Preparation method of deuterated vitamin A

Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a preparation method of deuterated vitamin A. According to the method, glycolic acid is taken as a raw material, an isotope labeled methyl Grignard reagent is added to synthesize a deuterated intermediate based on a series of reactions such as an HWE reaction, reduction and oxidation, and the deuterated intermediate and BETA-cyclocitral are subjected to a series of reactions to synthesize the deuterated vitamin A, specifically VA-D6. The deuterated vitamin A prepared by the method is relatively high in deuteration rate, and the deuteration rate of the deuterated vitamin A is higher than 99%. The invention provides a synthetic method which is relatively high in deuteration rate, good in reaction selectivity, relatively high in yield, simple and convenient to operate and safe for preparation of deuterated vitamin A.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and relates to a method for preparing deuterated vitamin A. Background Art

[0002] Vitamin A (VA) is a class of fat-soluble vitamins based on the parent compound retinol. It is a monocyclic diterpenoid compound, and this family of compounds is usually called retinoids. Vitamin A is mainly found in the liver, blood, and retina. It plays an important role in promoting growth and development, maintaining mucous membrane health, and ensuring bone quality. It has multiple physiological functions, such as protecting vision, enhancing the immune system, promoting growth and development, protecting the nervous system, and maintaining skin health. It also participates in multiple antioxidant processes in the body and is one of the important nutrients for the body.

[0003] In pharmacokinetic studies, deuterated compounds can be used as stable isotope tracers to help researchers track the distribution and metabolism of drugs in the body. Through techniques such as mass spectrometry, analysts can clearly track the whereabouts of deuterated drugs and accurately measure the absorption, distribution, metabolism and excretion characteristics of drugs, providing an important basis for drug research and development. At present, the synthesis method of deuterated vitamin A mainly uses β-cyclocitral as the starting material, generates alkenyl borate through a series of chemical reactions, and then obtains vitamin A or its derivatives through reduction, esterification or oxidation. In this process, if deuterated allenol is used as a raw material, deuterated vitamin A and its derivatives can be obtained. Although this method has the advantages of a short synthesis route and simple operation, it has the problem of low deuteration rate.

[0004] The low deuterium substitution rate of deuterated compounds may affect the effect of isotope tracing, reducing the accuracy and reliability of the research. At the same time, the low deuterium substitution rate of deuterated compounds indicates that the compound still contains a large number of hydrogen atoms, which may still be affected by metabolic enzymes, resulting in the metabolic rate of the drug in the body not being significantly reduced, thereby affecting the therapeutic effect of the drug. Therefore, it is of great significance to explore a method for preparing deuterated vitamin A with a high deuterium substitution rate. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a method for preparing deuterated vitamin A. The method uses glycolic acid as a raw material, based on a series of reactions such as HWE reaction, reduction, oxidation, etc., adds an isotope-labeled methyl Grignard reagent to synthesize a deuterated intermediate, and synthesizes deuterated vitamin A, specifically VA-D6, by a series of reactions between the deuterated intermediate and BETA-cyclocitral. The present invention provides a synthesis method for the preparation of deuterated vitamin A with a high deuteration rate, good reaction selectivity, high yield, simple operation, and safety.

[0006] In order to achieve the technical purpose of the present invention, on the one hand, the present invention provides a method for preparing deuterated vitamin A, and its synthesis route is as follows. The deuterated vitamin A is VA-D6, and its structural formula is as follows: The D in VA-D6 represents that the hydrogen element is deuterated, and the deuteration rate of the deuterated vitamin A is higher than 99%. The synthesis method of deuterated vitamin A specifically comprises the following steps:

[0007] S1: Add N-methylmorpholine solution to the system of glycolic acid and EDCI. N -Methylmorpholine is dissolved in the first solvent, dimethylhydroxylamine hydrochloride is added with stirring at -30~0°C, and the reaction is stirred at room temperature for 10~30h; after the reaction is complete, the reaction is quenched with dilute hydrochloric acid, the aqueous phase is extracted with dichloromethane 3 times, the organic phases are combined, and then dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain an oily substance (Compound I).

[0008] Specifically, the first solvent is any one of methanol, 1,2-dichloroethane, dichloromethane, ethyl ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; preferably, the first solvent is dichloromethane or tetrahydrofuran; the weight volume ratio of glycolic acid to the first solvent is 1:2-1:30; The molar concentration ratio of glycolic acid to EDCI is 1:1 to 1:3; In the reaction system, glycolic acid and N -methylmorpholine has a molar concentration ratio of 1:1 to 1:3; the molar concentration ratio of glycolic acid to dimethylhydroxylamine hydrochloride in the reaction system is 1:1 to 1:5; The weight concentration of dilute hydrochloric acid is 2-15%, and the weight ratio of glycolic acid to dilute hydrochloric acid is 1:2-1:30; The weight volume ratio of glycolic acid to dichloromethane used in each extraction is 1:2-1:30; the weight ratio of glycolic acid to anhydrous sodium sulfate is 1:0.5-1:1.

[0009] S2: Add compound I obtained in S1 to the second solvent, then add a base and tert-butyldimethylsilyl chloride, and stir at room temperature for 5-15 hours. After the reaction is complete, extract the aqueous phase three times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain a colorless oil (compound II).

[0010] Specifically, the second solvent is 1,4-dioxane, N,N -Dimethylacetamide, N,N - any one of dimethylformamide and acetonitrile; preferably, the second solvent is N,N -dimethylacetamide or N,N-dimethylformamide; the weight volume ratio of compound I to the second solvent is 1:3~1:20; The base is pyridine, imidazole, N,N Any one of diisopropylethylamine and 4-dimethylaminopyridine; the molar ratio of compound I to the base is 1:1 to 1:5; The molar ratio of compound I to tert-butyldimethylsilyl chloride is 1:1.1 to 1:2.0; The weight-volume ratio of compound I to ethyl acetate used in each extraction is 1:2-1:30; the weight ratio of compound I to anhydrous sodium sulfate is 1:0.5-1:1.

[0011] S3: Add compound II obtained in S2 to the third solvent, cool to -5~6°C, add the pre-prepared isotope-labeled methyl grignard reagent to the system, stir at -5~6°C for 1~2h. After the reaction is complete, quench the reaction with saturated ammonium chloride, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain a colorless oil (compound III).

[0012] Specifically, the third solvent is an ether solvent, and the ether solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; the weight volume ratio of compound II to the third solvent is 1:2-1:30; The preparation method of isotope-labeled methyl Grignard reagent is as follows: under argon protection, magnesium chips, I2, a small amount of CD3I and anhydrous Et2O are added to a bottle with a reflux tube, the system is heated with a hair dryer at room temperature until the iodine in the system fades and starts to bubble, the remaining CD3I is slowly added dropwise, and stirring is continued at room temperature until the bubbling stops.

