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CN-121991131-A - Phosphite ligand, chiral quaternary carbonitrile derivative, preparation method and application

CN121991131ACN 121991131 ACN121991131 ACN 121991131ACN-121991131-A

Abstract

The invention relates to the technical field of organic synthetic chemistry, in particular to a phosphite ligand, a chiral quaternary carbonitrile derivative, a preparation method and application thereof. Phosphite ligands of the formula The phosphite ligands of the present invention incorporate a 7,7 '-substituent on the traditional binaphthol backbone with only a3, 3' -substituent. The structural modification can effectively change the dihedral angle of the binaphthol skeleton and enhance the overall rigidity of the binaphthol skeleton, thereby providing good space support for the coordination of the ligand and the metal center and the weak interaction between substituents. The phosphite ligand and the zero-valent nickel catalyst form a catalytic system, and the catalytic polysubstituted olefin and hydrocyanic acid equivalent are subjected to asymmetric hydrocyanic acid reaction, so that the chiral quaternary carbonitrile derivative is successfully prepared, the problems of high reaction temperature and low enantioselectivity in the prior art are overcome, and the chiral quaternary carbonitrile derivative has excellent practical value and popularization prospect.

Inventors

  • JIAO MINGDONG
  • WANG TING
  • LONG JINGUO
  • FANG XIANJIE

Assignees

  • 杭州师范大学

Dates

Publication Date
20260508
Application Date
20260324

Claims (10)

