Chiral alpha non-natural amino acid and method for preparing same using rare noble metal complex

Abstract

The present invention relates to a chiral α non-natural amino acid and a method for preparing the same using a rare noble metal complex. On the one hand, the present invention relates to a method for preparing a compound of formula Y, comprising the following steps: providing a complex of formula IV as a catalyst; placing a compound of formula V and a catalyst of the complex of formula IV in an autoclave, adding methanol and n-butanol, stirring under a certain hydrogen pressure to carry out a hydrogenation reaction, removing the solvent under reduced pressure, dissolving the solid residue in an alkaline solution, and removing the insoluble matter by silica gel column chromatography; acidifying the solution obtained by chromatography with concentrated hydrochloric acid, extracting with ether, adding an inorganic salt to dry, removing the solvent under reduced pressure, and drying to obtain a compound of formula Y in the form of an ester; optionally, hydrolyzing the compound of formula Y in which Rb is in the form of an ester by adding an acid or a base to obtain a compound of formula Y in the form of an acid. The present invention uses a rare noble metal complex as a catalyst to prepare a chiral α non-natural amino acid pharmaceutical compound by asymmetric hydrogenation catalysis, showing a high conversion rate.

Description

Technical Field

[0001] The present invention belongs to the field of synthesis of chiral drugs, and relates to a chemical synthesis method for chiral medicines, and in particular to a method for preparing chiral medicine compounds by asymmetric hydrogenation catalysis using a rare noble metal complex as a catalyst, in particular, the chiral medicine compound is a chiral α non-natural amino acid or a chiral α-non-natural amino acid, and the catalyst used in the method of the present invention is a complex catalyst prepared by using a rare noble metal and a chiral phosphine. Background Art

[0002] Amino acids are an important protein-based genetic engineering drug, and have important applications in recombinant R-cytokines, thrombolytic drugs, plasma proteins, protein hormones, soluble receptors, therapeutic antibodies, medicinal animal and plant proteins and other biological drugs. On the other hand, amino acids themselves are also important drug units or pharmaceutical intermediates, and they are important structural units of many clinically applied drugs.

[0003] As a part of amino acids, chiral non-natural amino acids have been widely used in the research of proteins, nucleosides and nucleic acids. Incorporating chiral non-natural amino acids into protein sequences to design and synthesize new proteins is of great significance for studying the folding and function of natural proteins. So far, more than thirty chiral non-natural amino acids have been artificially inserted into natural proteins synthesized by organisms. In addition, the presence of chiral non-natural amino acids can limit the flexibility of polypeptide conformation, provide deoxyribonucleic acid or RNA molecules with stable secondary structures, enhance the stability of polypeptides to enzymes, and improve pharmacokinetics and biological activity. At present, the efficient synthesis of non-natural amino acids has become an important research topic in the field of medicinal chemistry. Non-natural amino acids mainly refer to those amino acids that are not encoded by the genetic code and do not participate in protein synthesis. They have important uses in many fields such as medicine and pesticides. With the development of innovative drugs, the application scale of chiral drugs, peptidomimetics and peptide drugs from non-natural amino acids in the pharmaceutical field is getting larger and larger. In particular, the continued growth of the peptide drug market will drive the rapid development of upstream peptide raw material protection amino acids, synthetic reagents and other industries. Amino acids are the most basic components of peptide drugs. The introduction of unnatural amino acids into peptide drugs can significantly improve the stability of peptide drugs, enhance the ability of peptide drugs to penetrate the blood-brain barrier, and reduce the toxicity of peptide drugs. Therefore, the development of new multifunctional unnatural amino acid blocks plays a very important role in the research and development of peptide drugs. So far, the synthesis of photoactive unnatural amino acids with different configurations remains a challenging task.

[0004] The traditional industrial production process of non-natural amino acids is mainly chemical, including chemical splitting and chiral synthesis. The chemical splitting method has many disadvantages such as many synthetic side reactions, low chiral content and low utilization rate of invalid enantiomers. The preparation of chiral non-natural amino acids by chiral synthesis is a method worth looking forward to.

[0005] The prior art has disclosed some methods for preparing chiral non-natural amino acids by chiral synthesis. For example, CN101759601A (201010034064.5, Okainas) provides a method for preparing chiral α-non-natural amino acids using transition metal complexes, which comprises the following steps: preparing transition metal complex I with α-amino acid, chiral ligand and hydrochloride or nitrate of transition metal; reacting transition metal complex I with halogenated hydrocarbon under the action of base to prepare transition metal complex II; decomplexing transition metal complex II with metal complexing agent to obtain chiral α-non-natural amino acid. It is believed that the invention uses metal complexing agent instead of strong acid system for decomplexing, which can be used to synthesize chiral α-non-natural amino acids with acid-sensitive groups in the side chain, has a wide range of applications, and avoids complicated post-processing process; raw materials are easily available and low cost, and the optical selectivity of the product is good; reaction conditions are relatively mild, easy to operate and scale up, and suitable for large-scale production.

[0006] CN101817773A (201010101089.2, Okainas) relates to a method for preparing a transition metal complex and a method for preparing a chiral α-non-natural amino acid using the transition metal complex. The present invention uses a transition metal complex made of an α-amino acid, a chiral ligand and a transition metal, and then reacts the transition metal complex with a halide under the action of a base, and then recovers the chiral ligand through decomplexation to obtain a chiral α-non-natural amino acid. It is believed that the method described in the invention has a wide range of applicability and is suitable for synthesizing all α-non-natural amino acids whose side chains are stable to alkali; and the raw materials used are cheap, the reaction conditions are mild, and it is easy to operate and scale up; in addition, it is believed that the chirality of the chiral α-non-natural amino acid in the invention can be controlled by the chiral ligand, the optical purity is high, and the ee% of the target product is>97%.

[0007] CN112500303A (202011463840.3, Figure Wei An Chuang) discloses a method for preparing a β-fluoro chiral non-natural amino acid. The method uses N-Boc-protected aziridine and pyridine hydrogen fluoride as raw materials, adds a chiral ligand, reacts under the action of a transition metal catalyst, and uses a reagent to remove the Boc group from the reaction product to obtain a β-fluoro chiral non-natural amino acid. It is believed that the reaction conditions of the invention are mild, the cost is lower, the product stereoselectivity is high, and it has better yield and optical purity.

[0008] CN113861075A (202111184806.7, Wuhan University) discloses a chiral bisallyl substituted compound having three consecutive chiral centers and its preparation method and application, which belongs to the field of chemical medicine. The structure of the inventive compound is shown in Formula I, II or III. Using an iridium complex as a catalyst, substrate-1 and substrate-2 are catalytically reacted to obtain intermediate-I; intermediate-I is catalytically reacted with substrate-3 under the condition of an iridium complex as a catalyst to obtain a compound shown in Formula I. The compound shown in Formula I is hydrolyzed in acid to obtain a compound shown in Formula II; the compound shown in Formula I and water are added to an organic solvent, and the compound shown in Formula III is obtained by heating or microwave reaction in the presence of an alkali metal salt. It is believed that the compounds of the invention can be used to prepare chiral non-natural amino acids and their derivatives, as well as compounds having chiral amino acid structural units, chiral alkyl carboxylic acids and carboxylate structural units, and chiral amine structural units.

[0009] CN118005531A (202310528184.8, Inner Mongolia University) discloses a method for synthesizing chiral non-natural amino acid derivatives. Specifically, it is a method for synthesizing chiral non-natural amino acid derivatives by catalyzing asymmetric alkylation reaction with copper hexafluorophosphate tetraacetonitrile (Cu(CN)4PF6). In an inert gas, N-dibenzylidene glycine tert-butyl ester is used as a raw material, and an alkylation reaction occurs with a halogen in an organic solvent under the catalysis of Cu(CN)4PF6, the action of an efficient ligand and a base. The reaction mixture is extracted, the solvent is recovered by vacuum distillation, and the solvent is recovered by silica gel column chromatography to obtain a chiral non-natural amino acid derivative. It is believed that the enantiomeric excess (ee) of the product obtained by the invention is as high as 82%-99.5%. A series of chiral non-natural amino acid derivatives are synthesized with high enantioselectivity, which is expected to be applied to the synthesis of non-natural amino acid derivatives, and has a good promotion and application value in the field of amino acid derivative synthesis.

[0010] CN107879963A (201610871043.6, Chinese Academy of Sciences Shanghai) discloses a novel chiral ligand, metal chelate, a variety of non-natural amino acids, maraviroc and its key intermediate synthesis method, the invention uses (R)-2-methylproline as the starting material, uses nickel chelate to induce asymmetric splitting to obtain (S)-3-amino-3-phenylpropionic acid, and uses (S)-3-amino-3-phenylpropionic acid as the key intermediate to synthesize maraviroc, with a high yield and an ee value of more than 98.2%. It is believed that the method of the invention has a wide range of raw material sources, mild synthesis process conditions, easy control, and high product optical purity.

[0011] CN104016872A (201410231739.3, Zhejiang University of Technology) discloses a method for synthesizing chiral α-non-natural amino acids: using an α-amino acid 1,2,3-triazole derivative as a raw material, under the action of a palladium catalyst and an oxidant, using an aryl iodide R2-I as an arylation agent, in an organic solvent, at a reaction temperature of 60 to 120°C, the reaction is carried out in a closed state with stirring for 2h to 24h to obtain an α-non-natural amino acid derivative as shown in formula (II), and the α-non-natural amino acid derivative as shown in formula (II) is hydrolyzed and acidified to obtain an α-non-natural amino acid as shown in formula (III). It is believed that the advantages of the invention are mainly reflected in: using cheap and readily available α-natural amino acids as raw materials, α-non-natural amino acids can be directly obtained through simple reactions; the used directing group 1,2,3-triazole has the advantages of convenient synthesis, easy removal and recycling.

[0012] According to the definition of the International Union of Pure and Applied Chemistry, a catalyst generally refers to a substance that increases the reaction rate without changing the total standard Gibbs free energy change of the reaction, and its mass and chemical properties do not change before and after the chemical reaction. This effect is called catalysis, and the reaction involving a catalyst is called a catalytic reaction.

