Preparation method of chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine

Abstract

The present invention provides a preparation method of chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine, the preparation method comprising the following steps: (1) reacting 2-fluoro-3-(trifluoromethyl)benzoic acid with N,O-dimethylhydroxylamine hydrochloride, carbonyldiimidazole and a base to obtain compound 2; (2) reacting compound 2 with a Grignard reagent and a complexing agent to obtain compound 3; (3) reacting compound 3 with hydroxylamine hydrochloride and a base to obtain compound 4; (4) reacting compound 4 with a catalyst under a hydrogen atmosphere to obtain compound 5; (5) mixing compound 5 with D-mandelic acid to obtain compound 6, and then adjusting the pH to obtain compound 7, i.e., the chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine. The preparation method provided by the present invention has high total yield, high chiral purity, convenient post-processing, effectively reduced cost, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine, and in particular to a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine with high yield. Background Art

[0002] The traditional synthesis process for chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine produces a large amount of solids during post-processing, which is not conducive to scale-up production. The low overall yield and substandard chirality also lead to high unit costs. Therefore, there is an urgent need to provide a method for synthesizing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine with high overall yield, high chiral purity, and low cost. Summary of the Invention

[0003] In response to the shortcomings of the prior art, the present invention aims to provide a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine, and in particular to provide a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine in high yield. The preparation method provided by the present invention has a high overall yield, high chiral purity, convenient post-processing, and effectively reduced costs, making it suitable for industrial production.

[0004] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0005] The present invention provides a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine, which comprises the following steps:

[0006] (1) 2-Fluoro-3-(trifluoromethyl)benzoic acid is reacted with N,O-dimethylhydroxylamine hydrochloride, carbonyldiimidazole, and a base to obtain compound 2;

[0007] (2) Compound 2 is mixed with a Grignard reagent and a complexing agent to react to obtain compound 3;

[0008] (3) reacting compound 3 with hydroxylamine hydrochloride and a base to obtain compound 4;

[0009] (4) reacting compound 4 with a catalyst under a hydrogen atmosphere to obtain compound 5;

[0010] (5) Compound 5 is mixed with D-mandelic acid to obtain compound 6, and then the pH is adjusted to obtain compound 7, i.e., the chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine.

[0011] The specific reaction process is as follows:

[0012]

[0013] The above method, by adopting a specific preparation process, can achieve a high total yield, high chiral purity, convenient post-processing, and effectively reduced costs, making it suitable for industrial production; by adopting a complexing agent, the attack of the Grignard reagent on the fluorine in compound 2 can be effectively avoided, thereby effectively improving the yield.

[0014] Preferably, the molar ratio of 2-fluoro-3-(trifluoromethyl)benzoic acid to N,O-dimethylhydroxylamine hydrochloride, carbonyldiimidazole and base in step (1) is 1:(1.1-1.3):(1.1-1.3):(1.1-1.5), wherein the number of parts of N,O-dimethylhydroxylamine hydrochloride can be 1.1, 1.15, 1.2, 1.25 or 1.3, etc., the number of parts of carbonyldiimidazole can be 1.1, 1.15, 1.2, 1.25 or 1.3, etc., and the number of parts of the base can be 1.1, 1.2, 1.3, 1.4 or 1.5, etc., but are not limited to the values listed above, and other values not listed within the above numerical range are equally applicable.

[0015] Preferably, the reaction temperature in step (1) is 10-30°C, and the reaction time is 8-16h, wherein the temperature can be 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, 22°C, 24°C, 26°C, 28°C or 30°C, and the reaction time can be 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h or 16h, but is not limited to the values listed above. Other values not listed within the above numerical range are also applicable.

[0016] Preferably, the molar ratio of compound 2 to the Grignard reagent and the complexing agent in step (2) is 1:(1.1-1.3):(1.05-1.2), wherein the number of parts of the Grignard reagent can be 1.1, 1.15, 1.2, 1.25 or 1.3, etc., and the number of parts of the complexing agent can be 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19 or 1.2, etc., but are not limited to the values listed above, and other values not listed within the above numerical range are also applicable.

[0017] Preferably, the complexing agent in step (2) comprises any one of hexamethylphosphoramide, sodium pyrophosphate, sodium gluconate, and polyacrylamide, or a combination of at least two thereof, preferably hexamethylphosphoramide.

[0018] The above-mentioned specific complexing agent can further reduce the attack of the Grignard reagent on the fluorine in compound 2, and more effectively improve the yield of the reaction.

