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CN-121991003-A - Method for synthesizing chiral morpholine from propargyl alcohol ester

CN121991003ACN 121991003 ACN121991003 ACN 121991003ACN-121991003-A

Abstract

The invention discloses a method for synthesizing chiral morpholine from propargyl alcohol ester. Chiral morpholine is an important molecular skeleton of a drug, and is widely applied to the aspects of analgesia, anesthesia, anti-tumor, heart treatment and the like as a drug active ingredient, but a method for efficiently synthesizing the chiral morpholine is lacking, and the method enables propargyl alcohol ester to react with an affinity reagent under the regulation and control of aryl boric acid and a specific chiral ligand to obtain optically pure (87-97%ee) morpholine. The invention has the characteristics of wide sources of catalyst and ligand, low cost and easy obtainment of substrate, excellent enantioselectivity and good functional group compatibility, can be suitable for structural transformation of bioactive molecules and intermediates, and is a simple and efficient asymmetric catalytic strategy for synthesizing chiral morpholine.

Inventors

  • CHEN LIANGAN
  • WU BAIXUE
  • HU JINGZHOU
  • JIANG XINYUE

Assignees

  • 南京师范大学

Dates

Publication Date
20260508
Application Date
20251209

Claims (10)

  1. 1. A process for synthesizing chiral morpholine from propargyl alcohol ester, which is characterized in that propargyl alcohol ester is used in solvent Catalytic system and nucleophile of transition metal palladium Pd and chiral ligand in arylboronic acid are used as reaction substrates Carrying out reaction to obtain chiral morpholine product Wherein R 1 and R 2 independently represent an alkyl group OR an aryl group, OR 3 represents an ester group, R 4 represents an aryl group, and the chiral ligand represents a chiral phosphine ligand.
  2. 2. The method for synthesizing chiral morpholine from propargyl alcohol ester according to claim 1, wherein the alkyl substituent groups are each independently selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silicon, mercapto, amino or cyano, and the aryl groups are aryl groups substituted with a benzene ring selected from C1-C20 alkyl, C1-C20 halo substituted alkyl, C1-C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silicon, mercapto, amino or cyano substituted or unsubstituted biphenyl, naphthyl, anthracenyl or N, O, S penta-thirteen ring heteroaryl groups.
  3. 3. A method of synthesizing chiral morpholine from propargyl alcohol ester according to claim 1, wherein OR 3 is selected from one OR more of alkyl sulfonate, aryl sulfonate, sulfamate, alkyl carboxylate, aryl carboxylate, aminocarboxylate, alkoxycarboxylate, aryloxycarboxylate, alkyl phosphate, aryl phosphate, arylalkyl phosphate.
  4. 4. A method of synthesizing chiral morpholine from propargyl alcohol esters according to claim 1, wherein R 4 is selected from the group consisting of C1-C20 alkyl, C1-C20 halo substituted alkyl, C1-C20 alkylcarbonyl, nitro, hydroxy, ester, alkenyl, ether, amide, silicon, mercapto, amino or cyano substituted or unsubstituted biphenyl, naphthyl, anthracenyl and heteroaryl containing N, O, S penta-thirteen rings.
  5. 5. The method of synthesizing chiral morpholine from propargyl alcohol ester according to claim 1, wherein the chiral ligand comprises a bidentate chiral N ligand, a bidentate chiral P ligand, a bidentate chiral N-P ligand, a monodentate chiral N ligand, a monodentate chiral phosphine ligand, a tridentate chiral N-P-N ligand, a tridentate chiral N-S-P ligand, a tridentate chiral N-ligand. The chiral phosphine ligand comprises chiral oxazoline ligand, chiral diamine ligand, chiral monodentate phosphine ligand, chiral biphosphinamide ligand, chiral biphenyl bidentate phosphine ligand, chiral spiro bidentate phosphine ligand, chiral binaphthyl bidentate phosphine ligand or chiral sulfinamide substituted phosphine ligand.
  6. 6. The method of synthesizing chiral morpholine from propargyl alcohol ester according to claim 1, wherein the arylboronic acid is selected from one or more of 2, 8-dimethoxy-10H-dibenzo [ b, e ] [1,4] oxyboron-10-ol, 2, 8-bistrifluoromethyl-10H-dibenzo [ b, e ] [1,4] oxyboron-10-ol, 2, 8-di-tert-butyl-10H-dibenzo [ b, e ] [1,4] oxyboron-10-ol, 2, 8-dimethyl-10H-dibenzo [ b, e ] [1,4] oxyboron-10-ol, 2, 8-diethyl-10H-dibenzo [ b, e ] [1,4] oxyboron-10-ol, 10H-dibenzo [ b, e ] [1,4] oxyboron-10-ol.
  7. 7. The method of synthesizing chiral morpholine from propargyl alcohol ester according to claim 1, wherein the palladium is selected from palladium chloride, palladium bromide, palladium iodide, (1, 1' -bis (diphenylphosphino) ferrocene) dichloropalladium, palladium acetylacetonate, bis (hexafluoroacetylacetonate) palladium, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium, bis (tri-tert-butylphosphine) palladium, bis (dibenzylideneacetone) palladium, chloro (crotyl) (tricyclohexylphosphine) palladium, tris (dibenzylideneacetone) dipalladium-chloroform adduct, (1, 5-cyclooctadiene) dibromide, trifluoropalladium acetate, tetraphenyl tetrakis (phosphonite) palladium, tetrakis (tri-o-tolylphosphine) palladium, allylpalladium chloride dimer, (1-methallyl) palladium chloride dimer, allylpalladium, bis (tricyclohexylphosphine) palladium, bis (tri-o-tolylphosphine) palladium, tetrakis (acetonitrile) tetrafluoropalladium, phenylboronic acid or 1, 2-bis (phenylsulfonyl) acetic acid.
  8. 8. The method of synthesizing chiral morpholine from propargyl alcohol ester according to claim 1, wherein the organic solvent is selected from one or more of diethyl ether, t-butyl methyl ether, N-butyl ether, isopropyl ether, diphenyl ether, dimethyl sulfide, cyclopentyl methyl ether, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, benzonitrile, benzene, toluene, benzotrifluoride, acetone, methylene chloride, chloroform, 1, 2-dichloroethane, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, ethyl acetate, ethyl formate, propyl formate, 1, 4-dioxane, 1, 3-dioxolane, tetrahydrofuran, 2-methyltetrahydrofuran, or 1, 3-dimethyl-2-imidazolidinone.
  9. 9. The method for synthesizing chiral morpholine from propargyl alcohol ester according to claim 1, wherein the molar ratio of the nucleophile, propargyl alcohol ester, palladium and boric acid is 1 (1-2): 0.01-0.2): 0.1-1.
  10. 10. The method for synthesizing chiral morpholine from propargyl alcohol ester according to claim 1, wherein the reaction is carried out in an inert gas atmosphere at a reaction temperature of 10 to 50 ℃ for 8 to 36 hours.