[0013] The concentration of the isotope-labeled methyl Grignard reagent is 0.3-3 mol / L, and the molar ratio of the isotope-labeled methyl Grignard reagent to compound II is 1:1-3:1; The weight volume ratio of compound II to saturated ammonium chloride is 1:2~1:30; The weight-to-volume ratio of compound II to saturated saline is 1:2-1:30; The weight ratio of compound II to anhydrous sodium sulfate is 1:0.5~1:1.

[0014] S4: Add compound III prepared in S3 to the fourth solvent, cool to -5~6°C, add the first strong base to the system, and then add the first ester (Formula 1, ), warm to room temperature, stir and react for 3-6 hours. After the reaction is complete, neutralize the system with a weak acid, extract the aqueous phase with ethyl acetate three times, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain a colorless oil (Compound IV).

[0015] Specifically, the fourth solvent is an ether solvent, and the ether solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; the weight volume ratio of compound III to the ether solvent is 1:2-1:30; The first strong base is KHMDS, NaHMDS, LiHMDS, KO t -Bu, sodium hydride, potassium hydride; the molar ratio of compound III to the first strong base is 1:1~1:2; The first ester R 1 OEt, OMe, OBu; R 2 is any one of CO2CH3, CO2Et, and CO2Pr; the molar ratio of compound III to the first ester is 1:1 to 1:3; The weak acid is any one of formic acid, acetic acid, phosphoric acid and hydrofluoric acid; the weight ratio of compound III to the weak acid is 1:3-1:30; The weight-volume ratio of compound III to ethyl acetate used in each extraction is 1:2-1:30; the weight ratio of compound III to anhydrous sodium sulfate is 1:0.5-1:1.

[0016] S5: Add the fifth solvent to compound IV, then add tetrabutylammonium fluoride, cool to -5~8°C, and continue to stir the reaction at this temperature for 2~4 hours. After the reaction is complete, quench the reaction with dilute hydrochloric acid, extract the aqueous phase three times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain an oily substance (compound V).

[0017] Specifically, the fifth solvent is any one of methanol, 1,2-dichloroethane, dichloromethane, ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; preferably, the fifth solvent is dichloromethane or tetrahydrofuran; the weight volume ratio of compound IV to the fifth solvent is 1:3 to 1:30; The molar ratio of compound IV to tetrabutylammonium fluoride is 1:2 to 1:10; The weight concentration of dilute hydrochloric acid is 2-15%, and the weight ratio of compound IV to dilute hydrochloric acid is 1:3-1:30; The weight-volume ratio of compound IV to ethyl acetate used in each extraction is 1:2-1:30; the weight ratio of compound IV to anhydrous sodium sulfate is 1:0.5-1:1.

[0018] S6: Add compound V to the sixth solvent, then add triphenylphosphine and carbon tetrabromide, and stir at room temperature for 5 to 15 hours. After the reaction is complete, extract the aqueous phase three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain an oily substance (compound VI).

[0019] Specifically, the sixth solvent is any one of 1,2-dichloroethane, dichloromethane, ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; preferably, the sixth solvent is 1,2-dichloroethane or dichloromethane; the weight volume ratio of compound V to the sixth solvent is 1:2 to 1:20; The molar ratio of compound V to triphenylphosphine is 1:1 to 1:1.2; The molar ratio of compound V to carbon tetrabromide is 1:1 to 1:1.2; The weight-to-volume ratio of compound V to dichloromethane used in each extraction is 1:2~1:30; the weight ratio of compound ‌‌‌‌‌‌‌‌ V to anhydrous sodium sulfate is 1:0.5~1:1.

[0020] S7: Add the second ester (R 3 2POEt), heated to reflux, and after the reaction was complete, the system was concentrated and purified by column chromatography to obtain a colorless oil (Compound VII).

[0021] Specifically, R in the second ester 3 It is any one of OEt, OMe, and OBu; the molar ratio of compound VI to the second ester is 1:1.1~1:2; the heating reflux temperature is 100~150°C, and the heating reflux time is 2~4h.

[0022] S8: Add compound VII to the seventh solvent at -5-8°C, and then add the second strong base solution, N,N -dimethylpropylene urea (DMPU) and BETA-cyclocitral are stirred at -5~8°C for 1~2h. After the reaction is complete, the system is quenched with a saturated aqueous ammonium chloride solution, the aqueous phase is extracted three times with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate, and concentrated to obtain compound VIII.

[0023] Specifically, the seventh solvent is an ether solvent, and the ether solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; the weight volume ratio of compound VII to the ether solvent is 1:2 to 1:30; The solution of the second strong base is a n-hexane solution of the second strong base, the second strong base is any one of methyl lithium, ethyl lithium, n-butyl lithium, and sec-butyl lithium, the molar concentration of the solution of the second strong base is 1 to 2.5, and the molar ratio of compound VII to the second strong base is 1:1.1 to 1:3; Compound VII N,N - The molar ratio of dimethyl propylene urea is 1:1.2 to 1:1.5; The molar ratio of compound VII to BETA-cyclocitral is 1:1 to 1:2; The weight volume ratio of compound VII to saturated ammonium chloride aqueous solution is 1:2~1:30; The weight-volume ratio of compound VII to ethyl acetate used in each extraction is 1:2-1:30; the weight ratio of compound VII to anhydrous sodium sulfate is 1:0.5-1:1.

[0024] S9: Add the eighth solvent to compound VIII, and then add diisobutylaluminum hydride (DIBAL-H), stir at -5~5°C for 1~3h. After the reaction is complete, quench the system with a saturated aqueous solution of potassium sodium tartrate, extract the aqueous phase three times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain an oily substance (compound IX).

[0025] Specifically, the eighth solvent is any one of 1,2-dichloroethane, dichloromethane, diethyl ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; preferably, the eighth solvent is dichloromethane or diethyl ether; the weight volume ratio of compound VIII to the eighth solvent is 1:3 to 1:25; The molar ratio of compound VIII to DIBAL-H is 1:3 to 1:6; The weight volume ratio of compound VIII to the saturated aqueous solution of potassium sodium tartrate is 1:2 to 1:30; The weight-volume ratio of compound VIII to ethyl acetate used in each extraction is 1:2-1:30; the weight ratio of compound VIII to anhydrous sodium sulfate is 1:0.5-1:1.

[0026] S10: Add the ninth solvent to compound IX, and then add the oxidant, heat and reflux at 50-80°C for 3-8 hours. After the reaction is complete, cool the system to room temperature, filter with diatomaceous earth, concentrate the organic phase, and purify by column chromatography to obtain an oily substance (compound X).

