mmol) and methylene chloride (100 mL) were added to a reaction flask under nitrogen protection, and pyridine (15 mmol) was added to the reaction system. Subsequently, a methylene chloride solution of trifluoromethanesulfonic anhydride (13 mmol Tf) was added dropwise to the system 2 O in 60mL DCM), controlling the temperature to be 0-10 ℃, reacting for 6-12 hours after dripping, and obtaining the compound 6 by quenching column chromatography of the reaction liquid, wherein the yield is 88%.
Compound 6 (10 mmol) and methanol (100 mmol), HCOONa (30 mmol) were added to the reaction flask under nitrogen. Subsequently add PdCl to the system 2 (dppf) (0.5 mmol), after the addition, the nitrogen was replaced three times and reacted at 80℃for 16-24 hours, the reaction solution is subjected to quenching column chromatography to obtain the compound 7 with the yield of 84%.
Compound 7 (10 mmol) and DMSO (500 mL) were added to the reaction flask under nitrogen. Then 60% aqueous potassium hydroxide solution (100 mmol) is added into the system, the temperature is raised to 150 ℃ after the addition, the reaction is carried out for 16-24 hours, and the product B1 is obtained through quenching column chromatography, and the yield is 80%.
EXAMPLE 2 Synthesis of ligands
Compound B2 (9 mmol), N-dimethylformamide (DMF, 90. Mu.L) and dichloromethane (DCM, 10 mL) were added to the reaction flask under nitrogen protection, oxalyl chloride (13 mmol) was added dropwise, and the temperature was controlled between 0℃and 10℃during the addition. After the dripping is finished, the mixture is restored to room temperature, stirred and reacted for 2 to 3 hours, concentrated to dryness to obtain the acyl chloride of B2, and 10mL of dichloromethane is added for standby. Another reaction flask was charged with C2 (10 mmol), triethylamine (Et) 3 N,27 mmol) and dichloromethane (30 mL), the acid chloride solution of B2 obtained in the previous step was slowly added dropwise to C2 and triethylamine, stirred at room temperature for 3-4 hours, and the product A2 was obtained by quench column chromatography in 91% yield.
EXAMPLE 3 Synthesis of ligands
Compound B3 (10 mmol), N-dimethylformamide (DMF, 100. Mu.L) and dichloromethane (DCM, 10 mL) were added to the reaction flask under nitrogen protection, oxalyl chloride (15 mmol) was added dropwise to the reaction system, and the temperature was controlled between 0℃and 10℃during the addition. After the dripping is finished, the mixture is restored to room temperature, stirred and reacted for 2 to 3 hours, concentrated to dryness to obtain the acyl chloride of B3, and 10mL of dichloromethane is added for standby. Another reaction flask was charged with C3 (11 mmol), triethylamine (Et) 3 N,30 mmol) and dichloromethane (30 mL), the acyl chloride solution of B3 obtained in the previous step is slowly dripped into C3 and triethylamine, stirred for 3-4 hours at room temperature, and the product A3 is obtained by quenching column chromatography, and the yield is93%.
Example 4
To the reaction vessel was added 0.25mmol of compound D1,0.25mmol (1.0 eq) of butylboronic acid, 25. Mu. Mol (10 mol%) of catalyst Pd (OAc) under nitrogen protection 2 50. Mu. Mol (20 mol%) of the ligand prepared in example 1, 0.125mmol (0.5 eq) of BQ (terephthalquinone), 0.25mmol (1.0 eq) of Ag 2 O,1ml Tetrahydrofuran (THF), at 60 ℃ for 20 hours, concentrating, filtering and purifying to obtain the target product E1. 1 H NMR:δ0.88(3H,t,J＝6.5Hz),1.25-1.37(2H,1.31(h,J＝6.5Hz),1.31(h,J＝6.5Hz)),1.50-1.64(2H,1.57(tt,J＝7.3,6.5Hz),1.57(tt,J＝7.3,6.5Hz)),2.18-2.30(6H,2.23(s),2.25(s)),2.61-2.73(2H,2.67(t,J＝7.3Hz),2.67(t,J＝7.3Hz)),5.66(1H,s),6.98-7.34(9H,7.05(ddd,J＝8.0,7.8,2.1Hz),7.06(ddd,J＝8.0,1.5,0.6Hz),7.08(dd,J＝8.1,1.5Hz),7.09(ddd,J＝8.0,7.8,1.5Hz),7.09(t,J＝8.1Hz),7.09(dd,J＝8.1,1.5Hz),7.17(ddd,J＝8.0,2.1,0.6Hz),7.21(ddd,J＝7.4,5.1,1.5Hz),7.28(ddd,J＝7.9,1.5,0.6Hz)),7.69(1H,ddd,J＝7.9,7.4,1.9Hz),8.53(1H,ddd,J＝5.1,1.9,0.6Hz)。
The yield of the reaction was 93% and the ee value of the enantioselectivity was 90% as measured.
