Preparation method of chiral beta-hydroxyl-alpha-amino acid compound

Abstract

The invention relates to a preparation method of a chiral beta-hydroxyl-alpha-amino acid compound, which comprises the following step: under the catalysis of a pyridinium salt carbonyl catalyst, carrying out aldol addition reaction on an amino acid derivative and a carbonyl compound to generate the chiral beta-hydroxyl-alpha-amino acid compound. Compared with the prior art, the chiral pyridinium salt carbonyl catalyst is utilized to realize the bionic aldol reaction of the amino acid derivative and the carbonyl compound, and a series of beta-hydroxyl-alpha-amino acid compounds with extremely high enantioselectivity are synthesized.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and relates to a method for preparing a chiral beta-hydroxy-alpha-amino acid compound. Background Art

[0002] Chiral β-hydroxy-α-amino acid compounds have important application value in organic synthesis, medicinal chemistry and biomedicine. As precursors of bioactive molecules, these compounds provide rich structural diversity in the synthesis of peptides and protein mimetics. In particular, in the development of broad-spectrum antibiotics, the introduction of chiral β-hydroxy-α-amino acid derivatives has a significant effect on the effect of the drug, such as thiamphenicol (Thiamphenicol, DOI: 10.1002 / 9781118675014), florfenicol (Florfenicol, DOI: 10.1002 / 9781118675014), chloramphenicol (Chloramphenicol, DOI: 10.1002 / 9781118675014), vancomycin (Vancomycin, Hossion, AG Vancomycin: Biosynthesis, clinical uses and adverse effects. (Nova Science Publishers, Inc., 2013).), etc. In addition, Droxidopa (Mathias, CJ Clin. Auton. Res. 2008, 18, 25-29), a drug for the treatment of Parkinson's disease, and Eliglustat (DOI: 10.2147 / DDDT.S77760), a drug for the treatment of Gaucher disease, are both based on chiral β-hydroxy-α-amino acids as key synthetic precursors. These compounds are also widely used as chiral building blocks for chiral ligands and catalysts in the field of asymmetric synthesis. Despite this, the preparation of chiral β-hydroxy-α-amino acid compounds has always faced many challenges. First, the aldol reaction of glycine and aldehydes catalyzed by threonine aldolase can efficiently generate chiral β-hydroxy-α-amino acids. However, due to the specificity of the enzyme, the bioenzyme synthesis method with synthetic value is very limited, and the problems of β-carbon selectivity and reactivity have not yet been solved (Dückers, N. et al, Appl. Microbiol. Biotechnol. 2010, 88, 409-424; Fesko, K. et al, Appl. Microbiol. Biotechnol. 2016, 100, 2579-2590; Wang, S. et al, Appl. Microbiol. Biotechnol. 2021, 105, 3507-3520). Second, the chemical synthesis industry still uses a route based on chiral separation, resulting in a large amount of reagent waste and environmental costs for post-processing.Third, asymmetric synthesis involves many types of reactions, such as nucleophilic addition, reduction reaction, etc. The substrate structure used is special and needs to be prepared in advance, and the amino group needs to be protected. Therefore, the synthesis route is generally lengthy, which affects the yield of the final product (Zhang.Y.et al, Chem.Asian J.2014,9,1752-1764). Finally, the raw materials of some natural or non-natural β-hydroxy-α-amino acids are scarce and costly, so developing an economical and efficient synthesis method to synthesize this type of compound is one of the current research focuses.

[0003] In recent years, Zhao's group has developed direct asymmetric functionalization reactions of α-CH of primary amine compounds through carbonyl catalysis strategies, including asymmetric Mannich reaction of glycine esters, asymmetric aldol reaction, asymmetric Michael addition reaction and asymmetric α-allylation reaction of trifluoromethyl ketones, and asymmetric addition reaction of inert aromatic and alkynyl methylamines, and achieved quite good results (Chen, J. et al, Science 2018, 360, 1438-1442; Ma, J. et al, Angew. Chem. Int. Ed. 2021, 60, 10588-10592; Cheng, A. et al, Angew. Chem. Int. Ed. 2021, 60, 20166-20172; Ma, J. et al, Angew. Chem. Int. Ed. 2022, 61, e202200850; Hou, K ...2, 61, e202200850; Hou, K. et al, Science 2018, 360, 14 al, Nat. Catal. 2022, 5, 1061-1068; Ji, P. et al, Angew. Chem. Int. Ed. 2022, 61, e202206111; Zhang. R. et al, J. Am. Chem. Soc. 2024, 146, 25927-25933). The carbonyl-catalyzed asymmetric aldol reaction of glycine with aldehydes has always been a huge challenge. The main reasons are: (1) Carbonyl catalysts can also catalyze the reverse adol reaction of the product, resulting in product decomposition or racemization; (2) Under alkaline conditions, the product is prone to phase isomerization, and the control of enantioselectivity and diastereoselectivity is more difficult; (3) Carbonyl compounds and amino acid compounds quickly form imines, thereby inhibiting the aldol reaction. Summary of the invention

[0004] The purpose of the present invention is to provide a method for preparing chiral β-hydroxy-α-amino acid compounds in order to overcome at least one defect of the above-mentioned prior art. The present invention utilizes a chiral pyridinium salt carbonyl catalyst to realize a biomimetic aldol reaction of an amino acid derivative and a carbonyl compound to synthesize a series of β-hydroxy-α-amino acid compounds with extremely high enantioselectivity.

[0005] The purpose of the present invention can be achieved by the following technical solutions:

[0006] One of the technical solutions of the present invention is to provide a method for preparing a chiral β-hydroxy-α-amino acid compound, the method comprising the following steps:

[0007] Under the catalysis of pyridinium salt carbonyl catalyst 3, amino acid derivative 1 and carbonyl compound 2 undergo aldol addition reaction to generate chiral β-hydroxy-α-amino acid compound 4, the molar ratio of amino acid derivative 1 to carbonyl compound 2 is (0.6-6):1, the molar ratio of pyridinium salt carbonyl catalyst 3 to carbonyl compound 2 is (0.00002-1):1, the reaction temperature is -80-50°C, the reaction time is 1-168h, the absolute configuration of pyridinium salt carbonyl catalyst 3 determines the absolute configuration of chiral β-hydroxy-α-amino acid compound 4, and the reaction equation is:

[0008]

[0009] Among them, R 1 is selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, substituted or unsubstituted C 2～18 Alkenyl, substituted or unsubstituted C 2～24 Alkynyl, or C 1～18 Carbonyl, substituted with halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 an amine group, a carbonyl group selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group;

[0010] R 2 Selected from OR 9 or NR 10 R 11 , where R 9 is selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C3～18 Aryl, or C 1～18 Carbonyl, R 10 and R 11 are independently selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, C 1～18 Carbonyl, or R 10 and R 11 Together they form ring B, or NR 10 R 11 is selected from amino acid amine, amino acid ester amine, amino acid amide amine or polypeptide amine, and the substituent is selected from halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 The amine group, the carbonyl group is selected from an aldehyde group, a ketone carbonyl group, an ester carbonyl group, a carboxyl group or an amide group, and the ring B is a C containing 1 to 4 heteroatoms. 1～18 Ring, heteroatom is selected from O, N or S atom;

[0011] R 3 and R 4 are independently selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, substituted or unsubstituted C 2～18 Alkenyl, or substituted or unsubstituted C 2～24 Alkynyl, substituted with halogen, cyano, hydroxy, nitro, trifluoromethyl, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy, C 1～18 Amine or The carbonyl group is selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group;

[0012] R b , R 2b and R 3b are independently selected from hydrogen, C 1～10 Alkyl or C 3～10 Aryl.

[0013] Furthermore, the pyridinium salt carbonyl catalyst 3 has a chemical structure as shown in Formula 3:

[0014]

[0015] Among them, R 5 The structural formula is selected from one of the following:

[0016]

[0017] R 12 The structural formula is:

[0018]

[0019] R 21 and R 22 are independently selected from hydrogen, C 1～24 Alkyl or R 23 Selected from substituted or unsubstituted C 1～24 Alkyl, substituent selected from halogen, C 1～10 Alkyl, C 3～10 Cycloalkyl, C 3～10 Aryl, C 1～8 Carbonyl, C 1～8 Sulfonyl, C 1～8 Phosphoryl, C 1～10 Alkoxy or C 1～10 an amine group, a carbonyl group selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group;

[0020] R 13 , R 14 , R 15 , R 17 , R 18 , R 19 and R 20 are independently selected from hydrogen, C 1～24 Alkyl, C 1～24 Alkoxy, C 3～10 Cycloalkyl, CO2R d , halogen, nitro, cyano or trifluoromethyl;

[0021] R 16 Selected from hydrogen, C 1～24 Alkyl, C 1～24 Alkoxy, C 3～10 Cycloalkyl, CO2R d , halogen, nitro, cyano or trifluoromethyl;

[0022] R 6 Selected from hydrogen, C 1～24 Alkyl, C 1～24 Alkoxy, C 3～10 Cycloalkyl, CO2Rd , halogen, nitro, cyano or trifluoromethyl;

[0023] R 8 Selected from hydrogen, C 1～24 Alkyl, C 1～24 Alkoxy, C 3～10 Cycloalkyl, CO2R d , halogen, nitro, cyano or trifluoromethyl;

[0024] R a Selected from hydrogen, C 1～10 Alkyl, C 1～10 Alkoxy, C 3～10 Cycloalkyl, C 3～10 Aryl, halogen, nitro, cyano or trifluoromethyl, R b , R 2b , R 3b , R c , R 2c and R d are independently selected from hydrogen, C 1～10 Alkyl or C 3～10 Aryl, n is 0, 1, 2, 3, 4 or 5, x and y are independently 0, 1, 2 or 3;

[0025] R 7 is selected from substituted or unsubstituted C 1～24 Alkyl, substituent selected from halogen, C 1～10 Alkyl, C 3～10 Cycloalkyl, C 3～10 Aryl, C 1～8 Carbonyl, C 1～8 Sulfonyl, C 1～8 Phosphoryl, C 1～10 Alkoxy or C 1～10 an amine group, a carbonyl group selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group;

[0026] X - is an anion selected from fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, hexafluorophosphate, tetrafluoroborate, sulfate, sulfite, hydroxide, nitrate, phosphate, carbonate, silicate, bicarbonate, hydrogenphosphate, dihydrogenphosphate, iodate, cyanide or thiocyanate.