[0027] Specifically, the ninth solvent is an ether solvent, and the ether solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; the weight volume ratio of compound IX to the ninth solvent is 1:2-1:40; The oxidant is any one of chromic acid, hydrogen peroxide, and manganese dioxide; the molar ratio of compound IX to the oxidant is 1:20 to 1:50; The weight ratio of compound IX to diatomaceous earth is 1:2~1:3.

[0028] S11: Compound X is repeated to obtain compound XI, and compound XI is repeated in S9. After the reaction is complete, it is quenched with a saturated aqueous solution of potassium sodium tartrate, and the organic phase is concentrated to obtain a crude product, which is purified by silica gel column chromatography to obtain the finished product deuterated vitamin A (VA-D6); Specifically, the weight volume ratio of compound XI to the saturated aqueous solution of potassium sodium tartrate is 1:2 to 1:30.

[0029] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects or advantages: (1) The preparation method of deuterated vitamin A provided by the present invention uses glycolic acid as a raw material, based on a series of reactions such as HWE reaction reduction and oxidation, synthesizes a deuterated intermediate through an isotope-labeled methyl Grignard reagent, and synthesizes deuterated vitamin A, specifically VA-D6, through a series of reactions of the deuterated intermediate and BETA-cyclocitral. The deuterated vitamin A prepared by the present invention has a high deuteration rate, which is higher than 99%. The present invention provides a synthesis method for the preparation of deuterated vitamin A with good reaction selectivity, high yield, simple operation and safety.

[0030] (2) The deuterated vitamin A prepared by the present invention has a high deuteration rate and has great application prospects in drug development, drug metabolic stability and pharmacokinetic properties research. It has a better isotope tracing effect and a lower metabolic rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is the H NMR spectrum of compound Ⅰ.

[0032] Figure 2 This is the carbon NMR spectrum of compound Ⅰ.

[0033] Figure 3 This is the H NMR spectrum of compound II.

[0034] Figure 4 This is the carbon NMR spectrum of compound II.

[0035] Figure 5 This is the H NMR spectrum of compound III.

[0036] Figure 6 This is the carbon NMR spectrum of compound III.

[0037] Figure 7 This is the H NMR spectrum of compound IV.

[0038] Figure 8 This is the carbon NMR spectrum of compound IV.

[0039] Fig. 9 This is the hydrogen NMR spectrum of compound V.

[0040] Fig.10 This is the carbon NMR spectrum of compound V.

[0041] Fig.11 This is the hydrogen nuclear magnetic resonance spectrum of compound VI.

[0042] Fig.12 This is the carbon NMR spectrum of compound VI.

[0043] Fig.13 This is the hydrogen NMR spectrum of compound VII.

[0044] Fig.14 This is the carbon NMR spectrum of compound VII.

[0045] Fig.15 This is the hydrogen nuclear magnetic resonance spectrum of compound VIII.

[0046] Fig.16 This is the H NMR spectrum of compound IX.

[0047] Fig.17 is the hydrogen NMR spectrum of compound X.

[0048] Fig.18 is the carbon NMR spectrum of compound X.

[0049] Fig.19 This is the hydrogen NMR spectrum of compound XI.

[0050] Fig. 20 This is the carbon NMR spectrum of compound XI.

[0051] Fig.21 This is the hydrogen nuclear magnetic resonance spectrum of VA-D6.

[0052] Fig. 22 This is the carbon NMR spectrum of VA-D6.

[0053] Fig.23 This is a comparison chart of the H NMR spectra of VA-D6 and vitamin A. DETAILED DESCRIPTION

[0054] The technical scheme of the present invention is now described in conjunction with the embodiments, but the present invention is not limited to the following embodiments. The experimental methods and detection methods described in the following embodiments are conventional methods unless otherwise specified; the reagents and materials described are all commercially available unless otherwise specified.

[0055] The unit of weight to volume ratio in the present invention is g:mL.

[0056] The synthesis route of deuterated vitamin A of the present invention is as follows.

[0057]