[0013] Catalytic reactions involving catalysts have four basic characteristics: catalysts can only accelerate reactions that can be carried out thermodynamically; catalysts can only accelerate reactions to equilibrium and cannot change the equilibrium position of the reaction; catalysts are selective for reactions, and when the reaction may have more than one different direction, the catalyst only accelerates one of them, promoting the unity of reaction rate and selectivity; catalysts have a certain lifespan, and in the actual reaction process, the catalyst will be subjected to long-term heat and chemical action, and some irreversible physical and chemical changes will also occur. Generally speaking, catalysts have three important indicators: activity, selectivity, and stability.

[0014] There are many types of catalysts. According to their state, they can be divided into liquid catalysts and solid catalysts; according to the phase of the reaction system, they can be divided into homogeneous catalysts and heterogeneous catalysts. Homogeneous catalysts include acids, bases, soluble transition metal compounds and peroxide catalysts. Regarding homogeneous catalysis, the reaction that occurs when the catalyst and reactants are in the same phase without the existence of a phase boundary is called homogeneous catalysis. Catalysts that can play a homogeneous catalytic role are homogeneous catalysts. Homogeneous catalysts include liquid acid and base catalysts, solid acid and alkaline catalysts, soluble transition metal compounds (salts and complexes), etc. Homogeneous catalysts act independently as molecules or ions, with uniform active centers, high activity and high selectivity.

[0015] Chirality is one of the essential properties of nature. Biomolecules, which are important foundations of life activities, and many bioactive substances acting on receptors all have chiral characteristics. It can be seen that the asymmetry of molecules plays an important role in life processes. The biological activity of many drugs is achieved through strict chiral matching and molecular recognition between macromolecules. In fact, the enantiomers of chemical drugs containing chiral factors have significant differences in activity, metabolic processes and toxicity in the human body. Therefore, obtaining optically pure substances is an important and challenging task faced by pharmaceutical chemists. Resolving racemates and biological fermentation are classic methods for obtaining optically pure substances, but these methods have long operation steps, are not economically cost-effective, and bring pollution.

[0016] The catalytic asymmetric synthesis technology that appeared in the 1970s is also commonly known as chiral technology. It is one of the economical and scientific methods to obtain non-natural complex optically pure compounds, and has broad industrial uses and application prospects. A large amount of optically pure substances can be obtained under the action of a small amount of chiral catalysis. The key to this technology is the preparation of chiral catalysts, and the core work of preparing chiral catalysts is the selection of chiral ligands, which is the source of asymmetric induction and control of product stereochemistry by chiral catalysts.

[0017] Asymmetric catalytic hydrogenation is the earliest and most effective asymmetric reaction studied. Generally, chiral diphosphine compounds are used as ligands and complexed with transition metal rhodium or ruthenium to prepare in-situ or cationic catalysts. However, most trivalent organic phosphines are unstable and easily oxidized and hydrolyzed in the air. Therefore, water and oxygen must be excluded during synthesis, which is very troublesome to operate and difficult to prepare in large quantities. This greatly limits the application of chiral technology in industrial production.

[0018] Therefore, those skilled in the art are eager to provide a method for preparing chiral non-natural amino acids, especially for preparing chiral non-natural amino acids as medicinal chemical intermediates, especially for preparing chiral α non-natural amino acids as medicinal chemical intermediates, such as using an asymmetric hydrogenation catalyst of a rare noble metal-chiral phosphine complex. Summary of the invention

[0019] The object of the present invention is to provide a method for preparing chiral α non-natural amino acids, and in particular to provide a method for preparing chiral α non-natural amino acids that can be used as pharmaceutical chemical intermediates using an asymmetric hydrogenation catalyst of a rare noble metal-chiral phosphine complex. The applicant team has previously described a unique asymmetric hydrogenation catalyst of a rare noble metal-chiral phosphine complex and a method for preparing the catalyst in Chinese Patent Application No. 2024106678888, and the entire contents of Chinese Patent Application No. 2024106678888 are incorporated herein by reference. The above-mentioned asymmetric hydrogenation catalysis is a catalyst for preparing pharmaceutical compounds, and the catalyst is a complex made by using a rare noble metal and a chiral phosphine. It has been unexpectedly found that the catalyst of the rare noble metal-chiral phosphine complex that is stable in a common environment provided by the present invention can easily prepare chiral α non-natural amino acids in an efficient manner. The present invention is accomplished by such discoveries.

[0020] To this end, the first aspect of the present invention provides a method for preparing the compound of the following formula Y:

[0021] ,

[0022] in,

[0023] Ra represents hydrogen or 1 to 4 groups selected from the following: halogen (e.g. F, Cl, Br or I), C1-C6 alkoxy, e.g. C1-C4 alkoxy, e.g. methoxy, acetoxy, halogenated C1-C6 alkyl, e.g. halogenated C1-C4 alkyl, e.g. trifluoromethyl, C1-C4 alkanoyl, e.g. acetyl, CN, C1-C6 alkyl, e.g. C1-C4 alkyl, aromatic group (e.g. phenyl, or naphthyl forming a bicyclic ring with the benzene ring), C1-C6 alkyloxycarbonyl, e.g. C1-C4 alkyloxycarbonyl, e.g. methoxycarbonyl, nitro, carboxyl, sulfonic acid, sulfoxide, sulfone, hydroxyl, sulfoxide,

[0024] Rb represents hydrogen or C1-C4 alkyl (e.g. methyl);

[0025] The method comprises the following steps:

[0026] (a) providing a complex of the following formula IV as a catalyst:

[0027] , wherein X is boron and n is 4, or X is phosphorus and n is 6;

[0028] (b) 100 mmol of the following compound of formula V:

[0029]

[0030] and 0.2 mmol ~ 1.5 mmol of the complex catalyst of formula IV are placed in an autoclave, and 200 ~ 300 mL of methanol and 1 / 10 of the amount of n-butanol used for methanol are added. 2 The mixture was stirred under hydrogen pressure for 10 to 30 hours for hydrogenation reaction, the solvent was removed under reduced pressure, the solid residue was dissolved in NaOH solution, and the insoluble matter was removed by silica gel column chromatography;

[0031] (c) acidifying the solution obtained by chromatography with concentrated hydrochloric acid, extracting with diethyl ether 1 to 5 times (e.g., 1 to 3 times, e.g., 2 times), adding inorganic salt to dry, removing the solvent under reduced pressure, and drying (e.g., vacuum drying) to obtain a compound of formula Y in the form of an ester in which Rb is a C1-C4 alkyl group; optionally, hydrolyzing the compound of formula Y in the form of an ester in which Rb is a C1-C4 alkyl group by adding an acid or a base to obtain a compound of formula Y in the form of an acid in which Rb is H.

[0032] In the present invention, the phrase "100 mmol portion" means that in the preparation process of the previous and subsequent operations, 100 mmol of material is added or any amount of material is added in proportion to this amount, and other similar expressions for the amount of material added have similar meanings.

[0033] According to the method of the first aspect of the present invention, in step (c), the inorganic salt is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, anhydrous calcium chloride or a combination thereof.

[0034] According to the method of the first aspect of the present invention, in step (c), vacuum drying is performed at 40-50°C.

[0035] According to the method of the first aspect of the present invention, in step (c), the hydrolysis is carried out as follows: a mixture of a compound of formula Y in the form of an ester in which Rb is a C1-C4 alkyl group and a (5% to 20%, for example 10%) aqueous potassium hydroxide solution is refluxed, the resulting clear solution is acidified with excess concentrated hydrochloric acid while hot to precipitate the reactant, cooled to room temperature, filtered, the filter cake is resuspended in cold water, stirred, filtered, and dried to obtain a compound of formula Y in the acid form in which Rb is H.

[0036] According to the method of the first aspect of the present invention, the compound of formula Y is selected from:

[0037] .

[0038] According to the method of the first aspect of the present invention, in step (a), the complex of formula IV is prepared by a method comprising the following steps:

[0039] (i) under nitrogen protection, adding the compound of formula I, i.e. 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, the compound of formula II, i.e. (1,5-cyclooctadiene)chlororhodium (I) dimer, and C4-C12 alkanoic acid to an organic solvent in sequence, and stirring evenly;

[0040] (ii) adding a compound of formula III represented by the chemical formula MXFn, i.e., a fluoride salt, to the mixture obtained in step (i), and continuing stirring under nitrogen protection to allow the reaction to proceed to completion; wherein M is selected from Li + 、Na + , K + NH4 + , X is boron and n is 4 or X is phosphorus and n is 6;

[0041] (iii) washing with water, distilling off the solvent under reduced pressure, adding anhydrous ethanol, standing in a cold place to precipitate, and drying the collected precipitate to obtain a complex of formula IV.

[0042] According to the method of the first aspect of the present invention, the complex of formula IV has one of the following structures:

[0043] .

[0044] According to the method of the first aspect of the present invention, the compound of formula I is R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine or S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine.

[0045] According to the method of the first aspect of the present invention, the C4-C12 alkanoic acid is a linear monobasic alkanoic acid or a dibasic alkanoic acid.

[0046] According to the method of the first aspect of the present invention, the C4-C12 alkanoic acid is a linear monobasic alkanoic acid or a dibasic alkanoic acid with a carboxyl group at one or both ends.

[0047] According to the method of the first aspect of the present invention, the C4~C12 alkanoic acid is selected from butyric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, adipic acid, and azelaic acid.

[0048] According to the method of the first aspect of the present invention, the molar ratio of the compound of formula I to the compound of formula II is 2.5-5:1, for example 2.5-4:1.

[0049] According to the method of the first aspect of the present invention, the molar ratio of C4-C12 alkanoic acid to the compound of formula II is 0.1-0.6:1, for example 0.1-0.5:1.

[0050] According to the method of the first aspect of the present invention, the molar ratio of the fluorine-containing salt represented by the compound of formula III to the compound of formula II is 4-8:1, for example, 5-7:1.

[0051] According to the method of the first aspect of the present invention, the organic solvent in step (i) is selected from dichloromethane, trichloromethane, dichloroethane, tetrachloroethane, etc., and it is known that these organic solvents are commonly used and feasible in similar reactions in the field. In the present invention, the preferred organic solvent is dichloromethane. In one embodiment, the amount of the organic solvent used is 20 to 50 mL, for example 20 to 40 mL, per 1 mmol of the compound of formula II.

