Novel synthesis method of L (-)-threo-3-hydroxyaspartic acid hydrochloride

Abstract

The invention relates to the technical field of medical and chemical medicines, in particular to a novel synthesis method of L (-)-threo-3-hydroxyaspartic acid hydrochloride. The preparation method comprises the following steps: by taking cheap and easily available D-phenylglycinol as an initial raw material, firstly protecting amino with Boc anhydride, then oxidizing to obtain N-BOC-D-phenylalanine aldehyde 3, then carrying out Grignard reaction on the N-BOC-D-phenylalanine aldehyde 3 and vinyl magnesium bromide at low temperature to obtain corresponding o-amino alcohol, then reacting the o-amino alcohol with 2, 2-dimethoxypropane at 0 DEG C under the catalytic action of p-toluenesulfonic acid, and finally obtaining the 2, 2-dimethoxypropane. The obtained compound 4 is subjected to Upjohn dihydroxylation reaction and sodium periodate oxidation to obtain corresponding aldehyde, and then the aldehyde is oxidized by potassium permanganate under a weak acidic condition to obtain corresponding carboxylic acid 5. Oxidizing a benzene ring by taking ruthenium trichloride as a catalyst and sodium periodate as a co-oxidant to obtain dicarboxylic acid; and finally, refluxing and deprotecting by using hydrochloric acid to obtain the L (-)-chloro-3-hydroxyaspartic acid hydrochloride.

Description

Technical Field

[0001] This invention relates to the field of medical chemical pharmaceutical technology, and in particular to a novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride. Background Technology

[0002] L(-)-threo-3-hydroxyaspartic acid (1) is a highly effective EAAT inhibitor, with Ki values ​​of 11, 19, and 14 μM for EAAT1, EAAT2, and EAAT3 in HEK293 cells, respectively. Furthermore, it is a common key raw material compound for the synthesis of natural product molecules such as L-TFB-TBOA and Rakicidin A.

[0003] L-TFB-TBOA is a potent glutamate transporter blocker that effectively inhibits the activity of glial transporters; its IC50 values ​​against glutamate transporters EAAT1, EAAT2, and EAAT3 are 22, 17, and 300 nM, respectively. Rakicidin A belongs to a class of lipopeptide natural products produced by marine bacteria. It possesses the potential to fight cancer stem cells and exhibits stronger killing activity against solid tumor cells in hypoxic-reducing environments. Its biological activity is also stronger than that of typical anti-cancer stem cell compounds, making it highly suitable for drug development as a treatment for solid tumors.

[0004]

[0005] According to the methods for preparing compound (1) reported in the current literature, although these methods have their own characteristics, they also have many shortcomings: such as expensive chiral catalysts, poor stereoselectivity, inconvenient experimental operation, harsh reaction conditions, and long routes leading to low overall yield.

[0006] An ideal synthetic route should meet green chemistry standards, such as utilizing renewable resources, being recyclable, using reagents with low toxicity, and causing minimal environmental pollution after the reaction is treated. Other requirements include high overall yield, excellent stereoselectivity, low cost, simple and convenient separation and purification, and suitability for large-scale preparation. Therefore, how to efficiently use inexpensive and readily available raw materials to prepare compounds (1) is a problem that urgently needs to be solved. Summary of the Invention

[0007] Based on the above, this invention provides a novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride, overcoming the defects of existing technologies in preparing compound (1); this invention uses inexpensive and readily available starting materials, thereby improving the yield of L(-)-threo-3-hydroxyaspartic acid hydrochloride.

[0008] To achieve the above objectives, the present invention provides the following solution:

[0009] This invention provides a novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride, comprising the following steps:

[0010] Step 1: Dissolve D-phenylglycine in anhydrous dichloromethane, add triethylamine and Boc anhydride to react and obtain Boc-D-phenylglycine;

[0011] The Boc-D-phenylglycine was dissolved in ethyl acetate, and IBX (2-iodobenzoic acid) was added. The mixture was heated under reflux to give compound 3.

