A method for preparing deuterated vitamin A

Abstract

The present invention belongs to the technical field of chemical synthesis, and discloses a preparation method of deuterated vitamin A. This method uses glycolic acid as a raw material, and based on a series of reactions such as the HWE reaction, reduction, and oxidation, an isotopically labeled methyl Grignard reagent is added to synthesize a deuterated intermediate, and the deuterated intermediate and BETA-cyclocitral are synthesized into deuterated vitamin A through a series of reactions, specifically VA-D6. The deuterated vitamin A prepared by the present invention has a relatively high deuteration rate, and its deuteration rate is higher than 99%. The present invention provides a synthesis method for the preparation of deuterated vitamin A with a relatively high deuteration rate, good reaction selectivity, high yield, simple operation, and safety.

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] To achieve the technical object of the present invention, on the one hand, the present invention provides a preparation method of deuterated vitamin A, and its synthetic route is as follows. The deuterated vitamin A is VA-D6, and its structural formula is as follows. ; D in VA-D6 indicates 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 includes the following steps:

[0007]

[0008] S1: Add an N-methylmorpholine solution to the system of glycolic acid and EDCI. N N-methylmorpholine is dissolved in a first solvent, and dimethylhydroxylamine hydrochloride is added with stirring under the condition of -30~0 °C, and the reaction is stirred at room temperature for 10~30 h; after the reaction is complete, the reaction is quenched with dilute hydrochloric acid first, the aqueous phase is extracted with dichloromethane 3 times, the organic phases are combined, then dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain an oily substance (Compound I).

[0009] Specifically, the first solvent is any one of methanol, 1,2-dichloroethane, dichloromethane, ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; preferably, the first solvent is dichloromethane or tetrahydrofuran; the weight-to-volume ratio of glycolic acid to the first solvent is 1:2~1:30;

[0010] The molar concentration ratio of glycolic acid to EDCI is 1:1~1:3;

[0011] In the reaction system, the molar concentration ratio of glycolic acid to N N-methylmorpholine is 1:1~1:3; the molar concentration ratio of glycolic acid to dimethylhydroxylamine hydrochloride in the reaction system is 1:1~1:5;

[0012] The weight concentration of the dilute hydrochloric acid is 2~15%, and the weight ratio of glycolic acid to the dilute hydrochloric acid is 1:2~1:30;

[0013] The weight-to-volume ratio of glycolic acid to the dichloromethane used for each extraction is 1:2~1:30; the weight ratio of glycolic acid to anhydrous sodium sulfate is 1:0.5~1:1.

[0014] S2: Add the Compound I prepared in S1 to a second solvent, then add a base and tert-butyldimethylchlorosilane, and stir at room temperature for 5~15 h; after the reaction is complete, the aqueous phase is extracted with ethyl acetate 3 times, the organic phase is dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a colorless oily substance (Compound II).

[0015] Specifically, the second solvent is 1,4-dioxane, N,N 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;

[0016] The base is any one of pyridine, imidazole, N,N diisopropylethylamine, and 4 - dimethylaminopyridine; the molar ratio of compound I to the base is 1:1 - 1:5;

[0017] The molar ratio of compound I to tert - butyldimethylchlorosilane is 1:1.1 - 1:2.0;

[0018] The weight - volume ratio of compound I to ethyl acetate used for each extraction is 1:2 - 1:30; the weight ratio of compound I to anhydrous sodium sulfate is 1:0.5 - 1:1.

[0019] S3: Add the compound II prepared in S2 into a third solvent, cool it to - 5 - 6 °C, add the pre - prepared isotope - labeled methylmagnesium reagent to the system, stir for 1 - 2 h under the temperature condition of - 5 - 6 °C. After the reaction is complete, quench the reaction with saturated ammonium chloride, wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, concentrate it, and purify it by column chromatography to obtain a colorless oil (compound III).

[0020] 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;

[0021] The preparation method of the isotope - labeled methylmagnesium reagent is as follows: Under argon protection, add magnesium chips, I2, a small amount of CD3I, and anhydrous Et2O into a bottle equipped 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 to stir at room temperature until the bubbling ends, then the isotope - labeled methylmagnesium reagent is obtained.

[0022] The concentration of the isotope - labeled methylmagnesium reagent is 0.3 - 3 mol / L, and the molar ratio of the isotope - labeled methylmagnesium reagent to compound II is 1:1 - 3:1;

[0023] The weight - volume ratio of compound II to saturated ammonium chloride is 1:2 - 1:30;

[0024] The weight - volume ratio of compound II to saturated brine is 1:2 - 1:30;

[0025] The weight ratio of compound II to anhydrous sodium sulfate is 1:0.5 - 1:1.

[0026] S4: Add the compound Ⅲ prepared in S3 into a fourth solvent, cool to -5~6 °C, add a first strong base to the system, and then add a first ester (Formula 1, ), warm to room temperature, stir and react for 3~6 h. After the reaction is complete, neutralize the system with a weak acid, extract the aqueous phase 3 times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain a colorless oil (compound Ⅳ).

