A chiral preparation method for dricidopa

Abstract

This invention relates to a method for preparing chiral drosildopa. Specifically, the method uses compound 1 and glycine ester as starting materials, and an asymmetric aldol reaction occurs under the action of a pyridinium salt carbonyl catalyst, followed by hydrolysis to obtain drosildopa. Compared with the prior art, this invention utilizes the strong catalytic ability of small molecule pyridinium salt carbonyl catalysts, starts with inexpensive and readily available raw materials, reduces the steps of introducing and removing protecting groups, shortens the synthetic route, and efficiently synthesizes optically pure drosildopa. Furthermore, the preparation method of this invention is simple to operate and environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of chemical drug synthesis technology, specifically relating to a chiral preparation method of draldopa. Background Technology

[0002] Drolidinedopa is a chiral compound with the following structure:

[0003]

[0004] Droxidopa belongs to the catecholamine class of drugs and has several clinical advantages. It can be used to treat norepinephrine deficiency by treating neurogenic orthostatic hypotension and improving norepinephrine levels. Furthermore, droxidopa is known to be used as a treatment for peripheral orthostatic hypotension or Parkinson's disease.

[0005] Patent US3920728 (Route 1) first disclosed a reaction using 3,4-dihydroxybenzaldehyde and glycine protected by benzyloxy group as starting materials to obtain racemic compound 3, which was then resolved by dicyclohexylamine to obtain racemic compound 5. This compound was further resolved by ephedrine or compound 8 to obtain compound 9, and finally hydrogenated to deprotect the target product drosidopa compound 10 protected by benzyloxy group.

[0006]

[0007] Based on this route, EP0024210A1 and EP0084928A1 further improved the order of chiral resolving agent, protecting group and deprotecting group steps. However, this route still requires two resolving steps, so the problems of low overall yield and high cost have not been solved.

[0008] JPH01228946 discloses a novel method for synthesizing drosildopa (route two). This method uses (S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid as the starting material, and sequentially undergoes esterification, reduction, acetylation, and oxidation to obtain an oxazoline derivative compound 4. This compound is then subjected to ring-opening, oxidation, and deprotection to yield the target product, drosildopa compound 5. While this method can stereoselectively yield the target product, the experimental route is lengthy and cumbersome, and the starting material already contains a chiral center, resulting in high costs.

[0009]

[0010] Sang-Ho Baik [Biotechnology Letters (2010), 32(1), 143-149] synthesized drosildenafil in one step using 3,4-dihydroxybenzaldehyde and glycine as starting materials via aldolase catalysis (route three). The advantages of this method are its short route, mild reaction, and low cost. However, the enzyme reaction requires strict conditions, and currently, there is no large-scale, mature industrial production route for drosildenafil synthesis using enzyme catalysis, resulting in high production costs. Furthermore, the substrate chirality selectivity is not high in enzyme-catalyzed reactions, and a large number of impurity isomers remain, leading to low yields.

[0011]

[0012] Therefore, there is an urgent need in this field for a synthetic method for preparing chiral drosidopa that uses simple raw materials, is rapid and efficient, environmentally friendly, easy to operate, and economical. Summary of the Invention

[0013] To address the aforementioned issues, this invention utilizes a pyridinium salt carbonyl catalyst to provide a catalytic reaction mode similar to the highly efficient catalytic asymmetric aldol reaction of glycine and aldehyde by threonine aldolase in vivo. This provides a chiral synthesis method for the chiral preparation of drosidopa that is characterized by readily available raw materials, simple operation, avoidance of resolution, reduced heavy metal residues, high selectivity, high yield, and environmental friendliness.

[0014] In a first aspect, the present invention provides a chiral preparation method for draldopa, the preparation method comprising the following steps:

[0015]

[0016] (1) In the presence of pyridinium salt carbonyl catalyst 3, compound 1 and glycine ester compound 2 react to give intermediate I;

[0017] (2) Intermediate I undergoes a hydrolysis reaction to obtain dralidopal;

[0018] Wherein, R' is -C(O)R a ;where R a Selected from the following group: C 1～4 Alkyl, C 1～4 Alkoxy;

[0019] The R is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and cyclopentyl.

[0020] The pyridinium salt catalyst 3 has the chemical structure shown in Formula 3:

[0021]

[0022] Among them, R 1 Selected from the following group:

[0023]

[0024] X1 is N or CR 6 X2 is N or CR 7 X3 is N or CR 8 X4 is N or CR 9 X5 is N or CR 10 X6 is N or CR 11 ;

[0025] R 2 R 4 R 6 R 7 R 8 R 9 R 10 and R 11 Each is independently selected from the following groups: hydrogen, -(CH2). m -C 1～24 Alkyl group, -(CH2) m -C 3～24 cycloalkyl, C 1～16 Alkoxy, -C(O)OR d Halogen, nitro, cyano, trifluoromethyl;

[0026] m is 1, 2, or 3;

[0027] n is 0, 1, 2, 3, 4 or 5;

[0028] Each R a Independently selected from the following groups: hydrogen, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 aryl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms a Together with the ring carbon atoms it is attached to, they form C 6～12 Aryl;

[0029] R b R 2b R 3b R c R 2c and R d Each is independently selected from the following groups: hydrogen, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 Aryl;

[0030] R 3 C 1～24 Alkyl group, the above R3 Optionally by 1, 2 or 3 R f replace;

[0031] R f Selected from the following group: halogens, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 Aryl, C 1～10 Alkoxy, C 1～10 Alkylamine group, -R g -LR 2g -P(O)(OR) h )2;

[0032] L is selected from the following group: -C(O)-, -C(O)NR i -、-C(O)O-、-S(O)2-;

[0033] R g Selected from the following group: key, C 1～8 Alkylene, C 3～8 Cycloalkylene;

[0034] R 2g and R h Each is independently selected from the following groups: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl;