[0052] According to the method of the first aspect of the present invention, in step (i), the material is stirred under nitrogen protection for 10 to 30 minutes, for example, 10 to 20 minutes.

[0053] According to the method of the first aspect of the present invention, in step (ii), the compound of formula III is pre-dissolved in water. The amount of water used is generally as small as possible, for example, 10 to 30 mL of water can be used to dissolve every 6 mmol of the compound of formula III.

[0054] According to the method of the first aspect of the present invention, in step (ii), the material is stirred under nitrogen protection for 10 to 30 min, such as 30 to 60 min, such as 40 to 50 min, such as 45 min.

[0055] According to the method of the first aspect of the present invention, in step (iii), washing with water is performed for 1 to 5 times, for example, 2 to 4 times, for example, 3 times.

[0056] According to the method of the first aspect of the present invention, in step (iii), the amount of anhydrous ethanol added per 1 mmol of compound of formula II is 50-100 mL, for example 60-90 mL, for example 70-90 mL, for example 80 mL.

[0057] According to the method of the first aspect of the present invention, in step (iii), the material is left to stand at -10 to 0°C, for example, -5°C, for 5 to 15 hours, for example, 6 to 12 hours, for example, 7 to 9 hours, for example, 8 hours.

[0058] According to the method of the first aspect of the present invention, in step (iii), the precipitate is collected by centrifugation and the supernatant is discarded.

[0059] According to the method of the first aspect of the present invention, the complex of formula IV is prepared by a method comprising the following steps and feeding ratios:

[0060] (i) under nitrogen protection, 3 mmol of the compound of formula I, i.e., 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1 mmol of the compound of formula II, i.e., (1,5-cyclooctadiene)chlororhodium (I) dimer, and 0.2 mmol of C4-C12 alkanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min;

[0061] (ii) to the mixture obtained in step (i), 6 mmol of hexafluorophosphate or tetrafluoroborate of the compound of formula III pre-dissolved in 15 mL of water was added, stirring was continued for 45 min under nitrogen protection, the mixture was washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, the mixture was allowed to stand at -5°C for 8 h, centrifuged, the supernatant was discarded, the precipitate was harvested, and dried to obtain a complex of formula IV.

[0062] Further, the second aspect of the present invention provides a compound of the following formula Y:

[0063] ,

[0064] in,

[0065] Ra represents hydrogen or 1 to 4 groups selected from the following: halogen (e.g. F, Cl, Br or I), C1-C6 alkoxy, e.g. C1-C4 alkoxy, e.g. methoxy, acetoxy, halogenated C1-C6 alkyl, e.g. halogenated C1-C4 alkyl, e.g. trifluoromethyl, C1-C4 alkanoyl, e.g. acetyl, CN, C1-C6 alkyl, e.g. C1-C4 alkyl, aromatic group (e.g. phenyl, or naphthyl forming a bicyclic ring with the benzene ring), C1-C6 alkyloxycarbonyl, e.g. C1-C4 alkyloxycarbonyl, e.g. methoxycarbonyl, nitro, carboxyl, sulfonic acid, sulfoxide, sulfone, hydroxyl, sulfoxide,

[0066] Rb represents hydrogen or a C1-C4 alkyl group (eg, methyl).

[0067] Any embodiment of any aspect of the present invention can be combined with any other embodiment, as long as such combination does not cause contradiction. The present invention is further described below.

[0068] In the present invention, when referring to %, unless otherwise specified, for the case of a solid solute and a liquid solvent, it is a weight / volume percentage, and for the case of a solid distributed in a solid, it is a weight / weight percentage.

[0069] The following formula I compound having a molecular formula of C44H32P2 and a molecular weight of 622.69, i.e., 1,1'-binaphthyl-2,2'-bisdiphenylphosphine compound, has the structural formula of its two isomers, i.e., R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (CAS No. 76189-55-4) shown in the following formula Ir and S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (CAS No. 76189-56-5) shown in the following formula Is:

[0070]

[0071] The melting points of the two types of binaphthyl bis(diphenylphosphine) represented by the above formula Ir and formula Is are both 283-286°C (lit.), and the boiling points are both 724.3±55.0°C. The specific rotation of the R-(+)-configuration is [α]20 / D=240°(c=0.3, toluene) or [α]20 / D=222°(c=0.5%, benzene), and the refractive index is 235°(c=0.3, toluene), and the specific rotation of the S-(-)-configuration is [α]20 / D=-240°(c=0.3, toluene) or [α]20 / D=-222°(c=0.5%, benzene), and the refractive index is -235°(c=0.3, toluene). 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) can be stored at room temperature.

[0072] R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine are organophosphites that can be used as effective ligands for transition metal-catalyzed asymmetric reactions (including hydrogenation and disilylation). Their rhodium derivatives can be used as highly selective homogeneous catalysts for the reduction of aryl ketones, β-ketoesters and α-aminoketones, as well as for the asymmetric hydrogenation and hydroformylation of olefins, asymmetric Heck reactions and asymmetric isomerization of allyl groups. It is known that the Ag(I) complex of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine can be used to catalyze the asymmetric aldol reaction between alkenyl trichloroacetate and aldehydes, and can also be used to catalyze the asymmetric heterogeneous Diels-Alder reaction of azo compounds. In addition, 1,1'-binaphthyl-2,2'-bis-diphenylphosphine can also be used as a ligand in palladium-catalyzed asymmetric tandem Heck reactions. This carbon anion capture process can synthesize tricyclic sesquiterpenes. 1,1'-binaphthyl-2,2'-bis-diphenylphosphine can also be used in ruthenium-catalyzed asymmetric hydrogenation of α,β-unsaturated acids. 1,1'-binaphthyl-2,2'-bis-diphenylphosphine is a C2-axial chiral diphosphine compound used as an inducer of chiral reactions; as an effective ligand in transition metal-catalyzed asymmetric reactions, including hydroxylation reactions and disilylation reactions; 1,1'-binaphthyl-2,2'-bis-diphenylphosphine is also used in asymmetric hydroxylation reactions and hydroxyl formation reactions of olefins, asymmetric Heck reactions, and asymmetric isomerization reactions of allyl groups.

[0073] As we all know, rhodium (Rhodium, element symbol Rh) is a rare silvery white, hard platinum precious metal element, with an atomic number of 45 and an atomic weight of 102.9. It is a transition metal element of the fifth period VIII group in the periodic table. The density of rhodium is as high as 12.41 g / cm3, which is more than twice that of platinum. The hardness is 4~4.5 and the melting point is as high as 1966℃. Rhodium has strong corrosion resistance. It is not corroded by most acids and alkalis. Rhodium has high reflectivity. Rhodium metal usually does not form oxides. Molten rhodium absorbs oxygen, but releases it during the solidification process. The melting point of rhodium is higher than that of platinum and the density is lower than that of platinum. Rhodium is insoluble in most acids. It is completely insoluble in nitric acid and slightly soluble in aqua regia. Rhodium can react chemically with hot concentrated sulfuric acid, hot hydrobromic acid, sodium hypochlorite and free halogens at 200-600℃. It does not react with many molten metals, such as gold, silver, sodium and potassium, and molten alkalis. Platinum group metals have a high melting point, high strength, stable electrothermal properties, high resistance to electric spark erosion, excellent corrosion resistance, strong high-temperature antioxidant properties, and good catalytic activity. They are widely used in automobile exhaust purification, chemical industry, aerospace, glass fiber, electronics and electrical industries. Although the amount used is small, they play a key role and are known as "industrial vitamins."

[0074] The compound (1,5-cyclooctadiene) rhodium chloride (I) dimer represented by the following formula II:

[0075] ,

[0076] It is also known as rhodium chloride COD, bis(1,5-cyclooctadiene rhodium chloride), etc. Its CAS number is 12092-47-6, molecular formula C16H24Cl2Rh2, and molecular weight is 493.08. The melting point of (1,5-cyclooctadiene) rhodium chloride (I) dimer is 243°C (dec.) (lit.), soluble in chloroform, dichloromethane and methanol, and slightly soluble in most common solvents. (1,5-cyclooctadiene) rhodium chloride (I) dimer is orange to orange-brown crystals or crystalline powders, with a water solubility of 1.56g / L (20℃). (1,5-cyclooctadiene) rhodium chloride (I) dimer is often used to synthesize metal ligands for catalytic reactions, such as catalysts for the reaction of 1,3-dienes and activated hydrocarbons and the preparation of chiral complexes. It can be typically used for coupling reactions, asymmetric hydrogenation reactions, and hydroboration reactions.

[0077] In the present invention, when preparing the catalyst involved, a fluoride-containing compound represented by the chemical formula shown in the following formula III is used:

[0078] ,

[0079] Wherein, M is selected from lithium (such as Li + ), sodium (such as Na + ), potassium (such as K +), ammonium ions (such as NH4 + ), X is boron or phosphorus, n is 4 or 6, especially the compound of formula III is a lithium salt, sodium salt, potassium salt or ammonium salt of boron tetrafluoride, or the compound of formula III is a lithium salt, sodium salt, potassium salt or ammonium salt of hexafluorophosphate. Wherein, when X is boron, the compound of formula III can be recorded as formula IIIb or formula IIIb compound, and when X is phosphorus, the compound of formula III can be recorded as formula IIIp or formula IIIp compound.

[0080] The method of the present invention presents excellent technical effects as described above and below, in particular, using the complex described in formula IV of the present invention as a catalyst to catalytically hydrogenate the compound of formula V, a chiral α-unnatural amino acid can be obtained with high yield and high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Figure 1 : Typical HPLC spectrum of R-2-amino-3-bromophenyl propionic acid methyl ester. DETAILED DESCRIPTION

[0082] The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be appreciated by those skilled in the art that various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. The present invention provides general and / or specific descriptions of the materials and test methods used in the test. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described in as much detail as possible here.

[0083] In the following experiments of the present invention, the feeding amount of each material can be proportionally enlarged or reduced according to specific needs. In addition, various materials used in the present invention can be easily obtained through commercial channels, for example, it is easy to find suppliers of various materials from https: / / www.chemicalbook.com / .