[0019] Preferably, the reaction temperature in step (2) is -80 to -50°C, and the reaction time is 2-3h, for example, -80°C, -75°C, -70°C, -65°C, -60°C, -55°C or -50°C, etc., and the reaction time can be 2h, 2.1h, 2.2h, 2.3h, 2.4h, 2.5h, 2.6h, 2.7h, 2.8h, 2.9h or 3h, etc., but are not limited to the values listed above. Other values not listed within the above numerical range are also applicable.

[0020] The above-mentioned specific reaction condition control can effectively reduce the reaction activity, reduce the attack of the Grignard reagent on the fluorine in compound 2, and more effectively improve the reaction yield.

[0021] Preferably, the molar ratio of compound 3 to hydroxylamine hydrochloride and base in step (3) is 1:(1.3-2):(1.3-2), wherein the number of hydroxylamine hydrochloride can be 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2, and the number of base can be 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2, but are not limited to the values listed above. Other values not listed within the above numerical range are also applicable.

[0022] Preferably, the reaction temperature in step (3) is 10-30°C, and the reaction time is 8-16h, wherein the temperature can be 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, 22°C, 24°C, 26°C, 28°C or 30°C, and the reaction time can be 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h or 16h, but are not limited to the values listed above. Other values not listed within the above numerical range are also applicable.

[0023] Preferably, the catalyst in step (4) comprises any one of Raney nickel, palladium carbon or palladium hydroxide, or a combination of at least two thereof.

[0024] Preferably, the reaction temperature in step (4) is 10-30°C, and the reaction time is 8-16h, wherein the temperature can be 10°C, 12°C, 14°C, 16°C, 18°C, 20°C, 22°C, 24°C, 26°C, 28°C or 30°C, and the reaction time can be 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h or 16h, but are not limited to the values listed above. Other values not listed within the above numerical range are also applicable.

[0025] Preferably, the molar ratio of compound 5 to D-mandelic acid in step (5) is (0.8-1.2):(0.8-1.2), for example, 0.8:1.2, 0.9:1.1, 1:1, 1.1:0.9 or 1.2:0.8, etc., but is not limited to the values listed above. Other values not listed within the above numerical range are also applicable.

[0026] Preferably, step (5) is carried out by mixing with D-mandelic acid in a solvent, wherein the solvent comprises any one of isopropyl alcohol, ethanol, methyl tert-butyl ether, isopentanol or ethylene glycol monomethyl ether or a combination of at least two thereof, preferably a combination of isopropyl alcohol and ethanol, preferably a combination of isopropyl alcohol and ethanol.

[0027] The above-mentioned specific solvent can effectively improve the selectivity of the product and increase the yield of the target chiral product.

[0028] Preferably, the volume ratio of isopropanol to ethanol is (8-12):1, such as 8:1, 9:1, 10:1, 11:1 or 12:1, but is not limited to the above-listed values. Other values not listed within the above numerical range are also applicable.

[0029] The above specific volume ratio can further enhance the effect of the solvent and increase the yield of the target chiral product.

[0030] Preferably, the pH in step (5) is adjusted to a pH of 8.5-9.5, such as 8.5, 8.6, 8.7, 8.8, 8.9, 9, 9.1, 9.2, 9.3, 9.4 or 9.5, but is not limited to the values listed above. Other values not listed within the above numerical range are also applicable.

[0031] Preferably, the base comprises any one of triethylamine, potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide, or a combination of at least two thereof.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The present invention provides a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine. By adopting a specific preparation process, the preparation method can achieve high total yield, high chiral purity, convenient post-processing, effectively reduced costs, and is suitable for industrial production. By adopting a complexing agent, the attack of the Grignard reagent on the fluorine in compound 2 can be effectively avoided, thereby effectively improving the yield. DETAILED DESCRIPTION

[0034] In order to further illustrate the technical means and effects adopted by the present invention, the technical solutions of the present invention are further described below in conjunction with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0035] Example 1

[0036] This embodiment provides a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine, and the specific steps are as follows:

[0037]

[0038] (1) 100 g (480.5 mmol) of 2-fluoro-3-(trifluoromethyl)benzoic acid was dissolved in 1 L of dichloromethane and cooled to 0°C. 93.5 g (576.6 mmol) of carbonyldiimidazole was slowly added. After addition, the temperature was raised to 25°C and maintained for 2 hours. 65.6 g (648.54 mmol) of triethylamine was added. The mixture was cooled to 0°C and 56.2 g (576.17 mmol) of N,O-dimethylhydroxylamine hydrochloride was added in batches. The temperature was controlled below 10°C. After addition, the mixture was reacted at 20°C for 12 hours. After the reaction, 200 mL of water was added for washing, followed by 200 mL of 2N hydrochloric acid for washing. The mixture was dried over anhydrous sodium sulfate and concentrated to obtain 108 g of the product compound 2 with a yield of 89.5%. 1H NMR(DMSO-d6): δ3.28(s,3H),3.475(s,3H),7.499(t,1H),7.86(m,2H);