[0035] R i Selected from the following group: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl, C 1～10 Alkoxy, C 1～10 Alkylamine group;

[0036] R 5 Selected from the following group:

[0037]

[0038] in,

[0039] x and y are each independently 0, 1, 2 or 3;

[0040] R 12 and R 13 Each is independently selected from the following groups: hydrogen, C 1～24 alkyl,

[0041] R 14 Selected from the following group: hydrogen, C 1～24 alkyl, Halogens, trifluoromethyl;

[0042] Each R eIndependently selected from the following groups: hydrogen, C 1～10 Alkyl, C 1～10 Alkoxy, C 6～12 aryl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms e Together with the ring carbon atoms it is attached to, they form C 6～12 Aryl;

[0043] X - The anions selected from the following group are: fluoride ion, chloride ion, bromide ion, iodide ion, trifluoromethanesulfonate ion, hexafluorophosphate ion, tetrafluoroborate ion, sulfate ion, sulfite ion, hydroxide ion, nitrate ion, phosphate ion, carbonate ion, silicate ion, bicarbonate ion, hydrogen phosphate ion, dihydrogen phosphate ion, iodate ion, cyanide ion, and thiocyanate ion.

[0044] In another preferred embodiment, the C 1～24 Alkyl or C 1～10 The alkyl group is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0045] In another preferred embodiment, the C 3～24 cycloalkyl or C 3～8 The cycloalkyl group is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0046] In another preferred embodiment, the C 6～12 The aryl group is phenyl, biphenyl, or naphthyl.

[0047] In another preferred embodiment, the Each of the following is independently selected: phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2,6-diphenyl, 3,5-diphenyl, 1-naphthyl, 2-naphthyl, 3,5-di-tert-butylphenyl, 4-tert-butylphenyl, 3,5-difluorophenyl, 4-fluorophenyl, 3,5-dichlorophenyl, 4-chlorophenyl, 3,5-di-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 4-methylphenyl, 4-methoxyphenyl.

[0048] In another preferred embodiment, the R 1 for Preferred More preferably

[0049]

[0050] In another preferred embodiment, each R e Independently selected from the following groups: hydrogen, C 1～8Alkyl, C 1～8 Alkoxy, phenyl, naphthyl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms e Together with the ring carbon atom it is attached to, they form a phenyl group;

[0051] Preferably, each R e Independently selected from the following groups: hydrogen, C 1～6 Alkyl, C 1～6 Alkoxy, phenyl, naphthyl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms e Together with the ring carbon atom it is attached to, they form a phenyl group;

[0052] More preferably, each R e Independently selected from the following groups: hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, phenyl, naphthyl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms e Together with the ring carbon atom it is attached to, they form a phenyl group;

[0053] Most preferably, each R e Selected independently from the group consisting of: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and n-hexyl.

[0054] In another preferred embodiment, the R 2 Selected from the following group: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl, C 1～8 Alkoxy, -C(O)OR d Halogen, nitro, cyano, trifluoromethyl;

[0055] Preferably, the R 2 Selected from the following group: hydrogen, C 1～4 Alkyl, C 3～8 cycloalkyl, C 1～4 Alkoxy, -C(O)OR d Halogen, nitro, cyano, trifluoromethyl;

[0056] More preferably, the R 2 Selected from the following group: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl.

[0057] In another preferred embodiment, the R 3 C 1～12 alkyl;

[0058] Preferably, the R 3 C 1～6 alkyl;

[0059] More preferably, the R 3 C 1～4 alkyl;

[0060] Most preferably, the R 3 Selected from the following group: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl.

[0061] In another preferred embodiment, R' is tert-butyloxycarbonyl.

[0062] In a preferred embodiment, in step (1), the R of the pyridinium salt carbonyl catalyst 3 1 It forms an axial chirality with the pyridine ring, wherein the axial chirality configuration is an R or S configuration;

[0063] The catalyst 3 has the following properties as shown in Formula I a , Formula I b Formula II a Or Formula II b The structure shown; where, Equation I a With Equation I b They are enantiomers, Formula II a With Equation II b Enantiomers:

[0064]

[0065] In a preferred embodiment, in step (1), the reaction is carried out in the presence of base 1; and

[0066] The alkali is selected from the group consisting 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, diisopropylethylamine, tetramethylethylenediamine, N,N-diethylmethylamine, N,N-dimethylethylamine, N,N-dimethylpropylamine, N,N-diethylethylenediamine, etc. Methylbutane, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane, 1-azabicyclo[2.2.2]octane, 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, pyridine, or combinations thereof.

[0067] In a preferred embodiment, in step (1), the reaction is carried out in the presence of an additive; and

[0068] The additive is selected from compounds and their hydrates from the group consisting of: ammonium phosphate, lithium phosphate, sodium phosphate, potassium phosphate, ammonium dihydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, diammonium hydrogen phosphate, dilithium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ammonium acetate, lithium acetate, sodium acetate, potassium acetate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or combinations thereof.

[0069] In a preferred embodiment, in step (1), the molar ratio of compound 1 to glycine ester compound 2 is 1:(0.1-5), preferably 1:(1.0-3.5), and more preferably 1:(1-3).

[0070] In a preferred embodiment, in step (1), the molar ratio of compound 1 to pyridinium salt carbonyl catalyst 3 is 1:(0.00001-0.1), preferably 1:(0.0001-0.02), more preferably 1:(0.001-0.008), and most preferably 1:(0.001-0.003).

[0071] In another preferred embodiment, in step (1), the molar ratio of compound 1 to base 1 is 1:(0.1 to 5), preferably 1:(0.5 to 2.5), and more preferably 1:(1 to 2).

[0072] In another preferred embodiment, in step (1), the molar ratio of compound 1 to the additive is 1:(0.1 to 5), preferably 1:(0.5 to 2.5), and more preferably 1:(1 to 2).