[0058] Example 1 This embodiment provides a method for preparing deuterated vitamin A, which specifically comprises the following steps: S1: Add 40 mL of 1.98 g glycolic acid and 5.48 g EDCI to the system. N -Methylmorpholine in dichloromethane ( N-methylmorpholine mass is 2.89g), a white suspension is obtained, 2.79g dimethylhydroxylamine hydrochloride is added under -30℃, and then stirred at room temperature for 30h. After the reaction is complete, 5g of dilute hydrochloric acid with a weight concentration of 2% is added to quench the reaction, and the aqueous phase is extracted 3 times with 40mL of dichloromethane, the organic phases are combined, dried with 1.6g of anhydrous sodium sulfate, and the organic phases are concentrated and purified by silica gel column chromatography (the volume ratio of dichloromethane to methanol is 100:1) to obtain an oil (Compound I), with a yield of 60%. The hydrogen nuclear magnetic resonance spectrum of Compound I is as follows Figure 1 As shown, 1 H NMR (500 MHz,CDCl3):δ 4.21 (s,2H),3.61(s,3H),3.24 (s, 1H),3.15(s,3H). The carbon NMR spectrum of compound Ⅰ is shown in Figure 2 As shown, 13 C NMR (126 MHz, CDCl3): δ 172.91, 61.14, 59.47, 32.15. S2: Add 2.14 g of compound I to 15 mL of N,N -dimethylformamide, then add 2.45g of imidazole and 3.25g of tert-butyldimethylsilyl chloride, stir at room temperature for 10h; after the reaction is complete, extract the aqueous phase with 20mL of ethyl acetate three times, dry the organic phase with 2g of anhydrous sodium sulfate, concentrate the organic phase, and purify it by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain a colorless oil (Compound II) with a yield of 70%. The hydrogen nuclear magnetic resonance spectrum of Compound II is as follows Figure 3 As shown, 1 H NMR (500 MHz, CDCl3): δ 4.37 (s, 2H), 3.62 (s, 3H), 3.12 (s, 3H), 0.87 (s, 9H), 0.06 (s, 6H). The carbon NMR spectrum of compound II is shown in Figure 4 As shown, 13 C NMR (126 MHz, CDCl3): δ61.13, 32.23, 25.60, 18.26, -5.60. S3: Add 3.27g of compound II to 30mL of tetrahydrofuran, cool to -3°C, add 21mL of pre-prepared isotope-labeled methyl Grignard reagent (concentration of 1mol / L) to the system, stir at -3°C for 1.5h, after the reaction is complete, quench the reaction with 10mL of saturated ammonium chloride, wash the organic phase with 10mL of saturated brine, dry with 3g of anhydrous sodium sulfate, concentrate the organic phase, purify by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 100:1), and obtain compound III with a yield of 45%. The preparation method of the isotope-labeled methyl Grignard reagent is as follows: under argon protection, add magnesium chips, I2, a small amount of CD3I and anhydrous Et2O to a bottle with a reflux tube, heat the system with a hair dryer at room temperature until the iodine in the system fades and starts to bubble, slowly add the remaining CD3I, and continue stirring at room temperature until the bubbling stops. The hydrogen nuclear magnetic resonance spectrum of compound III is as follows Figure 5 As shown, 1 H NMR (500 MHz,CDCl3): δ 4.13 (s, 2H), 0.91 (s, 9H), 0.08 (s, 6H). The carbon NMR spectrum of compound III is shown in Figure 6 As shown, 13 C NMR (126 MHz, CDCl3): δ 209.52, 69.70, 25.88, 18.41, -5.39. S4: Add 1.76g of compound III to 20mL of tetrahydrofuran, cool to -3°C, add 368mg of sodium hydride (60% in mineral oil) to the system, then add 1.74mL of triethyl phosphonoacetate, warm to room temperature and stir for 5h. After the reaction is complete, neutralize the system with 10mL of acetic acid, extract the aqueous phase three times with 10mL of ethyl acetate, dry the organic phase with 1.4g of anhydrous sodium sulfate, concentrate the organic phase, purify by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 100:1), and obtain a colorless oil (compound IV) with a yield of 48%. The hydrogen nuclear magnetic resonance spectrum of compound IV is as follows: Figure 7 As shown, 1 H NMR (500 MHz, CDCl3): δ6.03 (t, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.15 (d, J = 1.9 Hz, 2H), 1.33 (t, J= 7.1 Hz, 3H), 0.97 (s, 9H), 0.13 (s, 6H). The carbon NMR spectrum of compound IV is shown in Figure 8 As shown, 13CNMR (126 MHz, CDCl3): δ 167.22, 157.19, 113.54, 67.20, 59.71, 26.01, 18.50,14.49, -5.31. S5: Add 1.92g of compound IV to 20mL of tetrahydrofuran, then add 14.7mL of tetrabutylammonium fluoride (concentration of 1mol / L), cool to -5°C, and continue stirring at this temperature for 4h. After the reaction is complete, quench the reaction with 6g of 2wt% dilute hydrochloric acid, then extract the aqueous phase 3 times with 20mL of ethyl acetate, dry the organic phase with 2g of anhydrous sodium sulfate, concentrate the organic phase, and purify it by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 30:1) to obtain an oil (compound V), with a yield of 70%. The hydrogen nuclear magnetic resonance spectrum of compound V is as follows Fig. 9 As shown, 1 H NMR (500 MHz, CDCl3): δ 5.94 (d, J = 1.8 Hz, 1H),4.13 (q, J = 7.1 Hz, 2H), 4.09 (s, 2H), 2.73 (s, 1H), 1.25 (t, J = 7.1, 1.6Hz, 3H). The carbon NMR spectrum of compound Ⅴ is shown in Figure 2. Fig.10 As shown, 13 C NMR (126 MHz, CDCl3): δ 167.15,157.50, 113.71, 66.97, 59.90, 14.34. S6: Add 865.4 mg of compound V to 12 mL of dichloromethane, then add 1.70 g of triphenylphosphine and 2.15 g of carbon tetrabromide, and stir at room temperature for 7 h; after the reaction is complete, extract the aqueous phase three times with 20 mL of dichloromethane, dry the organic phase with 0.8 g of anhydrous sodium sulfate, concentrate the organic phase, and purify it by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 200:1) to obtain an oil (compound VI), with a yield of 60%. The hydrogen nuclear magnetic resonance spectrum of compound VI is as follows Fig.11 As shown, 1 H NMR (500 MHz, CDCl3): δ5.94 (s, 1H), 4.16 (q, J = 7.1 Hz, 4H), 3.93 (s, 2H), 1.27 (t, J = 7.1 Hz,3H). The carbon NMR spectrum of compound VI is shown in Fig.12 As shown, 13 C NMR (126 MHz, CDCl3): δ 166.01,152.32, 119.71, 60.21, 38.34, 14.35. S7: Add 0.9 mL of triethyl phosphite to 1.05 g of compound VI, heat under reflux and stir. After the reaction is complete, concentrate the system and purify it by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 100:1) to obtain a colorless oil (compound VII) with a yield of 60%. The hydrogen nuclear magnetic resonance spectrum of compound VII is as follows Fig.13 As shown, 1 H NMR (500 MHz, CDCl3): δ 5.75 (d, J = 5.3 Hz, 1H), 4.15 – 4.04 (m, 6H), 2.64 (d, J = 23.4 Hz, 2H), 1.29 (t,J = 7.1 Hz, 6H), 1.23 (t, J = 7.1 Hz, 3H). The carbon NMR spectrum of compound VII is shown in Figure 2. Fig.14 As shown, 13 C NMR (126 MHz, CDCl3): δ 166.09, 166.06, 149.57, 149.48, 120.21, 120.11,62.32, 62.26, 59.82, 39.10, 38.03, 16.49, 16.44, 14.34. S8: At -5°C, slowly drop 1.82 mL of n-butyl lithium (2.5 M in hexane) into 0.55 mL N,N -dimethylpropylene urea (DMPU) and 3mL ether (containing 586mg BETA-cyclocitral), add 935mg compound VII to 7mL ether, add to the system, then stir at this temperature for 2h. After the reaction is complete, quench the system with 10mL saturated ammonium chloride aqueous solution, extract the aqueous phase with 10mL ethyl acetate 3 times, dry the organic phase with 1g anhydrous sodium sulfate, and concentrate to obtain compound VIII with a yield of 50%. The hydrogen nuclear magnetic resonance spectrum of compound VIII is as follows Fig.15 As shown, 1 H NMR (500 MHz, CDCl3): δ 6.55 (d, 1H), 6.09(d, J = 16.1 Hz, 1H), 5.74 (s, 1H), 4.20 – 4.14 (m, 2H), 2.09 (s, 2H), 1.69(d, J = 1.0 Hz, 3H), 1.60 – 1.57 (m, 2H), 1.49 – 1.42 (m, 2H), 1.30 – 1.26(m, 3H), 1.01 (s, 6H). S9: 796.23 mg of compound VIII was added to 17 mL of dichloromethane, followed by 6 mL of DIBAL-H (1.5 M intoluene), and stirred at -5 °C for 1 h. After the reaction was complete, the system was quenched with 20 mL of saturated aqueous potassium sodium tartrate solution, and the aqueous phase was extracted 3 times with 20 mL of ethyl acetate. The organic phase was dried with 0.6 g of anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate was 50:1) to obtain an oil (compound IX) with a yield of 60%. The hydrogen nuclear magnetic resonance spectrum of compound IX is as follows: Fig.16 As shown, 1 H NMR (500 MHz, CDCl3): δ 6.16 – 5.97 (m, 2H), 5.62 (t, J = 7.0Hz, 1H), 4.30 (d, J = 7.0 Hz, 2H), 2.00 (t, 2H), 1.68 (s, 3H), 1.63 – 1.58(m, 2H), 1.48 – 1.43 (m, 2H), 1.00 (s, 6H). S10: Add 11 mL of tetrahydrofuran to 496 mg of compound IX, then add 3.86 g of manganese dioxide, heat and reflux for 5 h. After the reaction is complete, cool the system to room temperature, filter with 1 g of diatomaceous earth, concentrate the organic phase, and perform silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain an oil (compound X), with a yield of 50%. The hydrogen nuclear magnetic resonance spectrum of compound X is as follows Fig.17 As shown, 1 H NMR (500 MHz, CDCl3): δ 10.09 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 16.1Hz, 1H), 6.18 (d, J = 16.2 Hz, 1H), 5.91 (d, J = 8.1 Hz, 1H), 2.01 (t, J =6.5 Hz, 2H), 1.70 (s, 3H), 1.62 – 1.56 (m, 2H), 1.47 – 1.42 (m, 2H), 1.01 (s,6H). The carbon NMR spectrum of compound ‌‌X is shown in Figure 2. Fig.18 As shown, 13 C NMR (126 MHz, CDCl3): δ 191.38,155.02, 137.11, 135.74, 135.62, 132.77, 128.86, 77.42, 77.16, 76.91, 39.58,34.31, 33.29, 28.99, 21.81, 19.12. S11: Repeat S8 with 362 mg of compound Ⅹ to obtain compound Ⅺ, and repeat S9 with compound Ⅺ. After the reaction is complete, quench with 20 mL of saturated aqueous solution of potassium sodium tartrate, concentrate the organic phase to obtain a crude product, and perform silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain 200 mg of finished product deuterated vitamin A (VA-D6), with a yield of 50%. The H NMR spectrum of compound Ⅺ is as follows: Fig.19 As shown, 1 H NMR (500 MHz, CDCl3) δ 7.07 – 6.89 (m, 1H), 6.31 – 6.24 (m, 2H),6.17 – 6.09 (m, 2H), 5.77 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 2.02 (t, J = 6.4Hz, 2H), 1.71 (s, 3H), 1.64 – 1.58 (m, 2H), 1.49 – 1.44 (m, 2H), 1.29 (t, J =7.1 Hz, 3H), 1.03 (s, 6H). The carbon NMR spectrum of compound Ⅺ is shown in Figure 1. Fig. 20 As shown, 13 C NMR (126 MHz, Chloroform-d) δ 167.4 , 152.8 , 139.6 , 137.8 , 137.4 , 135.3 , 131.1 , 130.1, 129.7 , 128.8 , 118.8 , 59.8 , 39.7 , 34.4 , 33.3 , 29.1 , 21.9 , 19.4 ,14.5 . The H NMR spectrum of VA-D6 is as follows: Fig.21 As shown, 1 H NMR (500 MHz, CDCl3): δ 6.64 – 6.54 (m,1H), 6.28 (d, J = 15.2 Hz, 1H), 6.20 – 6.06 (m, 3H), 5.68 (t, J = 7.0 Hz,1H), 4.30 (d, J = 7.0 Hz, 2H), 2.01 (t, J = 6.4 Hz, 2H), 1.71 (s, 3H), 1.63 –1.57 (m, 2H), 1.48 – 1.44 (m, 2H), 1.02 (s, 6H). Fig. 22 As shown, 13C NMR (126 MHz, CDCl3): δ 137.95, 137.77, 137.01, 136.42, 136.26, 130.22,130.10, 129.42, 126.90, 125.35, 77.41, 77.36, 77.16, 76.91, 59.64, 39.74,34.39, 33.19, 29.09, 21.87, 19.40. The present invention further compares the H NMR spectra of VA-D6 and vitamin A and finds that there is a difference in the H NMR spectra of the two within the chemical shift range of 1.8 to 2.0. Vitamin A has two absorption peaks here, which are signals of methyl hydrogen atoms that have not been deuterated. The deuteration rate of VA-D6 is calculated to be: ((3-0.02) / 3)×100%=99.3%.