[0027] Specifically, the fourth solvent is an ether solvent, and the ether solvent is any one of ethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; the weight-to-volume ratio of compound Ⅲ to the ether solvent is 1:2~1:30;

[0028] The first strong base is any one of KHMDS, NaHMDS, LiHMDS, KO t -Bu, sodium hydride, and potassium hydride; the molar ratio of compound Ⅲ to the first strong base is 1:1~1:2;

[0029] R of the first ester 1 is OEt, OMe, or OBu; R 2 is any one of CO2CH3, CO2Et, and CO2Pr; the molar ratio of compound Ⅲ to the first ester is 1:1~1:3;

[0030] 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;

[0031] The weight-to-volume ratio of compound Ⅲ to the ethyl acetate used for each extraction is 1:2~1:30; the weight ratio of compound Ⅲ to anhydrous sodium sulfate is 1:0.5~1:1.

[0032] S5: Add a fifth solvent to compound Ⅳ, then add tetrabutylammonium fluoride, cool to -5~8 °C, and continuously stir and react at this temperature for 2~4 h. After the reaction is complete, first quench the reaction with dilute hydrochloric acid, then extract the aqueous phase 3 times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain an oil (compound Ⅴ).

[0033] Specifically, the fifth solvent is any one of methanol, 1,2-dichloroethane, dichloromethane, ethyl ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; preferably, the fifth solvent is dichloromethane or tetrahydrofuran; the weight-to-volume ratio of compound Ⅳ to the fifth solvent is 1:3~1:30;

[0034] The molar ratio of compound Ⅳ to tetrabutylammonium fluoride is 1:2~1:10;

[0035] The weight concentration of the dilute hydrochloric acid is 2~15%, and the weight ratio of compound Ⅳ to the dilute hydrochloric acid is 1:3~1:30;

[0036] The weight - volume ratio of Compound Ⅳ to ethyl acetate used for each extraction is 1:2 to 1:30; the weight ratio of Compound Ⅳ to anhydrous sodium sulfate is 1:0.5 to 1:1.

[0037] S6: Add Compound Ⅴ into the sixth solvent, then add triphenylphosphine and carbon tetrabromide, and stir at room temperature for 5 - 15 h; after the reaction is complete, extract the aqueous phase with dichloromethane 3 times, dry the organic phase with anhydrous sodium sulfate, concentrate it, and purify it by column chromatography to obtain an oily substance (Compound Ⅵ).

[0038] 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;

[0039] The molar ratio of Compound Ⅴ to triphenylphosphine is 1:1 to 1:1.2;

[0040] The molar ratio of Compound Ⅴ to carbon tetrabromide is 1:1 to 1:1.2;

[0041] The weight - volume ratio of Compound Ⅴ to dichloromethane used for each extraction is 1:2 to 1:30; the weight ratio of Compound Ⅴ to anhydrous sodium sulfate is 1:0.5 to 1:1.

[0042] S7: Add the second ester (R 3 2POEt) to Compound Ⅵ, heat under reflux, after the reaction is complete, concentrate the system, and purify it by column chromatography to obtain a colorless oily substance (Compound Ⅶ).

[0043] Specifically, R in the second ester 3 is any one of OEt, OMe, and OBu; the molar ratio of Compound Ⅵ to the second ester is 1:1.1 to 1:2; the temperature of heating under reflux is 100 - 150 °C, and the time of heating under reflux is 2 - 4 h.

[0044] S8: At - 5 - 8 °C, add Compound Ⅶ into the seventh solvent, then add a solution of the second strong base, N,N 1,3 - dimethyl - 3,4,5,6 - tetrahydro - 2(1H) - pyrimidinone (DMPU) and β - cyclocitral, stir at - 5 - 8 °C for 1 - 2 h, after the reaction is complete, quench the system with saturated ammonium chloride aqueous solution, extract the aqueous phase with ethyl acetate 3 times, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain Compound Ⅷ.

[0045] Specifically, the seventh solvent is an ether solvent, and the ether solvent is any one of 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;

[0046] 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 methyllithium, ethyllithium, n-butyllithium, and sec-butyllithium. 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;

[0047] Compound VII and N,N The molar ratio of -dimethylallylurea is 1:1.2 to 1:1.5;

[0048] The molar ratio of compound VII to BETA-cyclocitral is 1:1 to 1:2;

[0049] The weight-to-volume ratio of compound VII to saturated ammonium chloride aqueous solution is 1:2 to 1:30;

[0050] The weight-to-volume ratio of compound VII to ethyl acetate used for each extraction is 1:2 to 1:30; the weight ratio of compound VII to anhydrous sodium sulfate is 1:0.5 to 1:1.

[0051] S9: Add the eighth solvent to compound VIII, then add diisobutylaluminum hydride (DIBAL-H), stir at -5 to 5 °C for 1 to 3 h. After the reaction is complete, quench the system with saturated aqueous sodium potassium tartrate, extract the aqueous phase with ethyl acetate 3 times, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain an oily substance (compound IX).

[0052] 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-to-volume ratio of compound VIII to the eighth solvent is 1:3 to 1:25;

[0053] The molar ratio of compound VIII to DIBAL-H is 1:3 to 1:6;

[0054] The weight-to-volume ratio of compound VIII to saturated aqueous sodium potassium tartrate is 1:2 to 1:30;

[0055] The weight-to-volume ratio of compound VIII to ethyl acetate used for each extraction is 1:2 to 1:30; the weight ratio of compound VIII to anhydrous sodium sulfate is 1:0.5 to 1:1.