[0039] (2) Add 800 mL of tetrahydrofuran and 100 g (398.4 mmol) of compound 2 to a 2 L reaction flask and cool to -75 ° C. Add 160 mL of 3 M methylmagnesium bromide (1.2 eq) and hexamethylphosphoramide (1.1 eq) dropwise, and control the temperature to -70 ° C. After the addition is complete, keep the reaction warm for 3 hours, add 2 L of 1 M hydrochloric acid to quench, and control the temperature below 5 ° C. After quenching, add 300 mL of ethyl acetate to separate the layers. The aqueous layer is extracted once with 300 mL of ethyl acetate. The organic layers are combined, dried, and concentrated to obtain 75.54 g of compound 3, with a yield of 92%. 1H NMR (500 MHz, DMSO-d6) δ 8.17-8.10 (m, 1H), 8.09-7.99 (m, 1H), 7.54 (t, J = 7.8 Hz, 1H), 2.64 (d, J = 4.1 Hz, 3H);

[0040] (3) 60 g (291.1 mmol) of the product from the second step was added to 1200 mL of ethanol, followed by 44 g (435 mmol) of triethylamine and 32 g (460.5 mmol) of hydroxylamine hydrochloride. The mixture was reacted at 20°C for 12 h. After the reaction, the mixture was concentrated to dryness, 200 mL of dichloromethane was added, and the mixture was washed with 200 mL of 10% citric acid and 100 mL of saturated brine, dried, and concentrated to obtain 61.2 g of compound 4 with a yield of 95%. The mixture was directly used for the next step.

[0041] (4) 60 g (271.1 mmol) of compound 4 was added to 300 mL of methanol, and 10 g of Raney nickel was added. The mixture was replaced with a hydrogen balloon three times and allowed to react at 20°C for 12 h. After the reaction, the mixture was filtered, concentrated, and purified to obtain 42 g (202.73 mmol) of compound 5 in a yield of 75%. 1H NMR (CDCl3-d6): δ1.43 (d, 3H), 1.65 (m, 2H), 4.48 (q, 1H), 7.23 (q, 1H), 7.499 (t, 1H), 7.86 (t, 1H);

[0042] (5) To a mixed solution of 200 mL of isopropanol and 20 mL of ethanol was added 30 g (197.17 mmol) of D-mandelic acid, heated to 60°C for complete dissolution, and then slowly added 40 g (193.1 mmol) of compound 5. Stirred for 1 hour, the mixture was cooled to 20°C. Filtered with suction, the solid was rinsed with isopropanol, and 26 g of a white solid (compound 6) was obtained. The solid was dissolved in 100 mL of water, and potassium carbonate solid was added to adjust the pH to 9. The mixture was extracted three times with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 15 g of an oily product (compound 7) with a yield of 37.5% and an ee of 99.2%. 1H NMR (CDCl3-d6): δ1.43 (d, 3H), 1.65 (m, 2H), 4.48 (q, 1H), 7.23 (q, 1H), 7.499 (t, 1H), 7.86 (t, 1H).

[0043] Example 2

[0044] This embodiment provides a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine. The specific steps are consistent with those of Example 1 except for step (2):

[0045] (2) Add 800 mL of tetrahydrofuran and 100 g (398.4 mmol) of compound 2 to a 2 L reaction flask and cool to -75°C. Add 160 mL of 3 M methylmagnesium bromide (1.2 eq) and sodium pyrophosphate (1.1 eq) dropwise, controlling the temperature to -70°C. After the addition is complete, the reaction is kept warm for 3 hours, and then quenched by adding 2 L of 1 M hydrochloric acid, controlling the temperature below 5°C. After quenching, add 300 mL of ethyl acetate, separate the layers, extract the aqueous layer once with 300 mL of ethyl acetate, combine the organic layers, dry, and concentrate to obtain 71.4 g of compound 3, with a yield of 87%.

