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CN-121990962-A - Asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol

CN121990962ACN 121990962 ACN121990962 ACN 121990962ACN-121990962-A

Abstract

The invention relates to the technical field of organic compound synthesis, in particular to an asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol. And under the condition of preset temperature and hydrogen atmosphere, in a solvent and in the presence of alkali, carrying out asymmetric catalytic hydrogenation reaction on the compound shown in the formula I by taking a complex formed by the chiral metallocene ligand and ruthenium salt as a catalyst to form the compound shown in the formula II. The method has the advantages of convenient sources of raw material reagents, high substrate conversion rate, good stereoselectivity, economy, high efficiency, simple and reliable operation and is more suitable for industrial amplification.

Inventors

  • ZHANG WANBIN
  • LIU DELONG
  • XU WENQI
  • HE JINGLI

Assignees

  • 郑州上海交大产业技术研究院

Dates

Publication Date
20260508
Application Date
20260130

Claims (10)

  1. 1. A method for synthesizing chiral aryl (pyrrolidine-2-yl) methanol by asymmetric catalytic hydrogenation is characterized in that a compound shown in a formula I takes a complex formed by a chiral metallocene ligand and ruthenium salt as a catalyst to carry out asymmetric catalytic hydrogenation reaction to form a compound shown in a formula II, wherein the reaction formula is as follows: 。
  2. 2. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidin-2-yl) methanol according to claim 1, wherein Ar comprises a substituted or unsubstituted aromatic hydrocarbon group and a substituted or unsubstituted heteroaromatic hydrocarbon group in the formula I-II, and R comprises aroyl and alkyl (oxy) acyl.
  3. 3. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidin-2-yl) methanol according to claim 1, wherein the chiral metallocene ligand comprises a compound shown in formula III to formula VI: 。
  4. 4. The method for asymmetric catalytic hydrogenation of chiral aryl (pyrrolidin-2-yl) methanol according to claim 3, wherein R comprises H, a straight-chain alkyl group containing 1-8 carbons, a branched-chain alkyl group containing 1-8 carbons, a cycloalkyl group containing 1-8 carbons, an aryl group and a benzyl group, ar comprises a substituted or unsubstituted aromatic hydrocarbon group and a substituted or unsubstituted heteroaromatic hydrocarbon group, and R' comprises phenyl, tolyl, p-cymene, triarylphosphine, trialkylphosphine and 1, 5-cyclooctadiene.
  5. 5. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidin-2-yl) methanol according to claim 3, wherein the catalyst comprises a compound represented by the formula Ru cat.1-Ru cat.16: 。
  6. 6. the asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidin-2-yl) methanol according to claim 1, wherein the asymmetric catalytic hydrogenation reaction is carried out at a temperature of-78 to 100 ℃ and a pressure of 1 to 100bar.
  7. 7. The method for asymmetric catalytic hydrogenation of chiral aryl (pyrrolidin-2-yl) methanol according to claim 1, wherein the solvent for the asymmetric catalytic hydrogenation comprises methanol, ethanol, isopropanol, propanol, butanol, isobutanol, acetone, 1, 4-dioxane, tetrahydrofuran/water, dichloromethane/water, acetonitrile, toluene/water, xylene, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidine, and N-ethylpyrrolidine.
  8. 8. The method for synthesizing chiral aryl (pyrrolidin-2-yl) methanol by asymmetric catalytic hydrogenation according to claim 1, wherein a base is added in the asymmetric catalytic hydrogenation, and the base comprises t BuOK、 t BuONa、 t BuOLi、NaOH、KOH、MeONa、EtONa、TMSOK、TMSONa、Na 2 CO 3 、Cs 2 CO 3 、NaHCO 3 and 1, 4-diazabicyclo [2.2.2] octane.
  9. 9. The method for synthesizing chiral aryl (pyrrolidin-2-yl) methanol by asymmetric catalytic hydrogenation according to claim 8, wherein the molar ratio of the compound shown in formula I to the base is 1:0.1-3.
  10. 10. The asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidin-2-yl) methanol according to claim 1, wherein the molar ratio of the compound shown in the formula I to the catalyst is 100000-100:1.