[0056] S10: Add the ninth solvent to compound IX, then add an oxidant, heat under reflux at 50 to 80 °C for 3 to 8 h. After the reaction is complete, cool the system to room temperature, filter through diatomaceous earth, concentrate the organic phase, and purify by column chromatography to obtain an oily substance (compound X).

[0057] 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 to 1:40;

[0058] The oxidizing agent is any one of chromic acid, hydrogen peroxide, and manganese dioxide; the molar ratio of compound IX to the oxidizing agent is 1:20 to 1:50;

[0059] The weight ratio of compound IX to diatomaceous earth is 1:2 to 1:3.

[0060] S11: Repeat compound X to obtain compound XI. Repeat S9 for compound XI. After the reaction is complete, quench with a saturated aqueous solution of sodium potassium tartrate, concentrate the organic phase to obtain a crude product, and purify by silica gel column chromatography to obtain the finished product deuterated vitamin A (VA-D6);

[0061] Specifically, the weight-volume ratio of compound XI to the saturated aqueous solution of sodium potassium tartrate is 1:2 to 1:30.

[0062] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects or advantages:

[0063] (1) The preparation method of deuterated vitamin A provided by the present invention uses glycolic acid as a raw material, and through a series of reactions such as reduction and oxidation based on the HWE reaction, synthesizes a deuterated intermediate through an isotope-labeled methyl Grignard reagent, and synthesizes deuterated vitamin A, specifically VA-D6, by reacting the deuterated intermediate with BETA-cyclocitral. The deuterated vitamin A prepared by the present invention has a high deuteration rate, and its deuteration rate is higher than 99%. The present invention provides a synthesis method for deuterated vitamin A with good reaction selectivity, high yield, simple operation, and safety.

[0064] (2) The deuterated vitamin A prepared by the present invention has a high deuteration rate, has great application prospects in drug research and development, drug metabolic stability, and pharmacokinetic property research, and has excellent isotope tracing effects and a low metabolic rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 is the 1H NMR spectrum of compound I.

[0066] Figure 2 is the 13C NMR spectrum of compound I.

[0067] Figure 3 is the 1H NMR spectrum of compound II.

[0068] Figure 4 is the 13C NMR spectrum of compound II.

[0069] Figure 51H NMR spectrum of Compound Ⅲ.

[0070] Figure 6 13C NMR spectrum of Compound Ⅲ.

[0071] Figure 7 1H NMR spectrum of Compound Ⅳ.

[0072] Figure 8 13C NMR spectrum of Compound Ⅳ.

[0073] Figure 9 1H NMR spectrum of Compound Ⅴ.

[0074] Figure 10 13C NMR spectrum of Compound Ⅴ.

[0075] Figure 11 1H NMR spectrum of Compound Ⅵ.

[0076] Figure 12 13C NMR spectrum of Compound Ⅵ.

[0077] Figure 13 1H NMR spectrum of Compound Ⅶ.

[0078] Figure 14 13C NMR spectrum of Compound Ⅶ.

[0079] Figure 15 1H NMR spectrum of Compound Ⅷ.

[0080] Figure 16 1H NMR spectrum of Compound Ⅸ.

[0081] Figure 17 1H NMR spectrum of Compound Ⅹ.

[0082] Figure 18 13C NMR spectrum of Compound Ⅹ.

[0083] Figure 19 1H NMR spectrum of Compound Ⅺ.

[0084] Figure 20 13C NMR spectrum of Compound Ⅺ.

[0085] Figure 21 1H NMR spectrum of VA-D6.

[0086] Figure 22 13C NMR spectrum of VA-D6.

[0087] Figure 23 1H NMR comparison spectrum of VA-D6 and Vitamin A. Detailed implementation method

[0088] The technical solution of the present invention will now be described in conjunction with embodiments. However, the present invention is not limited to the following embodiments. The experimental methods and detection methods described in the following embodiments are all conventional methods unless otherwise specified; the reagents and materials are all commercially available unless otherwise specified.

[0089] The unit of weight / volume ratio in the present invention is g:mL.

[0090] The synthetic route of deuterated vitamin A of the present invention is as follows.

[0091]

[0092] Example 1

[0093] This example provides a method for preparing deuterated vitamin A, which specifically includes the following steps:

[0094] S1: Add 40 mL of N a dichloromethane solution of N-methylmorpholine ( N the mass of N-methylmorpholine is 2.89 g) to a system of 1.98 g of glycolic acid and 5.48 g of EDCI to obtain a white suspension. Stir and add 2.79 g of dimethylhydroxylamine hydrochloride at -30 °C, and then stir and react at room temperature for 30 h. After the reaction is complete, add 5 g of dilute hydrochloric acid with a weight concentration of 2% to quench the reaction. Extract the aqueous phase 3 times with 40 mL of dichloromethane, combine the organic phases, dry with 1.6 g of anhydrous sodium sulfate, concentrate the organic phase, and purify by silica gel column chromatography (the volume ratio of dichloromethane to methanol is 100:1) to obtain an oily substance (Compound I) with a yield of 60%. The 1H NMR spectrum of Compound I is as Figure 1 shown, 1 1H NMR (500 MHz, CDCl3): δ 4.21 (s, 2H), 3.61 (s, 3H), 3.24 (s,1H), 3.15 (s, 3H). The 13C NMR spectrum of Compound I is as Figure 2 shown, 13 13C NMR (126 MHz, CDCl3): δ172.91, 61.14, 59.47, 32.15.

