CN113816865B - Preparation method of chiral alpha-amino acetal compound and derivative thereof - Google Patents

Preparation method of chiral alpha-amino acetal compound and derivative thereof Download PDF

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CN113816865B
CN113816865B CN202111145351.8A CN202111145351A CN113816865B CN 113816865 B CN113816865 B CN 113816865B CN 202111145351 A CN202111145351 A CN 202111145351A CN 113816865 B CN113816865 B CN 113816865B
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solvent
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CN113816865A (en
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史永杰
张绪穆
殷勤
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Southwest University of Science and Technology
Shenzhen Bay Laboratory
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Shenzhen Bay Laboratory
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • 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
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Abstract

A preparation method of chiral alpha-amino acetal compound and derivative thereof comprises the following steps: and (3) contacting the compound shown in the formula (I) with a catalyst, an ammonia source and a reducing agent, and reacting to obtain the compound shown in the formula (II). The preparation method of the chiral a-amino acetal compound has the characteristics of high enantioselectivity, small environmental pollution and high yield.

Description

Preparation method of chiral alpha-amino acetal compound and derivative thereof
Technical Field
The invention relates to the technical field of molecular synthesis of pharmaceutical intermediates and organic chiral building blocks, in particular to a preparation method of chiral alpha-amino acetals and derivatives thereof.
Background
Chiral alpha-amino acetals are an important class of organic synthons, because the acetal functional groups in the compounds can be efficiently and conveniently converted into compounds with important functional groups such as hydroxyl, carboxyl, ester, amide and the like. In addition, α -functionalized chiral amines are also an important class of compounds, such as α -amino acids, α -amino acid esters, α -aminoamides, α -aminoalcohols, diamines, etc., that are widely found in natural products and pharmaceutically active molecules and are widely used as chiral synthetic building blocks and chiral catalysts.
In the prior art, various methods are available for asymmetric chemical synthesis of alpha-functionalized amino compounds, such as asymmetric hydrogenation reaction of transition metal catalyzed dehydroamino acid and alpha-imine ester or amide, which can obtain high enantioselective products with higher conversion number of reaction, less equivalent amount of catalyst, less waste of reaction products, and environmental protection. However, the products obtained by asymmetric hydrogenation are generally amine-protected products, so that further deprotection steps are generally required to obtain primary amines in the subsequent step, and the reaction substrates are obtained in advance from condensation of ketone substrates with amine compounds, the overall route being lacking in atomic economy and cumbersome to operate. ( J.chem.soc.chem.com. 1971,481; j.chem.soc.chem.com. 1972,10; j.chem.soc.chem.com. 1985,922; tetrahedran,1994,50,4399-4428; org.lett.,2001,3,313-315; am.chem.soc.,2015,137,2763-2768. )
Disclosure of Invention
According to a first aspect, in one embodiment, there is provided a method for preparing an α -amino acetal compound, comprising:
contacting a compound shown in a formula (I) with a catalyst, an ammonia source and a reducing agent to obtain a compound shown in a formula (II), wherein the reaction formula is as follows:
in the formula (I) and the formula (II), R 1 Including but not limited to aromatic rings, heterocyclic rings, saturated hydrocarbon groups, R 2 Including but not limited to alkyl groups.
According to a second aspect, in one embodiment, there is provided a process for preparing a compound of formula (II'), comprising: contacting the compound of formula (II) produced in the first aspect with a protecting reagent to react to produce a compound of formula (II'), wherein the reaction formula is as follows:
r in the compounds represented by the formula (II) and the formula (II') 1 、R 2 As defined in the first aspect.
According to a third aspect, in an embodiment, there is provided a method for producing a compound represented by formula (III), comprising: contacting the compound of formula (II') produced in the second aspect with a reducing agent to produce a compound of formula (III), wherein the reaction formula is as follows:
r in the compound represented by the formula (II') and the formula (III) 1 As defined in the first aspect.
According to a fourth aspect, in one embodiment, there is provided a process for preparing a compound of formula (IV), comprising: contacting the compound of formula (II') produced in the second aspect with an oxidizing agent to produce a compound of formula (IV), wherein the reaction formula is as follows:
according to the preparation method of the alpha-amino acetal compound and the derivative thereof, the asymmetric reductive amination reaction is adopted, and the method has the characteristics of high enantioselectivity, small environmental pollution and high yield, and the compound shown in the formula (II) with high enantioselectivity is synthesized by asymmetric catalytic reaction for the first time.
Detailed Description
The present invention will be described in further detail with reference to the following specific embodiments. Wherein like elements in different embodiments are numbered alike in association. In the following embodiments, numerous specific details are set forth in order to provide a better understanding of the present application. However, one skilled in the art will readily recognize that some of the features may be omitted, or replaced by other elements, materials, or methods in different situations. In some instances, some operations associated with the present application have not been shown or described in the specification to avoid obscuring the core portions of the present application, and may not be necessary for a person skilled in the art to describe in detail the relevant operations based on the description herein and the general knowledge of one skilled in the art.
Furthermore, the described features, operations, or characteristics of the description may be combined in any suitable manner in various embodiments. Also, various steps or acts in the method descriptions may be interchanged or modified in a manner apparent to those of ordinary skill in the art. Thus, the various orders in the description are for clarity of description of only certain embodiments, and are not meant to be required, unless otherwise indicated, to be followed.
The numbering of the components itself, e.g. "first", "second", etc., is used herein merely to distinguish between the described objects and does not have any sequential or technical meaning.
As used herein, "saturated hydrocarbon group" refers to a hydrocarbon group containing only single carbon-carbon bonds, and "unsaturated hydrocarbon group" refers to a hydrocarbon group containing double or triple bonds.
As used herein, "Ph" means phenyl, "Me" means methyl, "DTBM" means 3, 5-di-tert-butyl-4-methoxyphenyl, "Et" means ethyl, "Bu" means tert-butyl.
As used herein, "room temperature" refers to 23 ℃ ±2 ℃.
As used herein, atm refers to standard atmospheric pressure, 1 atm=101 325pa.
As used herein, "saturated sodium bicarbonate solution" refers to a saturated aqueous sodium bicarbonate solution.
As used herein, yield = (actual yield of desired product/theoretical yield of desired product) ×100%.