[0073] In a preferred embodiment, in step (1), the reaction is carried out in the presence of solvent 1; and

[0074] The solvent 1 is selected from the group consisting of: dichloromethane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, trifluoroethanol, acetonitrile, diethyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, or combinations thereof.

[0075] In a preferred embodiment, in step (1), the temperature of the reaction is -60°C to 90°C, preferably -60°C to 0°C, and more preferably -50°C to -10°C.

[0076] In another preferred embodiment, in step (1), the reaction time is 1 to 80 hours, preferably 20 to 75 hours, more preferably 30 to 60 hours, and most preferably 40 to 55 hours.

[0077] In another preferred embodiment, step (1) includes the following steps:

[0078] (1A) Add compound 1, pyridinium salt carbonyl catalyst 3, and additives to the reaction vessel;

[0079] (1B) At -50℃ to -10℃, solvent 1 and base 1 were added first, followed by compound 2. The reaction was carried out for 40 to 55 hours to obtain intermediate I.

[0080] In a preferred embodiment, in step (2), the hydrolysis reaction is carried out in the presence of acid and solvent 2; and

[0081] The acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, trifluoroformic acid, or combinations thereof;

[0082] The solvent 2 is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, or combinations thereof.

[0083] In another preferred embodiment, in step (2), the mass-to-volume ratio of intermediate I to solvent 2 is 1:(0.1-20)g / mL, preferably 1:(1-10)g / mL, and more preferably 1:(2-8)g / mL.

[0084] In another preferred embodiment, in step (2), the mass-to-volume ratio of intermediate I to acid is 1:(0.1-10) g / mL, preferably 1:(1-8) g / mL, and more preferably 1:(1-5) g / mL.

[0085] In another preferred embodiment, step (2) includes the following steps: adding intermediate I, solvent 2 and acid to a reaction vessel and reacting at 10°C to 25°C for 20 to 40 hours.

[0086] In a preferred embodiment, in step (2), the hydrolysis reaction is carried out in the presence of base 2; and

[0087] The alkali 2 is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, or combinations thereof.

[0088] In another preferred embodiment, in step (2), the hydrolysis reaction is carried out in the presence of an aqueous solution of base 2; and

[0089] The aqueous solution of the alkali 2 is selected from the following group: 1-5M sodium hydroxide aqueous solution, 1-5M potassium hydroxide aqueous solution, and 1-5M lithium hydroxide aqueous solution.

[0090] In another preferred embodiment, in step (2), the mass-to-volume ratio of intermediate I to alkali 2 is 1:(1-15) g / mL, preferably 1:(1-10) g / mL, and more preferably 1:(2-8) g / mL.

[0091] In another preferred embodiment, step (2) includes the following steps: adding intermediate I and base 2 to the reaction vessel and reacting at 20°C to 30°C for 10 to 30 hours.

[0092] In another preferred embodiment, in step (2), the temperature of the reaction is 5°C to 40°C, preferably 10°C to 35°C, and more preferably 20°C to 30°C.

[0093] In another preferred embodiment, in step (2), the reaction time is 5 to 50 hours, preferably 10 to 40 hours, more preferably 10 to 30 hours, and most preferably 12 to 20 hours.

[0094] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0095] Through long-term and in-depth research and extensive screening, the inventors have developed a chiral preparation method for drosildopa for the first time. The preparation method of this invention uses 3,4-dihydroxybenzaldehyde with protecting groups and glycine ester as starting materials, and carries out an asymmetric aldol reaction under the action of a pyridinium salt carbonyl catalyst, followed by a hydrolysis process to obtain drosildopa. The preparation method of this invention features readily available raw materials, simple operation, no need for resolution, no heavy metal residue, high selectivity, high yield, and is environmentally friendly. Based on these advantages, the inventors completed this invention.

[0096] the term

[0097] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed-ended. In other words, the terms also include “consistently made of” or “made of”.

[0098] As used herein, the term "alkyl" refers to a monovalent, straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, for example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl. In this application, alkyl is also intended to include deuterated alkyl groups, examples of which include, but are not limited to, CD3, CD2CD3, and CD2CD2CD3.

[0099] As used herein, the term "alkylene" refers to the group obtained by removing a hydrogen atom from an alkyl group as described above, such as methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0100] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of carbon and hydrogen atoms, such as "C". 3-8 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, preferably C14. 3-6 Cycloalkyl groups. Cycloalkyl groups can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or similar groups, or bicyclic, such as fused rings, bridged rings or spirocyclic rings.

[0101] As used herein, the term "alkoxy" refers to -O-alkyl, and examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, tert-butoxy, etc.

[0102] As used herein, "halogen" refers to F, Cl, Br, I, or their isotopes, including but not limited to F, 18 F, Cl, 32 Cl, Br, I.

[0103] As used in this article, the term "nitro" refers to -NO2.

[0104] As used in this article, the term "cyano" refers to -CN.

[0105] As used in this article, the term "amino" refers to -NH2.

[0106] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group (including monocyclic, bicyclic, or polycyclic groups), such as "C 6-12 "Aryl" refers to an aromatic cyclic hydrocarbon group having 6-12 (6, 7, 8, 9, 10, 11, or 12) ring carbon atoms. It contains two or more aromatic rings (such as bicyclic rings), and the aromatic rings of the aryl group can be linked by single bonds (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). Examples of aryl groups (especially monocyclic and bicyclic groups) include, but are not limited to, phenyl, biphenyl, or naphthyl. Aryl groups can be fused with heterocyclic groups through single bonds or any two adjacent ring carbon atoms, for example: benzotetrahydrofuranyl, benzotetrahydropyranyl, benzodioxane, etc. wait.

[0107] When a group loses one hydrogen atom, it becomes a subunit of the corresponding group, and it is a divalent group. For example, an alkyl group loses one hydrogen atom to become an alkylene group (e.g., methylene, ethylene, propylene, isopropylene). ), butylide (such as) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as ) etc.; cycloalkyl corresponds to cyclohexane (e.g.: wait).