[0059] Example 2 This embodiment provides a method for preparing deuterated vitamin A, which specifically comprises the following steps: S1: Add 4 mL of 1,2-dichloroethane solution (containing 3.42 g of N -methylmorpholine), a white suspension was obtained, 7.6 g of dimethylhydroxylamine hydrochloride was added under stirring at -15 °C, and then stirred at room temperature for about 15 h. After the reaction was completed, 2 g of dilute hydrochloric acid with a weight concentration of 5% was added to quench the reaction, and the aqueous phase was extracted 3 times with 3.96 mL of dichloromethane. The organic phases were combined and dried with 1 g of anhydrous sodium sulfate. The organic phases were concentrated and purified by silica gel column chromatography (the volume ratio of dichloromethane to methanol was 100:1) to obtain an oil (Compound I), with a yield of 55%; S2: Add 1.07 g of compound I to 3.21 mL of N,N -dimethylacetamide, then add 611.53g of imidazole and 1.49g of tert-butyldimethylsilyl chloride, and stir at room temperature for 5h; after the reaction is complete, extract the aqueous phase with 2.2mL of ethyl acetate three times, dry the organic phase with 0.54g of anhydrous sodium sulfate, concentrate the organic phase, and purify it by silica gel column chromatography (the volume ratio of petroleum ether and ethyl acetate is 50:1) to obtain a colorless oil (Compound II) with a yield of 60%; S3: Add 1.6 g of compound II to 3.2 mL of ether, cool to -5°C, add 22.85 mL of pre-prepared isotope-labeled methyl Grignard reagent (concentration of 0.3 mol / L) to the system, stir at -5°C for 1 h, and after the reaction is complete, quench the reaction with 3.2 mL of saturated ammonium chloride. Wash the organic phase with 3.2 mL of saturated brine, dry with 0.8 g of anhydrous sodium sulfate, concentrate the organic phase, and purify it by silica gel column chromatography (the volume ratio of petroleum ether and ethyl acetate is 100:1) to obtain a colorless oil (compound III), with a yield of 40%; S4: 0.9 g of compound III was added to 1.8 mL of dimethyl ether, cooled to -5 °C, 628.39 mg of potassium hydride (30% in mineral oil) was added to the system, followed by 0.9 mL of diethyl methylphosphoryl acetate, and the mixture was heated to room temperature and stirred for 3 h. After the reaction was complete, the system was neutralized with 2.7 mL of formic acid, the aqueous phase was extracted three times with 1.8 mL of ethyl acetate, the organic phase was dried with 0.45 g of anhydrous sodium sulfate, the organic phase was concentrated, and purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 100:1) to obtain a colorless oil (compound IV) with a yield of 40%; S5: 1 g of compound IV was added to 3 mL of dichloromethane, followed by 7.6 mL of tetrabutylammonium fluoride, cooled to -7 °C, and stirred at this temperature for 2 h. After the reaction was complete, the reaction was quenched with 4 g of 5 wt% dilute hydrochloric acid, and the aqueous phase was extracted three times with 2 mL of ethyl acetate. The organic phase was dried with 0.5 g of anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate was 30:1) to obtain an oil (compound V) with a yield of 58%; S6: 430 mg of compound V was added to 0.86 mL of tetrahydrofuran, followed by 766.25 mg of triphenylphosphine and 968.82 mg of carbon tetrabromide, and stirred at room temperature for 5 h; after the reaction was complete, the aqueous phase was extracted three times with 0.85 mL of dichloromethane, the organic phase was dried with 215 mg of anhydrous sodium sulfate, the organic phase was concentrated, and purified by silica gel column chromatography (the volume ratio of petroleum ether and ethyl acetate was 200:1) to obtain an oil (compound VI), with a yield of 48%; S7: 403.42 mg of dimethyl ethyl phosphite was added to 0.5 g of compound VI, and the mixture was heated under reflux with stirring. After the reaction was complete, the system was concentrated and purified by silica gel column chromatography (volume ratio of petroleum ether and ethyl acetate was 100:1) to obtain a colorless oil (compound VII) with a yield of 51%; S8: At -7°C, slowly drip 1.26 mL of ethyl lithium (1.5 M in hexane) into 0.25 mL N,N-dimethylpropylene urea (DMPU) and 2mL tetrahydrofuran (containing 261.85mg BETA-cyclocitral), add 460mg compound VII to 4mL tetrahydrofuran, add to the system, then stir at this temperature for 1h. After the reaction is complete, quench the system with 0.92mL saturated ammonium chloride aqueous solution, extract the aqueous phase with 0.92mL ethyl acetate 3 times, dry the organic phase with 230mg anhydrous sodium sulfate, and concentrate to obtain compound VIII with a yield of 43%; S9: 1.197 mL 1,2-dichloroethane was added to 399 mg of compound VIII, followed by 4 mL DIBAL-H (1.5 Min toluene), and the mixture was stirred at -7 °C for 2 h. After the reaction was complete, the system was quenched with 0.798 mL saturated aqueous solution of potassium sodium tartrate, and the aqueous phase was extracted three times with 0.798 mL ethyl acetate. The organic phase was dried with 0.2 g anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate was 50:1) to obtain an oil (compound IX) with a yield of 54%; S10: Add 0.5 mL of methyl tert-butyl ether to 250 mg of compound IX, then add 761 mg of hydrogen peroxide, heat and reflux for 3 h. After the reaction is complete, cool the system to room temperature, filter with 0.6 g of diatomaceous earth, concentrate the organic phase, and perform silica gel column chromatography (volume ratio of petroleum ether and ethyl acetate is 50:1) to obtain an oil (compound X), with a yield of 43%; S11: Repeat S8 with 362 mg of compound Ⅹ to obtain compound Ⅺ. Repeat S9 with compound Ⅺ. After the reaction is complete, quench with 12 mL of saturated aqueous potassium sodium tartrate solution. Concentrate the organic phase to obtain a crude product. Perform silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain 120 mg of finished deuterated vitamin A (VA-D6) with a yield of 41%.