[0027] Furthermore, the pyridinium salt carbonyl catalyst 3 has a chemical structure as shown in Formula 3:

[0028]

[0029] Among them, R5 The structural formula is selected from one of the following:

[0030]

[0031] R 12 The structural formula is:

[0032]

[0033] R 21 and R 22 are independently selected from hydrogen, C 1～24 Alkyl or R 23 is selected from substituted or unsubstituted C 1～24 Alkyl, substituent selected from halogen, C 1～10 Alkyl, C 3～10 Cycloalkyl, C 3～10 Aryl or C 1～10 Alkoxy;

[0034] R 13 , R 14 , R 15 , R 17 , R 18 , R 19 and R 20 are independently selected from hydrogen, C 1～24 Alkyl, C 3～10 Cycloalkyl, C 1～24 Alkoxy, halogen, nitro, cyano or trifluoromethyl;

[0035] R 16 Selected from hydrogen, C 1～24 Alkyl, C 3～10 Cycloalkyl, C 1～24 Alkoxy, halogen, nitro, cyano or trifluoromethyl;

[0036] R 6 Selected from hydrogen, C 1～24 Alkyl, C 3～10 Cycloalkyl, C 1～24 Alkoxy, halogen, nitro, cyano or trifluoromethyl;

[0037] R 8 Selected from hydrogen, C 1～24 Alkyl, C 3～10 Cycloalkyl, C 1～24 Alkoxy, halogen, nitro, cyano or trifluoromethyl;

[0038] R a Selected from hydrogen, C1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl, C 3～10 Aryl, halogen, nitro, cyano or trifluoromethyl, n is 0, 1, 2, 3, 4 or 5, x and y are independently 0, 1, 2 or 3;

[0039] R 7 is selected from substituted or unsubstituted C 1～24 Alkyl, substituent selected from halogen, C 1～10 Alkyl, C 3～10 Cycloalkyl, C 3～10 Aryl or C 1～10 Alkoxy;

[0040] X - is an anion selected from fluoride ion, chloride ion, bromide ion, iodide ion, hexafluorophosphate ion, and tetrafluoroborate ion.

[0041] As a more preferred technical solution, the pyridinium salt carbonyl catalyst 3 has a chemical structure as follows:

[0042]

[0043] Among them, R 12 The structural formula is:

[0044]

[0045] R 22 is selected from methyl or phenyl, R 23 Selected from methyl, ethyl, tert-butyl, isopropyl, cyclohexyl or diphenylmethyl.

[0046] As the most preferred technical solution, the pyridinium salt carbonyl catalyst 3 has the following chemical structure:

[0047]

[0048] Furthermore, the R of the pyridinium salt carbonyl catalyst 3 is 5 It forms axial chirality with the pyridine ring, and the configuration of the axial chirality is R or S configuration.

[0049] Furthermore, the pyridinium salt carbonyl catalyst 3 has the following formula I a , Formula I b , Formula II a Or Formula II b The structure of formula I a With formula I b are enantiomers of each other, formula II a With formula II b Enantiomers:

[0050]

[0051] As a preferred technical solution, the chiral β-hydroxy-α-amino acid compound 4 includes different configurations of syn-4A, anti-4A and syn-4B, anti-4B.

[0052] Furthermore, R 1 is selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, or substituted or unsubstituted C 3～18 Aryl, substituent selected from halogen, nitro, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy or C 3～18 Aryloxy, carbonyl is selected from aldehyde, ketocarbonyl, estercarbonyl, carboxyl or amide;

[0053] R 2 Selected from OR 9 or NR 10 R 11 , where R 9 is selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, or substituted or unsubstituted C 3～18 Aryl, R 10 and R 11 are independently selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, or R 10 and R 11 Together they form ring B, or NR 10 R 11 is selected from amino acid amine, amino acid ester amine, amino acid amide amine or polypeptide amine, and the substituent is selected from halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 The amine group, the carbonyl group is selected from an aldehyde group, a ketone carbonyl group, an ester carbonyl group, a carboxyl group or an amide group, and the ring B is a C containing 1 to 4 heteroatoms. 1～18 Ring, heteroatom is selected from O, N or S atom;

[0054] R 3 and R 4are independently selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, or substituted or unsubstituted C 3～18 Aryl, substituted with halogen, cyano, hydroxy, nitro, trifluoromethyl, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy, C 1～18 Amine or The carbonyl group is selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group;

[0055] R b , R 2b and R 3b are independently selected from hydrogen, C 1～10 Alkyl or C 3～10 Aryl.

[0056] As a more preferred technical solution, R 1 is selected from hydrogen, or substituted or unsubstituted C 1～24 Alkyl, substituent selected from C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Alkoxy or C 3～18 Aryloxy;

[0057] R 2 Selected from OR 9 or NR 10 R 11 , where R 9 is selected from hydrogen, or substituted or unsubstituted C 1～24 Alkyl, R 10 and R 11 are independently selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, or R 10 and R 11 Together they form ring B, or NR 10 R 11 is selected from amino acid amine, amino acid ester amine, amino acid amide amine or polypeptide amine, and the substituent is selected from halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18The amine group, the carbonyl group is selected from an aldehyde group, a ketone carbonyl group, an ester carbonyl group, a carboxyl group or an amide group, and the ring B is a C containing 1 to 4 heteroatoms. 1～18 Ring, heteroatom is selected from O, N or S atom;

[0058] R 3 and R 4 are independently selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, or substituted or unsubstituted C 3～18 Aryl, substituted with halogen, cyano, hydroxy, nitro, trifluoromethyl, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy, C 1～18 Amine or The carbonyl group is selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group;

[0059] R b , R 2b and R 3b are independently selected from hydrogen, C 1～10 Alkyl or C 3～10 Aryl.

[0060] Furthermore, the molar ratio of the amino acid derivative 1 to the carbonyl compound 2 is (1.2-3):1, the molar ratio of the pyridinium salt carbonyl catalyst 3 to the carbonyl compound 2 is (0.0001-0.005):1, the reaction temperature is -40--5°C, and the reaction time is 6-72h.

[0061] As a more preferred technical solution, the molar ratio of the amino acid derivative 1 to the carbonyl compound 2 is (2-2.5):1, the molar ratio of the pyridinium salt carbonyl catalyst 3 to the carbonyl compound 2 is (0.001-0.002):1, the reaction temperature is -40--30°C, and the reaction time is 12-48h.

[0062] As the most preferred technical solution, the molar ratio of the amino acid derivative 1 to the carbonyl compound 2 is 2:1 or 2.5:1, the molar ratio of the pyridinium salt carbonyl catalyst 3 to the carbonyl compound 2 is 0.001:1 or 0.002:1, the reaction temperature is -40°C or -30°C, and the reaction time is 12h, 20h or 48h.

[0063] Further, the base used in the reaction is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydride, potassium hydride, calcium hydride, trimethylamine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, tetramethylethylenediamine, N,N-diethylmethylamine, N,N-dimethylethylamine, N,N-dimethylpropylamine, N,N-dimethylbutylamine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane, diazabicyclododecane, 1,5-diazabicyclo[4.3.0]-5-nonene, n-butyllithium, 1,4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, n-butylamine, tert-butylamine, diethylamine, ethylenediamine, quinoline, and pyridine.

[0064] As a preferred technical solution, the base used in the reaction is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trimethylamine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, tetramethylethylenediamine, N,N-diethylmethylamine, N,N-dimethylethylamine, N,N-dimethylpropylamine, N,N-dimethylbutylamine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane, n-butylamine, tert-butylamine, diethylamine, ethylenediamine, quinoline, and pyridine.

[0065] As a more preferred technical solution, the base used in the reaction is selected from one or more of cesium carbonate, sodium phosphate, potassium phosphate, triethylamine, and N,N-diisopropylethylamine.

[0066] As the most preferred technical solution, the base used in the reaction is triethylamine.

[0067] Furthermore, the additive used in the reaction is selected from ammonium phosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, lithium phosphate, lithium dihydrogen phosphate, dilithium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium acetate, potassium acetate, potassium fluoride, sodium fluoride, sodium sulfate, magnesium sulfate, and one or more corresponding hydrates of the additives.

[0068] As a preferred technical solution, the additive used in the reaction is selected from one or more of ammonium dihydrogen phosphate, diammonium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, lithium dihydrogen phosphate, dilithium hydrogen phosphate, sodium sulfate, magnesium sulfate, and the corresponding hydrates of the additives.

[0069] As a more preferred technical solution, the additive used in the reaction is selected from one or more of ammonium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, disodium hydrogen phosphate heptahydrate, potassium dihydrogen phosphate, lithium dihydrogen phosphate, and magnesium sulfate.

[0070] As the most preferred technical solution, the additive used in the reaction is ammonium dihydrogen phosphate or sodium dihydrogen phosphate.