[0108] Unless otherwise specified, the groups described in this invention may be substituted with substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclic groups, C3-C6 alkyl, ... 12 cycloalkyl, 5-10 heteroaryl and C6-C 10 Aryl.

[0109] In this document, “optionally” means that the event or condition described below may, but is not required to, occur, and the description includes both the possibility that the event or condition occurs and the possibility that the event or condition does not occur.

[0110] In this article, the term "multiple" refers to 2, 3, 4, 5, or a positive integer greater than 5.

[0111] As used in this article, “ee” is an abbreviation for enantiomeric excess, which refers to the enantiomeric excess rate, defined as the percentage of the total amount of one isomer a that is more abundant than another isomer b in an enantiomeric mixture.

[0112] As used in the text, "dr" is an abbreviation for "diastereomeric ratio," which refers to the ratio of one set of diastereomers to another set of diastereomers.

[0113] Preparation of pyridine-onium salt carbonyl catalyst 3

[0114] The catalyst used in this invention is prepared according to the method described in patent PCT / CN2024 / 102778, and the specific preparation process is shown below:

[0115]

[0116] in, Selected from the following group:

[0117] x, y, X1, X2, X3, X4, R 2 R 3 R 4 R 12 R 13 and R 14 The definition is as described above;

[0118] S1. Chiral compound 4 undergoes a condensation reaction with dimethyl squaric acid to give compound 5;

[0119] S2. Compound 5 and primary amine NHR 14A condensation reaction is carried out to obtain an amide intermediate; the amide intermediate reacts with the halogenated product XR. 3 The reaction proceeds to obtain a quaternary ammonium salt intermediate; the quaternary ammonium salt intermediate is hydrolyzed under acidic conditions to obtain a pyridinium salt carbonyl catalyst 3a.

[0120] Other catalysts can also be prepared using the methods disclosed in the above-mentioned literature.

[0121] Compared with the prior art, the method for synthesizing drolidine of the present invention has the following advantages:

[0122] 1. The preparation method of the present invention uses inexpensive and readily available raw materials, mild reaction conditions, and simple operation. In the presence of a chiral pyridinium salt carbonyl catalyst, there is no need to pre-protect the active raw materials, and optically pure chiral intermediate I can be obtained in one step.

[0123] 2. The preparation method of the present invention utilizes the asymmetric catalytic aldol reaction, which can introduce the two chiral centers of draldopa in high yield and with high stereoselectivity in just one step. The target product obtained has high diastereoselectivity (dr>20:1) and enantioselectivity (ee>99%), and the theoretical conversion rate can reach 100%.

[0124] 3. In the route of the present invention, the hydrolysis of phenolic hydroxyl groups and esters can be completed in one step, saving operations and improving production efficiency.

[0125] 4. The entire route of this invention does not use any environmentally polluting metal reagents, which is in line with the principles of green chemistry, environmentally friendly, and more in line with the requirements of industrial production.

[0126] The present invention will now be described in detail with reference to specific embodiments. These embodiments are only used to illustrate the technical solutions of the present invention more clearly, and should not be used to limit the scope of protection of the present invention.

[0127] This embodiment is based on the technical solution of the present invention. Unless otherwise specified, the other raw materials or processing techniques are conventional commercially available raw materials or conventional processing techniques in the art. The following embodiments help to further understand the present invention, but do not limit the scope of the invention.

[0128] Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0129] Example 1: Synthesis of pyridinium salt carbonyl catalysts 3a-1, 3a-2 and 3a-3

[0130]

[0131] Using the primary amine compound NH2R 14 (where R) 14Catalysts (S,S)-3a-1, (S,S)-3a-2, and (S,S)-3a-3 were prepared from 3,5-di-tert-butylphenyl, 3,5-dimethylphenyl, and 3,5-ditrifluoromethylphenyl, respectively, as described below:

[0132]

[0133] Compound (S,S)-4 (2.06 mmol) and dimethyl squaric acid (10.30 mmol) were dissolved in anhydrous methanol (10 mL) and reacted at 50 °C for 12 hours. After the reaction was completed, the solvent was removed and compound (S,S)-5a was purified by column chromatography.

[0134] Compound (S,S)-5a (0.54 mmol) and the primary amine compound NH2R were mixed. 14 (where R) 14 3,5-di-tert-butylphenyl, 3,5-dimethylphenyl, and 3,5-ditrifluoromethylphenyl (2.95 mmol) were dissolved in anhydrous ethanol (3.0 mL) and reacted at 40 °C for 48 hours. The system was concentrated and column chromatography was performed to obtain an amide intermediate. The amide intermediate was dissolved in CH3CN (3.0 mL), and CH3I (1.52 g, 10.7 mmol) was added. The reaction was performed at room temperature for 12 hours. The reaction system was concentrated, and column chromatography was performed followed by rotary evaporation to obtain a quaternary ammonium salt intermediate. Tetrahydrofuran (3.0 mL) and hydrochloric acid (1.0 M, 4.0 mL) were then added to the intermediate, and the reaction was performed at 50 °C for 4 hours. After the reaction was completed, the tetrahydrofuran was rotary evaporated and dried under vacuum with phosphorus pentoxide until dry. After grinding the obtained solid, 5 mL of diethyl ether was added, followed by 10 drops of tetrahydrofuran. The mixture was then shaken and washed, and allowed to stand to separate into layers. The supernatant was aspirated and repeated three times. Finally, the supernatant and solid were filtered together, and the filter cake was dried to obtain brown solid pyridinium salt carbonyl catalysts (S,S)-3a, (S,S)-3a-2, and (S,S)-3a-3.