Description

Method for synthesizing chiral morpholine from propargyl alcohol ester Technical Field The invention belongs to the fields of catalytic synthesis technology and fine chemical synthesis, and relates to a method for synthesizing chiral morpholine from propargyl alcohol ester. Background Chiral morpholine and its derivative have been the indispensable dominant skeleton in pharmaceutical chemistry and molecular design by virtue of their unique molecular structure and physicochemical properties, play a key role in bioactive molecule and drug development, and have wide application as pharmaceutical active ingredients in analgesia, anesthesia, anti-tumor, cardiovascular disease treatment and other aspects, and also have potential in neurodegenerative diseases and anti-infection drug development. The efficient and green synthesis of optically pure morpholine from simple raw materials has been a research hotspot in the field of organic synthesis, and has received great attention from chemists. At present, chiral morpholine is researched, and various strategies such as asymmetric catalysis, metal-mediated cyclization and the like are involved, but the chiral morpholine still has certain limitations. At present, most methods for synthesizing chiral morpholine are limited to inducing enantioselectivity by depending on a substrate, so that compatibility of a reaction substrate is poor, and although a new thought is provided for chiral control of morpholine through an allyl metal intermediate approach, the substrate application range is limited to Jian Shanlian-shaped olefin, and the method is difficult to be applied to complex molecule construction with multiple functional groups, so that the wide application potential of the chiral morpholine in innovative drug design is restricted, and challenges such as unstable enantioselectivity are faced. Transition metal catalyzed asymmetric substitution reactions of propargyl esters are powerful tools for synthesizing chiral molecules, and have been favored by chemists in recent years, emerging a range of reaction modes such as asymmetric propargylation, dienylation, and alkenylation. However, the research of asymmetric alkenylation reactions is relatively scarce compared to the development of mature asymmetric propargylation and dienylation, and there are more regional, chemical and stereoselective challenges. The existing asymmetric alkenyl strategy successfully realizes the construction of a series of chiral cyclic allyl molecules, and the synthesis of acyclic molecules is limited to the application of a racemization mode. Therefore, the novel propargyl alcohol ester asymmetric alkenyl strategy is developed to realize the synthesis of the acyclic chiral allyl compound, and the method is applied to the efficient and asymmetric construction of chiral morpholine, so that the method has practical significance, can expand a reaction mode of propargyl alcohol ester alkenyl, and can develop a brand-new efficient and green process for synthesizing chiral morpholine. The nucleophilic reagent, arylboronic acid and other raw materials of the method are simple and easy to obtain, the required palladium catalyst, ligand and solvent are wide in sources and low in cost, the enantioselectivity is excellent, the functional group compatibility is good, the method can be suitable for structural transformation of bioactive molecules and intermediates, and the method is a simple and efficient asymmetric catalytic strategy for synthesizing chiral morpholine. Disclosure of Invention Aiming at the problems existing in the prior art, the invention provides a method for synthesizing chiral morpholine from propargyl alcohol ester. The method provides a revolutionary path through the efficient and selective construction of the directional conversion of internal aliphatic substituted propargyl alcohol ester and nucleophilic reagent into chiral morpholine skeleton by using proper chiral ligand and aryl boric acid and regio-stereoselectively and chemoselectively. Not only the asymmetric alkenylation of the propargyl ester is realized for the first time to construct an acyclic chiral allyl compound, but also the efficient and rapid conversion from the propargyl ester to the chiral morpholine is finished for the first time. In general, the invention provides an asymmetric catalytic mode of transition metal catalyzed propargyl alcohol ester at an unconventional site, and establishes a catalytic synthesis system with high efficiency, conciseness and high selectivity for constructing chiral morpholine frameworks. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: a process for synthesizing chiral morpholine from propargyl alcohol ester in solvent As a reaction substrate, a catalytic system of transition metal Pd and chiral ligand (CHIRAL LIGAND) in arylboronic acid (Boric acid) and a nucleophilic reagent are usedCarrying out reaction to obtain chiral morpholine p