[0084] In the following specific examples of the present invention, a rare noble metal-chiral phosphine complex catalyst is first prepared as described in the previously filed Chinese Patent Application No. 2024106678888, and then such catalyst is used to prepare the chiral non-natural amino acid expected by the present invention, especially to prepare the chiral α-non-natural amino acid expected by the present invention.

[0085] Example 1: Preparation of rare noble metal and chiral phosphine complex catalyst

[0086] In this embodiment, potassium hexafluorophosphate is used as a fluoride-containing salt and R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine is used as a chiral phosphine. A catalyst of a rare noble metal and a chiral phosphine complex is prepared according to the following scheme, which is represented by Formula IVp or a catalyst of Formula IVp (other examples can also be prepared by referring to similar schemes):

[0087] .

[0088] Under nitrogen protection, 3 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (compound of formula I, specifically formula Ir) and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer (compound of formula II) and 0.2 mmol of hexanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 (compound of formula III, specifically formula IIIp) pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5°C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain 946 mg of the complex of binaphthyl configuration shown in the following formula IVpr:

[0089] ;

[0090] Wherein IV represents the number of the complex, p represents the salt formed with fluorine-containing phosphoric acid, r represents that the chiral phosphine used is R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and the meanings of other symbols can be deduced by analogy.

[0091] The molecular formula of the IVpr complex is C52H44F6P3Rh, and the molecular weight Mr=978.7; the elemental analysis results (%): C63.82, H4.54, F11.63, P9.49, Rh (%)=10.36%, the elemental analysis results are consistent with the theoretical value; the purity is 98.47%, and the recovery rate calculated by precious metals is 95.1%; 1 H NMR(400 MHz, CDCl3) δ:7.89(d, J=8.6Hz,2H), 7.82(d, J=8.0Hz, 2H), 7.46(d, J=8.0Hz, 2H), 7.36(t, J=7.1Hz, 2H), 7.21-7.05(m, 20H), 6.93(t, J=6.7Hz, 2H), 6.84(d, J=8.3Hz, 2H), 5.20~5.34(m, 4H), 2.00~2.09(m, 8H); 31P NMR ((CD3)2CO, 162MHz): 24.46 (d, J(P-Rh)=138.5Hz); 27.64 (d, J(P-Rh)=141.5Hz) ppm; IR (solid) v max 3048.4, 2926.2, 1702.4, 1433.5, 1238.4,813.8.

[0092] In the present invention, the hexanoic acid and the butanoic acid, heptanoic acid, nonanoic acid, etc. used herein can be collectively referred to as alkanoic acid. Unless otherwise specified, the alkanoic acid is a linear monobasic alkanoic acid or a dibasic alkanoic acid with a carboxyl group at one or both ends. As described herein, the preferred alkanoic acid is a monobasic alkanoic acid or a dibasic alkanoic acid with a chain length of C4 to C12.

[0093] Test Example 1: Determination of the rhodium content in the complex

[0094] In this test example, the rhodium content in the complex is determined by referring to the methods described in the prior art, such as the national standard GB1485-79, and the reagents used are all routinely available to those skilled in the art.

[0095] Samples and reagents: The test sample (the complex of formula IVpr obtained in Example 1) was vacuum dried at 75°C for 4 hours before testing; the hexaamminecobalt nitrate washing solution was a 0.05% hexaamminecobalt nitrate aqueous solution; the hexaamminecobalt nitrate saturated solution (as a precipitant solution) was weighed 17 g of crystalline hexaamminecobalt nitrate, added 300 mL of deionized water, heated to dissolve, filtered with a rapid filter paper, and then diluted with high-purity water to 1000 mL.

[0096] Determination method: Accurately weigh 0.5g (w, accurate to 0.1mg) of the test sample, place it in a conical beaker, add 15mL of 98% w / v concentrated sulfuric acid, cover with a watch glass, place the conical beaker on a hot plate with asbestos wire mesh, and boil slightly for 150 minutes. Remove the watch glass, continue heating until the residual liquid is 2ml, repeatedly add 65% w / v concentrated nitric acid until no more white smoke, at which point the residual liquid should be transparent dark red and contain no black, red or white precipitates. Add 36% w / v hydrochloric acid to the residual liquid, continue heating until no more red steam (about 2ml of hydrochloric acid), at which point the residual liquid should be a darker rose red. After cooling to room temperature, add 300ml of deionized water to the residual liquid, at which point the solution should be rose red. If the solution becomes turbid or white, red or black precipitates appear, the sample should be weighed and redone. The solution was heated to 60°C, sodium nitrite (about 6 g) was added in portions until the color of the solution faded, heating and boiling were continued, saturated hexaamminecobalt nitrate solution was added dropwise with vigorous stirring, and heating and stirring were continued (a large amount of yellow precipitate was precipitated) until no more yellow precipitate was precipitated (the amount of saturated hexaamminecobalt nitrate solution was about 25 ml), and a slight boil was maintained for 10 minutes, and heating was stopped. The precipitate was aged at the residual temperature for 20 minutes; after the beaker was cooled to room temperature, it was filtered with a No. 4 glass sand crucible that had been cleaned, vacuum dried and weighed to constant weight (w2) in advance, and the precipitate adhering to the beaker and the wall was completely transferred into the crucible with a glass rod with a rubber head, and the precipitate was washed twice with hexaamminecobalt nitrate washing solution, washed three times with anhydrous ethanol, and washed once with ether. Place the crucible in a vacuum drying oven, vacuum dry it at room temperature for 1 hour, then weigh it, and then vacuum dry it for 0.5 hour, then weigh it (w3 is the sum of the weight of the precipitate w1 and the weight of the crucible w2), and repeat this operation until the difference between the two weighings is ≤0.3mg. The percentage content of rhodium Rh (%) is calculated as follows:

[0097] ,

[0098] Wherein, w1 is the precipitate weight (mg), w2 is the crucible weight (mg), w is the sample weight (mg), and 0.19054 is the conversion coefficient of rhodium complex to rhodium.

[0099] The Rh (%) calculated using the above formula is the absolute percentage content of metal rhodium in the complex. After measurement, the Rh (%) of the complex obtained in Example 1 is 10.36%, and the theoretical content of rhodium in the complex shown in Formula IV is 10.52%, indicating that the purity of the obtained complex is as high as 98.47%, calculated by 10.36% ÷ 10.52%. The complexes obtained in other examples of the present invention can also be measured for their rhodium content and purity using the method of this Test Example 1.

[0100] Example 2: Preparation of rare noble metal and chiral phosphine complex catalyst

[0101] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (compound of formula I, specifically formula Is) and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer (compound of formula II) and 0.2 mmol of hexanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 (compound of formula III, specifically formula IIIp) pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain a complex of binaphthyl configuration shown in the following formula IVps, and the elemental analysis results were consistent with the theoretical value, the product purity was 97.73%, and the recovery rate was 95.8%.

[0102] .

[0103] Example 3: Preparation of rare noble metal and chiral phosphine complex catalyst

[0104] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of butyric acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain a complex shown in formula IVpr of the corresponding binaphthyl configuration. The elemental analysis results were consistent with the theoretical value, the product purity was 98.25%, and the recovery rate was 91.7%.

[0105] Example 4: Preparation of rare noble metal and chiral phosphine complex catalyst

[0106] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of butyric acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVps of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 97.64%, and the recovery rate was 91.2%.

[0107] Example 5: Preparation of rare noble metal and chiral phosphine complex catalyst

[0108] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of octanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVpr of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 98.14%, and the recovery rate was 96.1%.

[0109] Example 6: Preparation of rare noble metal and chiral phosphine complex catalyst

[0110] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of octanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVps of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 98.06%, and the recovery rate was 95.6%.

[0111] Example 7: Preparation of rare noble metal and chiral phosphine complex catalyst

[0112] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of decanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain a complex shown in formula IVpr of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 97.61%, and the recovery rate was 95.6%.

[0113] Example 8: Preparation of rare noble metal and chiral phosphine complex catalyst

[0114] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of decanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVps of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 97.37%, and the recovery rate was 95.4%.

[0115] Example 9: Preparation of rare noble metal and chiral phosphine complex catalyst

[0116] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of nonanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVpr of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 98.03%, and the recovery rate was 96.2%.

[0117] Example 10: Preparation of rare noble metal and chiral phosphine complex catalyst

[0118] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of nonanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVps of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 97.87%, and the recovery rate was 95.5%.

[0119] Example 11: Preparation of rare noble metal and chiral phosphine complex catalyst

[0120] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of heptanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVpr of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 98.27%, and the recovery rate was 96.0%.

[0121] Example 12: Preparation of rare noble metal and chiral phosphine complex catalyst

[0122] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of heptanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVps of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 97.58%, and the recovery rate was 95.8%.

[0123] Example 13: Preparation of rare noble metal and chiral phosphine complex catalyst

[0124] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of valeric acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain a complex shown in formula IVpr of the corresponding binaphthyl configuration. The elemental analysis results were consistent with the theoretical value, the product purity was 97.03%, and the recovery rate was 93.8%.

[0125] Example 14: Preparation of rare noble metal and chiral phosphine complex catalyst

[0126] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.2 mmol of valeric acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVps of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 97.26%, and the recovery rate was 93.5%.

[0127] Example 15: Preparation of rare noble metal and chiral phosphine complex catalyst

[0128] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.12 mmol of azelaic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVpr of the corresponding binaphthyl configuration. The elemental analysis results were consistent with the theoretical value, the product purity was 97.94%, and the recovery rate was 96.0%.

[0129] Example 16: Preparation of rare noble metal and chiral phosphine complex catalyst

[0130] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.12 mmol of azelaic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection. The mixture was washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain a complex of formula IVps of the corresponding binaphthyl configuration. The elemental analysis results were consistent with the theoretical values, the product purity was 98.21%, and the recovery rate was 95.8%.

[0131] Example 17: Preparation of rare noble metal and chiral phosphine complex catalyst

[0132] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.12 mmol of adipic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVpr of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 97.73%, and the recovery rate was 96.2%.