[0095] S2: Add 2.14 g of Compound I to 15 mL of N,NIn N,N-dimethylformamide, 2.45 g of imidazole and 3.25 g of tert-butyldimethylchlorosilane were then added, and the mixture was stirred at room temperature for 10 h. After the reaction was complete, the aqueous phase was extracted three times with 20 mL of ethyl acetate. The organic phase was dried with 2 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 a colorless oil (Compound II) with a yield of 70%. The 1H NMR spectrum of Compound II is as follows Figure 3 shown 1 1H 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 13C NMR spectrum of Compound II is as follows Figure 4 shown 13 13C NMR (126 MHz, CDCl3): δ 61.13, 32.23, 25.60, 18.26, -5.60.

[0096] S3: 3.27 g of Compound II was added to 30 mL of tetrahydrofuran, and the mixture was cooled to -3 °C. 21 mL of pre-prepared isotopically labeled methylmagnesium reagent (concentration: 1 mol / L) was added to the system, and the mixture was stirred at -3 °C for 1.5 h. After the reaction was complete, the reaction was quenched with 10 mL of saturated ammonium chloride. The organic phase was washed with 10 mL of saturated brine, dried with 3 g of anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate was 100:1) to obtain Compound III with a yield of 45%. The preparation method of the isotopically labeled methylmagnesium reagent was as follows: Under argon protection, magnesium chips, I2, a small amount of CD3I, and anhydrous Et2O were added to a flask equipped with a reflux tube. The system was heated with a hair dryer at room temperature until the iodine in the system faded and bubbles started to form. The remaining CD3I was slowly added dropwise, and the mixture was continuously stirred at room temperature until the bubbling ended, thus obtaining the reagent. The 1H NMR spectrum of Compound III is as follows Figure 5 shown 1 1H NMR (500 MHz, CDCl3): δ 4.13 (s, 2H), 0.91 (s, 9H), 0.08 (s, 6H). The 13C NMR spectrum of Compound III is as follows Figure 6 shown 13 13C NMR (126 MHz, CDCl3): δ 209.52, 69.70, 25.88, 18.41, -5.39.

[0097] S4: Add 1.76 g of Compound Ⅲ to 20 mL of tetrahydrofuran, cool to -3 °C, add 368 mg of sodium hydride (60% in mineral oil) to the system, then add 1.74 mL of triethyl phosphonoacetate, raise the temperature to room temperature and stir for 5 h. After the reaction is complete, neutralize the system with 10 mL of acetic acid, extract the aqueous phase with 10 mL of ethyl acetate three times, dry the organic phase with 1.4 g of anhydrous sodium sulfate, concentrate the organic phase, and purify by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 100:1) to obtain a colorless oil (Compound Ⅳ) with a yield of 48%. The 1H NMR spectrum of Compound Ⅳ is as Figure 7 shown, 1 1H NMR (500 MHz, CDCl3): δ 6.03 (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 13C NMR spectrum of Compound Ⅳ is as Figure 8 shown, 13 13C NMR (126 MHz, CDCl3): δ 167.22, 157.19, 113.54, 67.20, 59.71, 26.01, 18.50, 14.49, -5.31.

[0098] S5: Add 1.92 g of Compound Ⅳ to 20 mL of tetrahydrofuran, then add 14.7 mL of tetrabutylammonium fluoride (concentration 1 mol / L), cool to -5 °C, and stir continuously at this temperature for 4 h. After the reaction is complete, quench the reaction with 6 g of 2 wt% dilute hydrochloric acid first, then extract the aqueous phase with 20 mL of ethyl acetate three times, dry the organic phase with 2 g of anhydrous sodium sulfate, concentrate the organic phase, and purify 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 1H NMR spectrum of Compound Ⅴ is as Figure 9 shown, 1 1H 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, 1.6 Hz, 3H). The 13C NMR spectrum of Compound Ⅴ is as Figure 10 shown, 1313C NMR (126 MHz, CDCl3): δ 167.15, 157.50, 113.71, 66.97, 59.90, 14.34.

[0099] S6: 865.4 mg of compound V was added to 12 mL of dichloromethane, followed by the addition of 1.70 g of triphenylphosphine and 2.15 g of carbon tetrabromide, and the mixture was stirred at room temperature for 7 h; after the reaction was complete, the aqueous phase was extracted 3 times with 20 mL of dichloromethane, the organic phase was dried with 0.8 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 oily substance (compound VI) with a yield of 60%. The 1H NMR spectrum of compound VI is as Figure 11 shown 1 1H NMR (500 MHz, CDCl3): δ 5.94 (s, 1H), 4.16 (q, J = 7.1 Hz, 4H), 3.93 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H). The 13C NMR spectrum of compound VI is as Figure 12 shown 13 13C NMR (126 MHz, CDCl3): δ 166.01, 152.32, 119.71, 60.21, 38.34, 14.35.