[0135]

[0136] The basic parameters of catalyst (S,S)-3a-1 are as follows: brown solid, yield 68%; 1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),9.91(s,1H),9.37(d,J=10.0Hz,1H),8.93(s,1H) ,8.24(d,J=8.8Hz,1H),8.13(d,J=8.0Hz,1H),7.69(d,J=8.0Hz,1H),7.64(t,J=8.4Hz, 1H),7.53(t,J=8.0Hz,1H),7.48-7.42(m,2H),7.37-7.30(m,4H),7.20(d,J=7.2Hz,2H) ,7.10(t,J=1.6Hz,1H),6.25(d,J=9.6Hz,1H),4.30(s,3H),1.83(s,3H),1.27(s,18H); 13 C NMR (100MHz, DMSO-d6) δ189.0,182.9,179.9,167.1,164.5,155.3,151.6,145.6,140.1,138.1,137.6,136.9,136.1,133.2 ,132.3,131.2,130.5,129.2,128.5,128.1,127.7,127.1,127.0,125.1,124.3,116.8,112.6,58.2,47.4,34.7,31.2,15.9.

[0137]

[0138] The basic parameters of catalyst (S,S)-3a-2 are as follows: brownish-yellow solid, yield 67%; 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.84(s,1H),9.73(d,J=9.6Hz,1H),8.91(s,1H),8.20(d, J=8.4Hz,1H),8.06(d,J=8.0Hz,1H),7.73(d,J=8.8Hz,1H),7.60(t,J=7.6Hz,1H),7.48(dd,J=8 .4,6.8Hz,1H),7.43-7.38(m,2H),7.35(d,J=7.2Hz,1H),7.28(d,J=8.4Hz,1H),7.20(d,J=7.2H z,2H),7.12(s,2H),6.66(s,1H),6.20(d,J=9.6Hz,1H),4.27(s,3H),2.22(s,6H),1.76(s,3H); 13C NMR(100MHz,DMSO-d6)δ188.9,183.1,179.7,167.0,164.2,155.0,145.4,139.9,138.6,138.4,137.5,136.8,136.1,133.4, 132.2,131.3,130.4,129.1,128.8,128.4,128.0,127.8,127.2,127.1,125.1,124.5,124.4,115.8,58.4,47.4,21.1,15.9.

[0139]

[0140] The basic parameters of catalyst (S,S)-3a-3 are as follows: brownish-yellow solid, yield 53%; 1 H NMR (400MHz, DMSO-d6) δ11.31(s,1H),9.89(s,1H),9.71(d,J=9.6Hz,1H),8.91(s,1H),8.22(d ,J=8.4Hz,1H),8.12(s,2H),8.07(d,J=8.0Hz,1H),7.74(d,J=8.8Hz,1H),7.67(s,1H),7.62(t ,J=7.2Hz,1H),7.49(ddd,J=8.4,6.8,1.2Hz,1H),7.41(t,J=7.2Hz,2H),7.36(d,J=7.2Hz,1H) ,7.33(d,J=8.4Hz,1H),7.19(d,J=7.2Hz,2H),6.23(d,J=9.6Hz,1H),4.27(s,3H),1.74(s,3H); 13 C NMR (100MHz, DMSO-d6) δ189.6,184.4,180.4,168.2,163.8,155.6,146.0,141.6,140.1,138.2,137.1,136.4,133.9,132.8,131.9(q,J C-F =32.8Hz),131.7,130.9,129.5,129.3,128.9,128.6,128.3,127.6,127.5,125.7,124.7,123.6(q,J C-F =271.2Hz),118.3,115.5,59.0,47.9,16.4; 19 F NMR (376MHz, DMSO-d6) δ-61.7.

[0141] Example 2: A chiral synthesis of dricidopa

[0142] (1) Synthesis of intermediate I (catalyst: (S,S)-3a-1)

[0143]

[0144] In a glove box, (S,S)-3a-1 (1.0 mg, 0.00126 mmol), compound 1a (0.426 g, 1.26 mmol), and sodium dihydrogen phosphate (0.181 g, 1.51 mmol) were added to a 50 mL Shrek tube. The Shrek tube was then removed from the glove box, and tetrahydrofuran (6.0 mL) and triethylamine (0.26 mL, 1.89 mmol) were added at -40 °C, and the mixture was stirred for 10 minutes. After the temperature stabilized, glycine tert-butyl ester (0.247 g, 1.89 mmol) was added dropwise to the system over 5 minutes at this temperature, and the reaction was continued at -40 °C for 48 hours. After the reaction was complete, an aqueous solution of hydroxylamine (0.05 mL, 50 wt.% in water) was added to quench the reaction. The reaction was maintained at this temperature for 1 hour, then the temperature was raised to room temperature and the reaction continued for another 30 minutes. The system was then filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to obtain a dry crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:1) to obtain intermediate I-1 (0.549 g, 93% yield, >20:1 dr, 99% ee).

[0145] NMR data of intermediate I-1: 1 H NMR (400MHz, CDCl3) δ7.28 (s, 1H), 7.25-7.21 (m, 2H), 4.81 (d, J = 4.4Hz, 1H), 3.53 (d, J = 4.4Hz, 1H), 1.54 (s, 18H), 1.40 (s, 9H); 13 C NMR (100MHz, CDCl3) δ172.1,150.74,150.68,142.4,141.9,140.2,124.2,122.9,121.2,83.8,82.1,73.5,60.7,27.94,27.67.

[0146] (2) Synthesis of the final product dricidopa

[0147]

[0148] Intermediate I-1 (0.549 g, 1.17 mmol) was added to a 25 mL flask. The flask was sealed and purged with nitrogen. Isopropanol (2.0 mL) and 6 M HCl (1.0 mL) were then added to the reaction system. The reaction system was stirred at 15 °C for 36 hours. Methanol was added to the system until it was completely dissolved (about 3 mL). The pH was then adjusted to about 6 with triethylamine under ice bath conditions, and a solid precipitated. After filtration, dralidopa (0.224 g, 90% yield) was obtained.