[0133] Example 18: Preparation of rare noble metal and chiral phosphine complex catalyst

[0134] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 3 mmol of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.12 mmol of adipic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; then 6 mmol of KPF6 pre-dissolved in 15 mL of water was added to the reaction solution, and stirring was continued for 45 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain the complex shown in formula IVps of the corresponding binaphthyl configuration, and the elemental analysis results were consistent with the theoretical value, the product purity was 98.05%, and the recovery rate was 95.4%.

[0135] Example 19: Preparation of rare noble metal and chiral phosphine complex catalyst

[0136] Reference Example 1 method was used to prepare a catalyst of a rare noble metal and a chiral phosphine complex, wherein the caproic acid used was replaced by an equimolar amount of formic acid, acetic acid or propionic acid, and the recovery rates of the three batches of products calculated by precious metals were 73.3%, 79.6% and 84.4%, respectively. Reference Example 2 method was used to prepare a catalyst of a rare noble metal and a chiral phosphine complex, wherein the caproic acid used was replaced by an equimolar amount of formic acid, acetic acid or propionic acid, and the recovery rates of the three batches of products calculated by precious metals were 75.1%, 81.4% and 85.3%, respectively. The results of this example show that the recovery rate is significantly reduced when short-chain acids are used, and the shorter the chain, the lower the recovery rate.

[0137] Example 20: Preparation of rare noble metal and chiral phosphine complex catalyst

[0138] Reference Example 1 method for preparing a catalyst of a rare noble metal and a chiral phosphine complex, wherein the amount of hexanoic acid used is changed to 0, 0.05mmol, 0.1mmol, 0.3mmol or 0.6mmol, and the recovery rates of 5 batches of products calculated by precious metals are 51.4%, 81.6%, 92.7%, 95.7%, and 96.1%, respectively. Reference Example 2 method for preparing a catalyst of a rare noble metal and a chiral phosphine complex, wherein the amount of hexanoic acid used is changed to 0, 0.05mmol, 0.1mmol, 0.3mmol or 0.6mmol, and the recovery rates of 5 batches of products calculated by precious metals are 53.7%, 80.3%, 93.2%, 95.3%, and 96.4%, respectively. In further experiments, with reference to Examples 3 to 14, but when the amount of organic acid is changed to 0, the recovery rates are all less than 60%. In further experiments, with reference to Examples 3 to 14, but when the amount of organic acid is changed to 0.05mmol, the recovery rates are all less than 85%. In further experiments, referring to Examples 3 to 14, but when the amount of organic acid was changed to 0.1 mmol, the recovery rates were all within the range of 90% to 94%. In further experiments, referring to Examples 3 to 14, but when the amount of organic acid was changed to 0.6 mmol, the recovery rates were all within the range of 93% to 97%. The results of this embodiment show that the recovery rate is significantly reduced when the amount of organic acid is less than 0.1 mmol, and the organic acid has a good recovery rate when the amount is in the range of 0.1 to 0.6 mmol.

[0139] Example 21: Preparation of rare noble metal and chiral phosphine complex catalyst

[0140] Reference Examples 1 to 18 methods are used to prepare catalysts of rare precious metals and chiral phosphine complexes, wherein the KPF6 used is replaced by an equimolar amount of sodium hexafluorophosphate, and the obtained products have a recovery rate calculated as precious metals in the range of 93% to 96%, and the product purity is greater than 98%. Reference Examples 1 to 18 methods are used to prepare catalysts of rare precious metals and chiral phosphine complexes, wherein the KPF6 used is replaced by an equimolar amount of potassium tetrafluoroborate, and the obtained products have a recovery rate calculated as precious metals in the range of 93% to 96%, and the product purity is greater than 97%. Reference Examples 1 to 18 methods are used to prepare catalysts of rare precious metals and chiral phosphine complexes, wherein the KPF6 used is replaced by an equimolar amount of sodium tetrafluoroborate, and the obtained products have a recovery rate calculated as precious metals in the range of 94% to 96%, and the product purity is greater than 97%. The catalyst prepared using tetrafluoroborate has the structural formula shown in the following formula IVbr or IVbs (molecular formula C52H44F4P2BRh, molecular weight Mr=920.6):

[0141] .

[0142] Example 22: Preparation of rare noble metal and chiral phosphine complex catalyst

[0143] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 2.5 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.15 mmol of hexanoic acid were added to 25 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 10 min; then 5 mmol of KPF6 pre-dissolved in 20 mL of water was added to the reaction solution, and stirring was continued for 40 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain a complex of formula IVpr. The results of elemental analysis were consistent with the theoretical value, the product purity was 97.26%, and the recovery rate was 95.3%.

[0144] Example 23: Preparation of rare noble metal and chiral phosphine complex catalyst

[0145] Reference Example 1 Method for preparing a catalyst of a rare noble metal and a chiral phosphine complex: Under nitrogen protection, 4 mmol of R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine and 1 mmol of (1,5-cyclooctadiene)chlororhodium (I) dimer and 0.3 mmol of hexanoic acid were added sequentially to 45 mL of dichloromethane in a round-bottom flask, and stirred for 25 min; then 7 mmol of KPF6 pre-dissolved in 10 mL of water was added to the reaction solution, and stirring was continued for 60 min under nitrogen protection, washed with water 3 times, the solvent was evaporated under reduced pressure, 80 mL of anhydrous ethanol was added, and the mixture was allowed to stand at -5 ° C for 8 h, centrifuged, the supernatant was discarded, the light yellow precipitate was harvested, and dried to obtain IVpr complex. The results of elemental analysis were consistent with the theoretical value, the product purity was 97.76%, and the recovery rate was 95.8%.

[0146] In some supplementary experiments, the inventors referred to the methods of Examples 1, 3 and 6, but used equimolar amounts of the following compounds of Formula III: ammonium hexafluorophosphate, ammonium tetrafluoroborate, lithium hexafluorophosphate and lithium tetrafluoroborate. The purity of the obtained products was greater than 96% and the recovery rate was within the range of 95% to 97%, indicating that these fluoride-containing salts are also effective.

[0147] Test Example 2: Stability of Complex Catalyst

[0148] The catalysts obtained in Examples 1 to 18 and Examples 21 to 23 were placed open at room temperature for 12 months, and the purity of each catalyst was measured using the method of Test Example 1. The results were all within the range of 95% to 98%. For example, the purity of the catalyst in Example 23 after being placed at room temperature for 12 months was 96.93%, which was substantially unchanged from the initial purity. This indicates that the catalyst obtained in the present invention has excellent stability.

[0149] The hydrogenation reactions involved below were carried out in an autoclave.

[0150] Example 24: Preparation of R-2-amino-3-bromophenyl propionic acid methyl ester

[0151] Using the IVpr complex prepared with R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine as described in Example 1 as a catalyst, 2-acetylamino-3-m-bromophenyl methyl acrylate was hydrogenated in an autoclave to obtain R-2-amino-3-m-bromophenyl methyl propionate. The schematic reaction process is shown below:

[0152] .

[0153] Preparation method:

[0154] (a) providing a catalyst of formula IVpr (obtained from Example 1);

[0155] (b) 100 mmol of 2-acetylamino-3-bromophenyl methyl acrylate and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 20 hours, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter (rhodium phosphine complex) by silica gel column chromatography;

[0156] (c) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with ether (45 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and vacuum dried at 40°C to obtain the target product with a molar conversion of 95.6% and an optical purity of 98.4%ee. Elemental analysis calculated values: C 43.82%, H 4.41%, O 17.51%, N 5.11%, Br 29.15%, found values: C 43.83%, H 4.40%, O 17.50%, N 5.13%, Br 29.14%. 1H NMR (400 MHz, D2O, KOH) δ 7.47 - 7.31(m, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.20 - 7.14 (m, 1H), 5.91 (dd, J = 7.1,5.9 Hz, 1H), 5.81 (dd, J = 7.1, 5.9 Hz, 1H), 3.95 (tt, J = 6.8, 5.7 Hz, 1H), 3.00 (ddt, J = 14.5, 6.8, 1.0 Hz, 1H), 2.91 (ddt, J = 14.4, 6.6, 1.0 Hz, 1H).

[0157] The optical purity or HPLC purity of the chiral α-amino acids prepared in this article can be determined using the following HPLC method: a chromatographic column (4.6*250mm, 5um) filled with octylsilane bonded silica gel is used; mobile phase A is phosphate buffer, that is, 2g of diammonium hydrogen phosphate is dissolved in 800ml of water, the pH value is adjusted to 5.5 with phosphoric acid, and then diluted to 1000ml with water; mobile phase B is acetonitrile; detection wavelength is 254nm; column temperature is 25°C; flow rate is 1.0ml / min; injection volume is 20uL; the sample is dissolved in a mixed solution of mobile phase A / mobile phase B=50:50 to a concentration of about 0.2mg / ml, and the gradient elution program is as shown in the following table:

[0158]

[0159] The typical HPLC spectrum of R-2-amino-3-bromophenyl propionic acid methyl ester obtained in this Example 24 is shown in Figure 1 The retention time of the main component peak is about 9.6 min, and 10.1 min is the S isomer peak obtained as in Example 25.

[0160] In addition, referring to the method of the above-mentioned Example 24, the catalyst was replaced by an equal molar amount of the catalyst of formula IVbr prepared by referring to Example 1 in Example 21 but using potassium tetrafluoroborate to obtain R-2-amino-3-bromophenylpropionic acid methyl ester with a molar conversion rate of 95.4% and an optical purity of 98.5%ee.

[0161] Example 25: Preparation of S-2-amino-3-bromophenyl propionic acid methyl ester

[0162] Using the IVps complex prepared with S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine as described in Example 2 as a catalyst, 2-acetylamino-3-m-bromophenyl methyl acrylate was hydrogenated in an autoclave to obtain S-2-amino-3-m-bromophenyl methyl propionate. The schematic reaction process is shown below:

[0163] .