[0046] Example 3

[0047] This embodiment provides a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine. The specific steps are consistent with those of Example 1 except for step (2):

[0048] (2) Add 800 mL of tetrahydrofuran and 100 g (398.4 mmol) of compound 2 to a 2 L reaction flask and cool to -75 ° C. Add 160 mL of 3 M methylmagnesium bromide (1.2 eq) and polyacrylamide (purchased from Merck, 1.1 eq) dropwise, and control the temperature to -70 ° C. After the addition is complete, keep the reaction warm for 3 hours, add 2 L of 1 M hydrochloric acid to quench, control the temperature below 5 ° C, add 300 mL of ethyl acetate after quenching, separate the layers, extract the aqueous layer with 300 mL of ethyl acetate once, combine the organic layers, dry, and concentrate to obtain 65.7 g of compound 3, with a yield of 80%.

[0049] Example 4

[0050] This embodiment provides a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine. The specific steps are consistent with those of Example 1 except for step (2):

[0051] (2) Add 800 mL of tetrahydrofuran and 100 g (398.4 mmol) of compound 2 to a 2 L reaction flask and cool to -75 ° C. Add 160 mL of 3 M methylmagnesium bromide (1.2 eq) and sodium gluconate (1.1 eq) dropwise, and control the temperature to -70 ° C. After the addition is complete, keep the reaction warm for 3 hours, add 2 L of 1 M hydrochloric acid to quench, and control the temperature below 5 ° C. After quenching, add 300 mL of ethyl acetate to separate the layers. The aqueous layer is extracted once with 300 mL of ethyl acetate. The organic layers are combined, dried, and concentrated to obtain 60 g of compound 3 with a yield of 73%.

[0052] Example 5

[0053] This embodiment provides a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine. The specific steps are consistent with those of Example 1 except for step (5):

[0054] (5) To a mixed solution of 200 mL of isopropanol and 20 mL of methyl tert-butyl ether was added 30 g (197.17 mmol) of D-mandelic acid, heated to 60°C for complete dissolution, and then slowly added 40 g (193.1 mmol) of compound 5. Stirred for 1 hour, the mixture was cooled to 20°C. Filtered with suction, the solid was rinsed with isopropanol, and 13.88 g of a white solid (compound 6) was obtained. The solid was dissolved in 100 mL of water, and potassium carbonate solid was added to adjust the pH to 9. The mixture was extracted three times with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain 8 g of an oily product (compound 7) with a yield of 20% and an ee of 98.1%.

[0055] Example 6

[0056] This embodiment provides a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine. The specific steps are consistent with those of Example 1 except for step (5):

[0057] (5) To a mixed solution of 200 mL of isopropanol and 20 mL of isoamyl alcohol was added 30 g (197.17 mmol) of D-mandelic acid, heated to 60°C for complete dissolution, and then slowly added 40 g (193.1 mmol) of compound 5. Stir for 1 hour and cool naturally to 20°C. Filter with suction and rinse the solid with isopropanol to obtain 20.8 g of a white solid (compound 6). The solid was dissolved in 100 mL of water, and potassium carbonate solid was added to adjust the pH to 9. The product was extracted three times with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain 12 g of an oily product (compound 7) with a yield of 30% and an ee of 99.5%.

[0058] Example 7

[0059] This embodiment provides a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine. The specific steps are consistent with those of Example 1 except for step (5):

[0060] (5) To a mixed solution of 200 mL of isoamyl alcohol and 20 mL of ethanol was added 30 g (197.17 mmol) of D-mandelic acid, heated to 60°C for complete dissolution, and then slowly added 40 g (193.1 mmol) of compound 5. Stir for 1 hour and cool naturally to 20°C. Filter with suction, and rinse the solid with isopropanol to obtain 15.7 g of a white solid (compound 6). The solid was dissolved in 100 mL of water, and potassium carbonate solid was added to adjust the pH to 9. The product was extracted three times with 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain 9.3 g of an oily product (compound 7) with a yield of 23.2% and an ee of 98.3%.

[0061] Comparative Example 1

[0062] This comparative example provides a method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine. The specific steps are consistent with those of Example 1 except for step (2):

[0063] (2) Add 800 mL of tetrahydrofuran and 100 g (398.4 mmol) of compound 2 to a 2 L reaction flask and cool to -75°C. Add 160 mL of 3 M methylmagnesium bromide (1.2 eq) dropwise, controlling the temperature to -70°C. After the addition is complete, the reaction is kept warm for 3 hours, and then quenched by adding 2 L of 1 M hydrochloric acid, controlling the temperature below 5°C. After quenching, add 300 mL of ethyl acetate and separate the layers. The aqueous layer is extracted once with 300 mL of ethyl acetate. The organic layers are combined, dried, and concentrated to obtain 56.7 g of compound 3, with a yield of 63%.