Example 2
In a reaction vessel under nitrogen, 0.25mmol of compound D2, 0.25mmol (1.0 eq) of butylboronic acid, 25. Mu. Mol (10 mol%) of Pd (OAc) were introduced 2 Catalyst, 50. Mu. Mol (20 mol%) of the ligand prepared in example 2, 0.125mmol (0.5 eq) of BQ,0.25mmol (1.0 eq) of Ag 2 O,1ml of THF was reacted at 50℃for 24 hours, concentrated, filtered and purified to give the target product E2. 1 H NMR:δ0.88(3H,t,J＝6.5Hz),1.25-1.37(2H,1.31(h,J＝6.5Hz),1.31(h,J＝6.5Hz)),1.49-1.63(2H,1.56(tt,J＝7.3,6.5Hz),1.56(tt,J＝7.3,6.5Hz)),2.61-2.73(2H,2.67(t,J＝7.3Hz),2.67(t,J＝7.3Hz)),5.68(1H,s),6.99-7.39(11H,7.05(ddd,J＝7.8,1.6,0.6Hz),7.17(td,J＝7.8,2.0Hz),7.19(ddd,J＝8.1,7.8,1.6Hz),7.18(ddd,J＝8.1,2.0,0.6Hz),7.20(tt,J＝7.7,1.3Hz),7.21(ddd,J＝7.4,5.1,1.5Hz),7.28(ddd,J＝7.9,1.5,0.6Hz),7.28(dtd,J＝7.6,1.3,0.5Hz),7.33(tdd,J＝7.7,1.9,0.5Hz)),7.69(1H,ddd,J＝7.9,7.4,1.9Hz),8.53(1H,ddd,J＝5.1,1.9,0.6Hz)。
The yield of the reaction was 94% and the ee value of the enantioselectivity was 92% as determined.
Example 3
To the reaction vessel was added 0.25mmol of compound D3,0.25mmol (1.0 eq) of butylboronic acid, 25. Mu. Mol (10 mol%) of Pd (OAc) under nitrogen protection 2 50. Mu. Mol (20 mol%) of the ligand prepared in example 3, 0.125mmol (0.5 eq) of BQ,0.25mmol (1.0 eq) of Ag 2 O,1ml of THF was reacted at 60℃for 20 hours, concentrated, filtered and purified to give the target product E3. 1 H NMR:δ0.88(3H,t,J＝6.5Hz),1.25-1.37(2H,1.31(h,J＝6.5Hz),1.31(h,J＝6.5Hz)),1.44-1.57(2H,1.50(tt,J＝7.4,6.5Hz),1.50(tt,J＝7.4,6.5Hz)),2.51-2.63(2H,2.57(t,J＝7.4Hz),2.57(t,J＝7.4Hz)),3.67-3.80(6H,3.72(s),3.75(s)),5.67(1H,s),6.59-6.79(2H,6.65(dd,J＝2.9,0.5Hz),6.72(dd,J＝8.1,2.9Hz)),6.81-7.06(4H,6.88(ddd,J＝8.2,2.7,2.5Hz),6.90(td,J＝2.7,0.5Hz),6.99(ddd,J＝7.9,2.7,2.5Hz),7.00(dd,J＝8.1,0.5Hz)),7.14-7.34(3H,7.21(ddd,J＝7.4,5.1,1.5Hz),7.22(ddd,J＝8.2,7.9,0.5Hz),7.28(ddd,J＝7.9,1.5,0.6Hz)),7.69(1H,ddd,J＝7.9,7.4,1.9Hz),8.53(1H,ddd,J＝5.1,1.9,0.6Hz)。
The yield of the reaction was 92% and the ee value of the enantioselectivity was 91%.
Comparative example
Similar to example 4, the difference is that: the ligand is replaced with a ligand of the formula.
The yield of the reaction was 45% and the ee value of the enantioselectivity was 46% as measured.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (10)
1. A method for synthesizing diphenyl-2-pyridylmethane derivatives, characterized by: mixing and stirring a compound D, butyl boric acid, a catalyst, a ligand, an additive, an oxidant and an organic solvent 1, reacting, and separating and purifying to obtain a diphenyl-2-pyridylmethane derivative E, wherein the chemical reaction formula is as follows:
wherein R is 1 、R 2 Each independently selected from one of hydrogen, alkyl, alkoxy, aryl, heteroaryl.
2. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the catalyst is Pd (OAc) 2 The ligand is
Wherein R is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
3. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the oxidant is terephthalquinone, and the additive is silver oxide.
4. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the organic solvent 1 is tetrahydrofuran.
5. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the molar ratio of the compound D to the butyl boric acid to the catalyst to the ligand to the oxidant to the additive is 1:1:0.1:0.2:0.5:1.0.
6. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the reaction temperature is 50-60 ℃ and the reaction time is 20-24h.
7. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, wherein: the preparation method of the ligand comprises the following steps: in the presence of an organic solvent 2, an acylating agent, a catalyst and an organic base, a 7-carboxyl-1, 1' -spiroindane compound shown in a formula B reacts with a compound shown in a formula C to prepare a compound shown in a formula A, wherein the reaction formula is as follows:
wherein R is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl and substituted benzyl.
8. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 7, wherein: the acylating agent is oxalyl chloride, the catalyst is N, N-dimethylformamide, the organic base is triethylamine, and the organic solvent 2 is dichloromethane.
9. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 7, wherein: the molar ratio of the 7-carboxyl-1, 1' -spiroindane compound shown in the formula B to the acylating agent to the organic base is 0.9-1:1-1.1:1.3-1.5:3;
the 7-carboxyl-1, 1' -spiroindane compound shown in the formula A and the catalyst are 1:0.01 in mol/L.
10. A method of synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 7, wherein: the reaction time is 5-7 hours, and the reaction temperature is 0-room temperature.
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| CN105732502A (en) * | 2014-12-09 | 2016-07-06 | 中国科学院大连化学物理研究所 | Method for preparing chiral 4,5-dihydropyrazole compounds |
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