[0100] S7: 0.9 mL of triethyl phosphite was added to 1.05 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 (the volume ratio of petroleum ether to ethyl acetate was 100:1) to obtain a colorless oily substance (compound VII) with a yield of 60%. The 1H NMR spectrum of compound VII is as Figure 13 shown 1 1H 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 13C NMR spectrum of compound VII is as Figure 14 shown 13 13C 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.

[0101] S8: At -5 °C, 1.82 mL of n-butyllithium (2.5 M in hexane) was slowly added dropwise to a solution of 0.55 mL N,N of 1,3-dimethylpropyleneurea (DMPU) and 3 mL of diethyl ether (containing 586 mg of β-cyclocitral). 935 mg of compound VII was added to 7 mL of diethyl ether and then added to the system. Subsequently, the mixture was stirred at this temperature for 2 h. After the reaction was complete, the system was quenched with 10 mL of saturated aqueous ammonium chloride. The aqueous phase was extracted three times with 10 mL of ethyl acetate. The organic phase was dried over 1 g of anhydrous sodium sulfate and concentrated to obtain compound VIII in a yield of 50%. The 1H NMR spectrum of compound VIII is as Figure 15 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).

[0102] S9: 796.23 mg of compound VIII was added to 17 mL of dichloromethane, and then 6 mL of DIBAL-H (1.5 M in toluene) was added. The mixture was 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. The aqueous phase was extracted three times with 20 mL of ethyl acetate. The organic phase was dried over 0.6 g of anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 50:1) to obtain an oily substance (compound IX) in a yield of 60%. The 1H NMR spectrum of compound IX is as Figure 16 shown 1 H NMR (500 MHz, CDCl3): δ 6.16 – 5.97 (m, 2H), 5.62 (t, J = 7.0 Hz, 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).

[0103] S10: Add 11 mL of tetrahydrofuran to 496 mg of Compound Ⅸ, then add 3.86 g of manganese dioxide, and reflux the mixture for 5 h. After the reaction is complete, cool the system to room temperature, filter it through 1 g of diatomaceous earth, concentrate the organic phase, and perform silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain an oily substance (Compound Ⅹ) with a yield of 50%. The 1H NMR spectrum of Compound Ⅹ is as follows Figure 17 shown as 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 13C NMR spectrum of Compound Ⅹ is as follows Figure 18 shown as 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.

[0104] S11: Repeat S8 with 362 mg of Compound Ⅹ to obtain Compound Ⅺ. Then repeat S9 with Compound Ⅺ. After the reaction is complete, quench it with 20 mL of a saturated aqueous solution of potassium sodium tartrate, concentrate the organic phase to obtain a crude product, and perform silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain 200 mg of the finished product deuterated vitamin A (VA-D6) with a yield of 50%. The 1H NMR spectrum of Compound Ⅺ is as follows Figure 19 shown as 11H 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 = 6.4 Hz, 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 13C NMR spectrum of Compound Ⅺ is as shown in Figure 20 as follows 13 13C 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 1H NMR spectrum of VA-D6 is as shown in Figure 21 as follows 1 1H 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). The 13C NMR spectrum of VA-D6 is as shown in Figure 22 as follows 13 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.

[0105] Further comparison of the 1H NMR spectra of VA-D6 and vitamin A in the present invention reveals that there are differences in the 1H NMR spectra of the two in the range of chemical shift 1.8 - 2.0. Vitamin A shows two absorption peaks here, which are the signals of non-deuterated methyl hydrogen atoms. After calculation, the deuteration rate of VA-D6 is: ((3 - 0.02) / 3) × 100% = 99.3%.

[0106] Example 2

[0107] This example provides a preparation method of deuterated vitamin A, which specifically includes the following steps:

[0108] S1: Add 4 mL of 1,2-dichloroethane solution (containing 3.42 g N -methylmorpholine) to a system of 1.98 g of glycolic acid and 6.48 g of EDCI to obtain a white suspension. Stir and add 7.6 g of dimethylhydroxylamine hydrochloride at -15°C, and then stir at room temperature for about 15 h. After the reaction is complete, add 2 g of dilute hydrochloric acid with a weight concentration of 5% to quench the reaction. Extract the aqueous phase 3 times with 3.96 mL of dichloromethane, combine the organic phases, dry with 1 g of anhydrous sodium sulfate, concentrate the organic phase, and purify by silica gel column chromatography (the volume ratio of dichloromethane to methanol is 100:1) to obtain an oily substance (Compound I) with a yield of 55%;

[0109] S2: Add 1.07 g of Compound I to 3.21 mL of N,N -dimethylacetamide, then add 611.53 g of imidazole and 1.49 g of tert-butyldimethylchlorosilane, and stir at room temperature for 5 h; after the reaction is complete, extract the aqueous phase 3 times with 2.2 mL of ethyl acetate, dry the organic phase with 0.54 g of anhydrous sodium sulfate, concentrate the organic phase, and purify by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain a colorless oily substance (Compound II) with a yield of 60%;

[0110] S3: Add 1.6 g of Compound II to 3.2 mL of ether, cool to -5°C, add the pre-prepared 22.85 mL of isotope-labeled methyl Grignard reagent (concentration 0.3 mol / L) to the system, stir at -5°C for 1 h, 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 by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 100:1) to obtain a colorless oily substance (Compound III) with a yield of 40%;