According to a first aspect, in one embodiment, there is provided a method for preparing an α -amino acetal compound, comprising:
contacting a compound shown in a formula (I) with a catalyst, an ammonia source and a reducing agent to obtain a compound shown in a formula (II), wherein the reaction formula is as follows:
in the formula (I) and the formula (II), R 1 Including but not limited to aromatic rings, heterocyclic rings, saturated hydrocarbon groups, R 2 Including alkyl groups.
In one embodiment, the preparation method of the chiral alpha-amino acetal compound provided by the invention has the characteristics of high enantioselectivity, small environmental pollution and high yield.
In one embodiment, the aromatic ring includes, but is not limited to, at least one of phenyl, substituted phenyl, naphthyl, and the like, the heterocycle includes, but is not limited to, at least one of pyridine, thiophene, furan, indole, and the like, and the saturated hydrocarbon group includes, but is not limited to, at least one of methyl, ethyl, cyclic saturated hydrocarbon group, and the like.
In one embodiment, the alkyl group includes, but is not limited to, at least one of methyl, ethyl, isopropyl, cyclohexyl, and the like.
In one embodiment, the catalyst comprises a phosphine ligand metal catalyst.
In one embodiment, the phosphine ligand metal catalyst includes, but is not limited to, phosphine ligand ruthenium catalyst.
In one embodiment, the phosphine ligand ruthenium catalyst includes, but is not limited to, compounds represented by the following general formula: ru (OAc) 2 (L), wherein ligand L includes, but is not limited to, any one of the following compounds:
ar in L2 and L3 is Ph, 4-MeO-3,5- t Bu 2 C 6 H 2 、C 6 H 5 、4-Me-C 6 H 5 、3,5-Me 2 C 6 H 3 、3,5- t Bu 2 C 6 H 3 Any one of the following.
In one embodiment, ligand L includes, but is not limited to, any of the following compounds:
in one embodiment, the reaction system further comprises a solvent.
In one embodiment, the solvent includes, but is not limited to, an organic solvent.
In one embodiment, the organic solvent includes, but is not limited to, at least one of methanol, ethanol, isopropanol, trifluoroethanol, hexafluoroisopropanol.
In one embodiment, the ammonia source includes, but is not limited to, at least one of ammonium salt, ammonia gas.
In one embodiment, the ammonium salt includes, but is not limited to, at least one of ammonium acetate, ammonium formate, ammonium benzoate, ammonium salicylate, ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, and the like.
In one embodiment, the solvent is added in an amount of 5mL to 10mL per millimole of the compound of formula (I).
In one embodiment, the reaction is carried out in a closed vessel.
In one embodiment, the gas pressure of the reducing agent charged into the closed container may be 30 to 50atm, including but not limited to 30atm, 40atm, 50atm, etc.
In one embodiment, the reducing agent includes, but is not limited to, hydrogen.
In one embodiment, the reaction is carried out at 70-90 ℃. The vessel containing the reaction solution is heated to a desired temperature, and the reaction vessel may be heated by means of an oil bath or the like.
In one embodiment, the molar ratio of the compound of formula (I) to the catalyst is 1: (0.00001-0.01), including but not limited to 1:0.00001, 1:0.0001, 1:0.001, 1:0.002, 1:0.003, 1:0.004, 1:0.005, 1:0.006, 1:0.007, 1:0.008, 1:0.009, 1:0.01, preferably 1:0.01. The catalyst consumption in the reaction system is small, and the catalytic efficiency is high.
In one embodiment, the molar ratio of the compound of formula (I) to the ammonia source is 1: (1-5), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, preferably 1:2.
In one embodiment, the ratio of the molar amount of the compound of formula (I) to the volume of the solvent is 1mmol: (5-10) mL.
In one embodiment, the compound of formula (I) includes, but is not limited to, at least one of the following:
in one embodiment, the method further comprises adding a quenching solution to the reaction solution after the reaction is completed, and quenching the reaction.
In one embodiment, the quenching solution includes, but is not limited to, saturated aqueous sodium bicarbonate (also known as saturated sodium bicarbonate solution).
In one embodiment, the volume of quench solution required per millimole of compound of formula (I) is 20mL.
According to a second aspect, in one embodiment, there is provided a process for preparing a compound of formula (II'), comprising: contacting the compound of formula (II) produced in the first aspect with a protecting reagent to react to produce a compound of formula (II'), wherein the reaction formula is as follows:
r in the compounds represented by the formula (II) and the formula (II') 1 、R 2 As defined in the first aspect. This is an acetal hydrolysis reaction.
In one embodiment, the protective agent includes, but is not limited to, benzoyl chloride (BzCl).
In one embodiment, the reaction is performed at room temperature.
In one embodiment, the reaction comprises the steps of:
1) Contacting the compound shown in the formula (II) prepared in the first aspect with a protecting reagent, an alkaline reagent and a first solvent, and reacting to obtain a first product;
2) The first product is contacted with an acid reagent and a second solvent to react to obtain the compound shown in the formula (II').
In one embodiment, the base reagent includes, but is not limited to, at least one of triethylamine (TEA, CAS registry number: 121-44-8), N-diisopropylethylamine (CAS registry number: 7087-68-5), butylamine (also known as N-butylamine, CAS registry number: 109-73-9).
In one embodiment, the first solvent includes, but is not limited to, dichloromethane (DCM).
In one embodiment, the acid reagent includes, but is not limited to, at least one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid. The acid reagent is mainly used for providing an acidic environment, and is preferably a strong acid. The criterion for strong acids is their ionization constant in aqueous solution, generally strong acids with pKa (acidity coefficient, negative logarithm of ionization constant) less than 1.
In one embodiment, the second solvent includes, but is not limited to, an organic solvent. Preferably a water-soluble organic solvent.
In one embodiment, the organic solvent includes, but is not limited to, at least one of acetone, dimethyl sulfoxide (DMSO).
In one embodiment, steps 1) and 2) are all performed at room temperature.
In one embodiment, the molar ratio of the compound of formula (II) to the protecting agent is 1: (1-1.5), including but not limited to 1:1. 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, preferably 1:1.5.
In one embodiment, the first solvent is added in an amount of 5mL to 10mL per millimole of the compound of formula (II).
In one embodiment, after the reaction is completed, the method further comprises adding a quenching solution to the reaction solution to quench the reaction.
In one embodiment, the volume of quench solution required per millimole of compound of formula (II) is from 10 to 30mL.