[0071] Furthermore, the solvent used in the reaction is selected from one or more of water, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, 1,4-dioxane, trifluoroethanol, benzene, toluene, xylene, trimethylbenzene, acetonitrile, ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

[0072] As a preferred technical solution, the solvent used in the reaction is selected from one or more of methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, 1,4-dioxane, trifluoroethanol, benzene, toluene, xylene, trimethylbenzene, acetonitrile, ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, and dichloromethane.

[0073] As a more preferred technical solution, the solvent used in the reaction is selected from one or more of methanol, toluene, acetonitrile, ether, tetrahydrofuran, chloroform and dichloromethane.

[0074] As the most preferred technical solution, the solvent used in the reaction is tetrahydrofuran.

[0075] In any of the above technical solutions, C 1～24 The alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, 3-pentyl, cyclopentyl, n-hexyl, 2-hexyl, 3-hexyl, cyclohexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, cycloheptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, cyclooctyl, n-nonyl, 2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl, cyclononyl, n-decyl, 2-decyl, 3-decyl, 4-decyl, 5-decyl, cyclodecyl, n-undecane The invention can be selected from the group consisting of cycloundecyl, n-dodecyl, cyclododecyl, n-tridecyl, cyclotridecyl, n-tetradecyl, cyclotetradecyl, n-pentadecyl, cyclopentadecyl, n-hexadecyl, cyclohexadecyl, n-heptadecyl, cycloheptadecyl, n-octadecyl, cyclooctadecyl, n-nonadecyl, cyclononadecyl, n-eicosyl, cycloeicosyl, n-heneicosyl, cycloheneicosyl, n-docosanyl, cyclodocosanyl, n-tricosanyl, cyclotricosanyl, n-tetracosanyl, and cyclotetracosanyl.

[0076] In any of the above technical solutions, C 1～18 The alkyl group is selected from one or more of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, 3-pentyl, cyclopentyl, n-hexyl, 2-hexyl, 3-hexyl, cyclohexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, cycloheptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, cyclooctyl, n-nonyl, 2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl, cyclononyl, n-decyl, 2-decyl, 3-decyl, 4-decyl, 5-decyl, cyclodecyl, n-undecyl, cycloundecyl, n-dodecyl, cyclododecyl, n-tridecyl, cyclotridecyl, n-tetradecyl, cyclotetradecyl, n-pentadecyl, cyclopentadecyl, n-hexadecyl, cyclohexadecyl, n-heptadecyl, cycloheptadecyl, n-octadecyl, and cyclooctadecyl.

[0077] In any of the above technical solutions, C 1～10 The alkyl group is selected from one or more of methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, 3-pentyl, cyclopentyl, n-hexyl, 2-hexyl, 3-hexyl, cyclohexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, cycloheptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, cyclooctyl, n-nonyl, 2-nonyl, 3-nonyl, 4-nonyl, 5-nonyl, cyclononyl, n-decyl, 2-decyl, 3-decyl, 4-decyl, 5-decyl and cyclodecyl.

[0078] In any of the above technical solutions, C 3～18 The aryl group is selected from 1-naphthyl, 2-naphthyl, 9-anthryl, 10-anthryl, 9-phenanthrenyl, 10-phenanthrenyl, 1-pyrenyl, 2-pyrenyl, 5-naphthyl, 2-peryl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 2-indolyl, 3-indolyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, and one or more of the benzoheteroaromatic ring groups of the above heteroaromatic ring groups, wherein R a , R b and R c Independently selected from one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, cyclobutyl, n-pentyl, cyclopentyl, n-hexyl, cyclohexyl, phenyl, halogen, methoxy, ethoxy, dimethylamino, diethylamino, nitro, and trifluoromethyl.

[0079] In any of the above technical solutions, C 3～10 The aryl group is selected from 1-naphthyl, 2-naphthyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 2-indolyl, 3-indolyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, and one or more of the benzoheteroaromatic ring groups of the above heteroaromatic ring groups, wherein R a , R b and R c Independently selected from one or more of hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, cyclobutyl, phenyl, halogen, methoxy, ethoxy, dimethylamino, diethylamino, nitro, and trifluoromethyl.

[0080] In any of the above technical solutions, C 2～18 The alkenyl group is selected from the group consisting of vinyl, prop-1-en-1-yl, prop-2-en-1-yl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, hex-1-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl, hept-1-en-1-yl, hept-2-en-1-yl, hept-3-en-1-yl, hept-4-en-1-yl, hept-5-en-1-yl, hept-6-en-1-yl, oct-1-en-1-yl, oct-2-en-1-yl, oct-3-en-1-yl, 1-en-1-yl, oct-4-en-1-yl, oct-5-en-1-yl, oct-6-en-1-yl, oct-7-en-1-yl, non-1-en-1-yl, non-2-en-1-yl, non-3-en-1-yl, non-4-en-1-yl, non-5-en-1-yl, dec-1-en-1-yl, dec-2-en-1-yl, dec-3-en-1-yl, dec-4-en-1-yl, dec-5-en-1-yl, undec-1-en-1-yl, dodec-1-en-1-yl, tridec-1-en-1-yl, tetradec-1-en-1-yl, pentadec-1-en-1-yl, hexadec-1-en-1-yl, heptadeca-1-en-1-yl, and octadec-1-en-1-yl.

[0081] In any of the above technical solutions, C 2～24The alkynyl group is selected from the group consisting of ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-2-yn-1-yl, but-3-yn-1-yl, pent-1-yn-1-yl, pent-2-yn-1-yl, pent-3-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl, hex-2-yn-1-yl, hex-3-yn-1-yl, hex-4-yn-1-yl. yn-1-yl, hex-5-yn-1-yl, hept-1-yn-1-yl, hept-2-yn-1-yl, hept-3-yn-1-yl, hept-4-yn-1-yl, hept-5-yn-1-yl, hept-6-yn-1-yl, oct-1-yn-1-yl, oct-2-yn-1-yl, oct-3-yn-1-yl, oct-4-yn-1-yl, oct-5-yn-1-yl, oct-6-yn-1-yl, oct-7 ...6-yn-1-yl, oct-7-yn-1-yl, oct-2-yn-1-yl, oct-3-yn-1-yl, oct-4-yn-1-yl, oct-5-yn-1-yl, oct-6-yn-1-yl, oct-7-yn-1-yl, oct-6-yn-1-yl, oct-7-yn-1-yl, oct-6-yn-1-yl, oct-7-yn-1-yl, oct-6-yn-1-yl, oct-7-yn-1-yl, oct-6-yn-1-yl, oct-6-yn-1-yl, oct-7-yn-1-yl, oct-1-yn-1-yl, oct-2-yn-1-yl, oct-3-yn-1-yl, oct-4-yn 1-ynyl, 1-nonyn-1-yl, 1-nonyn-2-yn-1-yl, 1-nonyn-3-yn-1-yl, 1-nonyn-4-yn-1-yl, 1-nonyn-5-yn-1-yl, 1-decyn-1-yl, 1-decyn-2-yn-1-yl, 1-decyn-3-yn-1-yl, 1-decyn-4-yn-1-yl, 1-decyn-5-yn-1-yl, 1-undecyn-1-yl, 1-dodecyn-1-yl, 1-tridecyn-1-yl The invention can be selected from the group consisting of 1-yn-1-yl, 1-tetra-1-yn-1-yl, 1-pentade-1-yn-1-yl, 1-hexa-1-yn-1-yl, 1-hepta-1-yn-1-yl, 1-octa-1-yn-1-yl, 1-nonade-1-yn-1-yl, 1-eicos-1-yn-1-yl, 1-undec-1-yn-1-yl, 1-dicos ... and 1-dicos-1-yn-1-yl.

[0082] In any of the above technical solutions, C 1～18 Alkoxy is selected from methoxy, methylene-1,1-dioxy Ethyl-1,2-dioxy One or more of ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, tert-butoxy, isobutoxy, cyclobutyloxy, n-pentyloxy, isopentyloxy, cyclopentyloxy, n-hexyloxy, cyclohexyloxy, n-heptyloxy, cycloheptyloxy, n-octyloxy, cyclooctyloxy, n-nonyloxy, cyclononyloxy, n-decyloxy, cyclodecyloxy, n-undecyloxy, cycloundecyloxy, n-dodecyloxy, cyclododecyloxy, n-tridecyloxy, cyclotridecyloxy, n-tetradecyloxy, cyclotetradecyloxy, n-pentadecyloxy, cyclopentadecyloxy, n-hexadecyloxy, cyclohexadecyloxy, n-heptadecyloxy, cycloheptadecyloxy, n-octadecyloxy, and cyclooctadecyloxy.

[0083] In any of the above technical solutions, the halogen is selected from one or more of fluorine, chlorine, bromine and iodine.

[0084] The present invention relates to a method for preparing chiral β-hydroxy-α-amino acid compounds by using a chiral pyridinium salt carbonyl catalyst through a biomimetic asymmetric aldol reaction. The method has mild conditions, is easy to operate, has good repeatability, and has extremely high DR and EE values, as well as relatively high to extremely high yields, and provides a new method for the asymmetric synthesis of β-hydroxy-α-amino acid compounds.

[0085] Compared with the prior art, the present invention has the following beneficial effects:

[0086] (1) Chiral β-hydroxy-α-amino acid compounds have important application value in organic synthesis, medicinal chemistry and biomedicine, but there is still no economical and efficient synthesis method for synthesizing such compounds. The present invention utilizes a class of chiral pyridinium salt carbonyl catalysts to catalyze the biomimetic aldol reaction process of amino acid derivatives and carbonyl compounds with high activity and high stereoselectivity, thereby achieving efficient synthesis of chiral β-hydroxy-α-amino acid compounds.