  1. 1. A phosphite ligand, wherein the phosphite ligand has the structural formula: ; Wherein R 1 、R 5 、R 8 and R 12 are each independently selected from halogen, hydroxy, mercapto, nitro, cyano, amino, alkyl of C 1 ~C 8 , substituted OR unsubstituted aryl, -CXOR, -CXR, -CXH, -XCXR, -CXSR, -CXNH 2 , -OP (OR) (OR '), OPRR', PRR ', P (X) RR', P (X) (OR) (OR '), SOR, OR S (O) 2 R, wherein R and R' are each independently selected from hydrogen, alkyl of C 1 ~C 8 , aryl of C 6 ~C 10 , OR heteroaryl of 5-to 10-membered, X is selected from oxygen OR sulfur; The substituent of the substituted aryl is at least one selected from-OCF 3 、C 1 ~C 4 alkyl and C 1 ~C 4 alkoxy; R 2 、R 3 、R 4 、R 6 、R 7 、R 9 、R 10 、R 11 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 And R 24 are each independently selected from hydrogen, halogen, hydroxy, mercapto, cyano, or amino.
  2. 2. The phosphite ligand of claim 1, wherein R 1 、R 5 、R 8 、R 12 is independently selected from Cl, br, I, nitro, cyano, substituted or unsubstituted aryl.
  3. 3. The phosphite ligand of claim 2, wherein R 1 、R 5 、R 8 、R 12 is each independently selected from substituted or unsubstituted aryl, and the substituent of the substituted aryl is-OCF 3 .
  4. 4. The phosphite ligand of claim 1, wherein ,R 2 、R 3 、R 4 、R 6 、R 7 、R 9 、R 10 、R 11 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 and R 24 are each independently selected from hydrogen.
  5. 5. A process for preparing a phosphite ligand as claimed in any one of claims 1 to 4, comprising the steps of: Taking multiaxial chiral (S) -7,7 '-dibromo- [1,1' -binaphthyl ] -2,2 '-diphenol and a first organic boride as raw materials, SPhos as a ligand, and carrying out Suzuki coupling reaction in a liquid phase in the presence of a catalyst and alkali to obtain a7, 7' -substituted binaphthyl diphenol skeleton; Taking 7,7' -substituted binaphthol skeleton and chloromethyl methyl ether as raw materials, and carrying out hydroxyl protection reaction in a liquid phase in the presence of alkali to obtain a hydroxyl protected intermediate; taking a hydroxyl-protected intermediate as a raw material, carrying out lithium-hydrogen exchange reaction on the hydroxyl-protected intermediate and alkyl lithium in a liquid phase, and then carrying out 3,3 '-iodination reaction on the hydroxyl-protected intermediate and iodine to obtain a3, 3' -iodination intermediate; Taking a3, 3' -position iodized intermediate and a second organic boride as raw materials, taking SPhos as a ligand, and carrying out Suzuki coupling reaction in a liquid phase in the presence of a catalyst and alkali to obtain a hydroxyl-protected 3,3' -position and 7,7' -position substituted binaphthol skeleton; deprotection reaction is carried out on the 3,3 '-position and 7,7' -position substituted binaphthol framework protected by hydroxyl groups to obtain the 3,3 '-position and 7,7' -position substituted binaphthol framework; under alkaline condition, 3 '-position and 7,7' -position substituted binaphthol skeletons and phosphoryl chloride compounds undergo substitution reaction to obtain phosphite ester ligands; Wherein the first organoboride is the same as or different from the second organoboride.
  6. 6. A process for the preparation of chiral quaternary carbonitrile derivatives based on phosphite ligands according to claim 1, characterized in that it comprises the following steps: Taking polysubstituted olefin and hydrocyanic acid equivalent as raw materials, taking phosphite ligand and zero-valent nickel catalyst as catalytic systems, dissolving polysubstituted olefin, phosphite ligand, hydrocyanic acid equivalent and zero-valent nickel catalyst in a solvent together, carrying out asymmetric hydrocyanation reaction on carbon-carbon double bonds of the polysubstituted olefin and cyano carbon atoms of the hydrocyanic acid equivalent, wherein the condition of the asymmetric hydrocyanation reaction is that stirring reaction is carried out for 36-72 h at 30-50 ℃, and chiral quaternary carbonitrile derivatives are obtained through separation and purification treatment; The reaction formula is: ; The polysubstituted olefin is selected from 1, 1-disubstituted olefin or trisubstituted olefin, and has a structure shown in a formula (I): ; Wherein R 'is selected from C 1 ~C 8 alkyl, C 6 ~C 10 aryl, C 4 heteroaryl, R' 'and R' '' are each independently selected from hydrogen, substituted or unsubstituted groups selected from C 1 ~C 8 alkyl, C 6 ~C 10 aryl, hydroxy, cyano, amide, -CXOR, -CXR, -CXH, -XCXR, -CXSR, -CXNH 2 , silane or siloxane groups.
  7. 7. The method for preparing chiral quaternary carbonitrile derivatives according to claim 6, wherein the molar ratio of the polysubstituted olefins, phosphite ligands and hydrocyanic acid equivalents is 1:0.05-0.2:1-10.
  8. 8. The method for preparing chiral quaternary carbonitrile derivatives according to claim 6, wherein the molar ratio of phosphite ligands to zero-valent nickel catalyst is 1:0.1-30.
  9. 9. A chiral quaternary carbonitrile derivative, which is prepared by the method for preparing a chiral quaternary carbonitrile derivative according to any one of claims 6 to 8, wherein the chiral quaternary carbonitrile derivative is selected from the group consisting of 、 、 、 Or (b) 。
  10. 10. A method of preparing a pharmaceutical or pharmaceutical intermediate comprising the step of reacting a chiral quaternary carbonitrile derivative of claim 9, 、 、 Or (b) Is used as an intermediate of the medicine, Is a medicine.