In one embodiment, 0.5 to 5mL of the acid reagent and 0.5 to 5mL of the second solvent, preferably 2.5mL of the acid reagent and 2.5mL of the second solvent, are added per millimole of the compound of formula (II). In one embodiment, the acid reagent may be hydrochloric acid and the second reagent may be acetone.
In one embodiment, the initial concentration of the acid reagent added to the reaction system (acetal hydrolysis reaction system) is 2 to 6mol/L. The initial concentration of the acid agent refers to the concentration of the acid agent before it is added to the reaction system.
According to a third aspect, in an embodiment, there is provided a method for producing a compound represented by formula (III), comprising: contacting the compound of formula (II') produced in the second aspect with a reducing agent to produce a compound of formula (III), wherein the reaction formula is as follows:
r in the compound represented by the formula (II') and the formula (III) 1 As defined in the first aspect.
In one embodiment, the molar ratio of the compound of formula (II) to the reducing agent is 1: (1-5), including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, preferably 1:1.2.
In one embodiment, the reducing agent includes, but is not limited to, sodium borohydride (NaBH 4 )。
In one embodiment, the reaction system further comprises a solvent.
In one embodiment, the solvent includes, but is not limited to, methanol.
In one embodiment, the reaction is carried out at 0 to 25℃including, but not limited to, 0 ℃,5 ℃,10 ℃,15 ℃,20 ℃,25 ℃, preferably 0 ℃.
In one embodiment, the method further comprises adding a quenching solution to the reaction solution after the reaction is completed.
In one embodiment, the volume of quench solution required per millimole of compound of formula (II) is from 10 to 30mL.
In one embodiment, the quenching solution includes, but is not limited to, a saturated aqueous ammonium chloride solution (also known as a saturated ammonium chloride solution).
According to a fourth aspect, in one embodiment, there is provided a process for preparing a compound of formula (IV), comprising: contacting the compound of formula (II') produced in the second aspect with an oxidizing agent to produce a compound of formula (IV), wherein the reaction formula is as follows:
r in the compound shown in the formula (II') and the formula (IV) 1 As defined in the first aspect.
In one embodiment, the oxidizing reagent comprises jones reagent.
The Jones reagent is also called Jones reagent, and is an aqueous solution prepared from chromium trioxide, sulfuric acid and water. 26.72 g of chromium trioxide is dissolved in a small amount of water, 23 ml of concentrated sulfuric acid is slowly dripped into the solution, and the solution is diluted to 100 ml by water to obtain the chromium trioxide. Is a reagent for selectively oxidizing organic compounds. The jones reagent oxidizes the secondary alcohol to the corresponding ketone without affecting the double or triple bonds present in the molecule; allyl alcohol (primary alcohol) can also be oxidized to aldehydes. The secondary alcohol or allyl alcohol is typically dissolved in acetone or dioxymethane, and the reagent is then added dropwise to effect the oxidation reaction, typically at a temperature below room temperature.
In one embodiment, the ratio of the molar amount of the compound of formula (II) to the volume of oxidizing agent is 1.0mol: (0.1 to 0.3) L, including but not limited to 1.0mol:0.1L, 1.0mol:0.15L, 1.0mol:0.2L, 1.0mol:0.25L, 1.0mol:0.3L, preferably 1.0mol:0.15L.
In one embodiment, the reaction system further comprises a solvent.
In one embodiment, the solvent includes, but is not limited to, acetone.
In one embodiment, the reaction is carried out at a temperature of-10℃to 25℃including, but not limited to, -10 ℃, -5 ℃,0 ℃,5 ℃,10 ℃,15 ℃,20 ℃,25 ℃, etc., preferably 0 ℃.
In one embodiment, the method further comprises adding a quenching reagent to the reaction solution after the reaction is completed.
In one embodiment, 2mL of quenching reagent is required per millimole of the compound of formula (II).
In one embodiment, the quenching agent includes, but is not limited to, isopropyl alcohol.
In one embodiment, the preparation method of the alpha-amino acetal compound and the derivative thereof provided by the invention adopts no reductive amination reaction, and has the advantages of high yield, excellent enantioselectivity of products, high atom economy and the like.
Example 1
Under the argon atmosphere of a glove box, different metal catalysts Ru (OAc) are respectively added into a 2mL reaction bottle 2 (L) (0.001 mmol), the compound of formula I (0.1 mmol), ammonium acetate (0.2 mmol, also known as ammonium acetate) and trifluoroethanol (0.5 mL, also known as 2, 2-trifluoroethanol, abbreviated as TFE), the reaction flask was put into a high-pressure hydrogen atmosphereAnd filling hydrogen with 50 atmospheres into the chemical reaction kettle. The reaction vessel was placed in an oil bath at 80℃and stirred for 20h. After the reaction is finished, 2mL of saturated sodium bicarbonate aqueous solution is added for quenching reaction, 3mL of dichloromethane is used for extraction three times, the organic phases are combined, the organic phases are dried by anhydrous sodium sulfate, the solvent is removed after filtration, and the crude product is separated by a silica gel column to obtain a product, wherein the eluent is methanol: dichloromethane=1:49 (volume ratio). After the product has been protected by acetylation, the enantiomeric excess is determined by HPLC.
The metal catalyst is synthesized autonomously, and the synthesis method refers to the literature: a) H.Takaya, T.Ohta, S.Inoue, M.Tokunaga, M.Kitamura and r.noyori.organic Syntheses,1995,74-85.8. B) X.Tan, S.Gao, W.Zeng, S.Xin, Q.Yin and x.zhang.j.am.chem.soc, 2018,140,2024-2027.
The substrate (compound of formula I) is synthesized by reference: B.Qin, X.Liu, J.Shi, K.Zheng, H.Zhao, X.Feng.J.Org.Chem.,2007,72,2374-2378.
Table 1: effect of different catalysts on product stereoselectivity
L3b, L3c and L3a are all of the same configuration and belong to the S-SEGPHOS series.
In Table 1, the yields refer to the total yield of a pair of enantiomers, and the yields in the subsequent examples are the same.
It can be seen from table 1 that the enantioselectivity of the reaction catalyzed by the L3c ligand is highest and the reaction yield catalyzed by the L3a ligand is highest, with the solvent unchanged and only the ligand changed.