[0012] Step 2: Dissolve compound 3 in anhydrous dichloromethane, cool to 0°C in an ice-water bath, add vinyl magnesium bromide to react, and obtain o-amino alcohol;

[0013] The o-amino alcohol was dissolved in anhydrous dichloromethane, cooled to 0°C in an ice-water bath, and then p-toluenesulfonic acid and 2,2-dimethoxypropane were added to react, giving compound 4 (trans-oxazolidine compound) stereospecifically.

[0014] Step 3: Dissolve compound 4 in mixed solvent 1, add potassium osmium tetroxide dihydrate and N-methylmorpholine-N-oxide, stir at room temperature until the raw material disappears (24h-30h), then add sodium periodate and water to react and obtain intermediate aldehyde;

[0015] The intermediate aldehyde was dissolved in mixed solvent 2, and an aqueous solution of potassium permanganate was added and reacted (0.5h to 1h) to obtain compound 5;

[0016] Step 4: Dissolve compound 5 in mixed solvent 3, add sodium bicarbonate, sodium periodate and ruthenium trichloride in sequence, heat and reflux and stir to react, and obtain intermediate dicarboxylic acid;

[0017] The intermediate dicarboxylic acid was suspended in hydrochloric acid and heated under reflux to give compound 6.

[0018] Compound 6 is L(-)-threo-3-hydroxyaspartic acid hydrochloride, with the structural formula [structure omitted].

[0019] Compound 3 is N-BOC-D-phenylalanine, with the structural formula [structure omitted].

[0020] The structural formula of compound 4 is as follows:

[0021] The structural formula of compound 5 is as follows:

[0022] In a preferred embodiment of the present invention, in step 1, the molar ratio of D-phenylglycine:triethylamine:Boc anhydride:IBX is 1.0:(1.5-2.0):(1.0-1.05):(2.0-4.0).

[0023] In a preferred embodiment of the present invention, in step 1, when preparing Boc-D-phenylglycine, the reaction is specifically carried out at room temperature for 8 to 12 hours; when preparing compound 3, the heating and reflux reaction time is 3 to 5 hours.

[0024] In step 1, when preparing Boc-D-phenylglycine, after the reaction is completed, the process further includes dilution with dichloromethane, washing the organic phase sequentially with 1M potassium hydrogen sulfate aqueous solution, washing with saturated brine, separating the liquid, drying the organic phase with anhydrous sodium sulfate, and concentrating and vacuum drying the filtrate obtained by filtration.

[0025] In step 1, when preparing compound 3, after the heating and reflux reaction is completed, the process also includes cooling to room temperature, direct filtration, washing the filter residue twice with ethyl acetate, concentrating the filtrate under reduced pressure, and then vacuum drying.

[0026] In a preferred embodiment of the present invention, in step 2, the molar ratio of compound 3: vinyl magnesium bromide: p-toluenesulfonic acid: 2,2-dimethoxypropane is 1:(2.0-3.0):(0.05-0.1):(3.0-5.0).

[0027] In a preferred embodiment of the present invention, in step 2, when preparing the o-amino alcohol, the reaction is specifically carried out at 0°C for 15 min to 30 min; when preparing compound 4, the reaction is specifically carried out at 0°C for 20 min to 40 min.

[0028] In step 2, when preparing o-amino alcohol, after the reaction is completed, the process also includes quenching with saturated ammonium chloride aqueous solution, concentrating under reduced pressure to remove dichloromethane, diluting with water and then extracting with ethyl acetate, combining the organic phases and washing with saturated brine, separating the liquids, drying the organic phase with anhydrous sodium sulfate, and concentrating the filtrate under reduced pressure.

[0029] In step 2, when preparing compound 4, after the reaction is completed, the reaction is further quenched with excess triethylamine at 0 degrees, then concentrated under reduced pressure, and subjected to rapid column chromatography using petroleum ether:ethyl acetate volume ratio of 20:1 as eluent.

[0030] In a preferred embodiment of the present invention, in step 3, the molar ratio of compound 4: potassium osmium dihydrate: N-methylmorpholine-N-oxide: sodium periodate: potassium permanganate is 1:0.01-0.02:3.0-5.0:1.5-3.0:6.01-0.0.