Description

Phosphite ligand, chiral quaternary carbonitrile derivative, preparation method and application Technical Field The invention relates to the technical field of organic synthetic chemistry, in particular to a phosphite ligand, a chiral quaternary carbonitrile derivative, a preparation method and application thereof. Background Chiral quaternary carbonitriles are a very important class of building blocks, which not only have their biocompatibility and metabolic stability, which are favorable for interactions between drug molecules and receptors, but also improve the toxicological properties of the molecules, which have important research value in the pharmaceutical field, and which are widely present in natural products, drugs such as the novel coronavirus drug, rituxevir, and other biologically active molecules. In addition, the chiral quaternary carbonitrile can be efficiently and conveniently converted into the corresponding quaternary carbon chiral carbonyl compound, quaternary carbon chiral amine and quaternary carbon chiral nitrogen heterocycle, so that the chiral quaternary carbonitrile can be widely used as an important intermediate in organic synthesis. Therefore, the development of an asymmetric synthesis methodology for efficiently and stereoselectively constructing chiral quaternary carbonitriles has definitely important scientific significance and application prospect. The asymmetric hydrocyanation of olefins is certainly one of the ways to build open-chain chiral quaternary carbonitriles efficiently and economically. In 2020, fang Xianjie teaches that nickel and phosphite ligands catalyze hydrocyanation of 1, 1-disubstituted styrenes to build chiral quaternary carbonitrile derivatives. However, the reaction needs to be carried out at a high temperature of 120 ℃ and the enantioselectivity is low. The traditional binaphthol ligand skeleton is replaced by 3,3' -position, the ligand is flexible, the chiral environment of the metal center continuously shifts in a ' conformation ' in the catalytic cycle, and the enantiomer recognition capability is attenuated. Disclosure of Invention Aiming at the defects existing in the prior art, the invention provides a phosphite ligand, a chiral quaternary carbonitrile derivative, a preparation method and application. The invention provides a novel phosphite ligand with 3,3 '-position and 7,7' -position aryl substitution, which is used as a catalytic system to be applied to the asymmetric hydrocyanation reaction of polysubstituted olefin and hydrocyanic acid equivalent, and can realize the efficient and high enantioselective preparation of chiral quaternary carbonitrile derivatives under the low temperature condition, thereby overcoming the problems of high reaction temperature and low enantioselectivity in the prior art. Compared with the traditional binaphthol skeleton with only 3,3 '-substituent, the phosphite ligand of the invention is newly added with 7,7' -substituent, and through steric hindrance and electronic effect, the dihedral angle of the binaphthol skeleton is effectively changed, the overall rigidity is increased, and good space support is provided for the coordination of metal center and weak interaction between substituents. Meanwhile, the conformation of the ligand framework is precisely regulated and controlled by utilizing non-covalent interactions including the actions of C-H.pi.pi.pi.pi.stacking and C-H.F, so that the chiral environment around the complex center of nickel and the ligand is critically molded, the chiral environment is still accurate at low temperature, and the problems of high reaction temperature and low enantioselectivity in the prior art are effectively solved. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: It is a first object of the present invention to provide a phosphite ligand having the structure of formula II: 。 Wherein R 1、R5、R8 and R 12 are respectively and independently selected from halogen, hydroxyl, sulfhydryl, nitro, cyano, amino, C 1~C8 alkyl, substituted OR unsubstituted aryl, -CXOR, -CXR, -CXH, -XCXR, -CXSR, -CXNH 2, -OP (OR) (OR '), OPRR', PRR ', P (X) RR', P (X) (OR) (OR '), SOR OR S (O) 2 R, wherein R and R' are respectively and independently selected from hydrogen, C 1~C8 alkyl, C 6~C10 aryl OR 5-to 10-membered heteroaryl, X is selected from oxygen OR sulfur, and the substituent of the substituted aryl is selected from at least one of-OCF 3、C1~C4 alkyl and C 1~C4 alkoxy. Wherein R 1 and R 12 are substituents at the 3,3 '-position and R 5 and R 8 are substituents at the 7,7' -position at 33. R2、R3、R4、R6、R7、R9、R10、R11、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23 And R 24 is independently selected from hydrogen, halogen, hydroxy, mercapto, cyano, amino, OR optionally substituted alkyl of C 1~C8, aryl of C 6~C10, heteroaryl of 5-to 10-membered, silane, -CXOR, -CXR, -CXH, -XCXR, -CXSR, -CXNH 2, -OP (OR) (OR '), OPRR', PRR ', P (X) RR', P (X) (OR) (OR '), SO