Implementation of the embodimentsExample 2
Under the argon atmosphere of a glove box, four 2mL reaction bottles were respectively charged with metal catalyst Ru (OAc) 2 (L3 c) (0.001 mmol), the compound of formula I (0.1 mmol), ammonium acetate (0.2 mmol) and various solvents of methanol (MeOH), ethanol (EtOH), isopropanol (I-PrOH), trifluoroethanol (TFE), all 0.5mL in volume, the reaction flask was placed in a high pressure hydrogenation reactor and hydrogen gas was introduced to 50 atmospheres. The reaction vessel was placed in an oil bath at 80℃and stirred for 20h. After the reaction is finished, 2mL of saturated sodium bicarbonate solution is added for quenching reaction, 3mL of dichloromethane is used for extraction three times, the organic phases are combined, the organic phases are dried by anhydrous sodium sulfate, the solvent is removed after filtration, and the crude product is separated by a silica gel column to obtain a product, wherein the eluent is methanol: dichloromethane=1:49 (volume ratio). The enantiomeric excess values were measured by HPLC after the product had been protected by acetylation.
Table 2: effect of different organic solvents on stereoselectivity of the product
It can be seen from table 2 that the highest yields and enantioselectivities were obtained when the solvent was trifluoroethanol, with other conditions kept unchanged and only the solvent species was changed.
Example 3
Under the argon atmosphere of a glove box, a 2mL reaction flask was charged with a metal catalyst Ru (OAc) respectively 2 (L3 c) (0.001 mmol), the compound of formula I (0.1 mmol), ammonium acetate (0.2 mmol) and trifluoroethanol (0.5 mL) were placed in a high-pressure hydrogenation reactor, and hydrogen gas was filled to 40, 50 and 60 atmospheres, respectively. The reaction vessel was placed in an oil bath at 80℃and stirred for 20h. After the reaction, 2mL of saturated sodium bicarbonate solution is added to quench the reaction, 3mL of dichloromethane is used for extraction for three times,the organic phases are combined, dried with anhydrous sodium sulfate, filtered and the solvent is removed, and the crude product is separated by a silica gel column to obtain the product, wherein the eluent is methanol: dichloromethane=1:49 (volume ratio). The enantiomeric excess values were measured by HPLC after the product had been protected by acetylation.
Table 3: influence of different Hydrogen pressures on the stereoselectivity
It can be seen from Table 3 that the reaction yield was close to that obtained by changing only the hydrogen pressure under other conditions, and the highest enantioselectivity was obtained when the hydrogen pressure was 50atm.
Example 4
Under the argon atmosphere of a glove box, a 2mL reaction flask was charged with the metal catalyst Ru (OAc) respectively 2 (L3 c) (0.001 mmol), the compound of formula I (0.1 mmol), ammonium acetate (0.2 mmol) and trifluoroethanol (0.5 mL) were placed in a high-pressure hydrogenation reactor, and hydrogen gas was filled to 50 atmospheres. The reaction kettles are respectively placed in oil baths at 30 ℃,70 ℃, 80 ℃ and 90 ℃ to be stirred and reacted for 20 hours. After the reaction is finished, 2mL of saturated sodium bicarbonate solution is added for quenching reaction, 3mL of dichloromethane is used for extraction three times, the organic phases are combined, the organic phases are dried by anhydrous sodium sulfate, the solvent is removed after filtration, and the crude product is separated by a silica gel column to obtain a product, wherein the eluent is methanol: dichloromethane=1:49 (volume ratio). The enantiomeric excess values were measured by HPLC after the product had been protected by acetylation.
Table 4: influence of different temperatures on the stereoselectivity
As can be seen from Table 4, the reaction yield was low at a low temperature (30 ℃) and close to that at 70℃to 90℃under other conditions, and the highest enantioselectivity was obtained at a temperature of 90℃with the temperature being kept unchanged and only the temperature being changed.
Example 5
Under the argon atmosphere of a glove box, a 2mL reaction flask was charged with the metal catalyst Ru (OAc) respectively 2 (L3 c) (0.001-0.01 mol%), the compound represented by formula I (0.1 mmol), ammonium acetate (0.2 mmol) and trifluoroethanol (0.5 mL), and the reaction flask was placed in a high-pressure hydrogenation reactor and charged with hydrogen gas to 50 atmospheres. The reaction vessel was placed in an oil bath at 90℃and stirred for 20h. After the reaction is finished, 2mL of saturated sodium bicarbonate solution is added for quenching reaction, 3mL of dichloromethane is used for extraction three times, the organic phases are combined, the organic phases are dried by anhydrous sodium sulfate, the solvent is removed after filtration, and the crude product is separated by a silica gel column to obtain a product, wherein the eluent is methanol: dichloromethane=1:49 (volume ratio). The enantiomeric excess values were measured by HPLC after the product had been protected by acetylation.
Table 5: influence of different catalyst amounts on stereoselectivity
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It can be seen from table 4 that the highest enantioselectivity and yield can be obtained when using 1% molar equivalent of catalyst, with other conditions kept unchanged only changing the substrate and catalyst ratio.
Example 6
The reaction formula of this example is as follows:
the structural formula of the substrate compound 1a is as follows:
the method for synthesizing the compound 2a by taking the compound 1a as a substrate is as follows:
under the argon atmosphere of a glove box, a 50mL reaction flask was charged with the metal catalyst Ru (OAc) separately 2 (L3 c) (0.05 mmol), compound 1a (5 mmol), ammonium acetate (10 mmol) and trifluoroethanol (20 mL) were placed in a high-pressure hydrogenation reactor, and hydrogen gas was filled to 50 atmospheres. The reaction kettles are respectively placed in oil baths at 90 ℃ to be stirred and reacted for 20 hours. After the reaction, 50mL of saturated sodium bicarbonate solution was added to quench the reaction, 50mL of dichloromethane was used for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed after filtration, and the crude product was separated by silica gel column to obtain the product, the eluent was methanol: dichloromethane=1:49 (volume ratio).