[0060] Example 3 This embodiment provides a method for preparing deuterated vitamin A, which specifically comprises the following steps: S1: Add 59.4 mL of tetrahydrofuran solution (containing 7.9 g of N -methylmorpholine), a white suspension was obtained, 11.2 g of dimethylhydroxylamine hydrochloride was added under stirring at 0°C, and then stirred at room temperature for about 30 h. After the reaction was completed, 59.4 g of dilute hydrochloric acid with a weight concentration of 15% was added to quench the reaction, and the aqueous phase was extracted 3 times with 60 mL of dichloromethane. The organic phases were combined and dried with 1.98 g of anhydrous sodium sulfate. The organic phase was concentrated and purified by silica gel column chromatography (the volume ratio of dichloromethane to methanol was 100:1) to obtain an oil (Compound I), with a yield of 61%; S2: Add 2.14 g of compound I to 42.8 mL of N,N-dimethylformamide, then add 6.13g of imidazole and 5.43g of tert-butyldimethylsilyl chloride, and stir at room temperature for 15h; after the reaction is complete, extract the aqueous phase three times with 64.2mL of ethyl acetate, dry the organic phase with 2.14g of anhydrous sodium sulfate, concentrate the organic phase, and purify it by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain a colorless oil (Compound II) with a yield of 72%; S3: Add 3.27g of compound II to 98.1mL of dimethyl ether, cool to 6°C, add 14mL of pre-prepared isotope-labeled methyl Grignard reagent (concentration of 3mol / L) to the system, stir at 6°C for 2h, and after the reaction is complete, quench the reaction with 98.1mL of saturated ammonium chloride, wash the organic phase with 98.1mL of saturated brine, dry with 3.27g of anhydrous sodium sulfate, concentrate the organic phase, and purify it by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 100:1) to obtain a colorless oil (compound III) with a yield of 44%; S4: 1.76 g of compound III was added to 52.8 mL of methyl tert-butyl ether, cooled to 6°C, 736 mg of sodium hydride was added to the system, followed by 4.75 mL of triethyl phosphonoacetate, and the mixture was heated to room temperature and stirred for 6 h. After the reaction was complete, the system was neutralized with 52.8 mL of formic acid, the aqueous phase was extracted 3 times with 52.8 mL of ethyl acetate, the organic phase was dried with 1.76 g of anhydrous sodium sulfate, the organic phase was concentrated, and purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 100:1) to obtain a colorless oil (compound IV) with a yield of 46%; S5: 1.92 g of compound IV was added to 57.6 mL of toluene, followed by 73.44 mL of tetrabutylammonium fluoride, cooled to 8 °C, and stirred at this temperature for 4 h. After the reaction was complete, 57.6 g of 15 wt% dilute hydrochloric acid was used to quench the reaction, and then the aqueous phase was extracted three times with 57.6 mL of ethyl acetate. The organic phase was dried with 1.92 g of anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate was 30:1) to obtain an oil (compound V) with a yield of 71%; S6: 866 mg of compound V was added to 17.32 mL of 1,2-dichloroethane, followed by 1.85 g of triphenylphosphine and 2.34 g of carbon tetrabromide, and stirred at room temperature for 15 h; after the reaction was complete, the aqueous phase was extracted three times with 25.98 mL of dichloromethane, the organic phase was dried with 0.866 g of anhydrous sodium sulfate, the organic phase was concentrated, and purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 200:1) to obtain an oil (compound VI), with a yield of 62%; S7: Add 1.2 mL of triethyl phosphite to 1.05 g of compound VI, heat under reflux and stir. After the reaction is complete, concentrate the system and purify it by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 100:1) to obtain a colorless oil (compound VII) with a yield of 60%; S8: At 8°C, slowly add 4.20 mL of n-butyl lithium (2.5 M in hexane) to 0.63 mL N,N -dimethylpropylene urea (DMPU) and 4mL dimethyl ether (containing 1.07g BETA-cyclocitral), 936mg compound VII was added to 28.05mL tetrahydrofuran, added to the system, and then stirred at this temperature for 2h. After the reaction was complete, the system was quenched with 28.08mL saturated ammonium chloride aqueous solution, and the aqueous phase was extracted 3 times with 28.08mL ethyl acetate. The organic phase was dried with 0.936g anhydrous sodium sulfate and concentrated to obtain compound VIII with a yield of 46%; S9: 780 mg of compound VIII was added to 19.5 mL of tetrahydrofuran, followed by 11.73 mL of DIBAL-H (1.5 Min toluene), and stirred at 5 °C for 3 h. After the reaction was complete, the system was quenched with 23.4 mL of saturated aqueous solution of potassium sodium tartrate, and the aqueous phase was extracted three times with 23.4 mL of ethyl acetate. The organic phase was dried with 0.78 g of anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate was 50:1) to obtain an oil (compound IX) with a yield of 58%; S10: 19.2 mL of ether was added to 480 mg of compound IX, followed by 9.34 g of manganese dioxide, and the mixture was heated under reflux for 8 h. After the reaction was complete, the system was cooled to room temperature, filtered with 1.44 g of diatomaceous earth, the organic phase was concentrated, and subjected to silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate was 50:1) to obtain an oil (compound X), with a yield of 47%; S11: Repeat S8 with 350 mg of compound Ⅹ to obtain compound Ⅺ. Repeat S9 with compound Ⅺ. After the reaction is complete, quench with 30 mL of saturated aqueous potassium sodium tartrate solution. Concentrate the organic phase to obtain a crude product. Perform silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain 192 mg of finished deuterated vitamin A (VA-D6) with a yield of 48%.