[0031] In a preferred embodiment of the present invention, in step 3, when preparing intermediate aldehyde and compound 5, the reactions are all carried out at room temperature; the mixed solvent 1 is a mixed solvent of acetone and water; the mixed solvent 2 is a mixed solvent of tert-butanol and 5% sodium dihydrogen phosphate aqueous solution.

[0032] In step 3, when preparing the intermediate aldehyde, after the reaction with sodium periodate and water is completed, the process also includes quenching with a saturated sodium sulfite aqueous solution, concentrating under reduced pressure to remove acetone, acidifying with dilute hydrochloric acid to pH=3, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, separating the liquids, drying the organic phase with anhydrous sodium sulfate, and concentrating the filtrate under reduced pressure.

[0033] In step 3, when preparing compound 5, after the reaction is complete, the reaction is quenched with a saturated sodium sulfite aqueous solution, then acidified with dilute hydrochloric acid to pH=3, extracted with ethyl acetate, the organic phases are combined and washed with saturated brine, separated, the organic phases are dried with anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure.

[0034] In a preferred embodiment of the present invention, in step 4, the molar ratio of compound 5: sodium bicarbonate: sodium periodate: ruthenium trichloride is 1:(10.0-15.0):(15.0-25.0):(0.05-0.1).

[0035] In a preferred embodiment of the present invention, in step 4, when preparing the intermediate dicarboxylic acid, the heating and reflux stirring reaction time is 2h to 5h; when preparing compound 6, the heating and reflux reaction time is 2h to 3h; the mixed solvent 3 is a mixed solvent of carbon tetrachloride, acetonitrile and water.

[0036] In step 4, when preparing the intermediate dicarboxylic acid, after the reaction is heated and stirred under reflux, the process also includes quenching with a saturated sodium sulfite aqueous solution, concentrating under reduced pressure to remove the organic solvents carbon tetrachloride and acetonitrile, then acidifying with dilute hydrochloric acid to pH=3, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, separating the liquids, drying the organic phases with anhydrous sodium sulfate, and concentrating the filtrate under reduced pressure.

[0037] In step 4, when preparing compound 6, after the heating and reflux reaction is completed, the process also includes cooling to room temperature, then diluting with water, washing twice with ethyl acetate to remove organic impurities, concentrating the aqueous phase under reduced pressure, and drying under vacuum.

[0038] The present invention discloses the following technical effects:

[0039] 1) This invention uses inexpensive and readily available D-phenylglycine (2) as the starting material, and the target product L(-)-threo-3-hydroxyaspartic acid hydrochloride is finally obtained through four major steps (eight steps) of conversion. The synthesis method has mild reaction conditions, is green and environmentally friendly, has very good stereoselectivity, and has a high overall yield.

[0040] 2) The raw materials and reagents used in the method of this invention are inexpensive and readily available, resulting in low cost. The post-processing is simple, and the separation and purification are simple and convenient, creating favorable conditions for the industrial-scale production and commercialization of the product.

[0041] 3) The raw materials and auxiliary materials used in the method of this invention are non-toxic, the production process is pollution-free, and it is environmentally friendly. Detailed Implementation

[0042] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0043] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0044] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0045] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0046] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0047] Unless otherwise specified, "room temperature" in this invention refers to 20-35°C.

[0048] This invention discloses a novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride. Starting with readily available and inexpensive D-phenylglycine, the amino group is first protected with Boc anhydride and then oxidized to obtain N-BOC-D-phenylalanine 3. This N-phenylalanine then undergoes a Grignard reaction with vinyl magnesium bromide at low temperature to yield the corresponding o-amino alcohol. Subsequently, it reacts with 2,2-dimethoxypropane at 0°C under p-toluenesulfonic acid catalysis, resulting in stereospecific cyclization to give the trans-oxazolidine compound 4. Compound 4 is then subjected to Upjohn dihydroxylation and oxidation with sodium periodate to obtain the corresponding aldehyde. The aldehyde is then oxidized with potassium permanganate under weakly acidic conditions to give the corresponding carboxylic acid 5. Next, the benzene ring is oxidized using ruthenium trichloride as a catalyst and sodium periodate as a co-oxidant to obtain a dicarboxylic acid. Finally, the protection is removed by reflux with 6N hydrochloric acid to obtain L(-)-threo-3-hydroxyaspartic acid hydrochloride.