(S)-2-bromo-5,6-dihydro-[1,1'-biphenyl]-3(4H)-ol(2a)
The product was compound 2a as a pale yellow oily liquid (light yellow oil), mass 0.9g, yield 87%,97% ee, [ alpha ]] 27 D ＝27(c＝0.5,CHCl 3 ). 1 H NMR(600MHz,Chloroform-d)δ7.41(d,J＝7.3Hz,2H),7.32(t,J＝7.5Hz,2H),7.27–7.24(m,1H),4.38(d,J＝6.1Hz,1H),4.00(d,J＝6.1Hz,1H),3.80–3.73(m,1H),3.58–3.52(m,1H),3.52–3.45(m,1H),3.26–3.18(m,1H),1.22(t,J＝7.0Hz,3H),1.02(t,J＝7.1Hz,3H). 13 C NMR (151 MHz, chloroform-d) delta 141.6,128.2,127.9,127.4,107.1,64.2,63.9,58.9,15.4,15.2 the product was protected by acetylation and then tested by HPLCEnantiomeric excess value, chiracel OD-H Column (250 mm); detected at 210nm; n-hexane/i-propanol=90/10; flow=0.8 mL/min; retention time:6.9min (minor), 8.5min (major).
In this example, compounds 2b to 2n were also synthesized, respectively, and the synthesis method was performed with reference to compound 2 a.
The data for the synthesized compounds 2 b-2 n are characterized as follows:
(S)-2,2-diethoxy-1-(naphthalen-2-yl)ethan-1-amine(2b)
the product was compound 2b,0.2 mmol scale reacted as a pale yellow oily liquid (light yellow oil) with a mass of 47.1mg in 91% yield, 98% ee, [ alpha ]] 24 D ＝+7.6(c＝0.5,CHCl 3 ). 1 H NMR(600MHz,Chloroform-d)δ7.89–7.87(m,1H),7.84–7.81(m,2H),7.80(d,J＝8.7Hz,1H),7.56(dd,J＝8.4,1.7Hz,1H),7.47–7.43(m,2H),4.48(d,J＝6.2Hz,1H),4.18(d,J＝6.1Hz,1H),3.84–3.73(m,1H),3.59–3.48(m,2H),3.26–3.18(m,1H),1.23(t,J＝7.0Hz,3H),1.00(t,J＝7.0Hz,3H). 13 C{ 1 H } NMR (151 MHz, chloroform-d) delta 139.2,133.4,133.1,128.1,127.8,127.7,126.6,126.3,126.0,125.8,107.1,64.3,64.0,59.0,15.5,15.3 the product was protected by acetylation and the enantiomeric excess was measured by HPLC, chiracel ODH Column (250 mm); detected at 210nm; n-hexane/i-propanol=95/5; flow=0.8 mL/min; retention time 16.8min (minor), 25.8min (major) HRMS (ESI), M/z: [ M+Na ]] + Calcd for C 16 H 22 NO 2 + :260.1645；Found:260.1644.
(S)-2,2-diethoxy-1-(m-tolyl)ethan-1-amine(2c)
The product was compound 2c,0.2 mmol scale reaction as a pale yellow oily liquid (light yellow oil),27.1mg of the product with a yield of 61%,>99％ee,[α] 22 D ＝+6.4(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,Chloroform-d)δ7.25–7.17(m,3H),7.10–7.04(m,1H),4.39(d,J＝6.1Hz,1H),3.96(d,J＝6.1Hz,1H),3.84–3.71(m,1H),3.61–3.44(m,2H),3.29–3.18(m,1H),2.35(s,3H),1.22(t,J＝7.0Hz,3H),1.03(t,J＝7.0Hz,3H). 13 C{ 1 h } NMR (101 MHz, chloroform-d). Delta. 141.5,137.8,128.6,128.2,128.1,125.0,107.1,64.1,63.9,58.8,21.6,15.4,15.2 the product was protected by acetylation and the enantiomeric excess was measured by HPLC, chiracel ODH Column (250 mm); detected at 210nm; n-hexane/i-propanol=95/5; flow=0.8 mL/min; retention time 9.8min (minor), 11.5min (major) HRMS (ESI), M/z: [ M+H ]] + Calcd for C 13 H 22 NO 2 + :224.1645；Found:224.1643.
(S)-2,2-diethoxy-1-(p-tolyl)ethan-1-amine(2d)
The product was compound 2d,0.2 mmol scale reacted as a pale yellow oily liquid (light yellow oil) 34.3mg, 77% yield, 97% ee, [ alpha ]] 21 D ＝+11.8(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,Chloroform-d)δ7.28(d,J＝8.0Hz,2H),7.13(d,J＝7.9Hz,2H),4.37(d,J＝6.1Hz,1H),3.96(d,J＝6.1Hz,1H),3.81–3.71(m,1H),3.59–3.44(m,2H),3.28–3.18(m,1H),2.33(s,3H),1.22(t,J＝7.0Hz,3H),1.03(t,J＝7.0Hz,3H). 13 C{ 1 H } NMR (101 MHz, chloro form-d). Delta. 138.5,137.0,128.9,127.7,107.1,64.1,63.9,58.6,21.2,15.4,15.3 the product was protected by acetylation and the enantiomeric excess was measured by HPLC, chiracel OD-3Column (250 mm); detected at 210nm; n-hexane/i-propanol=95/5; flow=1.0 mL/min; retention time 8.9min (major), 10.6min (minor) HRMS (ESI), M/z: [ M+H ]] + Calcd for C 13 H 22 NO 2 + :224.1645；Found:224.1642.
(S)-1-([1,1'-biphenyl]-4-yl)-2,2-diethoxyethan-1-amine(2e)
The product was compound 2e,0.2 mmol scale reacted as a pale yellow oily liquid (light yellow oil) 49.6mg, yield 87%,94% ee, [ alpha ]] 26 D ＝+21.3(c＝0.5,CHCl 3 ). 1 H NMR(600MHz,Chloroform-d)δ7.59(d,J＝8.0Hz,2H),7.56(d,J＝7.9Hz,2H),7.48(d,J＝7.9Hz,2H),7.42(t,J＝7.5Hz,2H),7.33(t,J＝7.1Hz,1H),4.45(d,J＝6.0Hz,1H),4.05(d,J＝6.0Hz,1H),3.83–3.74(m,1H),3.63–3.48(m,2H),3.33–3.23(m,1H),1.23(t,J＝7.0Hz,3H),1.05(t,J＝7.0Hz,3H). 13 C{ 1 H } NMR (151 MHz, chloro form-d). Delta. 141.0,140.4,140.3,128.9,128.3,127.3,127.1,127.0,106.8,64.2,64.0,58.5,15.4,15.3 the enantiomeric excess value of the product was measured by HPLC after acetylation protection, chiracel OD-3Column (250 mm); detected at 210nm; n-hexane/i-propanol=95/5; flow=1.0 mL/min; retention time 11.4min (major), 12.8min (minor) HRMS (ESI), M/z: [ M+H ]] + Calcd for C 18 H 24 NO 2 + :286.1802；Found:286.1806.