[0061] The above embodiments and descriptions are merely descriptions of preferred implementations of the present invention. The present invention is not limited by the above embodiments. Without departing from the spirit and scope of the present invention, various changes and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the protection scope determined by the present invention.

Claims

1. A method for preparing deuterated vitamin A, characterized in that: The following synthetic routes are included: ； Using BETA-cyclocitral and the compound VII as raw materials to prepare the deuterated vitamin A; The deuterated vitamin A is VA-D6, and its structural formula is shown below: ; The D in VA-D6 indicates that the hydrogen element is substituted with deuterium. R of the compound VII 2 Any one of CO2CH3, CO2Et, and CO2Pr; R of the compound VII 3 It is any one of OEt, OMe and OBu.

2. The preparation method according to claim 1, characterized in that: include: S1: Add the first solvent dissolved in glycolic acid and EDCI to the system N -Methylmorpholine undergoes amidation reaction under the action of dimethylhydroxylamine hydrochloride to generate compound Ⅰ; S2: adding the compound I into a second solvent to generate compound II under the action of a base and tert-butyldimethylsilyl chloride; S3: adding the compound II into a third solvent, and causing a methylation reaction under the action of an isotope-labeled methyl grignard reagent to generate a compound III; S4: adding the compound III to a fourth solvent, and causing a HWE reaction under the action of a first strong base and a first ester to generate a compound IV; S5: adding a fifth solvent to the compound IV, and then adding tetrabutylammonium fluoride to react to generate compound V; S6: adding the compound V to a sixth solvent to generate a compound VI under the action of triphenylphosphine and carbon tetrabromide; S7: Add the second ester to the compound VI, and heat under reflux to generate compound VII.

3. The preparation method according to claim 2, characterized in that: The reaction temperature of the amidation reaction is -30~0°C, and the reaction time is 10~30h; The reaction temperature of S2 is room temperature, and the reaction time is 5 to 15 hours; The reaction temperature of the methylation reaction is -5~6°C, and the reaction time is 1~2h; The reaction temperature of the HWE reaction is -5~6°C and the reaction time is 3~6h; The reaction temperature of S5 is -5~8°C, and the reaction time is 2~4h; The reaction temperature of S6 is room temperature, and the reaction time is 5 to 15 hours; The temperature of heating reflux of S7 is 100-150° C., and the time of heating reflux is 2-4 hours.

4. The preparation method according to claim 2, characterized in that: The first solvent is any one of methanol, 1,2-dichloroethane, dichloromethane, ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; The second solvent is 1,4-dioxane, N,N -Dimethylacetamide, N,N - Any one of dimethylformamide and acetonitrile; The base is pyridine, imidazole, N,N Any one of diisopropylethylamine and 4-dimethylaminopyridine; The third solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether and tetrahydrofuran; The fourth solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether and tetrahydrofuran; The first strong base is KHMDS, NaHMDS, LiHMDS, KO t - Any one of Bu, sodium hydride, and potassium hydride; The structural formula of the first ester is shown in Formula 1, ; The first ester R 1 Any one of OEt, OMe and OBu; The first ester R 2 Any one of CO2CH3, CO2Et, and CO2Pr; The fifth solvent is any one of methanol, 1,2-dichloroethane, dichloromethane, ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; The sixth solvent is any one of 1,2-dichloroethane, dichloromethane, ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; The second ester is R 3 2POEt, the second ester R 3 It is any one of OEt, OMe and OBu.

5. The preparation method according to claim 4, characterized in that: The weight volume ratio of the glycolic acid to the first solvent is 1:2 to 1:30; The molar ratio of the glycolic acid to the EDCI is 1:1 to 1:3; The glycolic acid and the N -The molar ratio of methylmorpholine is 1:1 to 1:3; The molar ratio of the glycolic acid to the dimethylhydroxylamine hydrochloride is 1:1 to 1:5; The weight-to-volume ratio of the compound I to the second solvent is 1:3-1:20; The molar ratio of the compound I to the base is 1:1 to 1:5; The molar ratio of the compound I to the tert-butyldimethylsilyl chloride is 1:1.1 to 1:2.0; The weight volume ratio of the compound II to the third solvent is 1:2-1:30; The concentration of the isotope-labeled methyl grignard reagent is 0.3-3 mol / L, and the molar ratio of the isotope-labeled methyl grignard reagent to the compound II is 1:1-3:1; The weight volume ratio of the compound III to the fourth solvent is 1:2-1:30; The molar ratio of the compound III to the first strong base is 1:1 to 1:2; The molar ratio of the compound III to the first ester is 1:1 to 1:3; The weight-to-volume ratio of the compound IV to the fifth solvent is 1:3-1:30; The molar ratio of the compound IV to the tetrabutylammonium fluoride is 1:2 to 1:10; The weight volume ratio of the compound V to the sixth solvent is 1:2 to 1:20; The molar ratio of the compound V to the triphenylphosphine is 1:1 to 1:1.2; The molar ratio of the compound V to the carbon tetrabromide is 1:1 to 1:1.2; The molar ratio of the compound VI to the second ester is 1:1.1 to 1:

2.