[0111] S4: Add 0.9 g of Compound Ⅲ to 1.8 mL of dimethyl ether, cool to -5 °C, add 628.39 mg of potassium hydride (30% in mineral oil) to the system, then add 0.9 mL of diethyl methylphosphonoacetate, raise the temperature to room temperature and stir for 3 h. After the reaction is complete, neutralize the system with 2.7 mL of formic acid, extract the aqueous phase 3 times with 1.8 mL of ethyl acetate, dry the organic phase with 0.45 g of anhydrous sodium sulfate, concentrate the organic phase, and purify by silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 100:1) to obtain a colorless oil (Compound Ⅳ) with a yield of 40%;

[0112] S5: Add 1 g of Compound Ⅳ to 3 mL of dichloromethane, then add 7.6 mL of tetrabutylammonium fluoride, cool to -7 °C, and stir continuously at this temperature for 2 h. After the reaction is complete, first quench the reaction with 4 g of 5 wt% dilute hydrochloric acid, then extract the aqueous phase 3 times with 2 mL of ethyl acetate, dry the organic phase with 0.5 g of anhydrous sodium sulfate, concentrate the organic phase, and purify 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 58%;

[0113] S6: Add 430 mg of Compound Ⅴ to 0.86 mL of tetrahydrofuran, then add 766.25 mg of triphenylphosphine and 968.82 mg of carbon tetrabromide, and stir at room temperature for 5 h; after the reaction is complete, extract the aqueous phase 3 times with 0.85 mL of dichloromethane, dry the organic phase with 215 mg of anhydrous sodium sulfate, concentrate the organic phase, and purify 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 48%;

[0114] S7: Add 403.42 mg of diethyl methylphosphite to 0.5 g of Compound Ⅵ, heat under reflux and stir. After the reaction is complete, concentrate the system and purify 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 51%;

[0115] S8: At -7 °C, slowly drop 1.26 mL of ethyl lithium (1.5 M in hexane) into 0.25 mL of N,N -dimethylpropyleneurea (DMPU) and 2 mL of tetrahydrofuran (containing 261.85 mg of BETA-cyclocitral). Add 460 mg of Compound Ⅶ to 4 mL of tetrahydrofuran and add it to the system, then stir at this temperature for 1 h. After the reaction is complete, quench the system with 0.92 mL of saturated ammonium chloride aqueous solution, extract the aqueous phase 3 times with 0.92 mL of ethyl acetate, dry and concentrate the organic phase with 230 mg of anhydrous sodium sulfate to obtain Compound Ⅷ with a yield of 43%;

[0116] S9: Add 1.197 mL of 1,2-dichloroethane to 399 mg of Compound VIII, then add 4 mL of DIBAL-H (1.5 M in toluene), stir at -7 °C for 2 h. After the reaction is complete, quench the system with 0.798 mL of saturated aqueous sodium potassium tartrate solution, extract the aqueous phase with 0.798 mL of ethyl acetate three times, dry the organic phase with 0.2 g of anhydrous sodium sulfate, concentrate the organic phase, and purify by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain an oily substance (Compound IX) with a yield of 54%;

[0117] S10: Add 0.5 mL of methyl tert-butyl ether to 250 mg of Compound IX, then add 761 mg of hydrogen peroxide, heat under reflux for 3 h. After the reaction is complete, cool the system to room temperature, filter through 0.6 g of diatomaceous earth, concentrate the organic phase, and perform silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain an oily substance (Compound X) with a yield of 43%;

[0118] S11: Repeat S8 for 362 mg of Compound X to obtain Compound XI, and repeat S9 for Compound XI. After the reaction is complete, quench with 12 mL of saturated aqueous sodium potassium tartrate solution, concentrate the organic phase to obtain a crude product, and perform silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain 120 mg of the finished product deuterated vitamin A (VA-D6) with a yield of 41%.

[0119] Example 3

[0120] This example provides a method for preparing deuterated vitamin A, which specifically includes the following steps:

[0121] S1: Add 59.4 mL of tetrahydrofuran solution (containing 7.9 g of N -methylmorpholine) to a system of 1.98 g of glycolic acid and 15 g of EDCI to obtain a white suspension. Stir and add 11.2 g of dimethylhydroxylamine hydrochloride at 0 °C, then stir at room temperature for about 30 h. After the reaction is complete, add 59.4 g of dilute hydrochloric acid with a weight concentration of 15% to quench the reaction, extract the aqueous phase with 60 mL of dichloromethane three times, combine the organic phases, dry with 1.98 g of anhydrous sodium sulfate, concentrate the organic phase, and purify by silica gel column chromatography (the volume ratio of dichloromethane to methanol is 100:1) to obtain an oily substance (Compound I) with a yield of 61%;

[0122] S2: Add 2.14 g of Compound I to 42.8 mL of N,NIn N,N-dimethylformamide, 6.13 g of imidazole and 5.43 g of tert-butyldimethylchlorosilane were then added, and the mixture was stirred at room temperature for 15 h. After the reaction was complete, the aqueous phase was extracted 3 times with 64.2 mL of ethyl acetate. The organic phase was dried with 2.14 g of anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate was 50:1) to obtain a colorless oil (Compound II) with a yield of 72%.