[0164] Preparation method:

[0165] (a) providing a catalyst of formula IVps (obtained from Example 2);

[0166] (b) 100 mmol of 2-acetylamino-3-bromophenyl methyl acrylate and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 20 hours, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter (rhodium phosphine complex) by silica gel column chromatography;

[0167] (c) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with ether (45 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and vacuum dried at 40°C to obtain the target product with a molar conversion of 95.3% and an optical purity of 98.2%ee. Elemental analysis calculated values: C 43.82%, H 4.41%, O 17.51%, N 5.11%, Br 29.15%, found values: C 43.84%, H4.39%, O 17.52%, N 5.12%, Br 29.13%. 1 H NMR (400 MHz, D2O, KOH) δ 7.49 - 7.39 (m,2H), 7.27 (t, J = 7.8 Hz, 1H), 7.24 - 7.11 (m, 1H), 5.91 (dd, J = 7.1, 5.9Hz, 1H), 5.79 (dd, J = 7.1, 5.9 Hz, 1H), 3.97 (tt, J = 6.8, 5.7 Hz, 1H), 3.00(ddt, J = 14.5, 6.8, 1.0 Hz, 1H), 2.93 (ddt, J = 14.4, 6.6, 1.0 Hz, 1H).

[0168] In addition, referring to the method of the above-mentioned Example 25, the catalyst was replaced with an equal molar amount of the catalyst of formula IVbs prepared by referring to Example 2 in Example 21 but using potassium tetrafluoroborate to obtain S-2-amino-3-bromophenylpropionic acid methyl ester with a molar conversion rate of 95.5% and an optical purity of 98.6%ee.

[0169] The methyl ester compound obtained above can be further hydrolyzed to obtain S-2-amino-3-m-bromophenylpropionic acid.

[0170] Example 26: Preparation of Levodopa

[0171] Using the IVps complex prepared with S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine as described in Example 2 as a catalyst, 2-acetylamino-3-(3-methoxy-4-acetoxyphenyl)acrylic acid was hydrogenated in an autoclave to obtain S-2-amino-3-(3-methoxy-4-acetoxyphenyl)acrylic acid, which was then hydrolyzed to obtain levodopa. The schematic reaction process is shown below:

[0172] .

[0173] Preparation method:

[0174] (a) providing a catalyst of formula IVps (obtained from Example 2);

[0175] (b) 100 mmol of 2-acetylamino-3-(3-methoxy-4-acetoxyphenyl)acrylic acid and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 20 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0176] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product S-2-amino-3-(3-methoxy-4-acetoxyphenyl)acrylic acid with a molar conversion of 95.3% and an optical purity of 98.3% ee;

[0177] (c2) After the solvent was removed under reduced pressure, a mixture of another half of the material (of course, it can also be S-2-amino-3-(3-methoxy-4-acetoxyphenyl) acrylic acid after vacuum drying, and other embodiments of the present invention can be understood in the same way) and 10% potassium hydroxide aqueous solution (100 ml) was refluxed for 1 hour, and the clear solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant, cooled to room temperature, filtered, and the filter cake was resuspended in 100 mL of cold water, vigorously stirred for several minutes, filtered, and the filter cake was dried under reduced pressure to obtain a needle-shaped crystalline powder of levodopa, HPPC purity 99.3%, mp 276-278°. Elemental analysis calculated values: C 54.82%, H 5.62%, N 7.10%, O 32.45%, measured values: C 54.85%, H 5.60%, N 7.08%, O32.47%. 1 H NMR (400 MHz, D2O, KOH) δ 7.46 (s, 1H), 7.39 (s, 1H), 6.66 (d, J = 8.4Hz, 1H), 6.55 (dt, J = 1.9, 1.0 Hz, 1H), 6.44 (ddt, J = 8.4, 1.8, 1.1 Hz,1H), 6.09 (dd, J = 7.1, 5.7 Hz, 1H), 5.90 (dd, J = 7.1, 5.7 Hz, 1H), 4.02(tt,J = 6.9, 5.7 Hz, 1H), 2.98 - 2.85 (m, 2H).

[0178] Example 27: Preparation of R-2-amino-3-phenylpropionic acid methyl ester and R-2-amino-3-phenylpropionic acid

[0179] Using the complex of formula IVpr prepared in Examples 1 to 18 or Example 21 as a catalyst, 2-acetylamino-3-phenylacrylate methyl is hydrogenated in an autoclave to obtain R-2-amino-3-phenylpropionic acid methyl ester, and then the methyl ester compound is hydrolyzed to obtain R-2-amino-3-phenylpropionic acid. The schematic reaction process is shown below:

[0180] .

[0181] Preparation method:

[0182] (a) providing a catalyst of formula IVpr;

[0183] (b) 100 mmol of 2-acetylamino-3-phenyl methyl acrylate and 0.75 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 15 kg / cm 2 , stirring at room temperature for 25 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0184] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product R-2-amino-3-phenylpropionic acid methyl ester with a molar conversion of 95.6% and an optical purity of 97.7% ee;

[0185] (c2) The mixture of the other half of the material after the solvent was removed under reduced pressure and 10% potassium hydroxide aqueous solution (75 ml) was refluxed for 1 hour, and the clarified solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant, cooled to room temperature, filtered, and the filter cake was resuspended in 100 mL of cold water, vigorously stirred for several minutes, filtered, and the filter cake was dried under reduced pressure to obtain an off-white powder, which was R-2-amino-3-phenylpropionic acid, with an HPPC purity of 97.8% and mp of 191-192°C. 1H NMR (400MHz, D2O, KOH): δ3.13(dd,J1=8.0Hz, J2=3.0Hz, 1H), 3.17(dd, J1=8.0Hz, J2=3.0Hz, 1H), 4.01(t, J=4.0Hz,1H), 7.32(d, J=3.0Hz, 2H), 7.37(d, J=6.0Hz, 1H), 7.44(d, J=6.0Hz, 2H).

[0186] Example 28: Preparation of R-2-amino-3-p-chlorophenylpropionic acid methyl ester and R-2-amino-3-p-chlorophenylpropionic acid

[0187] Referring to the operation of Example 27, the basic reaction flow is as follows:

[0188] .

[0189] Preparation method:

[0190] (a) providing a catalyst of formula IVpr;

[0191] (b) 100 mmol of 2-acetylamino-3-chlorophenyl methyl acrylate and 1.25 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 25 kg / cm 2 , stirring at room temperature for 15 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0192] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product R-2-amino-3-chlorophenylpropionic acid methyl ester with a molar conversion of 95.1% and an optical purity of 98.2% ee;

[0193] (c2) After the solvent was removed under reduced pressure, a mixture of the other half of the material and 10% potassium hydroxide aqueous solution (100 ml) was refluxed for 1 hour, and the clarified solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant, cooled to room temperature, filtered, and the filter cake was resuspended in 100 mL of cold water, vigorously stirred for several minutes, filtered, and the filter cake was dried under reduced pressure to obtain an off-white powder, which was R-2-amino-3-p-chlorophenylpropionic acid, with an HPPC purity of 98.3% and mp of 183-184°C. 1H NMR (400MHz, D2O, KOH): δ3.14(dd, J1=7.0Hz, J2=2.0Hz, 1H), 3.17(dd, J1=7.0Hz, J2=3.0Hz, 1H), 3.97(t,J=4.0Hz, 1H), 7.3(d, J=4.0Hz, 2H), 7.39(d, J=6.0Hz, 2H).

[0194] Example 29: Preparation of R-2-amino-3-(p-trifluoromethyl)phenylpropionic acid methyl ester and R-2-amino-3-(p-trifluoromethyl)phenylpropionic acid methyl ester Phenylpropionic acid

[0195] Referring to the operation of Example 27, the basic reaction flow is as follows:

[0196] .

[0197] Preparation method:

[0198] (a) providing a catalyst of formula IVpr;

[0199] (b) 100 mmol of 2-acetylamino-3-(p-trifluoromethyl)phenyl methyl acrylate and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 18 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0200] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product R-2-amino-3-(p-trifluoromethyl)phenylpropionic acid methyl ester with a molar conversion of 95.8% and an optical purity of 98.0% ee;

[0201] (c2) After the solvent was removed under reduced pressure, a mixture of another half of the material and 10% potassium hydroxide aqueous solution (80 ml) was refluxed for 1 hour. The clarified solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant. The mixture was cooled to room temperature and filtered. The filter cake was resuspended in 80 mL of cold water, stirred vigorously for several minutes, filtered, and the filter cake was dried under reduced pressure to obtain an off-white powder, which was R-2-amino-3-(p-trifluoromethyl)phenylpropionic acid. The HPPC purity was 98.1%, and the mp was 204-206°C. 1H NMR (400MHz, D2O, KOH): δ3.14(dd, J1=8.0Hz, J2=3.0Hz, 1H), 3.18(dd, dd, J1=8.0Hz, J2=3.0Hz, 1H), 3.98(t, J=4.0Hz, 1H), 7.34(d, J=3.0Hz, 2H), 7.42(d, J=6.0Hz, 2H).

[0202] Example 30: Preparation of R-2-amino-3-(p-trifluoromethyl)phenylpropionic acid methyl ester and R-2-amino-3-(p-trifluoromethyl)phenylpropionic acid methyl ester Phenylpropionic acid

[0203] Referring to the operation of Example 27, the basic reaction flow is as follows:

[0204] .

[0205] Preparation method:

[0206] (a) providing a catalyst of formula IVpr;

[0207] (b) 100 mmol of 2-acetylamino-3-p-acetylphenyl methyl acrylate and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 18 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0208] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product R-2-amino-3-acetylmethylphenylpropionic acid methyl ester with a molar conversion of 96.9% and an optical purity of 98.3% ee;

[0209] (c2) After the solvent was removed under reduced pressure, a mixture of another half of the material and 10% potassium hydroxide aqueous solution (80 ml) was refluxed for 1 hour, and the clarified solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant, cooled to room temperature, filtered, and the filter cake was resuspended in 80 mL of cold water, vigorously stirred for several minutes, filtered, and the filter cake was dried under reduced pressure to obtain an off-white powder, which was R-2-amino-3-acetylmethylphenylpropionic acid, with an HPPC purity of 97.4% and mp of 178-180°C. 1H NMR (400MHz, D2O, KOH): δ2.51(s, 3H), 3.11(dd, J1=8.0Hz, J2=2.0Hz, 1H), 3.20(dd, dd, J1=8.0Hz, J2=2.0Hz, 1H), 3.95(t, J=4.0Hz, 1H), 7.32(d, J=3.0Hz, 2H), 7.44(d, J=6.0Hz, 2H).