6. The preparation method according to claim 2, characterized in that: After the amidation reaction is completed, 2-15 wt % dilute hydrochloric acid is used to quench the reaction, dichloromethane is used for extraction, and the mixture is dried over anhydrous sodium sulfate. The weight ratio of the glycolic acid to the dilute hydrochloric acid is 1:2-1:30, the weight volume ratio of the glycolic acid to the dichloromethane used for each extraction is 1:2-1:30, and the weight ratio of the glycolic acid to the anhydrous sodium sulfate is 1:0.5-1:1; After the reaction of S2 is completed, the aqueous phase is extracted with ethyl acetate and dried with anhydrous sodium sulfate. The weight-volume ratio of the compound I to the ethyl acetate used in each extraction is 1:2-1:30, and the weight ratio of the compound I to the anhydrous sodium sulfate is 1:0.5-1:1; After the methylation reaction is completed, saturated ammonium chloride is used to quench the reaction, the organic phase is washed with saturated brine, and dried over anhydrous sodium sulfate, the weight volume ratio of the compound II to the saturated ammonium chloride is 1:2-1:30, the weight volume ratio of the compound II to the saturated brine is 1:2-1:30, and the weight ratio of the compound II to the anhydrous sodium sulfate is 1:0.5-1:1; After the HWE reaction is completed, a weak acid is used for neutralization, the aqueous phase is extracted with ethyl acetate, and the mixture is dried over anhydrous sodium sulfate. The weak acid is any one of formic acid, acetic acid, phosphoric acid, and hydrofluoric acid. The weight ratio of the compound III to the weak acid is 1:3 to 1:30, the weight-volume ratio of the compound III to the ethyl acetate used for each extraction is 1:2 to 1:30, and the weight ratio of the compound III to the anhydrous sodium sulfate is 1:0.5 to 1:1; After the reaction of S5 is completed, 2-15wt% dilute hydrochloric acid is used to quench the reaction, the aqueous phase is extracted with ethyl acetate, and dried over anhydrous sodium sulfate, the weight ratio of the compound IV to the dilute hydrochloric acid is 1:3-1:30, the weight volume ratio of the compound IV to the ethyl acetate used in each extraction is 1:2-1:30, and the weight ratio of the compound IV to the anhydrous sodium sulfate is 1:0.5-1:1; After the S6 reaction is completed, the aqueous phase is extracted with dichloromethane and dried over anhydrous sodium sulfate. The weight-to-volume ratio of the compound V to the dichloromethane used in each extraction is 1:2-1:30, and the weight ratio of the compound V to the anhydrous sodium sulfate is 1:0.5-1:

1.

7. The preparation method according to claim 1, characterized in that: The method of preparing the deuterated vitamin A using the compound VII and BETA-cyclocitral as raw materials comprises: S8: adding the compound VII to the seventh solvent, and then adding the compound VII to the solution of the second strong base, N,N - Compound VIII is generated under the action of dimethylpropylene urea and BETA-cyclocitral; S9: adding the eighth solvent to the compound VIII to generate compound IX under the action of diisobutylaluminum hydride; S10: adding a ninth solvent to the compound IX, heating under reflux under the action of an oxidant to generate a compound X; S11: Repeat S8 with the compound X to generate compound XI, and repeat S9 with the compound XI to generate deuterated vitamin A.

8. The preparation method according to claim 7, characterized in that: The seventh solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; The weight volume ratio of the compound VII to the seventh solvent is 1:2 to 1:30; The solution of the second strong base is a n-hexane solution of the second strong base, the second strong base is any one of methyl lithium, ethyl lithium, n-butyl lithium, and sec-butyl lithium, and the molar concentration of the solution of the second strong base is 1 to 2.5; The molar ratio of the compound VII to the second strong base is 1:1.1 to 1:3; The compound VII and the N,N - The molar ratio of dimethyl propylene urea is 1:1.2 to 1:1.5; The molar ratio of the compound VII to the BETA-cyclocitral is 1:1 to 1:2; The eighth solvent is any one of 1,2-dichloroethane, dichloromethane, diethyl ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; The weight volume ratio of the compound VIII to the eighth solvent is 1:3 to 1:25; The molar ratio of the compound VIII to the diisobutylaluminum hydride is 1:3 to 1:6; The ninth solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; The weight-to-volume ratio of the compound IX to the ninth solvent is 1:2-1:40; The oxidant is any one of chromic acid, hydrogen peroxide, and manganese dioxide; The molar ratio of the compound IX to the oxidant is 1:20 to 1:

50.

9. The preparation method according to claim 7, characterized in that: The reaction temperature of S8 is -5~8°C, and the reaction time is 1~2h; The reaction temperature of S9 is -5~5°C, and the reaction time is 1~3h; The heating reflux temperature of S10 is 50-80°C, and the heating reflux time is 3-8h; After the reaction of S8 is completed, a saturated aqueous ammonium chloride solution is used to quench the reaction, the aqueous phase is extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The weight volume ratio of the compound VII to the saturated aqueous ammonium chloride solution is 1:2-1:30, the weight volume ratio of the compound VII to the ethyl acetate used for each extraction is 1:2-1:30, and the weight ratio of the compound VII to the anhydrous sodium sulfate is 1:0.5-1:1; After the reaction of S9 is completed, a saturated aqueous solution of potassium sodium tartrate is used to quench the reaction, the aqueous phase is extracted with ethyl acetate, and dried over anhydrous sodium sulfate, the weight volume ratio of the compound VIII to the saturated aqueous solution of potassium sodium tartrate is 1:2-1:30, the weight volume ratio of the compound VIII to the ethyl acetate used in each extraction is 1:2-1:30, and the weight ratio of the compound VIII to the anhydrous sodium sulfate is 1:0.5-1:1; After the reaction in S10 is completed, the mixture is cooled to room temperature and filtered using diatomaceous earth. The weight ratio of the compound IX to the diatomaceous earth is 1:2-1:

3.

10. Use of the preparation method according to any one of claims 1 to 9 in the preparation of deuterated vitamin A.

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