[0087] (2) The present invention utilizes the powerful catalytic ability of a small molecule pyridinium salt carbonyl catalyst, starts with cheap and readily available raw materials, reduces the steps of introducing and removing protecting groups, shortens the synthesis route, and synthesizes a variety of optically pure β-hydroxy-α-amino acid compounds with extremely high dr and ee values ​​and high yields under mild reaction conditions. The preparation method of the present invention is simple to operate and environmentally friendly, and is one of the most efficient methods for preparing optically active β-hydroxy-α-amino acid compounds.

[0088] (3) The chiral pyridinium salt carbonyl catalyst used in the present invention has a low dosage, and the minimum catalytic amount can be as low as one ten-thousandth; and the catalyst can be prepared by multi-step reactions of cheap and readily available raw materials, and the reaction conditions of most steps are mild, and most of them are easy to scale up and can be prepared on a large scale;

[0089] (4) The chiral β-hydroxy-α-amino acid compounds prepared by the biomimetic aldol reaction catalyzed by a pyridinium salt carbonyl catalyst can be used as important intermediates in the synthesis of drugs such as thiamphenicol, florfenicol, chloramphenicol, vancomycin, droxidopa and iliglostat, providing a new green synthesis process for the synthesis of these drug molecules. DETAILED DESCRIPTION

[0090] The present invention is described in detail below in conjunction with specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and a specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0091] Unless otherwise specified, the equipment used in the following examples are all conventional equipment in the art; the reagents used are all commercially available products or prepared by conventional methods in the art unless otherwise specified. Anything not described in detail in the following examples can be achieved by conventional experimental means in the art.

[0092] The structural formula of the chiral pyridinium salt carbonyl catalyst 3 in this embodiment and the reaction equation for preparing the β-hydroxy-α-amino acid compound 4 using the chiral pyridinium salt carbonyl catalyst 3 are as follows:

[0093]

[0094] The chiral pyridinium salt carbonyl catalyst 3 used in the present invention is prepared by the method described in patent PCT / CN2024 / 102778 and Nature Catalysis, Volume 5, November 28, 2022.

[0095] The preparation method of this embodiment can be further embodied by the preparation process of representative compounds as follows:

[0096] Embodiments 1 to 8:

[0097] A catalyst (S, S)-3 and a preparation method thereof, the reaction equation is:

[0098]

[0099] The general steps are as follows:

[0100] Compound (S,S)-5 (1.0 g, 2.06 mmol) and dimethyl squarate (1.46 g, 10.3 mmol) were dissolved in anhydrous methanol (10 mL), reacted at 50°C overnight, concentrated the system, and column chromatography was performed to obtain compound (S,S)-6 (colorless oil, 0.75 g, yield 61%);

[0101] Compound (S,S)-6 (0.15 g, 0.25 mmol) and a primary amine compound (1.38 mmol) were dissolved in anhydrous ethanol (1.5 mL), reacted at 42 °C for 48 h, concentrated the system, and obtained an amide intermediate by column chromatography; the amide intermediate was dissolved in CH3CN (1.5 mL), CH3I (20 equivalents of the amide intermediate) was added, reacted at 30 °C for 8 h, concentrated the system, and obtained a quaternary ammonium salt intermediate by column chromatography. After being spin-dried, tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added, and reacted at 55 °C for 6 h. After the reaction, tetrahydrofuran was spin-dried, and water was removed in vacuo with phosphorus pentoxide. After grinding into powder with a small spoon, 4 mL of Et2O was added first and then 7 drops of tetrahydrofuran were added. The solid was cleaned by ultrasonication and rolling, and the supernatant was sucked out. This was repeated 3 times. The supernatant and the solid were filtered together, and the filter cake was dried to obtain the catalyst (S,S)-3.

[0102] Embodiment 1:

[0103]

[0104] The basic parameters of the compound are as follows: (S,S)-6: colorless oil; [α] D 25 =4.1 (c = 0.10, CHCl3); 1 HNMR (400MHz, CDCl3) δ8.54 (s, 1H), 7.86-7.82 (m, 2H), 7.56 (s, 1H), 7.46 (t, J = 7.6 Hz,1H),7.36-7.31(m,3H),7.29-7.28(m,2H),7.20(d,J=8.0Hz,1H),7.14(d,J=6.4 Hz,2H),5.75(s,1H),5.43(s,1H),5.29(s,2H),4.10(s,3H),3.59(s,3H),3.45-3.2 9(m,3H),3.12-3.04(m,1H),1.86(s,3H),0.91(t,J=6.8Hz,3H),0.65-0.48(m,3H); 13 C NMR (100MHz, CDCl3) δ189.0,183.8,177.8,171.7,151.7,150.0,140.2,138.1,135.8,135.3,134.1,132.8,132.4,131.0 ,128.9,128.7,128.05,128.98,127.6,126.7,126.5,126.4,124.5,99.4,96.2,64.7,64.2,60.3,56.6,22.5,15.1,14.5.

[0105] Embodiment 2:

[0106]

[0107] The basic parameters of the catalyst are as follows: (S,S)-3a, brown-yellow solid, yield 69%; [α] D 25 = -4.0 (c = 0.10, MeOH); 1 H NMR(400MHz,DMSO-d6)δ9.89(s,1H),9.51(d,J=9.6Hz,1H),8.91(s,1H),8.51(s ,1H),8.16(d,J=8.8Hz,1H),8.04(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.59(t ,J=7.6Hz,1H),7.46(t,J=8.0Hz,1H),7.42-7.36(m,2H),7.35-7.27(m,2H),7.1 4(d,J=7.2Hz,2H),6.21(d,J=9.6Hz,1H),4.23(s,3H),1.69(s,3H),1.34(s,9H); 13 C NMR (100MHz, DMSO-d6) δ188.8,181.5,180.6,168.1,166.4,155.4,145.4,140.2,137.5,137.0,136.1,133.5,13 2.3,131.5,130.2,129.1,128.5,128.0,127.8,127.3,127.0,125.2,124.5,124.0,58.2,52.5,47.5,30.3,15.8.

[0108] Embodiment 3:

[0109]

[0110] The basic parameters of the catalyst are as follows: (S,S)-3b, brown-yellow solid, yield 54%; [α] D 25 = -28.0 (c = 0.050, MeOH); 1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.21(d,J=9.6Hz,1H),9.07(d,J=9.6Hz ,1H),8.87(s,1H),8.17(d,J=8.8Hz,1H),8.05(d,J=8.0Hz,1H),7.64-7.57(m ,2H),7.47(ddd,J=8.4,6.8,1.2Hz,1H),7.41-7.26(m,14H),7.14(d,J=7.6Hz ,2H),6.36(d,J=9.6Hz,1H),6.17(d,J=9.6Hz,1H),4.25(s,3H),1.76(s,3H); 13 C NMR(100MHz,DMSO-d6)δ188.9,183.0,179.7,167.0,164.3,155.0,145.6,139.9,138.8,138.4,137.5,136.8,136.1,133.4, 132.2,131.3,130.4,129.0,128.8,128.4,128.0,127.8,127.2,127.0,125.1,124.5,124.4,115.8,58.4,47.4,21.1,15.9.

[0111] Embodiment 4:

[0112]

[0113] The basic parameters of the catalyst are as follows: (S,S)-3c, brown-yellow solid, yield 57%; [α] D 25 = -6.9 (c = 0.10, MeOH); 1 H NMR(400MHz,DMSO-d6)δ9.87(s,1H),9.52(d,J=9.6Hz,1H),8.93(s,1H),8.52(s,1H),8 .17(d,J=8.4Hz,1H),8.05(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.58(t,J=7.6Hz,1H) ,7.46(t,J=8.0Hz,1H),7.43-7.35(m,2H),7.35-7.26(m,2H),7.14(d,J=7.2Hz,2H),6. 22(d,J=9.6Hz,1H),4.24(s,3H),4.07-4.01(m,1H),1.70(s,3H),1.15(d,J=6.4Hz,6H); 13C NMR (100MHz, DMSO-d6) δ188.9,181.5,180.7,168.0,166.5,155.3,145.4,140.2,137.4,137.0,136.0,133.4,13 2.2,131.6,130.2,129.2,128.6,128.1,127.8,127.4,127.0,125.2,124.6,124.0,58.3,52.4,47.2,30.4,15.9.

[0114] Embodiment 5:

[0115]

[0116] The basic parameters of the catalyst are as follows: (S,S)-3d, brown-yellow solid, yield 61%; [α] D 25 = -10.8 (c = 0.10, MeOH); 1 H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.53(d,J=9.6Hz,1H),8.92(s,1H),8.53(s,1H), 8.17(d,J=8.8Hz,1H),8.05(d,J=8.4Hz,1H),7.68(d,J=8.4Hz,1H),7.60(t,J=7.6Hz, 1H),7.47(t,J=8.0Hz,1H),7.43-7.37(m,2H),7.35-7.27(m,2H),7.19-7.12(m,2H),6 .19(d,J=9.6Hz,1H),4.28(s,3H),4.08-4.02(m,1H),1.73(s,3H),1.43-1.05(m,10H); 13 C NMR (100MHz, DMSO-d6) δ189.0,183.5,181.6,168.9,166.7,155.8,145.5,140.1,137.3,137.0,136.7,133.4,13 2.2,131.3,130.1,129.5,128.8,128.4,127.7,127.6,127.0,125.8,124.6,124.0,59.2,53.5,48.1,31.3,15.7.