[0149] Djurdidopa NMR data: 1 H NMR (400MHz, DMSO) δ8.75 (s, 1H), 6.80 (s, 1H), 6.72-6.60 (m, 2H), 4.90 (d, J = 4.0Hz, 1H), 3.26 (d, J = 4.0Hz, 1H).

[0150] Example 3: A chiral synthesis of dricidopa

[0151] (1) Synthesis of intermediate I (catalyst: (S,S)-3a-2)

[0152]

[0153] In a glove box, (S,S)-3a-2 (0.9 mg, 0.00126 mmol), compound 1a (0.426 g, 1.26 mmol), and sodium dihydrogen phosphate (0.181 g, 1.51 mmol) were added to a 50 mL Shrek tube. The Shrek tube was then removed from the glove box, and tetrahydrofuran (6.0 mL) and triethylamine (0.26 mL, 1.89 mmol) were added at -40 °C, and the mixture was stirred for 10 minutes. After the temperature stabilized, glycine tert-butyl ester (0.247 g, 1.89 mmol) was added dropwise to the system over 5 minutes at this temperature, and the reaction was continued at -40 °C for 48 hours. After the reaction was complete, an aqueous solution of hydroxylamine (0.05 mL, 50 wt.% in water) was added to quench the reaction. The reaction was maintained at this temperature for 1 hour, then the temperature was raised to room temperature and the reaction continued for another 30 minutes. The system was then filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to obtain a dry crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:1) to obtain intermediate I-1 (0.532 g, 90% yield, >20:1 dr, 99% ee).

[0154] (2) Synthesis of the final product dricidopa

[0155]

[0156] Intermediate I-1 (0.532 g, 1.13 mmol) was added to a 25 mL flask. The flask was sealed and purged with nitrogen. Isopropanol (2.0 mL) and 6 M HCl (1.0 mL) were then added to the reaction system. The reaction system was stirred at 15 °C for 36 hours. Methanol was added to the system until it was completely dissolved (about 3 mL). The pH was then adjusted to about 6 with triethylamine under ice bath conditions, and a solid precipitated. After filtration, dralidopal (0.213 g, 88% yield) was obtained.

[0157] Compared with Example 2, the catalyst in step (1) is different, but the yield of both is higher (≥85%), indicating that the chiral pyridinium salt carbonyl catalyst of the present invention has excellent catalytic activity.

[0158] Example 4: A chiral synthesis of dricidopa

[0159] (1) Synthesis of intermediate I (catalyst: (S,S)-3a-3)

[0160]

[0161] In a glove box, (S,S)-3a-3 (1.0 mg, 0.00126 mmol), compound 1a (0.426 g, 1.26 mmol), and sodium dihydrogen phosphate (0.181 g, 1.51 mmol) were added to a 50 mL Shrek tube. The Shrek tube was then removed from the glove box, and tetrahydrofuran (6.0 mL) and triethylamine (0.26 mL, 1.89 mmol) were added at -40 °C, and the mixture was stirred for 10 minutes. After the temperature stabilized, glycine ethyl ester and glycine tert-butyl ester (0.247 g, 1.89 mmol) were added dropwise to the system over 5 minutes at this temperature, and the reaction was continued at -40 °C for 48 hours. After the reaction was complete, an aqueous solution of hydroxylamine (0.05 mL, 50 wt.% in water) was added to quench the reaction. The reaction was maintained at this temperature for 1 hour, then the temperature was raised to room temperature and the reaction continued for another 30 minutes. The system was then filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to obtain a dry crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:1) to obtain intermediate I-1 (0.515 g, 87% yield, 15:1 dr, 99% ee).

[0162] (2) Synthesis of the final product dricidopa

[0163]

[0164] Intermediate I-1 (0.515 g, 1.09 mmol) was added to a 25 mL flask. The flask was sealed and purged with nitrogen. Isopropanol (2.0 mL) and 6 M HCl (1.0 mL) were then added to the reaction system. The reaction system was stirred at 15 °C for 36 hours. Methanol was added to the system until it was completely dissolved (about 3 mL). The pH was then adjusted to about 6 with triethylamine under ice bath conditions, and a solid precipitated. After filtration, dralidopal (0.208 g, 89% yield) was obtained.

[0165] Compared with Examples 2 and 3, the catalysts in step (1) are different, but the yields of all three are high (≥85%), indicating that the chiral pyridinium salt carbonyl catalysts of the present invention have excellent catalytic activity.

[0166] Example 5: A chiral synthesis of dricidopa

[0167] (1) Synthesis of intermediate I (catalyst: (S,S)-3a-1)

[0168]

[0169] In a glove box, (S,S)-3a-1 (1.0 mg, 0.00126 mmol), compound 1a (0.426 g, 1.26 mmol), and ammonium dihydrogen phosphate (0.173 g, 1.51 mmol) were added to a 50 mL Shrek tube. The Shrek tube was then removed from the glove box, and tetrahydrofuran (6.0 mL) and triethylamine (0.26 mL, 1.89 mmol) were added at -40 °C, and the mixture was stirred for 10 minutes. After the temperature stabilized, glycine tert-butyl ester (0.247 g, 1.89 mmol) was added dropwise to the system over 5 minutes at this temperature, and the reaction was continued at -40 °C for 48 hours. After the reaction was complete, an aqueous solution of hydroxylamine (0.05 mL, 50 wt.% in water) was added to quench the reaction. The reaction was maintained at this temperature for 1 hour, then the temperature was raised to room temperature and the reaction continued for another 30 minutes. The system was then filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to obtain a dry crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:1) to obtain intermediate I-1 (0.543 g, 92% yield, >20:1 dr, 99% ee).