(S)-2,2-diethoxy-1-(3-methoxyphenyl)ethan-1-amine(2f)
The product was compound 2f,0.2 mmol scale reacted as a pale yellow oily liquid (light yellow oil) 42.6mg, 89% yield, 95% ee, [ alpha ]] 26 D ＝+5.1(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,Chloroform-d)δ7.23(t,J＝8.1Hz,1H),7.02–6.96(m,2H),6.84–6.79(m,1H),4.38(d,J＝6.0Hz,1H),3.98(d,J＝6.1Hz,1H),3.83–3.72(m,4H),3.61–3.44(m,2H),3.29–3.19(m,1H),1.22(t,J＝7.1Hz,3H),1.04(t,J＝7.0Hz,3H). 13 C{ 1 H}NMR(101MHz,Chloroform-d)δ159.6,143.3,129.2,120.3,113.3,113.1,107.0,64.3,64.0,58.9,55.3,15.4,15.3 the enantiomeric excess value of the product was measured by HPLC after acetylation and protection, chiracel AD-3Column (250 mm); detected at 210nm; n-hexane/i-propanol=95/5; flow=0.8 mL/min; retention time 16.2min (minor), 20.2min (major) HRMS (ESI), M/z: [ M+H ]] + Calcd for C 13 H 22 NO 3 + :240.1594；Found:240.1592.
(S)-2,2-diethoxy-1-(4-methoxyphenyl)ethan-1-amine(2g)
The product was compound 2g,0.2 mmol scale reacted as pale yellow oily liquid (light yellow oil), 34.9mg mass, 73% yield, 92% ee, [ alpha ]] 22 D ＝+12.0(c＝0.5,CH 2 Cl 2 ). 1 H NMR(600MHz,Chloroform-d)δ7.32(d,J＝8.7Hz,2H),6.86(d,J＝8.7Hz,2H),4.34(d,J＝6.2Hz,1H),3.95(d,J＝6.1Hz,1H),3.80(s,3H),3.78–3.73(m,1H),3.58–3.44(m,2H),3.27–3.18(m,1H),1.22(t,J＝7.0Hz,3H),1.03(t,J＝7.0Hz,3H). 13 C{ 1 H } NMR (151 MHz, chloroform-d) delta 158.9,133.7,128.9,113.6,107.2,64.2,63.9,58.2,55.3,15.4,15.3 the product was protected by acetylation and the enantiomeric excess was measured by HPLC, chiracel ODH Column (250 mm); detected at 210nm; n-hexane/i-propanol=95/5; flow=0.8 mL/min; retention time 9.6min (major) HRMS (ESI), M/z: [ M+H ]] + Calcd for C 13 H 22 NO 3 + :240.1594；Found:240.1590.
(S)-1-(3,4-dimethoxyphenyl)-2,2-diethoxyethan-1-amine(2h)
The product was compound 2h,0.2 mmol scale reaction as a pale yellow oily liquid (light yellow oil) 42.0mg, 78% yield, 85% ee, [ alpha ]] 23 D ＝+4.3(c＝0.5,CHCl 3 ). 1 H NMR(600MHz,Chloroform-d)δ7.00(d,J＝1.9Hz,1H),6.95(dd,J＝8.2,1.9Hz,1H),6.83(d,J＝8.2Hz,1H),4.35(d,J＝6.2Hz,1H),3.95(d,J＝6.2Hz,1H),3.89(s,3H),3.87(s,3H),3.80–3.74(m,1H),3.57–3.46(m,2H),3.26–3.17(m,1H),1.23(t,J＝7.1Hz,3H),1.04(t,J＝7.0Hz,3H). 13 C{ 1 H } NMR (151 MHz, chloro form-d). Delta. 148.8,148.4,134.0,120.0,111.0,110.9,107.1,64.4,64.3,63.9,58.6,56.0,15.4,15.3 the enantiomeric excess value of the product was measured by HPLC after acetylation protection, chiracel OJ-3Column (250 mm); detected at 210nm; n-hexane/i-propanol=90/10; flow=0.8 mL/min; retention time 10.6min (minor), 13.9min (major) HRMS (ESI), M/z: [ M+H ]] + Calcd for C 14 H 24 NO 4 + :270.1700；Found:270.1969.
(S)-2,2-diethoxy-1-(4-fluorophenyl)ethan-1-amine(2i)
The product was compound 2i,0.2 mmol scale, as a pale yellow oily liquid (light yellow oil), 28.6mg in mass, 63% yield, 98% ee, [ alpha ]] 23 D ＝+7.0(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,Chloroform-d)δ7.42–7.35(m,2H),7.03–6.98(m,2H),4.34(d,J＝6.1Hz,1H),3.99(d,J＝6.1Hz,1H),3.81–3.70(m,1H),3.62–3.44(m,2H),3.28–3.16(m,1H),1.22(t,J＝7.0Hz,3H),1.03(t,J＝7.0Hz,3H). 13 C{ 1 H } NMR (101 mhz, chloro form-d) delta 162.3 (d, j=245.0 Hz), 137.2 (d, j=3.0), 129.4 (d, j=7.9 Hz), 115.0 (d, j=21.2 Hz), 107.0,64.4,64.0,58.2,15.4,15.2. The product was protected by acetylation and the enantiomeric excess was measured by HPLC, chiracel AD-3Column (250 mm); detected at 210nm; n-hexane/i-propanol=95/5; flow=0.8 mL/min; retention time 14.4min (minor), 16.3min (major) HRMS (ESI), M/z: [ M+H ]] + Calcd for C 12 H 19 FNO 2 + :228.1394；Found:228.1392.