[0117] Embodiment 6:

[0118]

[0119] The basic parameters of the catalyst are as follows: (S,S)-3e, brown-yellow solid, yield 59%; [α] D 25 = -11.5 (c = 0.10, MeOH); 1 H NMR (400MHz, DMSO-d6) δ9.92 (s, 1H), 9.53 (d, J = 9.6Hz, 1H), 8.95 (s, 1H), 8.48 (s, 1H), 8. 19(d,J=8.8Hz,1H),8.04(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.57(t,J=7.6Hz,1H), 7.48(t,J=8.0Hz,1H),7.42-7.36(m,2H),7.36-7.28(m,2H),7.13(d,J=7.2Hz,2H),6.23 (d,J=9.6Hz,1H),4.27(s,3H),3.83(q,J=6.8Hz,2H),1.63(s,3H),1.16(t,J=6.8Hz,3H); 13 C NMR(100MHz,DMSO-d6)δ188.1,183.5,181.6,169.1,167.4,155.1,145.2,140.9,137.8,137.1,136.5,133.6,13 2.8,131.7,130.9,129.6,128.3,128.1,127.9,127.4,127.1,125.5,124.1,124.0,58.9,52.8,46.8,30.3,16.8.

[0120] Embodiment 7:

[0121]

[0122] The basic parameters of the catalyst are as follows: (S,S)-3f, brown-yellow solid, yield 59%; [α] D 25 = -7.5 (c = 0.10, MeOH); 1H NMR (400MHz, DMSO-d6) δ9.94 (s, 1H), 9.53 (d, J = 9.6Hz, 1H), 8.98 (s, 1H), 8.47 (s ,1H),8.16(d,J=8.8Hz,1H),8.04(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.56(t ,J=7.6Hz,1H),7.49(t,J=8.0Hz,1H),7.42-7.36(m,2H),7.36-7.28(m,2H),7.1 3(d,J=7.2Hz,2H),6.28(d,J=9.6Hz,1H),4.30(s,3H),3.73(s,3H),1.63(s,3H); 13 C NMR(100MHz,DMSO-d6)δ189.1,182.9,181.6,169.3,167.5,156.0,145.9,141.2,137.7,137.1,136.5,133.1, 132.0,131.9,130.1,129.0,128.4,128.0,127.9,127.5,127.0,126.2,125.5,124.9,60.2,53.1,47.3,31.5.

[0123] Embodiment 8:

[0124]

[0125] The basic parameters of the catalyst are as follows: (S,S)-3g, brown-yellow solid, yield 71%; [α] D 25 = -10.7 (c = 0.10, MeOH); 1 H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H), 9.78 (d, J = 9.6Hz, 1H), 8.91 (s, 1H), 8.7 9(s,1H),8.16(d,J=8.8Hz,1H),8.04(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H), 7.59(t,J=7.6Hz,1H),7.46(t,J=8.0Hz,1H),7.42-7.36(m,1H),5.11(dq,J=9 .6,6.8Hz,1H),4.42(s,3H),2.17(s,3H),1.57(d,J=6.8Hz,1H),1.37(s,9H); 13C NMR(100MHz,DMSO-d6)δ189.8,182.5,180.7,168.5,166.9,155.8,145.5,140.1,137.3,133.4,131.6 ,129.1,128.8,128.1,127.9,127.1,127.0,125.5,124.9,124.2,59.3,53.5,47.9,31.3,16.3,15.7.

[0126] Embodiment 9:

[0127] A catalyst (R,R)-3h and a preparation method thereof, wherein the reaction equation is:

[0128]

[0129] The specific steps are as follows: Compound (R,R)-7 (0.247 g, 0.55 mmol) and dimethyl squarate (0.560 g, 3.3 mmol) were dissolved in anhydrous methanol (2.5 mL), reacted at 50°C overnight, concentrated the system, and column chromatography obtained compound (R,R)-8 (colorless oil, 0.1417 g, yield 53%);

[0130] The basic parameters of this compound are as follows: 1 H NMR (400MHz, CDCl3) δ8.54(s,1H),7.86-7.82(m,1H),7.56(s,1H),7.46(t,J=7.6Hz,1 H),7.36-7.31(m,1H),7.29-7.28(m,2H),7.20(d,J=8.0Hz,1H),7.14(d,J=6.4Hz,2H) ,5.75(s,1H),5.43(s,1H),5.29(s,2H),4.10(s,3H),3.59(s,3H),3.45-3.29(m,3H), 3.12-3.04(m,1H),2.0(s,3H),1.86(s,3H),0.91(t,J=6.8Hz,3H),0.65-0.48(m,3H).

[0131] Compound (R,R)-8 (0.1417 g, 0.25 mmol) and tert-butylamine (0.1009 g, 1.38 mmol) were dissolved in anhydrous ethanol (1.4 mL), and the mixture was reacted at 42 °C for 48 h. The system was concentrated and the amide intermediate was obtained by column chromatography. The amide intermediate (0.148 g, 0.21 mmol) was dissolved in CH3CN (1.5 mL), CH3I (20 equivalents of the amide intermediate) was added, and the mixture was reacted at 30 °C for 8 h. The system was concentrated and the quaternary The ammonium salt intermediate was spin-dried and tetrahydrofuran (1.5 mL) and hydrochloric acid (1.0 M, 2.0 mL) were added. The reaction was continued at 55 ° C for 6 h. After the reaction, the tetrahydrofuran was spin-dried and dehydrated with phosphorus pentoxide in a vacuum. After grinding into powder with a small spoon, 4 mL of Et2O was added and then 7 drops of tetrahydrofuran were added. The solid was washed by ultrasonic and rolling, and the supernatant was sucked out. The reaction was repeated 3 times. The supernatant and the solid were filtered together. The filter cake was dried to obtain the catalyst (R, R)-3h (brown solid, 0.1016 g, yield 65%).

[0132] The basic parameters of this compound are as follows: 1 H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 10.02 (s, 1H), 9.05 (d, J = 9.6Hz, 1H), 8.79(s,1H),7.49(t,J=7.6Hz,1H),7.44-7.33(m,2H),7.32(d,J=1.6Hz,1H ),7.22(d,J=7.6Hz,1H),7.14(dd,J=7.0,1.6Hz,2H),7.06(t,J=1.6Hz,1H) ,5.97(d,J=9.6Hz,1H),4.23(s,3H),1.94(s,3H),1.90(s,3H),1.34(s,9H); 13 C NMR (100MHz, DMSO-d6) δ188.7,181.6,180.5,168.2,166.5,155.3,145.6,140.4,137.1,136.2,132.4 ,130.1,129.2,128.6,127.7,127.2,127.1,125.3,124.6,124.1,58.4,52.3,47.6,31.4,30.2,16.1.

[0133] Examples 10 to 34:

[0134] This example screens the reaction conditions for the preparation of (2R, 3S) or (2S, 3R)-β-hydroxy-β-(p-methylsulfonylphenyl)-α-alanine tert-butyl ester. The general steps of this series of examples are as follows:

[0135] According to the specific requirements in Table 1, in a glove box, p-methylsulfonylbenzaldehyde 2a (0.2321 g, 1.26 mmol), additives (1.512 mmol) and chiral pyridinium salt carbonyl catalyst (0.00126 mmol) were weighed into a 50 mL Shrek tube, and then the solvent (7.0 mL) was added to the Shrek tube in sequence using a syringe at room temperature, and glycine tert-butyl ester 1a (0.4127 g, 3.15 mmol) was added at low temperature, and the reaction was carried out for the required time at this temperature; after the reaction was completed, anhydrous methanol (1.0 mL) and hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at the reaction temperature for 1 h, and then the reaction was continued at room temperature for 30 min, and then the mixture was filtered with diatomaceous earth, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude product of compound 4a; the NMR yield and dr value of compound 4a were obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative after the reaction with 1,1'-thiocarbonyldiimidazole;

[0136] The reaction equation is:

[0137]

[0138] The basic parameters of this compound are as follows:

[0139] 4a: white solid; 1 H NMR (400MHz, CDCl3) δ7.93 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 4.87 (d, J = 5.0 Hz, 1H), 3.53 (d, J = 5.0 Hz, 1H), 3.05 (s, 3H), 1.40 (s, 9H); 13 C NMR (100MHz, CDCl3) δ171.9,147.8,139.9,127.5,127.4,82.4,73.6,60.6,44.6,27.9.