[0064] Test example:

[0065] The total yields of Examples 1-7 and Comparative Example 1 were calculated as follows:

[0066]

[0067] From the above data, it can be found that the preparation method provided by the present invention has the advantages of high total yield and high chiral purity, and the post-processing is simple, which can effectively reduce costs; by comparing Examples 1-4, it can be found that the present invention can effectively reduce the reaction activity and reduce the attack of the Grignard reagent on the fluorine in compound 2 by adopting a specific complexing agent and controlling the reaction temperature, thereby further improving the yield of the reaction; by comparing Example 1 and Comparative Example 1, it can be found that the present invention can effectively reduce the attack of the Grignard reagent on the fluorine in compound 2 by adopting a complexing agent, thereby more effectively improving the yield of the reaction; by comparing Examples 1 and 5-7, it can be found that the present invention further improves the selectivity of the product by adopting a specific solvent, and improves the yield and optical purity of the target chiral product.

[0068] The applicant states that while the above-described examples illustrate the method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine, the present invention is not limited to these examples. This does not necessarily mean that the present invention must rely on these examples in order to be implemented. Those skilled in the art will appreciate that any improvements to the present invention, equivalent substitutions for raw materials in the product, addition of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

[0069] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0070] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for preparing chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine, characterized in that: The preparation method comprises the following steps: (1) 2-Fluoro-3-(trifluoromethyl)benzoic acid is reacted with N,O-dimethylhydroxylamine hydrochloride, carbonyldiimidazole, and a base to obtain compound 2; (2) Compound 2 is mixed with a Grignard reagent and a complexing agent to react to obtain Compound 3; the complexing agent includes any one or a combination of at least two of hexamethylphosphoramide, sodium pyrophosphate, sodium gluconate, and polyacrylamide; (3) reacting compound 3 with hydroxylamine hydrochloride and a base to obtain compound 4; (4) reacting compound 4 with a catalyst under a hydrogen atmosphere to obtain compound 5; (5) Compound 5 is mixed with D-mandelic acid to obtain compound 6, and then the pH is adjusted to obtain compound 7, i.e., the chiral 1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylamine; The specific reaction process is as follows: 。 2. The preparation method according to claim 1, characterized in that The molar ratio of 2-fluoro-3-(trifluoromethyl)benzoic acid to N,O-dimethylhydroxylamine hydrochloride, carbonyldiimidazole and base in step (1) is 1:(1.1-1.3):(1.1-1.3):(1.1-1.5).

3. The preparation method according to claim 1, characterized in that The reaction temperature of step (1) is 10-30°C and the reaction time is 8-16 h.

4. The preparation method according to claim 1, characterized in that The molar ratio of the compound 2 to the Grignard reagent and the complexing agent in step (2) is 1:(1.1-1.3):(1.05-1.2).

5. The preparation method according to claim 1, characterized in that The complexing agent is hexamethylphosphoramide.

6. The preparation method according to claim 1, characterized in that The reaction temperature in step (2) is -80~-50°C and the reaction time is 2-3 h.

7. The preparation method according to claim 1, characterized in that In step (3), the molar ratio of compound 3 to hydroxylamine hydrochloride and base is 1:(1.3-2):(1.3-2).

8. The preparation method according to claim 1, characterized in that The reaction temperature in step (3) is 10-30°C and the reaction time is 8-16 h.

9. The preparation method according to claim 1, characterized in that The catalyst in step (4) comprises any one of Raney nickel, palladium carbon or palladium hydroxide, or a combination of at least two thereof.

10. The preparation method according to claim 1, characterized in that The reaction temperature in step (4) is 10-30°C and the reaction time is 8-16 h.

11. The preparation method according to claim 1, characterized in that The molar ratio of compound 5 to D-mandelic acid in step (5) is (0.8-1.2):(0.8-1.2).

12. The preparation method according to claim 1, characterized in that The step (5) is carried out by mixing with D-mandelic acid in a solvent, wherein the solvent includes any one of isopropyl alcohol, ethanol, methyl tert-butyl ether, isopentanol or ethylene glycol monomethyl ether, or a combination of at least two thereof.

13. The preparation method according to claim 12, characterized in that The step (5) is carried out by mixing with D-mandelic acid in a solvent, wherein the solvent is a combination of isopropanol and ethanol.

14. The preparation method according to claim 13, characterized in that The volume ratio of the isopropyl alcohol to the ethanol is (8-12):

1.

15. The preparation method according to claim 1, characterized in that In step (5), the pH is adjusted to 8.5-9.

5.

16. The preparation method according to claim 1, characterized in that The base includes any one of triethylamine, potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide, or a combination of at least two thereof.

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