[0049] The synthetic route of this invention is convenient to operate, exhibits excellent stereoselectivity, mild reaction conditions, simple separation and purification, and high overall yield, allowing for scale-up preparation. The raw materials and reagents used are all non-toxic, the production process is pollution-free and environmentally friendly, creating favorable conditions for the industrial-scale production and commercialization of the product.

[0050] The method of this invention only requires one rapid silica gel column chromatography step during the preparation of compound 4, which is simple and convenient for separation and purification, creating favorable conditions for the industrial-scale production and commercialization of the product.

[0051] Unless otherwise specified, the technical solutions described in this invention are all conventional solutions in the field, and the reagents or raw materials used are all purchased from commercial channels or are publicly available unless otherwise specified.

[0052] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0053] The method for preparing L(-)-threo-3-hydroxyaspartic acid hydrochloride (compound 6) of this invention uses D-phenylglycine (2) as the starting material and undergoes four major steps (a total of eight steps) of conversion to finally obtain the target product. The reaction route is shown below:

[0054]

[0055] Example 1: Synthesis of Compound 3

[0056]

[0057] D-phenylglycine (3.0 g, 21.9 mmol) was dissolved in anhydrous dichloromethane (200 mL), cooled to 0 °C in an ice-water bath, and triethylamine (6.1 mL, 43.8 mmol) was added dropwise. After stirring until homogeneous, Boc anhydride (5.1 mL, 21.9 mmol) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 10 h. Then, the mixture was diluted with dichloromethane (500 mL). The organic phase was washed successively with 1 M potassium hydrogen sulfate aqueous solution (200 mL) and saturated brine (200 mL). The mixture was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and dried under vacuum to obtain Boc-D-phenylglycine. No further purification was required; the entire mixture was immediately used in the next reaction.

[0058] The above-mentioned Boc-D-phenylglycine was dissolved in ethyl acetate (250 mL), and IBX (18.4 g, 65.7 mmol) was added. The mixture was heated under reflux for 3 h, cooled to room temperature, and directly filtered. The residue was washed twice with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure and dried under vacuum to obtain N-BOC-D-phenylalanine 3. Compound 3 did not require further purification and was immediately used in the next reaction.

[0059] Example 2: Synthesis of Compound 4

[0060]

[0061] Compound 3 (21.9 mmol) was completely dissolved in anhydrous dichloromethane (300 mL), cooled to 0°C in an ice-water bath, and vinyl magnesium bromide (1.0 M solution in THF) (49 mL, 49 mmol) was added. After the addition, the reaction was continued at 0°C for 30 min, then quenched at 0°C with saturated ammonium chloride aqueous solution (300 mL). The mixture was concentrated under reduced pressure to remove the dichloromethane, diluted with water (200 mL), and extracted three times with ethyl acetate (300 mL). The combined organic phases were washed with saturated brine (200 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain the intermediate o-amino alcohol. No further purification was required; the entire amount was immediately used in the next reaction.

[0062] The above intermediate, o-amino alcohol, was dissolved in anhydrous dichloromethane (200 mL), cooled to 0°C in an ice-water bath, and p-toluenesulfonic acid (190 mg, 1.1 mmol) and 2,2-dimethoxypropane (8.1 mL, 65.7 mmol) were added. After the addition was complete, the reaction was stirred at 0°C for 30 min. After the reaction was complete, excess triethylamine (1 mL) was added at 0°C to quench the reaction, and then the mixture was concentrated under reduced pressure. Rapid column chromatography was performed using petroleum ether:ethyl acetate (v / v) at a ratio of 20:1 to obtain a colorless oily substance, i.e., 43.0 g of the compound. The overall yield of the four steps was 45% (starting from D-phenylglycine 2).