[0140] Table 1 Reaction conditions, yields, dr values ​​and ee values ​​of Examples 10 to 34

[0141] Example catalyst additive Solvent <![CDATA[Temperature / o °C]]> Reaction time / h Yield (%) dr value / ee value (% 10 (S,S)-3a / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Dichloromethane -20 8 85 4.5:1 / 74 11 (S,S)-3b / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Dichloromethane -20 8 90 7:1 / 90 12 (S,S)-3c / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Dichloromethane -20 8 81 3.5:1 / 70 13 (S,S)-3d / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Dichloromethane -20 8 83 5.2:1 / 79 14 (S,S)-3e / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Dichloromethane -20 8 82 3.2:1 / 73 15 (S,S)-3f / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Dichloromethane -20 8 85 2.5:1 / 70 16 (S,S)-3g / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Dichloromethane -20 8 87 1.9:1 / 65 17 (R,R)-3h / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Dichloromethane -20 8 75 1.5:1 / 59 18 (S,S)-3b / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Dichloromethane -20 8 81 8:1 / 96 19 (S,S)-3b / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Toluene -20 8 25 8:1 / 83 20 (S,S)-3b / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Methanol -20 8 NR -- 21 (S,S)-3b / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Ether -20 8 24 8:1 / 90 22 (S,S)-3b / 0.1mol% <![CDATA[Na2HPO4·12H2O]]> Tetrahydrofuran -20 8 88 5:1 / 92 23 (S,S)-3b / 0.1mol% <![CDATA[Na2HPO4]]> Tetrahydrofuran -20 6 68 7:1 / 92 24 (S,S)-3b / 0.1mol% none Tetrahydrofuran -20 6 80 7:1 / 90 25 (S,S)-3b / 0.1mol% <![CDATA[MgSO4]]> Tetrahydrofuran -20 6 43 4:1 / 54 26 (S,S)-3b / 0.1mol% <![CDATA[NaH2PO4]]> Tetrahydrofuran -20 6 91 9:1 / 96 27 (S,S)-3b / 0.1mol% <![CDATA[KH2PO4]]> Tetrahydrofuran -20 6 90 8:1 / 96 28 (S,S)-3b / 0.1mol% <![CDATA[LiH2PO4]]> Tetrahydrofuran -20 6 90 8:1 / 96 29 (S,S)-3b / 0.1mol% <![CDATA[NH4H2PO4]]> Tetrahydrofuran -20 6 92 9:1 / 96 30 (S,S)-3b / 0.1mol% <![CDATA[NH4H2PO4]]> Tetrahydrofuran -30 12 91 10:1 / 96 31 (S,S)-3a / 0.1mol% <![CDATA[NH4H2PO4]]> Tetrahydrofuran -30 12 88 5:1 / 94 32 (S,S)-3c / 0.1mol% <![CDATA[NH4H2PO4]]> Tetrahydrofuran -30 12 89 4:1 / 92 33 (S,S)-3d / 0.1mol% <![CDATA[NH4H2PO4]]> Tetrahydrofuran -30 12 90 6:1 / 95 34 (S,S)-3e / 0.1mol% <![CDATA[NH4H2PO4]]> Tetrahydrofuran -30 12 89 4:1 / 90 35 (S,S)-3b / 0.05mol% <![CDATA[NH4H2PO4]]> Tetrahydrofuran -20 24 90 9:1 / 95 36 (S,S)-3b / 0.01mol% <![CDATA[NH4H2PO4]]> Tetrahydrofuran -20 72 75 7:1 / 94

[0142] The reaction conditions were screened in Table 1. First, the catalysts were screened. From Examples 10 to 17, it can be seen that the chiral pyridinium salt carbonyl catalysts (S,S)-3a~g and (R,R)-3h can catalyze the reaction. By comparison, it was found that the yield, dr value and ee value of the reaction using (S,S)-3b as the catalyst were much better than those of the reaction using other chiral pyridinium salt carbonyl catalysts as the catalyst. Subsequently, (S,S)-3b was used as the preferred catalyst for condition screening (Example 11). Then, the solvent, additive, catalyst equivalent and temperature of the reaction were screened. In terms of solvent, five different solvents were screened, namely dichloromethane, toluene, methanol, ether and tetrahydrofuran (Examples 18 to 22). Except for methanol, which reacts with the catalyst to form acetal and causes the reaction to fail, the others can achieve the reaction, among which tetrahydrofuran has the highest yield, but the dr value is slightly lower (Example 22); in terms of additives, different solvents were screened, namely Na2HPO4·12H2O, Na2HPO4, no additive, MgSO4, NaH2PO4, KH2PO4, LiH2PO4 and NH4H2PO4 (Examples 22 to 29). These additive conditions can all achieve the reaction, among which NH4H2PO4 has the best reaction result, and the yield, dr value and ee value are improved at the same time (Example 29); in terms of temperature screening, the temperature was further lowered (-30 to -20°C, Examples 29 and 30), and it can be seen that the dr value of the reaction is still slightly improved as the temperature decreases (Example 30); then the catalyst was re-heated at this temperature After screening (Examples 30 to 34), we found that catalyst (S,S)-3b still had the best effect, so we finally determined Example 30 as the reaction condition for substrate expansion; in addition, we also tried to reduce the catalyst equivalent (0.01-0.1 mol%, Examples 35 and 36), and the lowest can be reduced to one ten-thousandth, and a yield of 75% can be achieved at -20°C and by extending the reaction time (24-72h) to 72h, and both the dr value and the ee value maintain good results (7:1 / 94%).

[0143] Examples 37 to 54:

[0144] This example screens the reaction conditions for the preparation of (2R, 3S) or (2S, 3R)-β-hydroxy-β-(p-phenylphenyl)-α-alanine tert-butyl ester. The general steps of this example are as follows:

[0145] According to the specific requirements in Table 2, in a glove box, p-phenylbenzaldehyde 2b (0.2293 g, 1.26 mmol), additives (1.512 mmol), solid base (1.89 mmol) and chiral pyridinium salt carbonyl catalyst (0.00126 mmol) were weighed into a 50 mL Shrek tube, and then a solvent (6.0 mL) and a liquid base (1.89 mmol) were added to the Shrek tube in sequence using a syringe at room temperature, and glycine tert-butyl ester 1a (0.4127 g, 3.15 mmol) was added at low temperature, and the reaction was carried out for the required time at this temperature; after the reaction was completed, anhydrous methanol (1.0 mL) and a hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at the reaction temperature for 1 h, and then the reaction was continued at room temperature for 30 min, and then the diatomaceous earth was filtered, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude product of compound 4b; the NMR yield and dr value of compound 4b were obtained by 1 The crude product was obtained by HNMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0146] The reaction equation is:

[0147]

[0148] The basic parameters of this compound are as follows:

[0149] 4b: white solid; 1 H NMR (400MHz, CDCl3) δ7.65-7.57(m,4H), δ7.51-7.42(m,4H), 7.37(t,J=7.2Hz,1H), 4.82(d,J=5.4Hz,1H), 3.59(d,J=5.4Hz,1H), 1.39(s,9H). 13 C NMR (100MHz, CDCl3) δ172.5,140.9,140.8,140.1,128.8,127.3,127.1,127.1,127.0,81.9,74.4,61.0,27.9.

[0150] Table 2 Reaction conditions, yields, dr values ​​and ee values ​​of Examples 37 to 54

[0151] Example catalyst additive Solvent Alkali <![CDATA[Temperature / o C]]> Reaction time / h Yield (%) dr value / ee value (%) 37 (S,S)-3a / 0.5mol% none Dichloromethane <![CDATA[Na3PO4]]> -5 48 35 1.3:1 / 52 38 (S,S)-3a / 0.5mol% none Dichloromethane <![CDATA[K3PO4]]> -5 48 25 1.3:1 / 58 39 (S,S)-3a / 0.5mol% none Dichloromethane <![CDATA[Cs2CO3]]> -5 48 32 1:0.8 / 55 40 (S,S)-3a / 0.5mol% none Dichloromethane DIPEA -5 48 60 1.7:1 / 51 41 (S,S)-3a / 0.5mol% none Dichloromethane <![CDATA[Et3N]]> -5 48 70 1.9:1 / 52 42 (S,S)-3a / 0.5mol% none Dichloromethane <![CDATA[Et3N]]> -5 24 71 2.3:1 / 68 43 (S,S)-3b / 0.5mol% none Dichloromethane <![CDATA[Et3N]]> -5 24 67 3:1 / 69 44 (S,S)-3b / 0.5mol% none Dichloromethane <![CDATA[Et3N]]> -20 24 86 5:1 / 93 45 (S,S)-3b / 0.5mol% none Chloroform <![CDATA[Et3N]]> -20 24 80 5:1 / 90 46 (S,S)-3b / 0.5mol% none Toluene <![CDATA[Et3N]]> -20 24 87 6:1 / 79 47 (S,S)-3b / 0.5mol% none Methanol <![CDATA[Et3N]]> -20 24 5 1:1 / 9 48 (S,S)-3b / 0.5mol% none Acetonitrile <![CDATA[Et3N]]> -20 24 55 5:1 / 87 49 (S,S)-3b / 0.5mol% none Tetrahydrofuran <![CDATA[Et3N]]> -20 24 89 7:1 / 91 50 (S,S)-3b / 0.25mol% none Tetrahydrofuran <![CDATA[Et3N]]> -20 24 87 8:1 / 93 51 (S,S)-3b / 0.1mol% none Tetrahydrofuran <![CDATA[Et3N]]> -20 24 85 8:1 / 94 52 (S,S)-3b / 0.1mol% none Tetrahydrofuran <![CDATA[Et3N]]> -30 48 94 10:1 / 98 53 (S,S)-3b / 0.1mol% none Tetrahydrofuran <![CDATA[Et3N]]> -40 48 94 11:1 / 98 54 (S,S)-3b / 0.1mol% <![CDATA[NaH2PO4]]> Tetrahydrofuran <![CDATA[Et3N]]> -40 48 95 11:1 / 99

[0152] In Table 2, the reaction conditions were screened. In Examples 37 to 41, five bases, Na3PO4, K3PO4, Cs2CO3, DIPEA and Et3N, were compared, and it was found that the base with the best result was Et3N (Example 41); the reaction time and the type of catalyst were screened (Examples 41 to 43), and it was found that shortening the time (20 to 48 h) could improve the selectivity of the reaction and the catalytic effect with (S,S)-3b was better than that with (S,S)-3a; then the temperature was lowered to -20°C (-20 to -5°C) and the solvents were screened, and dichloromethane, chloroform, toluene, methanol, acetonitrile and tetrahydrofuran were screened respectively (Examples 44 to 49). It was found that except for methanol, which had a very poor reaction effect, other solvents had good effects, among which tetrahydrofuran had the best effect (Example 49); then the equivalent of the catalyst was screened (0.1-0.5 mol%, Examples 49 to 51), and it was found that the yield could still be maintained at a good level when the equivalent was reduced to one thousandth, and the dr value continued to increase as the temperature decreased; finally, the temperature was screened (-40--20°C, Examples 51 to 53), and as the temperature decreased, the dr value and ee value increased; after adding NaH2PO4 in Example 54, the ee value of the reaction was increased to 99% while maintaining the yield and dr value, and the reaction conditions for substrate expansion were finally determined.