[0123] S3: 3.27 g of Compound II was added to 98.1 mL of dimethyl ether, and the mixture was cooled to 6 °C. 14 mL of pre-prepared isotope-labeled methylmagnesium reagent (concentration 3 mol / L) was added to the system, and the mixture was stirred at 6 °C for 2 h. After the reaction was complete, the reaction was quenched with 98.1 mL of saturated ammonium chloride. The organic phase was washed with 98.1 mL of saturated brine, dried with 3.27 g of anhydrous sodium sulfate, 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 III) with a yield of 44%.

[0124] S4: 1.76 g of Compound III was added to 52.8 mL of methyl tert-butyl ether, and the mixture was cooled to 6 °C. 736 mg of sodium hydride was added to the system, and then 4.75 mL of triethyl phosphonoacetate was added. The mixture was stirred at room temperature 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, 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%.

[0125] S5: 1.92 g of Compound IV was added to 57.6 mL of toluene, and then 73.44 mL of tetrabutylammonium fluoride was added. The mixture was cooled to 8 °C and stirred at this temperature for 4 h. After the reaction was complete, the reaction was first quenched with 57.6 g of 15 wt% dilute hydrochloric acid, and then the aqueous phase was extracted 3 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 (the volume ratio of petroleum ether to ethyl acetate was 30:1) to obtain an oil (Compound V) with a yield of 71%.

[0126] S6: 866 mg of Compound V was added to 17.32 mL of 1,2-dichloroethane, and then 1.85 g of triphenylphosphine and 2.34 g of carbon tetrabromide were added. The mixture was stirred at room temperature for 15 h. After the reaction was complete, the aqueous phase was extracted 3 times with 25.98 mL of dichloromethane. The organic phase was dried with 0.866 g of anhydrous sodium sulfate, 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%.

[0127] S7: Add 1.2 mL of triethyl phosphite to 1.05 g of Compound VI, heat under reflux with stirring. After the reaction is complete, concentrate the system and purify it by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 100:1) to obtain a colorless oil (Compound VII) with a yield of 60%;

[0128] S8: At 8 °C, slowly drip 4.20 mL of n-butyllithium (2.5 M in hexane) into a mixture of 0.63 mL N,N -dimethylpropyleneurea (DMPU) and 4 mL of dimethyl ether (containing 1.07 g of BETA-cyclocitral). Add 936 mg of Compound VII to 28.05 mL of tetrahydrofuran and add it to the system. Then stir at this temperature for 2 h. After the reaction is complete, quench the system with 28.08 mL of saturated ammonium chloride aqueous solution, extract the aqueous phase 3 times with 28.08 mL of ethyl acetate, dry the organic phase with 0.936 g of anhydrous sodium sulfate, and concentrate to obtain Compound VIII with a yield of 46%;

[0129] S9: Add 780 mg of Compound VIII to 19.5 mL of tetrahydrofuran, then add 11.73 mL of DIBAL-H (1.5 M in toluene), stir at 5 °C for 3 h. After the reaction is complete, quench the system with 23.4 mL of saturated aqueous potassium sodium tartrate solution, extract the aqueous phase 3 times with 23.4 mL of ethyl acetate, dry the organic phase with 0.78 g 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 an oil (Compound IX) with a yield of 58%;

[0130] S10: Add 19.2 mL of diethyl ether to 480 mg of Compound IX, then add 9.34 g of manganese dioxide, heat under reflux for 8 h. After the reaction is complete, cool the system to room temperature, filter it through 1.44 g of diatomaceous earth, concentrate the organic phase, and perform silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain an oil (Compound X) with a yield of 47%;

[0131] S11: Repeat S8 for 350 mg of Compound X to obtain Compound XI. Repeat S9 for Compound XI. After the reaction is complete, quench it with 30 mL of saturated aqueous potassium sodium tartrate solution, concentrate the organic phase to obtain a crude product, and perform silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain 192 mg of the finished product deuterated vitamin A (VA-D6) with a yield of 48%.

[0132] The above examples and the description are only for describing the preferred embodiments of the present invention. The present invention is not limited by the above examples. Without departing from the spirit and scope of the present invention, various changes and improvements made by those of ordinary skill in the art to the technical solutions of the present invention shall fall within the protection scope determined by the present invention.

Claims

1. A preparation method of deuterated vitamin A, characterized in that, It includes the following synthetic routes. Preparing the deuterated vitamin A using BETA-cyclocitral and the compound VII as raw materials, including: S8: Adding the compound VII into the seventh solvent, and then generating the compound VIII under the action of a solution of the second strong base, N,N-dimethylallylurea, and BETA-cyclocitral; S9: Adding the eighth solvent to the compound VIII, and generating the compound IX under the action of diisobutylaluminum hydride; S10: Adding the ninth solvent to the compound IX, and heating to reflux under the action of an oxidant to generate the compound X; S11: Adding the compound X into the seventh solvent, and then generating the compound XI under the action of a solution of the second strong base, N,N-dimethylallylurea, and the compound VII; adding the eighth solvent to the compound XI, and generating the deuterated vitamin A under the action of diisobutylaluminum hydride; The deuterated vitamin A is VA-D6, and its structural formula is as follows: In VA-D6, D represents that the hydrogen element is deuterated; The R of 1 is any one of OEt, OMe, and OBu; R of the said compound VII 2 is any one of CO2CH3, CO2Et, and CO2Pr; R of the said compound VII 3 is any one of OEt, OMe and OBu; The solution of the second strong base is a n-hexane solution of the second strong base, and the second strong base is any one of methyllithium, ethyllithium, n-butyllithium, and sec-butyllithium.