[0170] (2) Synthesis of the final product dricidopa

[0171]

[0172] Intermediate I (0.543 g, 1.15 mmol) was added to a 25 mL flask. The flask was sealed and purged with nitrogen. Isopropanol (2.0 mL) and 6 M HCl (1.0 mL) were then added to the reaction system. The reaction system was stirred at 15 °C for 36 hours. Methanol was added to the system until it was completely dissolved (about 3 mL). The pH was then adjusted to about 6 with triethylamine under ice bath conditions, and a solid precipitated. After filtration, dralidopal (0.221 g, 90% yield) was obtained.

[0173] Compared with Example 2, the additives in step (1) are different, but the yields of both are higher (≥85%). Therefore, sodium dihydrogen phosphate and ammonium dihydrogen phosphate are preferred additives in step (1).

[0174] Example 6: A chiral synthesis of dricidopa

[0175] (1) Synthesis of intermediate I-2 (catalyst: (S,S)-3a-1)

[0176]

[0177] In a glove box, (S,S)-3a-1 (1.0 mg, 0.00126 mmol), compound 1b (0.280 g, 1.26 mmol), and ammonium dihydrogen phosphate (0.173 g, 1.51 mmol) were added to a 50 mL Shrek tube. The Shrek tube was then removed from the glove box, and tetrahydrofuran (6.0 mL) and triethylamine (0.26 mL, 1.89 mmol) were added at -40 °C, and the mixture was stirred for 10 minutes. After the temperature stabilized, ethyl glycine (0.195 g, 1.89 mmol) was added dropwise to the system over 5 minutes at this temperature, and the reaction was continued at -40 °C for 48 hours. After the reaction was complete, hydroxylamine hydrochloride (0.044 g, 0.63 mmol) was added to quench the reaction. The reaction was maintained at this temperature for 1 hour, then the temperature was raised to room temperature and the reaction continued for another 30 minutes. The system was then filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure to obtain a dry crude product. The crude product was purified by silica gel column chromatography (dichloromethane:ethyl acetate:ammonia in ethanol = 25:25:1) to obtain intermediate I-2 (0.348 g, 85% yield, >20:1 dr, 99% ee).

[0178] (2) Synthesis of the final product dricidopa

[0179]

[0180] Take a 25 mL pear-shaped flask, add intermediate I-2 (0.348 g, 1.07 mmol) and 3 M sodium hydroxide aqueous solution (3.0 mL) in sequence, stir at room temperature for 16 hours, then neutralize with 1 M hydrochloric acid aqueous solution to neutral, and concentrate the solution with nitrogen gas to obtain crude product. The crude product is then washed with methanol and purified to obtain dralidopala (0.196 g, 86% yield).

[0181] Compared with Example 5, the reaction substrate 2 in step (1) is different, but the yields of both are higher (≥85%), indicating that the chiral pyridinium salt carbonyl catalyst of the present invention has universality;

[0182] Compared with Example 5, the hydrolysis conditions in step (2) are different, but both conditions can yield the target product drosidopa in high yield, indicating that both acidic and alkaline conditions can effectively hydrolyze intermediate I to obtain the target product drosidopa.

[0183] Comparative Example 1: Synthesis of Intermediate I-1 (catalyst is pyridine-type carbonyl catalyst)

[0184]

[0185] Add cat.-1 (13 mg, 0.025 mmol), compound 1a (1.69 g, 5.0 mmol), and ammonium dihydrogen phosphate (0.69 g, 6.0 mmol) sequentially to a clean 50 mL Shrek tube. After purging with nitrogen three times, cool to -40 °C. At this temperature, inject tetrahydrofuran (30 mL) and triethylamine (1.04 mL, 7.5 mmol) and maintain this temperature with stirring for 10 minutes. After the system temperature stabilizes, add compound 2a, glycine tert-butyl ester (1.74 g, 12.6 mmol), dropwise to the reaction system over 5 minutes, and return to -40 °C for 48 hours.

[0186] After the reaction was complete, 20 mL of hydroxylamine aqueous solution (50 wt.% in water) was added to the system to quench the reaction, and the mixture was diluted with methanol (20 mL). The reaction was maintained at this temperature for 1 hour, then the temperature was raised to room temperature and the reaction continued for another 30 minutes. Thin-layer chromatography analysis showed almost no product in the system.

[0187] Compared with Examples 1 to 5 of this application, the catalyst in step (1) is different. The catalyst in this comparative example is a pyridine-type carbonyl catalyst, which is not a pyridinium salt carbonyl catalyst for salt formation and has no catalytic effect on the reaction of the present invention. Therefore, the catalyst of the present invention is preferably a pyridinium salt carbonyl catalyst.

[0188] In the relevant reactions of benzylamine, the pyridinium salt carbonyl catalyst will undergo interconversion of carbonyl and amino groups under the action of benzylamine, causing the catalyst to lose its catalytic activity. Therefore, in the prior art, the preferred catalyst for the reaction of benzylamine with carbonyl-containing compounds is a pyridine-type carbonyl catalyst, rather than a salt-forming pyridinium salt carbonyl catalyst (Nat Catal. 2022, 1061–1068).

[0189] However, the inventors unexpectedly discovered during the experiment that when other non-benzylamine amine compounds (such as compound 2 glycine ester in this invention) react with carbonyl-containing compounds, the catalytic effect of pyridine-type carbonyl catalysts is inferior to that of pyridinium salt carbonyl catalysts (see Comparative Example 1 for details).

[0190] Therefore, in this invention, the applicant has selected a preferred class of pyridinium salt carbonyl catalysts for amino acid ester substrates, thereby obtaining acyl or oxycarbonyl protected (2S,3R)-3,4-dihydroxyphenylserine ester intermediate I in high yield and with high selectivity.

[0191] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any 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 invention should be within the protection scope of the present invention.