[0153] Examples 55 to 73:

[0154] This example screens the reaction conditions for the preparation method of (2R, 3S) or (2S, 3R)-β-hydroxy-β-(n-nonyl)-α-alanine tert-butyl ester. The general steps of this example are as follows:

[0155] According to the specific requirements in Table 3, in a glove box, NH4H2PO4 and chiral pyridinium salt carbonyl catalyst (S,S)-3b were weighed into a 50 mL Shrek tube, and then tetrahydrofuran, n-decyl aldehyde 2c (0.1969 g, 1.26 mmol) and triethylamine were added to the Shrek tube in sequence using a syringe at -30°C. After stirring at -30°C for 20 min, glycine tert-butyl ester 1a was added dropwise at low temperature, and the reaction was carried out for the required time at this temperature; after the reaction was completed, anhydrous methanol (1.0 mL) and hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at the reaction temperature for 1 h, and then the reaction was continued at room temperature for 30 min, and then the diatomaceous earth was filtered, the organic solvent was spun off, and water was removed in vacuo with phosphorus pentoxide to obtain a crude product of compound 4c; the NMR yield and dr value of compound 4c were obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0156] The reaction equation is:

[0157]

[0158] The basic parameters of this compound are as follows:

[0159] 4c: yellow oil; 1 H NMR(400MHz, CDCl3) δ3.70-3.62(m,1H),3.22(d,J=5.2Hz,1H),2.06(brs,3H),1.52-1 .49(m,1H),1.48(s,9H),1.46-1.44(m,1H),1.34-1.22(m,14H),0.87(t,J=6.8Hz,3H). 13 C NMR (100MHz, CDCl3) δ173.7,81.8,72.3,59.0,34.2,32.0,29.8,29.7,29.7,29.4,28.2,25.8,22.8,14.2.

[0160] Table 3 Reaction conditions, yields, dr values ​​and ee values ​​of Examples 55 to 73

[0161]

[0162]

[0163] In Table 3, the reaction conditions were screened. In Examples 55 to 58, the temperature was screened, and it was found that as the temperature decreased (-40 to -10°C), the reaction results gradually improved, and the best effect was obtained at -30°C (Example 57); in Examples 59 and 60, the equivalents of glycine tert-butyl ester 1a (1.2 and 3.0) were screened, and it was found that 2.0 equivalents still had the best effect; in Examples 61 to 63, the equivalents of NH4H2PO4 (0.6 to 1.0) were screened by shortening the reaction time (24 to 48h), and it was found that 1.0 equivalent had the best effect, the selectivity could be maintained when the yield was increased, and the result could be maintained even when the time was shortened by half; in Examples 63 to 66, the catalyst equivalents (0.1 to 1.0 mol%) were screened, and it was found that as the catalyst equivalents increased, the selectivity could be maintained. When the selectivity remained unchanged, the yield gradually increased, but the result from 0.5% to 10% was not significantly changed, and screening was continued at 0.5% (Example 65); in Examples 67 to 70, the concentration (solvent volume 6-20 mL) was screened, and it was found that with decreasing concentration, the yield gradually increased and the dr value gradually decreased. The reaction result was best when the solvent volume was 12 mL, and screening was continued at 12 mL (Example 68); in Examples 71 and 72, the catalyst equivalent (0.1-0.5 mol%) was screened again at this concentration, and it was found that the reaction result could still be maintained when it was reduced to 0.2%, and the yield decreased significantly at 0.1%; finally, in Example 73, the addition method of glycine tert-butyl ester 1a and the solvent was changed under the condition of 0.2% catalyst, and the reaction conditions for substrate expansion were determined.

[0164] Examples 74 to 122:

[0165] This example expands the aromatic aldehyde and alkyl aldehyde substrates adapted to the preparation method of chiral β-hydroxy-α amino acid derivatives catalyzed by quaternary ammonium salt of pyridoxal. The general steps of this example are as follows (Examples 74 to 80 use general method one, Examples 81 to 106 use general method two, and Examples 107 to 122 use general method three):

[0166] General method 1 (aromatic aldehyde with strong electron-withdrawing substituent): In a glove box, aromatic aldehyde 2 (1.26 mmol), NH4H2PO4 (0.1739 g, 1.512 mmol) and chiral pyridinium salt carbonyl catalyst (R,R)-3b were mixed. or(S,S)-3b (0.001 g, 0.00126 mmol) was weighed into a 50 mL Shrek tube, and then tetrahydrofuran (7.0 mL) was added to the Shrek tube in sequence using a syringe at room temperature, and glycine derivative 1 (3.15 mmol) was added at -30°C, and the reaction was carried out at this temperature for 10 h; after the reaction, anhydrous methanol (1.0 mL) and hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at -30°C for 10 min, at -20°C for 50 min, and after returning to room temperature for 30 min, diatomaceous earth was filtered, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude chiral β-hydroxy-α amino acid derivative; the NMR yield and dr value of the product were obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0167] General method 2 (strong electron donating, weak electron withdrawing and weak electron donating substituted aromatic aldehydes): In a glove box, aromatic aldehyde 2 (1.26 mmol), NaH2PO4 (0.1814 g, 1.512 mmol) and chiral pyridinium salt carbonyl catalyst (R,R)-3b were added. or(S,S)-3b (0.001 g, 0.00126 mmol) was weighed into a 50 mL Shrek tube, and then tetrahydrofuran (6.0 mL) and triethylamine (0.263 mL, 1.89 mmol) were added to the Shrek tube in sequence using a syringe at room temperature, and glycine derivative 1 (3.15 mmol) was added at -40°C, and the reaction was carried out at this temperature for 48 h; after the reaction was completed, anhydrous methanol (1.0 mL) and hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at -40°C for 10 min, at -20°C for 50 min, and after returning to room temperature for 30 min, the mixture was filtered with diatomaceous earth, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude chiral β-hydroxy-α amino acid derivative; the NMR yield and dr value of the product were obtained by 1 The crude product was obtained by H NMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0168] General Method III (Alkyl Aldehyde): In a glove box, alkyl aldehyde 2 (1.26 mmol), NH4H2PO4 (0.145 g, 1.26 mmol) and chiral pyridinium salt carbonyl catalyst (R,R)-3b were mixed. or(S,S)-3b (0.00252 mmol) was weighed into a 50 mL Shrek tube, and then tetrahydrofuran (11.5 mL) and triethylamine (350 μL, 2.52 mmol) were added to the Shrek tube in sequence using a syringe at -30°C. After stirring at -30°C for 20 min, glycine derivative 1 (3.15 mmol, dissolved in 0.5 mL tetrahydrofuran and frozen at -30°C for 30 min) was quickly added using a syringe, and the mixture was reacted at this temperature for 20 min. After the reaction was completed, anhydrous methanol (1.0 mL) and hydroxylamine aqueous solution (1.0 mL, 50 wt.% aqueous solution) were added, and the reaction was continued at -30°C for 10 min, at -20°C for 50 min, and after returning to room temperature for 30 min, the mixture was filtered with diatomaceous earth, the organic solvent was removed by rotation, and water was removed in vacuo with phosphorus pentoxide to obtain a crude chiral β-hydroxy-α amino acid derivative. The NMR yield and dr value of the product were obtained by 1 The crude product was obtained by HNMR analysis, and the ee value was obtained by HPLC analysis of the oxazolidine-2-thione derivative obtained after its reaction with 1,1'-thiocarbonyldiimidazole;

[0169] The reaction equation is:

[0170]

[0171] The basic parameters of the compounds are shown in Table 4.

[0172] Table 4 Product structures, yields, dr values, ee values ​​and NMR characterization of Examples 74 to 122

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing a chiral β-hydroxy-α-amino acid compound, characterized in that: The method comprises the following steps: Under the catalysis of pyridinium salt carbonyl catalyst 3, amino acid derivative 1 and carbonyl compound 2 undergo aldol addition reaction to generate chiral β-hydroxy-α-amino acid compound 4, the molar ratio of amino acid derivative 1 to carbonyl compound 2 is (0.6-6):1, the molar ratio of pyridinium salt carbonyl catalyst 3 to carbonyl compound 2 is (0.00002-1):1, the reaction temperature is -80-50°C, the reaction time is 1-168h, the absolute configuration of pyridinium salt carbonyl catalyst 3 determines the absolute configuration of chiral β-hydroxy-α-amino acid compound 4, and the reaction equation is: Among them, R 1 is selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, substituted or unsubstituted C 2～18 Alkenyl, substituted or unsubstituted C 2～24 Alkynyl, or C 1～18 Carbonyl, substituted with halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 an amine group, a carbonyl group selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group; R 2 Selected from OR 9 or NR 10 R 11 , where R 9 is selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, or C 1～18 Carbonyl, R 10 and R 11 are independently selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, C 1～18 Carbonyl, or R 10 and R 11 Together they form ring B, or NR 10 R 11 is selected from amino acid amine, amino acid ester amine, amino acid amide amine or polypeptide amine, and the substituent is selected from halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 The amine group, the carbonyl group is selected from an aldehyde group, a ketone carbonyl group, an ester carbonyl group, a carboxyl group or an amide group, and the ring B is a C containing 1 to 4 heteroatoms. 1～18 Ring, heteroatom is selected from O, N or S atom; R 3 and R 4 are independently selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, substituted or unsubstituted C 2～18 Alkenyl, or substituted or unsubstituted C 2～24 Alkynyl, substituted with halogen, cyano, hydroxy, nitro, trifluoromethyl, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy, C 1～18 Amine or The carbonyl group is selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group; R b , R 2b and R 3b are independently selected from hydrogen, C 1～10 Alkyl or C 3～10 Aryl.