(S)-1-(3,4-difluorophenyl)-2,2-diethoxyethan-1-amine(2j)
The product was compound 2j,0.2 mmol scale reacted as a pale yellow oily liquid (light yellow oil) 29.9mg, 61% yield, 98% ee, [ alpha ]] 25 D ＝+3.2(c＝0.5,CHCl 3 ). 1 H NMR(600MHz,Chloroform-d)δ7.31(ddd,J＝11.5,7.7,2.1Hz,1H),7.17–7.14(m,1H),7.13–7.07(m,1H),4.40(d,J＝5.9Hz,1H),4.01(d,J＝5.9Hz,1H),3.79–3.72(m,1H),3.64–3.57(m,1H),3.52(dq,J＝9.3,7.0Hz,1H),3.33–3.25(m,1H),1.22(t,J＝7.0Hz,3H),1.06(t,J＝7.0Hz,3H). 13 C{ 1 H } NMR (151 mhz, chloro form-d) delta 150.2 (dd, j=247.6, 13.8 hz), 149.9 (dd, j=247.6.8 hz) 137.2,124.2 (dd, j=6.2, 3.5 hz), 117.0 (d, j=10.7), 116.9 (d, j=9.9), 105.8,64.6,64.2,57.9,15.4,15.2. The product was protected by acetylation and the enantiomeric excess was measured by HPLC, chiracel OD-3Column (250 mm); detected at 210nm; n-hexane/i-propanol=95/5; flow=0.8 mL/min; retention time:10.1min (minor), 10.7min (major). HRMS (ESI), M/z: [ M+H ]] + Calcd for C 12 H 18 F 2 NO 2 + :246.1300；Found:246.1296.
(S)-1-(4-chlorophenyl)-2,2-diethoxyethan-1-amine(2k)
The product was compound 2k,0.2 mmol scale reacted as a pale yellow oily liquid (light yellow oil), 39.8mg mass, 79% yield,>99％ee,[α] 26 D ＝+8.2(c＝0.5,CHCl 3 ). 1 H NMR(600MHz,Chloroform-d)δ7.36(d,J＝8.4Hz,2H),7.29(d,J＝8.5Hz,2H),4.37(d,J＝6.0Hz,1H),4.00(d,J＝6.0Hz,1H),3.79–3.73(m,1H),3.60–3.54(m,1H),3.53–3.47(m,1H),3.28–3.22(m,1H),1.21(t,J＝7.0Hz,3H),1.04(t,J＝7.0Hz,3H). 13 C{ 1 H}NMR(151MHz,Chloroform-d)δ139.6,133.3,129.4,128.4,106.5,64.5,64.1,58.3,15.4,15.2 the enantiomeric excess value of the product was measured by HPLC after acetylation and protection, chiracel OJ-3Column (250 mm); detected at 210nm; n-hexane/i-propanol=95/5; flow=0.8 mL/min; retention time 15.7min (major) HRMS (ESI), M/z: [ M+H ]] + Calcd for C 12 H 19 ClNO 2 + :244.1099；Found:244.1096.
(S)-1-(4-bromophenyl)-2,2-diethoxyethan-1-amine(2l)
The product was compound 2l,0.2 mmol scale reacted as pale yellow oil (light yellow oil) 43.2mg, yield 74%,95% ee, [ alpha ]] 21 D ＝+9.4(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,Chloroform-d)δ7.57(d,J＝8.5Hz,2H),7.42(d,J＝8.4Hz,2H),4.46(d,J＝6.0Hz,1H),4.09(d,J＝6.1Hz,1H),3.93–3.84(m,1H),3.74–3.57(m,2H),3.41–3.31(m,1H),1.34(t,J＝7.0Hz,3H),1.17(t,J＝7.0Hz,3H). 13 C{ 1 H } NMR (101 MHz, chloro form-d). Delta. 140.7,131.3,129.7,121.3,106.8,64.4,64.0,58.4,15.4,15.2 the product was protected by acetylation and the enantiomeric excess was measured by HPLC, chiracel AD-3Column (250 mm); detected at 210nm; n-hexane/i-propanol=95/5; flow=0.8 mL/min; retention time 14.8min (minor), 16.7min (major) HRMS (ESI), M/z: [ M+H ]] + Calcd for C 12 H 19 BrNO 2 + :288.0594；Found:288.0598.
(S)-methyl-4-(1-amino-2,2-diethoxyethyl)benzoate(2m)
The product was compound 2m,0.2 mmol scale reacted as a pale yellow oily liquid (light yellow oil) 37.4mg in mass, 70% yield, 96% ee, [ alpha ]] 22 D ＝+2.6(c＝0.5,CHCl 3 ). 1 H NMR(600MHz,Chloroform-d)δ8.00(d,J＝8.4Hz,2H),7.49(d,J＝8.1Hz,2H),4.38(d,J＝6.0Hz,1H),4.07(d,J＝5.9Hz,1H),3.91(s,3H),3.79–3.71(m,1H),3.60–3.54(m,1H),3.52–3.45(m,1H),3.26–3.19(m,1H),1.21(t,J＝7.0Hz,3H),1.02(t,J＝7.0Hz,3H). 13 C{ 1 H } NMR (151 MHz, chloro form-d). Delta. 167.2,146.9,129.5,129.3,128.0,106.7,64.5,64.0,58.8,52.2,15.4,15.2 the enantiomeric excess value of the product was measured by HPLC after acetylation protection, chiracel AD-3Column (250 mm); detected at 210nm; n-hexane/i-propanol=90/10; flow=0.8 mL/min; retention time 12.0min (major), 14.9min (minor) HRMS (ESI), M/z: [ M+H ]] + Calcd for C 14 H 22 NO 4 + :268.1543；Found:268.1539.
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(R)-2,2-diethoxy-1-(thiophen-2-yl)ethan-1-amine(2n)
The product was compound 2n,0.2 mmol scale reacted as a pale yellow oily liquid (light yellow oil) 36.3mg, 85% yield, 62% ee, [ alpha ]] 22 D ＝+2.6(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,Chloroform-d)δ7.22(dd,J＝5.1,1.2Hz,1H),7.04(d,J＝3.4Hz,1H),6.97(dd,J＝5.1,3.5Hz,1H),4.39(d,J＝5.9Hz,1H),4.33–4.25(m,1H),3.84–3.74(m,1H),3.69–3.50(m,2H),3.41–3.29(m,1H),1.24(t,J＝7.0Hz,3H),1.12(t,J＝7.0Hz,3H). 13 C{ 1 H}NMR(101MHz,Chloroform-d)δ145.4,126.6,124.9,124.5,106.6,64.4,64.0,55.1,15.4,15.3.UPLC:Chiracel OD-3Column(250mm)；detected at 210nm；n-hexane/i-propanol＝95/5；flow＝0.5mL/min；Retention time:3.9min(major),4.4min(minor).HRMS(ESI),m/z:[M+H] + Calcd for C 10 H 18 NO 2 S + :216.1053；Found:216.1056.