[0063] -47.0(c1.0,EtOAc); 1 H NMR(600MHz,CDCl3)(exists as rotamers) δ7.36–7.21(m,5H),5.89(ddd,J=17.1,10.1,7.1Hz,1H),5.22(dd,J=29.5,13 .8Hz,2H),4.37(s,1H),4.27(t,J=7.1Hz,1H),1.76(d,J=13.5Hz,6H),1.47–1.02(m,9H); 13 C NMR(151MHz,CDCl3)(exists as rotamers)δ151.83,140.11,133.78,128.30,127.25,126.36,119.26,94.59,83.72,79.5 8,77.21,77.00,76.79,67.29,27.87,26.34,25.66,25.62; HR-ESIMSm / z:calculatedfor C 18 H 25 NO3Na +

[0064] [M+Na] + :326.1727,found 326.1729.

[0065] Example 3: Synthesis of Compound 5

[0066]

[0067] Compound 4 (2.8 g, 9.23 mmol) was dissolved in a mixed solvent of acetone and water (acetone:water volume ratio 5:1, 180 mL). Potassium osmium tetroxide dihydrate (34 mg, 0.0923 mmol) and N-methylmorpholine-N-oxide (5.4 g, 46.0 mmol) were added, and the mixture was stirred at room temperature until the starting material disappeared (30 h). Then, water (80 mL) and sodium periodate (4.0 g, 18.5 mmol) were added, and the mixture was stirred vigorously at room temperature for 1 h. After the reaction was complete, the mixture was quenched with a saturated sodium sulfite aqueous solution (300 mL), concentrated under reduced pressure to remove acetone, diluted with water (200 mL), and acidified to pH 3 with dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate (300 mL), and the combined organic phases were washed with saturated brine (200 mL). The mixture was separated, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the intermediate aldehyde. No further purification was required; the entire filtrate was immediately used in the next reaction.

[0068] The above intermediate aldehyde was dissolved in a mixed solvent of tert-butanol and 5% sodium dihydrogen phosphate aqueous solution (tert-butanol:5% sodium dihydrogen phosphate aqueous solution volume ratio 3:2, 150 mL), and 56 mL (56 mmol) of 1M potassium permanganate aqueous solution was added. The mixture was stirred vigorously at room temperature for 0.5 h. After the reaction was complete, 300 mL of saturated sodium sulfite aqueous solution was added to quench the reaction, and then the solution was acidified to pH 3 with dilute hydrochloric acid. The mixture was extracted three times with 300 mL of ethyl acetate. The combined organic phases were washed with 200 mL of saturated brine, separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain intermediate acid 5. No further purification was required, and the entire mixture was used immediately in the next reaction.

[0069] Example 4: Synthesis of Compound 6

[0070]

[0071] The intermediate acid 5 (9.23 mmol) was completely dissolved in a mixed solvent of carbon tetrachloride, acetonitrile, and water (carbon tetrachloride:acetonitrile:water volume ratio 1:1:2, 300 mL). Sodium bicarbonate (11.6 g, 138.45 mmol), sodium periodate (39.5 g, 184.6 mmol), and ruthenium trichloride hydrate (120 mg, 0.47 mmol) were added sequentially. The mixture was then heated under reflux with stirring until the starting material disappeared (3 h). After the reaction was complete, it was cooled to room temperature and quenched with a saturated sodium sulfite aqueous solution (300 mL). The mixture was concentrated under reduced pressure to remove carbon tetrachloride and acetonitrile. The solution was then acidified to pH 3 with dilute hydrochloric acid and extracted three times with ethyl acetate (300 mL). The combined organic phases were washed with saturated brine (200 mL), separated, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain the corresponding intermediate dicarboxylic acid. No further purification was required; the entire amount was immediately used in the next reaction.

[0072] The aforementioned intermediate dicarboxylic acid was suspended in 6N hydrochloric acid (200 mL) and heated under reflux for 2 h. After the reaction was complete, it was cooled to room temperature, diluted with water (200 mL), and washed twice with ethyl acetate (300 mL) to remove organic impurities. The aqueous phase was concentrated under reduced pressure and dried under vacuum to give 61.2 g of L(-)-threo-3-hydroxyaspartic acid hydrochloride. The overall yield of the four steps was 70% (starting from compound 4). No further purification was required, and characterization was performed directly.

[0073] -7.0 (c 0.75, 5N HCl); 1 H NMR(600MHz,D2O)δ4.86(bs,1H),4.42(bs,1H); 13CNMR(151MHz,D2O)δ173.34,169.80,68.54,55.36; HR-ESIMSm / z:calculated for C4H8NO5 + [M+H] + (free amine):150.0402, found 150.0404.