[0210] Example 31: Preparation of R-2-amino-3-m-cyanophenylpropionic acid methyl ester and R-2-amino-3-m-cyanophenylpropionic acid

[0211] Referring to the operation of Example 27, the basic reaction flow is as follows:

[0212] .

[0213] Preparation method:

[0214] (a) providing a catalyst of formula IVpr;

[0215] (b) 100 mmol of 2-acetylamino-3-cyanophenyl methyl acrylate and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 18 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0216] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product R-2-amino-3-m-cyanophenylpropionic acid methyl ester with a molar conversion of 98.2% and an optical purity of 98.5% ee;

[0217] (c2) After the solvent was removed under reduced pressure, a mixture of another half of the material and 10% potassium hydroxide aqueous solution (80 ml) was refluxed for 1 hour. The clarified solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant. The mixture was cooled to room temperature and filtered. The filter cake was resuspended in 80 mL of cold water and vigorously stirred for several minutes. The filter cake was filtered and dried under reduced pressure to obtain an off-white powder, which was R-2-amino-3-cyanophenylpropionic acid. The HPPC purity was 98.2% and the mp was 173-174°C. 1H NMR (400MHz, D2O, KOH): δ3.14(dd, J1=7.0Hz, J2=2.0Hz, 1H), 3.20(dd, J1=7.0Hz, J2=3.0Hz, 1H), 3.97(t, J=4.0Hz, 1H), 7.32(d, J=4.0Hz, 2H), 7.38(d, J=6.0Hz, 1H), 7.40(d, J=4.0Hz, 1H).

[0218] Example 32: Preparation of R-2-amino-3-p-fluorophenylpropionic acid methyl ester and R-2-amino-3-p-fluorophenylpropionic acid

[0219] Referring to the operation of Example 27, the basic reaction flow is as follows:

[0220] .

[0221] Preparation method:

[0222] (a) providing a catalyst of formula IVbr;

[0223] (b) 100 mmol of 2-acetylamino-3-(p-fluorophenyl) methyl acrylate and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 18 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0224] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product R-2-amino-3-p-fluorophenylpropionic acid methyl ester with a molar conversion of 96.9% and an optical purity of 98.0% ee;

[0225] (c2) After the solvent was removed under reduced pressure, a mixture of another half of the material and 10% potassium hydroxide aqueous solution (80 ml) was refluxed for 1 hour. The clarified solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant. The mixture was cooled to room temperature and filtered. The filter cake was resuspended in 80 mL of cold water and vigorously stirred for several minutes. The filter cake was filtered and dried under reduced pressure to obtain an off-white powder, which was R-2-amino-3-p-fluorophenylpropionic acid. The HPPC purity was 98.4%, and the mp was 186-187°C. 1H NMR (400MHz, D2O, KOH): δ3.13(dd, J1=6.0Hz, J2=2.0Hz, 1H), 3.16(dd, J1=6.1Hz, J2=3.0Hz, 1H), 3.98(t, J=4.0Hz, 1H), 7.33(d, J=4.0Hz, 2H), 7.38(d, J=6.0Hz, 2H).

[0226] Example 33: Preparation of R-2-amino-3-o-bromophenylpropionic acid methyl ester and R-2-amino-3-o-bromophenylpropionic acid

[0227] Referring to the operation of Example 27, the basic reaction flow is as follows:

[0228] .

[0229] Preparation method:

[0230] (a) providing a catalyst of formula IVbr;

[0231] (b) 100 mmol of 2-acetylamino-3-bromophenyl methyl acrylate and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 18 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0232] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product R-2-amino-3-o-bromophenylpropionic acid methyl ester with a molar conversion of 95.7% and an optical purity of 98.4% ee;

[0233] (c2) After the solvent was removed under reduced pressure, a mixture of another half of the material and 10% potassium hydroxide aqueous solution (80 ml) was refluxed for 1 hour. The clarified solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant. The mixture was cooled to room temperature and filtered. The filter cake was resuspended in 80 mL of cold water and vigorously stirred for several minutes. The filter cake was filtered and dried under reduced pressure to obtain an off-white powder, which was R-2-amino-3-o-bromophenylpropionic acid. The HPPC purity was 98.2%, and the mp was 193-195°C. 1H NMR (400MHz, D2O, KOH): δ3.15(dd, J1=6.0Hz, J2=2.0Hz, 1H), 3.17(dd, J1=6.0Hz, J2=3.0Hz, 1H), 3.98(t, J=4.0Hz, 1H), 7.30(d, J=4.0Hz, 2H), 7.38(d, J=6.0Hz, 1H), 7.42(t, J=4.0Hz, 1H).

[0234] Example 34: Preparation of R-2-amino-3-naphthylpropionic acid methyl ester and R-2-amino-3-naphthylpropionic acid

[0235] Referring to the operation of Example 27, the basic reaction flow is as follows:

[0236] .

[0237] Preparation method:

[0238] (a) providing a catalyst of formula IVbr;

[0239] (b) 100 mmol of 2-acetylamino-3-naphthyl methyl acrylate and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 18 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0240] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product R-2-amino-3-naphthylpropionic acid methyl ester with a molar conversion of 95.4% and an optical purity of 97.6% ee;

[0241] (c2) The mixture of the other half of the material after the solvent was removed under reduced pressure and 10% potassium hydroxide aqueous solution (80 ml) was refluxed for 1 hour, and the clarified solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant, cooled to room temperature, filtered, and the filter cake was resuspended in 80 mL of cold water, vigorously stirred for several minutes, filtered, and the filter cake was dried under reduced pressure to obtain an off-white powder, which was R-2-amino-3-naphthylpropionic acid, with an HPPC purity of 98.3% and mp of 206-208°C. 1H NMR (400MHz, D2O, KOH): δ3.13(dd,J1=6.0Hz, J2=2.0Hz, 1H), 3.17(dd, J1=6.0Hz, J2=3.0Hz, 1H), 3.98(t, J=4.0Hz,1H), 7.32(d, J=4.0Hz, 2H), 7.39(d, J=6.0Hz, 1H), 7.42(t, J=4.0Hz, 1H), 7.55(t, J=5.0Hz, 2H), 7.63(dd, J1=5.5Hz, J2=2.5Hz, 1H).

[0242] Example 35: Preparation of R-2-amino-3-p-phenylphenylpropionic acid methyl ester and R-2-amino-3-p-phenylphenylpropionic acid

[0243] Referring to the operation of Example 27, the basic reaction flow is as follows:

[0244] .

[0245] Preparation method:

[0246] (a) providing a catalyst of formula IVbr;

[0247] (b) 100 mmol of 2-acetylamino-3-p-phenylphenyl methyl acrylate and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 18 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0248] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product R-2-amino-3-p-phenylphenylpropionic acid methyl ester with a molar conversion of 95.9% and an optical purity of 98.3% ee;

[0249] (c2) After the solvent was removed under reduced pressure, a mixture of another half of the material and 10% potassium hydroxide aqueous solution (80 ml) was refluxed for 1 hour. The clarified solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant. The mixture was cooled to room temperature and filtered. The filter cake was resuspended in 80 mL of cold water, stirred vigorously for several minutes, filtered, and the filter cake was dried under reduced pressure to obtain an off-white powder, which was R-2-amino-3-p-phenylphenylpropionic acid. The HPPC purity was 97.5%, and the mp was 203-204°C. 1H NMR (400MHz, D2O, KOH): δ3.13(dd, J1=6.0Hz, J2=2.0Hz, 1H), 3.19(dd, J1=6.0Hz, J2=3.0Hz, 1H), 3.98(t, J=4.0Hz, 1H), 7.31(d, J=4.0Hz, 4H), 7.38(d, J=6.0Hz, 4H), 7.42(t, J=4.0Hz, 1H).

[0250] Example 36: Preparation of R-2-amino-3-m-methoxycarbonylphenylpropionic acid methyl ester and R-2-amino-3-m-methoxycarbonyl Phenylpropionic acid

[0251] Referring to the operation of Example 27, the basic reaction flow is as follows:

[0252] .

[0253] Preparation method:

[0254] (a) providing a catalyst of formula IVbr;

[0255] (b) 100 mmol of 2-acetylamino-3-methoxycarbonylphenyl methyl acrylate and 1 mmol of catalyst were placed in an autoclave, 250 mL of methanol and 25 mL of n-butanol were added, and the mixture was heated to 40 ℃ under a hydrogen pressure of 20 kg / cm 2 , stirring at room temperature for 18 h, removing the solvent under reduced pressure, dissolving the solid residue in 1N NaOH solution, and removing the insoluble matter by silica gel column chromatography;

[0256] (c1) The solution obtained by chromatography was acidified with concentrated hydrochloric acid, extracted twice with diethyl ether (45 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Half of the material was dried under vacuum at 45° C. to obtain the product R-2-amino-3-m-methoxycarbonylphenylpropionic acid methyl ester with a molar conversion of 95.4% and an optical purity of 98.7% ee;

[0257] (c2) After the solvent was removed under reduced pressure, a mixture of another half of the material and 10% potassium hydroxide aqueous solution (80 ml) was refluxed for 1 hour. The clarified solution was acidified with a slightly excess of concentrated hydrochloric acid while hot to precipitate the reactant. The mixture was cooled to room temperature and filtered. The filter cake was resuspended in 80 mL of cold water and vigorously stirred for several minutes. The filter cake was filtered and dried under reduced pressure to obtain an off-white powder, which was R-2-amino-3-m-methoxycarbonylphenylpropionic acid. The HPPC purity was 98.2%, and the mp was 187-189°C. 1H NMR (400MHz, D2O, KOH): 3.13(dd, J1=6.0Hz, J2=2.0Hz, 1H), 3.18(dd, J1=6.0Hz, J2=3.0Hz, 1H), 3.83(s,3H), 3.98(t, J=4.0Hz, 1H), 7.32(d, J=4.0Hz, 2H), 7.39(d, J=6.0Hz, 1H), 7.40(d, J=5.0Hz, 1H).