Claims

1. A chiral preparation method for draldopa, characterized in that, The preparation method includes the following steps: (1) In the presence of pyridinium salt carbonyl catalyst 3, compound 1 and glycine ester compound 2 react to give intermediate I; (2) Intermediate I undergoes a hydrolysis reaction to obtain dralidopal; Wherein, R' is -C(O)R a ;where R a Selected from the following group: C 1～4 Alkyl, C 1～4 Alkoxy; The R is selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and cyclopentyl. The pyridinium salt catalyst 3 has the chemical structure shown in Formula 3: Among them, R 1 Selected from the following group: X1 is N or CR 6 X2 is N or CR 7 X3 is N or CR 8 X4 is N or CR 9 X5 is N or CR 10 X6 is N or CR 11 ; R 2 R 4 R 6 R 7 R 8 R 9 R 10 and R 11 Each is independently selected from the following groups: hydrogen, -(CH2). m -C 1～24 Alkyl group, -(CH2) m -C 3～24 cycloalkyl, C 1～16 Alkoxy, -C(O)OR d Halogen, nitro, cyano, trifluoromethyl; m is 1, 2, or 3; n is 0, 1, 2, 3, 4 or 5; Each R a Independently selected from the following groups: hydrogen, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 aryl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms a Together with the ring carbon atoms it is attached to, they form C 6～12 Aryl; R b R 2b R 3b R c R 2c and R d Each is independently selected from the following groups: hydrogen, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 Aryl; R 3 C 1～24 Alkyl group, the above R 3 Optionally by 1, 2 or 3 R f replace; R f Selected from the following group: halogens, C 1～10 Alkyl, C 3～10 cycloalkyl, C 6～12 Aryl, C 1～10 Alkoxy, C 1～10 Alkylamine group, -R g -LR 2g -P(O)(OR) h )2; L is selected from the following group: -C(O)-, -C(O)NR i -、-C(O)O-、-S(O)2-; R g Selected from the following group: key, C 1～8 Alkylene, C 3～8 Cycloalkylene; R 2g and R h Each is independently selected from the following groups: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl; R i Selected from the following group: hydrogen, C 1～8 Alkyl, C 3～8 cycloalkyl, C 1～10 Alkoxy, C 1～10 Alkylamine group; R 5 Selected from the following group: in, x and y are each independently 0, 1, 2 or 3; R 12 and R 13 Each is independently selected from the following groups: hydrogen, C 1～24 alkyl, R 14 Selected from the following group: hydrogen, C 1～24 alkyl, Halogens, trifluoromethyl; Each R e Independently selected from the following groups: hydrogen, C 1～10 Alkyl, C 1～10 Alkoxy, C 6～12 aryl, halogen, nitro, cyano, trifluoromethyl, or two R atoms on adjacent ring carbon atoms e Together with the ring carbon atoms it is attached to, they form C 6～12 Aryl; X - The anions selected from the following group are: fluoride ion, chloride ion, bromide ion, iodide ion, trifluoromethanesulfonate ion, hexafluorophosphate ion, tetrafluoroborate ion, sulfate ion, sulfite ion, hydroxide ion, nitrate ion, phosphate ion, carbonate ion, silicate ion, bicarbonate ion, hydrogen phosphate ion, dihydrogen phosphate ion, iodate ion, cyanide ion, and thiocyanate ion.

2. The preparation method according to claim 1, characterized in that, In step (1), the R of the pyridinium salt carbonyl catalyst 3 1 It forms an axial chirality with the pyridine ring, wherein the axial chirality configuration is an R or S configuration; The catalyst 3 has the following properties as shown in Formula I a , Formula I b Formula II a Or Formula II b The structure shown; where, Equation I a With Equation I b They are enantiomers, Formula II a With Equation II b Enantiomers:

3. The preparation method according to claim 1, characterized in that, In step (1), the reaction is carried out in the presence of base 1; and The alkali is selected from the group consisting 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, diisopropylethylamine, tetramethylethylenediamine, N,N-diethylmethylamine, N,N-dimethylethylamine, N,N-dimethylpropylamine, N,N-diethylethylenediamine, etc. Methylbutane, N,N-dimethylaniline, N,N-diethylaniline, 1,4-diazabicyclooctane, 1-azabicyclo[2.2.2]octane, 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, pyridine, or combinations thereof.

4. The preparation method according to claim 1, characterized in that, In step (1), the reaction is carried out in the presence of an additive; and The additive is selected from compounds and their hydrates from the group consisting of: ammonium phosphate, lithium phosphate, sodium phosphate, potassium phosphate, ammonium dihydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, diammonium hydrogen phosphate, dilithium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ammonium acetate, lithium acetate, sodium acetate, potassium acetate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, or combinations thereof.

5. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound 1 to glycine ester compound 2 is 1:(0.1-5), preferably 1:(1.0-3.5), and more preferably 1:(1-3).

6. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound 1 to pyridinium salt carbonyl catalyst 3 is 1:(0.00001-0.1), preferably 1:(0.0001-0.02), more preferably 1:(0.001-0.008), and most preferably 1:(0.001-0.003).

7. The preparation method according to claim 1, characterized in that, In step (1), the reaction is carried out in the presence of solvent 1; and The solvent 1 is selected from the group consisting of: dichloromethane, trichloromethane, 1,2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, trifluoroethanol, acetonitrile, diethyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, or combinations thereof.

8. The preparation method according to claim 1, characterized in that, In step (1), the reaction temperature is -60℃ to 90℃, preferably -60℃ to 0℃, and more preferably -50℃ to -10℃.

9. The preparation method according to claim 1, characterized in that, In step (2), the hydrolysis reaction is carried out in the presence of acid and solvent 2; and The acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, trifluoroformic acid, or combinations thereof; The solvent 2 is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, or combinations thereof.

10. The preparation method according to claim 1, characterized in that, In step (2), the hydrolysis reaction is carried out in the presence of base 2; and The alkali 2 is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, or combinations thereof.

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