[0074] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride, characterized in that, Includes the following steps: Step 1: Dissolve D-phenylglycine in anhydrous dichloromethane, add triethylamine and Boc anhydride to react and obtain Boc-D-phenylglycine; The Boc-D-phenylglycine was dissolved in ethyl acetate, IBX was added, and the mixture was heated under reflux to give compound 3. Step 2: Dissolve compound 3 in anhydrous dichloromethane, cool to 0°C in an ice-water bath, add vinyl magnesium bromide to react, and obtain o-amino alcohol; The o-amino alcohol was dissolved in anhydrous dichloromethane, cooled to 0°C in an ice-water bath, and then p-toluenesulfonic acid and 2,2-dimethoxypropane were added to react and give compound 4. Step 3: Dissolve compound 4 in mixed solvent 1, add potassium osmium tetroxide dihydrate and N-methylmorpholine-N-oxide, stir at room temperature until the raw material disappears, then add sodium periodate and water to react and obtain intermediate aldehyde; The intermediate aldehyde was dissolved in mixed solvent 2, and then reacted with an aqueous solution of potassium permanganate to obtain compound 5; Step 4: Dissolve compound 5 in mixed solvent 3, add sodium bicarbonate, sodium periodate and ruthenium trichloride in sequence, heat and reflux and stir to react, and obtain intermediate dicarboxylic acid; The intermediate dicarboxylic acid was suspended in hydrochloric acid and heated under reflux to give compound 6. Compound 6 is L(-)-threo-3-hydroxyaspartic acid hydrochloride, with the structural formula [structure omitted]. Compound 3 is N-BOC-D-phenylalanine, with the structural formula [structure omitted]. The structural formula of compound 4 is as follows: The structural formula of compound 5 is as follows:

2. The novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride according to claim 1, characterized in that, In step 1, the molar ratio of D-phenylglycine:triethylamine:Boc anhydride:IBX is 1.0:(1.5-2.0):(1.0-1.05):(2.0-4.0).

3. The novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride according to claim 1, characterized in that, In step 1, when preparing Boc-D-phenylglycine, the reaction is specifically carried out at room temperature for 8 to 12 hours; when preparing compound 3, the reaction is carried out under reflux for 3 to 5 hours.

4. The novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride according to claim 1, characterized in that, In step 2, the molar ratio of compound 3: vinyl magnesium bromide: p-toluenesulfonic acid: 2,2-dimethoxypropane is 1:(2.0-3.0):(0.05-0.1):(3.0-5.0).

5. The novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride according to claim 1, characterized in that, In step 2, when preparing the o-amino alcohol, the reaction is specifically carried out at 0°C for 15 min to 30 min; when preparing compound 4, the reaction is specifically carried out at 0°C for 20 min to 40 min.

6. The novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride according to claim 1, characterized in that, In step 3, the molar ratio of compound 4: potassium osmium tetroxide dihydrate: N-methylmorpholine-N-oxide: sodium periodate: potassium permanganate is 1:0.01-0.02:3.0-5.0:1.5-3.0:6.0-10.

0.

7. The novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride according to claim 1, characterized in that, In step 3, the reactions for preparing intermediate aldehyde and compound 5 are all carried out at room temperature; the mixed solvent 1 is a mixture of acetone and water; the mixed solvent 2 is a mixture of tert-butanol and 5% sodium dihydrogen phosphate aqueous solution.

8. The novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride according to claim 1, characterized in that, In step 4, the molar ratio of compound 5: sodium bicarbonate: sodium periodate: ruthenium trichloride is 1:(10.0-15.0):(15.0-25.0):(0.05-0.1).

9. The novel method for synthesizing L(-)-threo-3-hydroxyaspartic acid hydrochloride according to claim 1, characterized in that, In step 4, when preparing the intermediate dicarboxylic acid, the heating and reflux reaction time is 2h to 5h; when preparing compound 6, the heating and reflux reaction time is 2h to 3h; the mixed solvent 3 is a mixed solvent of carbon tetrachloride, acetonitrile and water.

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