2. The method for preparing a chiral β-hydroxy-α-amino acid compound according to claim 1, characterized in that: The pyridinium salt carbonyl catalyst 3 has a chemical structure as shown in Formula 3: Among them, R 5 The structural formula is selected from one of the following: R 12 The structural formula is: R 21 and R 22 are independently selected from hydrogen, C 1～24 Alkyl or R 23 is selected from substituted or unsubstituted C 1～24 Alkyl, substituent selected from halogen, C 1～10 Alkyl, C 3～10 Cycloalkyl, C 3～10 Aryl, C 1～8 Carbonyl, C 1～8 Sulfonyl, C 1～8 Phosphoryl, C 1～10 Alkoxy or C 1～10 an amine group, a carbonyl group selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group; R 13 , R 14 , R 15 , R 17 , R 18 , R 19 and R 20 are independently selected from hydrogen, C 1～24 Alkyl, C 1～24 Alkoxy, C 3～10 Cycloalkyl, CO2R d , halogen, nitro, cyano or trifluoromethyl; R 16 Selected from hydrogen, C 1～24 Alkyl, C 1～24 Alkoxy, C 3～10 Cycloalkyl, CO2R d , halogen, nitro, cyano or trifluoromethyl; R 6 Selected from hydrogen, C 1～24 Alkyl, C 1～24 Alkoxy, C 3～10 Cycloalkyl, CO2R d , halogen, nitro, cyano or trifluoromethyl; R 8 Selected from hydrogen, C 1～24 Alkyl, C 1～24 Alkoxy, C 3～10 Cycloalkyl, CO2R d , halogen, nitro, cyano or trifluoromethyl; R a Selected from hydrogen, C 1～10 Alkyl, C 1～10 Alkoxy, C 3～10 Cycloalkyl, C 3～10 Aryl, halogen, nitro, cyano or trifluoromethyl, R b , R 2b , R 3b , R c , R 2c and R d are independently selected from hydrogen, C 1～10 Alkyl or C 3～10 Aryl, n is 0, 1, 2, 3, 4 or 5, x and y are independently 0, 1, 2 or 3; R 7 is selected from substituted or unsubstituted C 1～24 Alkyl, substituent selected from halogen, C 1～10 Alkyl, C 3～10 Cycloalkyl, C 3～10 Aryl, C 1～8 Carbonyl, C 1～8 Sulfonyl, C 1～8 Phosphoryl, C 1～10 Alkoxy or C 1～10 an amine group, a carbonyl group selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group; X - is an anion selected from fluoride, chloride, bromide, iodide, trifluoromethanesulfonate, hexafluorophosphate, tetrafluoroborate, sulfate, sulfite, hydroxide, nitrate, phosphate, carbonate, silicate, bicarbonate, hydrogenphosphate, dihydrogenphosphate, iodate, cyanide or thiocyanate.

3. The method for preparing a chiral β-hydroxy-α-amino acid compound according to claim 2, characterized in that: The pyridinium salt carbonyl catalyst 3 has a chemical structure as shown in Formula 3: Among them, R 5 The structural formula is selected from one of the following: R 12 The structural formula is: R 21 and R 22 are independently selected from hydrogen, C 1～24 Alkyl or R 23 is selected from substituted or unsubstituted C 1～24 Alkyl, substituent selected from halogen, C 1～10 Alkyl, C 3～10 Cycloalkyl, C 3～10 Aryl or C 1～10 Alkoxy; R 13 , R 14 , R 15 , R 17 , R 18 , R 19 and R 20 are independently selected from hydrogen, C 1～24 Alkyl, C 3～10 Cycloalkyl, C 1～24 Alkoxy, halogen, nitro, cyano or trifluoromethyl; R 16 Selected from hydrogen, C 1～24 Alkyl, C 3～10 Cycloalkyl, C 1～24 Alkoxy, halogen, nitro, cyano or trifluoromethyl; R 6 Selected from hydrogen, C 1～24 Alkyl, C 3～10 Cycloalkyl, C 1～24 Alkoxy, halogen, nitro, cyano or trifluoromethyl; R 8 Selected from hydrogen, C 1～24 Alkyl, C 3～10 Cycloalkyl, C 1～24 Alkoxy, halogen, nitro, cyano or trifluoromethyl; R a Selected from hydrogen, C 1～6 Alkyl, C 1～6 Alkoxy, C 3～10 Cycloalkyl, C 3～10 Aryl, halogen, nitro, cyano or trifluoromethyl, n is 0, 1, 2, 3, 4 or 5, x and y are independently 0, 1, 2 or 3; R 7 is selected from substituted or unsubstituted C 1～24 Alkyl, substituent selected from halogen, C 1～10 Alkyl, C 3～10 Cycloalkyl, C 3～10 Aryl or C 1～10 Alkoxy; X - is an anion selected from fluoride ion, chloride ion, bromide ion, iodide ion, hexafluorophosphate ion, and tetrafluoroborate ion.

4. The method for preparing a chiral β-hydroxy-α-amino acid compound according to claim 1, characterized in that: The R of the pyridinium salt carbonyl catalyst 3 5 It forms axial chirality with the pyridine ring, and the configuration of the axial chirality is R or S configuration.

5. The method for preparing a chiral β-hydroxy-α-amino acid compound according to claim 4, characterized in that: The pyridinium salt carbonyl catalyst 3 has the following formula I a , Formula I b , Formula II a Or Formula II b The structure of formula I a With formula I b are enantiomers of each other, formula II a With formula II b Enantiomers:

6. The method for preparing a chiral β-hydroxy-α-amino acid compound according to claim 1, characterized in that: R 1 is selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, or substituted or unsubstituted C 3～18 Aryl, substituent selected from halogen, nitro, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy or C 3～18 Aryloxy, carbonyl is selected from aldehyde, ketocarbonyl, estercarbonyl, carboxyl or amide; R 2 Selected from OR 9 or NR 10 R 11 , where R 9 is selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, or substituted or unsubstituted C 3～18 Aryl, R 10 and R 11 are independently selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, substituted or unsubstituted C 3～18 Aryl, or R 10 and R 11 Together they form ring B, or NR 10 R 11 is selected from amino acid amine, amino acid ester amine, amino acid amide amine or polypeptide amine, and the substituent is selected from halogen, cyano, hydroxyl, nitro, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy or C 1～18 The amine group, the carbonyl group is selected from an aldehyde group, a ketone carbonyl group, an ester carbonyl group, a carboxyl group or an amide group, and the ring B is a C containing 1 to 4 heteroatoms. 1～18 Ring, heteroatom is selected from O, N or S atom; R 3 and R 4 are independently selected from hydrogen, substituted or unsubstituted C 1～24 Alkyl, or substituted or unsubstituted C 3～18 Aryl, substituted with halogen, cyano, hydroxy, nitro, trifluoromethyl, C 1～18 Alkyl, C 3～18 Aryl, C 1～18 Carbonyl, C 1～18 Sulfonyl, C 1～18 Phosphoryl, C 1～18 Alkoxy, C 3～18 Aryloxy, C 1～18 Amine or The carbonyl group is selected from an aldehyde group, a keto carbonyl group, an ester carbonyl group, a carboxyl group or an amide group; R b , R 2b and R 3b are independently selected from hydrogen, C 1～10 Alkyl or C 3～10 Aryl.

7. The method for preparing a chiral β-hydroxy-α-amino acid compound according to claim 1, characterized in that: The molar ratio of the amino acid derivative 1 to the carbonyl compound 2 is (1.2-3):1, the molar ratio of the pyridinium salt carbonyl catalyst 3 to the carbonyl compound 2 is (0.0001-0.005):1, the reaction temperature is -40--5°C, and the reaction time is 6-72h.

8. The method for preparing a chiral β-hydroxy-α-amino acid compound according to claim 1, characterized in that: The base used in the reaction is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydride, potassium hydride, calcium hydride, trimethylamine, triethylamine, diisopropylamine, N,N-diisopropylethylamine, tetramethylethylenediamine, N,N-diethylmethylamine, N,N-dimethylethylamine, N,N-dimethylpropylamine, N,N-dimethylbutylamine, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane, diazabicyclododecane, 1,5-diazabicyclo[4.3.0]-5-nonene, n-butyllithium, 1,4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrole, n-butylamine, tert-butylamine, diethylamine, ethylenediamine, quinoline, and pyridine.

9. The method for preparing a chiral β-hydroxy-α-amino acid compound according to claim 1, characterized in that: The additive used in the reaction is selected from ammonium phosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, lithium phosphate, lithium dihydrogen phosphate, dilithium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium acetate, potassium acetate, potassium fluoride, sodium fluoride, sodium sulfate, magnesium sulfate, and one or more corresponding hydrates of the additives.

10. The method for preparing a chiral β-hydroxy-α-amino acid compound according to claim 1, characterized in that: The solvent used in the reaction is selected from one or more of water, methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, 1,4-dioxane, trifluoroethanol, benzene, toluene, xylene, trimethylbenzene, acetonitrile, ether, tetrahydrofuran, ethylene glycol dimethyl ether, chloroform, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone.

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