Example 7
The reaction formula for the synthesis of compound 2a' in this example is as follows:
step 1: 0.2mmol of the product 2a obtained in example 6 was taken, dissolved in 1.0mL of Dichloromethane (DCM), 40. Mu.L of BzCl and 80. Mu.L of Triethylamine (TEA) were added, and the reaction was stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was quenched with 3mL of saturated sodium bicarbonate solution, extracted three times with 3mL of methylene chloride, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed after filtration.
Step 2: to the product (0.2 mmol) obtained in step 1, 0.5mL of acetone and 0.5mL of 6mol/L hydrochloric acid were added, and the mixture was stirred at room temperature for 20 minutes. After the reaction, 2mL of water was added, followed by extraction three times with 5mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed after filtration, and the crude product was separated by a silica gel column to give the product as an eluent ethyl acetate: petroleum ether=15:85 (volume ratio).
Example 8
The reaction formula for the synthesis of compound 3a of this example is as follows:
the specific operation method is as follows:
jones reagent (0.3 mL, jones 'reagent) was slowly added dropwise to compound 2a' (0.2 mmol) dissolved in 1mL of acetone at 0deg.C, the reaction was stirred at that temperature for 3h, then quenched by adding a few drops of isopropanol, diluted with 5mL of water, extracted three times with 5mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the solvent was removed, and the crude product was isolated via a silica gel column as methanol, eluent: dichloromethane=10:90 (volume ratio). The obtained compound 3a was a white solid, the mass was 37.7mg, and the yield after two steps of reaction (including two steps of reaction using compound 2a as a substrate to synthesize product 3 a) was 74%, [ α] 23 D ＝+48.0(c＝0.5,CHCl 3 )， 1 H NMR(400MHz,Methanol-d 4 )δ7.92–7.83(m,2H),7.57–7.43(m,5H),7.30(dd,J＝8.3,6.7Hz,2H),7.26–7.18(m,1H),5.44(s,1H).HRMS(ESI),m/z:[M-H] + Calcd for C 15 H 12 NO 3 - :254.0823,Found:254.0819.
The reaction formula for the synthesis of compound 4a in this example is as follows:
the specific operation method is as follows:
sodium borohydride (0.24 mmol) was added to 2a' (0.2 mmol) dissolved in 1mL of methanol at 0 ℃ and after stirring at this temperature for 0.5h the reaction was quenched by adding 2mL of saturated ammonium chloride solution, extracted three times with 5mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed after filtration, and the crude product was isolated by column on silica gel with ethyl acetate: petroleum ether=30:70 (volume ratio). The obtained compound 4a was a white solid, the mass was 23.5mg, and the yield after two steps of reaction (including two steps of reaction using compound 2a as a substrate to synthesize the product 4 a) was 98%, [ α] 27 D ＝-27.0(c＝0.32,CHCl 3 ). 1 H NMR(600MHz,Methanol-d 4 )δ7.88–7.84(m,2H),7.53(t,J＝7.4Hz,1H),7.46(t,J＝7.6Hz,2H),7.41(d,J＝7.6Hz,2H),7.33(t,J＝7.5Hz,2H),7.25(t,J＝7.4Hz,1H),5.20(t,J＝6.6Hz,1H),3.86(d,J＝6.6Hz,2H). 13 C NMR(151MHz,Methanol-d 4 )δ170.4,141.4,135.9,132.7,129.5,129.5,128.4,128.4,128.0,66.1,57.8.HRMS(ESI),m/z:[M+H] + Calcd for C 15 H 16 NO 2 + :242.1176,Found:242.1174.
In one embodiment, the preparation method of the chiral alpha-amino acetal compound provided by the invention has the characteristics of high enantioselectivity, small environmental pollution and high yield.
In one embodiment, the chiral α -amino acetals may be hydrolyzed to aldehydes, after which the α -amino acids or amino alcohols may be built by simple oxidation or reduction reactions; more complex alpha-functionalized chiral amine compounds can also be synthesized as important intermediates.
The foregoing description of the invention has been presented for purposes of illustration and description, and is not intended to be limiting. Several simple deductions, modifications or substitutions may also be made by a person skilled in the art to which the invention pertains, based on the idea of the invention.

Claims (10)

1. The preparation method of the alpha-amino acetal compound is characterized by comprising the following steps:
contacting a compound shown in a formula (I) with a catalyst, an ammonia source and a reducing agent to obtain a compound shown in a formula (II), wherein the reaction formula is as follows:
the compound shown in the formula (I) is at least one of the following compounds:
；
the catalyst is selected from phosphine ligand metal catalysts;
the phosphine ligand metal catalyst is selected from phosphine ligand ruthenium catalysts;
the phosphine ligand ruthenium catalyst is selected from compounds represented by the following general formula: ru (OAc) 2 (L), wherein the ligand L is selected from any one of the following compounds:
the reaction system also contains a solvent, wherein the solvent is trifluoroethanol.
2. The method according to claim 1, wherein the ammonia source is at least one selected from the group consisting of ammonium salts and ammonia gas.
3. The method of claim 2, wherein the ammonium salt is selected from the group consisting of ammonium acetate.
4. The method of claim 1, wherein the reaction is carried out in a closed vessel.
5. The method according to claim 4, wherein the pressure of the reducing agent gas filled in the closed vessel is 30 to 50atm.
6. The method of claim 1, wherein the reducing agent is selected from the group consisting of hydrogen.
7. The process according to claim 1, wherein the reaction is carried out at 70 to 90 ℃.
8. The process according to claim 1, wherein the molar ratio of the compound of formula (I) to the catalyst is 1: (0.00001-0.01).
9. The process according to claim 1, wherein the molar ratio of the compound of formula (I) to the ammonia source is 1: (1-5).
10. The process according to claim 1, wherein the ratio of the molar amount of the compound of formula (I) to the volume of the solvent is 1mmol: (5-10) mL.
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