[0258] When a mixed solvent of methanol / n-butanol in a volume ratio of 10:1 is used in the hydrogenation reaction of Examples 24 to 36 above, the molar yield of the product obtained in step (c) or (c1) is greater than 95%, and the optical purity is greater than 97%.

[0259] In addition, in some supplementary experiments, referring to the methods of Examples 24 to 36 above, except that when the n-butanol used in step (b) was replaced by an equal volume of methanol, the molar yield was only 77% to 81%, and the optical purity was only 87% to 89%. For example, referring to the method of Example 36 but replacing the n-butanol by an equal volume of methanol, the molar yield was only 79.7%, and the optical purity was only 88.4%.

[0260] In addition, in some supplementary tests, referring to the methods of Examples 24 to 36 above, except that the n-butanol used in step (b) was replaced by an equal volume of methanol and the catalyst was changed to 3 mmol, the molar yield was 88% to 90%, and the optical purity was 91% to 93%. For example, referring to the method of Example 36, but the n-butanol was replaced by an equal volume of methanol and the catalyst was changed to 3 mmol, the molar yield was 89.2%, and the optical purity was 91.7%. In addition, in some supplementary tests, referring to the methods of Examples 24 to 36 above, except that the n-butanol used in step (b) was replaced by an equal volume of methanol and the catalyst was changed to 6 mmol, the molar yield was 94% to 96%, and the optical purity was 95% to 97%. For example, referring to the method of Example 36, but the n-butanol was replaced by an equal volume of methanol and the catalyst was changed to 6 mmol, the molar yield was 95.8%, and the optical purity was 96.6%. In addition, in some supplementary tests, referring to the methods of Examples 24 to 36 above, the difference is that when the catalyst used in step (b) is changed to 0.2 mmol, the molar yield is 93% to 95%, and the optical purity is 94% to 98%. For example, referring to the method of Example 36 but changing the catalyst to 0.2 mmol, the molar yield is 94.6%, and the optical purity is 97.1%. In addition, in some supplementary tests, referring to the methods of Examples 24 to 36 above, the difference is that when the catalyst used in step (b) is changed to 0.5 mmol, the molar yield is 94% to 98%, and the optical purity is 96% to 98%. For example, referring to the method of Example 36 but changing the catalyst to 0.5 mmol, the molar yield is 96.2%, and the optical purity is 97.4%. In addition, in some supplementary experiments, referring to the methods of Examples 24 to 36 above, except that when the catalyst used in step (b) was changed to 1.5 mmol, the molar yield was 95% to 98%, and the optical purity was 96% to 98%. For example, referring to the method of Example 36 but changing the catalyst to 1.5 mmol, the molar yield was 97.4% and the optical purity was 97.8%.

[0261] The above-mentioned supplementary test results show that when the catalyst of the present invention is used for hydrogenation reaction, when a relatively small amount of catalyst of 0.2 mmol to 1.5 mmol is used, a product with high molar yield and high optical purity can be obtained when a methanol / n-butanol mixed solvent is used, but when n-butanol is not used, the molar yield and optical purity of the hydrogenated product are significantly lower. Only when the catalyst is increased to 6 mmol can the effect of using a mixed solvent be basically achieved. Since the cost of n-butanol is significantly lower, the use of a mixed solvent has a considerable cost advantage.

[0262] In step (b) of Examples 24 to 36, 100 mmol of the starting acrylic acid compound is added, and the amount of the catalyst is feasible in the range of 0.2 mmol to 1.5 mmol; the amount of methanol is feasible in the range of 200 to 300 mL, and the amount of n-butanol is 1 / 10 of the amount of methanol; the hydrogen pressure of the hydrogenation reaction is 15 kg / cm 2 ~25kg / cm 2 The hydrogenation reaction can be carried out at room temperature, and the hydrogenation reaction time is feasible within the range of 10 to 30 hours, for example, 15 to 25 hours; the concentration of NaOH solution is feasible within the range of 0.5 to 2N, and the amount can be added according to the general experience of those skilled in the art, usually in an amount 2 to 3 times the solubility.

[0263] The operations in step (c) and step (c1) and step (c2) of Examples 24 to 36 are all conventional operations in the art. For example, when the solution obtained by chromatography is acidified with concentrated hydrochloric acid, the material can be acidified to neutrality. The amount of ether used for extraction and the number of extractions can be adjusted according to the general experience of those skilled in the art. It is usually preferred to select a lower temperature for vacuum drying. The hydrolysis of the ester in step (c2) is also a conventional hydrolysis method in the art. These hydrolysis operations can usually easily achieve a complete reaction. It is well known that the compounds of the present invention are hydrolyzed by adding alkali as an example above. In fact, they can also be hydrolyzed by using acid. These ester hydrolysis operations are easy to achieve by those skilled in the art.

[0264] The present invention is described in detail through the above examples, but the present invention is not limited to the above aspects, that is, it does not mean that the present invention must rely on the above details to be implemented.

Claims

1. A method for preparing the compound of the following formula Y: in, Ra represents hydrogen or 1 to 4 groups selected from the following: F, Cl, Br, acetyl, CN, phenyl, naphthyl forming a bicyclic ring together with the benzene ring, hydroxyl, sulfoxide, trifluoromethyl, methoxycarbonyl, Rb represents hydrogen or methyl; The method comprises the following steps: (a) providing a complex of the following formula IV as a catalyst: wherein X is boron and n is 4 or X is phosphorus and n is 6; (b) 100 mmol of the following compound of formula V: and 0.2 mmol to 1.5 mmol of the complex catalyst of formula IV are placed in an autoclave, 200 to 300 mL of methanol and 1 / 10 of the amount of n-butanol used for methanol are added, and the mixture is heated at 10 to 25 kg / cm 2 The mixture is stirred under hydrogen pressure for hydrogenation reaction for 10 to 30 hours, the solvent is removed under reduced pressure, the solid residue is dissolved in NaOH solution, and the insoluble matter is removed by silica gel column chromatography; (c) acidifying the solution obtained by chromatography with concentrated hydrochloric acid, extracting with ether for 1 to 5 times, drying with inorganic salt, removing the solvent under reduced pressure, and drying to obtain the ester form of the compound of formula Y in which Rb is methyl; hydrolyzing the ester form of the compound of formula Y with Rb being methyl by adding acid or base to obtain the acid form of the compound of formula Y in which Rb is H; in, The complex shown in formula IV has one of the following structures: The complex shown in formula IV is provided according to a method comprising the steps of: (i) under nitrogen protection, adding the compound of formula I, i.e. 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, the compound of formula II, i.e. (1,5-cyclooctadiene)chlororhodium (I) dimer, and alkanoic acid to the organic solvent of dichloromethane in sequence, and stirring for 10 to 30 minutes to make them uniform; the amount of the organic solvent used is 20 to 50 mL per 1 mmol of the compound of formula II; the alkanoic acid is selected from hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, adipic acid, and azelaic acid; the molar ratio of the compound of formula I to the compound of formula II is 2.5 to 5:1, and the molar ratio of the alkanoic acid to the compound of formula II is 0.1 to 0.6:1; (ii) adding a compound of formula III represented by the chemical formula MXFn, i.e., a fluoride salt, to the mixture obtained in step (i), and continuing stirring under nitrogen protection to allow the reaction to proceed to completion; the compound of formula III represented by the chemical formula MXFn is KPF6 or potassium tetrafluoroborate, and M is K + , X is boron and n is 4 or X is phosphorus and n is 6, the compound of formula III is pre-dissolved in water; the molar ratio of the compound of formula III to the compound of formula II is 4 to 8:1; (iii) washing with water, distilling off the solvent under reduced pressure, adding anhydrous ethanol, leaving the mixture in a cold place to allow precipitation, and drying the collected precipitate to obtain a complex.

2. The method according to claim 1, wherein in step (c), the inorganic salt is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, anhydrous calcium chloride or a combination thereof.

3. The method according to claim 1, wherein in step (c), vacuum drying is performed at 40-50°C.

4. The method according to claim 1, wherein in step (c), the hydrolysis is carried out as follows: a mixture of a compound of formula Y in the form of an ester in which Rb is methyl and a 5% to 20% aqueous potassium hydroxide solution is refluxed, the resulting clear solution is acidified with excess concentrated hydrochloric acid while hot to precipitate the reactant, cooled to room temperature, filtered, the filter cake is resuspended in cold water, stirred, filtered, and dried to obtain a compound of formula Y in the acid form in which Rb is H.

5. The method according to claim 1, wherein the compound of formula Y is selected from:

6. The method according to claim 1, wherein in step (ii), 10 to 30 mL of water is used to dissolve every 6 mmol of the compound of formula III.

7. According to the method of claim 1, in step (ii), the material is stirred for 10 to 30 minutes under nitrogen protection.

8. The method according to claim 1, wherein in step (iii), washing is performed with water for 1 to 5 times.

9. The method according to claim 1, wherein in step (iii), the amount of anhydrous ethanol added is 50-100 mL per 1 mmol of the compound of formula II.

10. The method according to claim 1, wherein in step (iii), the material is allowed to stand at -10 to 0°C for 5 to 15 hours.

11. The method according to claim 1, wherein the complex of formula IV is prepared by a method comprising the steps of: (i) under nitrogen protection, 3 mmol of the compound of formula I, i.e., 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 1 mmol of the compound of formula II, i.e., (1,5-cyclooctadiene)chlororhodium (I) dimer, and 0.2 mmol of alkanoic acid were added to 30 mL of dichloromethane in a round-bottom flask in sequence, and stirred for 15 min; (ii) adding 6 mmol of the compound of formula III, namely potassium hexafluorophosphate or potassium tetrafluoroborate, which was pre-dissolved in 15 mL of water, to the mixture obtained in step (i), and continuing stirring for 45 min under nitrogen protection; (iii) Wash with water three times, evaporate the solvent under reduced pressure, add 80 mL of anhydrous ethanol, incubate at -5°C for 8 h, centrifuge, discard the supernatant, harvest the precipitate, and dry to obtain a complex of formula IV.

Images