Description

Asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol Technical Field The invention relates to the technical field of organic compound synthesis, in particular to an asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol. Background Chiral aryl (pyrrolidin-2-yl) methanol having the structure: , Chiral aryl (pyrrolidin-2-yl) methanol is taken as a core structural unit derived from natural chiral amino acid-proline, and occupies a significant position in the fields of pharmaceutical chemistry and asymmetric synthesis due to the unique rigid pyrrolidine skeleton and flexible modification functional groups. First, chiral aryl (pyrrolidin-2-yl) methanols are key pharmacophores of numerous bioactive molecules, which are widely embedded in natural products and drug molecular frameworks with important physiological functions. For example, the high cytotoxicity antitumor drug Dolastatin 10, quinoline-prolyl derivatives which disrupt the formation of the biological membrane of Vibrio cholerae, and phenanthroline indole alkaloids (e.g. tylophoridine E) are all indistinguishable from the core structure. Second, chiral aryl (pyrrolidin-2-yl) methanol is a highly efficient synthetic tool for constructing more complex drug molecules. In synthetic chemistry, the chiral prolinol and aryl substituted analogues thereof derived from proline are chiral ligands or organic micromolecular catalysts with excellent performance, can efficiently and selectively synthesize various chiral enriched molecules, and further provides a graceful strategy for quickly constructing another important medicine skeleton-functionalized chiral piperidine (such as 2-aryl piperidine-3-alcohol) through ring-expanding reaction of nitrogen center ion intermediates thereof. Furthermore, chiral aryl (pyrrolidin-2-yl) methanol is directed to drug molecules of great clinical value. The chiral piperidine structure is a key drug effect unit of a potent neurokinin-1 (NK-1) receptor antagonist, classical ligands such as (+) -L-733,060 and (+) -CP-99,994, and Wo Fubi which enters the clinical study of post-traumatic stress disorder (PTSD) are all proved to have great potential in the aspects of anxiety treatment, antiemetic and the like of molecules based on the structural unit. From the basic active structure to the efficient synthesis tool and finally to the clinical medicine, chiral aryl (pyrrolidine-2-yl) methanol penetrates through a plurality of key links of the modern medicine discovery, and due to the extreme importance of the chiral aryl (pyrrolidine-2-yl) methanol on a multi-layer surface, a general synthesis method with high efficiency and high enantioselectivity is developed to realize the diversity preparation of the structure, so that the chiral aryl (pyrrolidine-2-yl) methanol is always a leading-edge hotspot for the efforts of synthesis chemists, and has profound scientific significance and application value. At present, various synthetic methods have been established for the preparation of chiral aryl (pyrrolidin-2-yl) methanol. The synthetic methods reported in literature Tetrahedron Lett.2001,42(36), 6223-6225;Org. Lett.2009,11(9), 1935-1938;Org. Lett.2020,22(24), 9740–9744 and the like have the advantages of lower yield, still further improved stereoselectivity, limited substrate range, more severe reaction conditions and the like, and are difficult to be used for large-scale production. The literature adv. synth. Catalyst.2011, 353 (11-12), 1955-1960 asymmetrically hydrogenates a range of aryl heterocycloalkylketones by dynamic kinetic resolution, however, for the structure of pyrrolidinylarylketones, the literature is only an example, and the reaction is carried out under conditions of 10bar hydrogen pressure, S/c=200. Therefore, there is a need in the art for a process for preparing chiral aryl (pyrrolidin-2-yl) methanol which is simpler to operate, has a wider substrate applicability, and can provide a product of high chiral purity. Disclosure of Invention The invention aims to provide an asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol, which aims to solve the problems that the existing synthesis method has lower yield, still further improved stereoselectivity, limited substrate range, more severe reaction conditions and the like, and is difficult to be used for large-scale production and the like. In order to achieve the aim, the technical scheme is that the asymmetric catalytic hydrogenation synthesis method of chiral aryl (pyrrolidine-2-yl) methanol is adopted, under the condition of preset temperature and hydrogen atmosphere, in the presence of a base and in a solvent, a compound shown in a formula I carries out asymmetric catalytic hydrogenation reaction by taking a complex formed by a chiral metallocene ligand and ruthenium salt as a catalyst (Ru Cat.) to form a compound shown in a formula II, wherein the rea