2. The preparation method according to claim 1, characterized in that, It includes: S1: Adding N-methylmorpholine dissolved in the first solvent to the system of glycolic acid and EDCI, and carrying out an amidation reaction under the action of dimethylhydroxylamine hydrochloride to generate the compound I; S2: Adding the compound I into the second solvent, and generating the compound II under the action of a base and tert-butyldimethylchlorosilane; S3: Adding the compound II into the third solvent, and carrying out a methylation reaction under the action of an isotope-labeled methyl Grignard reagent to generate the compound III; S4: Adding the compound III into the fourth solvent, and carrying out an HWE reaction under the action of the first strong base and the first ester to generate the compound IV; S5: Adding the fifth solvent to the compound IV, and then adding tetrabutylammonium fluoride to react to generate the compound V; S6: Adding the compound V into the sixth solvent, and generating the compound VI under the action of triphenylphosphine and carbon tetrabromide; S7: Adding the second ester to the compound VI, and heating to reflux to generate the compound VII The structural formula of the first ester is shown in Formula 1, The R of the first ester 1 is any one of OEt, OMe, and OBu; The R of the first ester 2 is any one of CO2CH3, CO2Et, and CO2Pr; The second ester is R 3 2POEt, and R in the second ester 3 is any one of OEt, OMe, and OBu; The first strong base is any one of KHMDS, NaHMDS, LiHMDS, KO t -Bu, sodium hydride, and potassium hydride.

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

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 any one of 1,4-dioxane, N,N-dimethylacetamide, N,N-dimethylformamide, and acetonitrile; The base is any one of pyridine, imidazole, N,N-diisopropylethylamine, and 4-dimethylaminopyridine; The third solvent is any one of ethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; The fourth solvent is any one of ethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; The fifth solvent is any one of methanol, 1,2-dichloroethane, dichloromethane, ethyl ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; The sixth solvent is any one of 1,2-dichloroethane, dichloromethane, ethyl ether, toluene, methyl tert-butyl ether, and tetrahydrofuran.

5. The preparation method according to claim 4, characterized in that, The weight-volume ratio of glycolic acid to the first solvent is 1:2 to 1:30; The molar ratio of glycolic acid to EDCI is 1:1 to 1:3; The molar ratio of glycolic acid to N-methylmorpholine is 1:1 to 1:3; The molar ratio of glycolic acid to dimethylhydroxylamine hydrochloride is 1:1 to 1:5; The weight-volume ratio of compound I to the second solvent is 1:3 to 1:20; The molar ratio of compound I to the base is 1:1 to 1:5; The molar ratio of compound I to tert-butyldimethylchlorosilane is 1:1.1 to 1:2.0; The weight-volume ratio of compound II to the third solvent is 1:2 to 1:30; The concentration of the isotope-labeled methyl Grignard reagent is 0.3 to 3 mol / L, and the molar ratio of the isotope-labeled methyl Grignard reagent to compound II is 1:1 to 3:1; The weight-volume ratio of compound III to the fourth solvent is 1:2 to 1:30; The molar ratio of compound III to the first strong base is 1:1 to 1:2; The molar ratio of compound III to the first ester is 1:1 to 1:3; 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-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 molar ratio of compound VI to the second ester is 1:1.1 to 1:

2.

6. The preparation method according to claim 2, wherein After the amidation reaction is completed, the reaction is quenched with 2 to 15 wt% dilute hydrochloric acid, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The weight ratio of glycolic acid to the dilute hydrochloric acid is 1:2 to 1:30, the weight-volume ratio of glycolic acid to the dichloromethane used for each extraction is 1:2 to 1:30, and the weight ratio of glycolic acid to the anhydrous sodium sulfate is 1:0.5 to 1:1; After the S2 reaction is completed, the aqueous phase is extracted with ethyl acetate and dried over anhydrous sodium sulfate. The weight-volume ratio of compound I to the ethyl acetate used for each extraction is 1:2 to 1:30, and the weight ratio of compound I to the anhydrous sodium sulfate is 1:0.5 to 1:1; After the methylation reaction is completed, the reaction is quenched with saturated ammonium chloride. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate. The weight-to-volume ratio of Compound II to saturated ammonium chloride is 1:2 to 1:30, the weight-to-volume ratio of Compound II to saturated brine is 1:2 to 1:30, and the weight ratio of Compound II to anhydrous sodium sulfate is 1:0.5 to 1:1; After the HWE reaction is completed, it is neutralized with a weak acid, and the aqueous phase is extracted with ethyl acetate and 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 Compound III to the weak acid is 1:3 to 1:30, the weight-to-volume ratio of Compound III to the ethyl acetate used for each extraction is 1:2 to 1:30, and the weight ratio of Compound III to anhydrous sodium sulfate is 1:0.5 to 1:1; After the S5 reaction is completed, the reaction is quenched with 2 - 15 wt% dilute hydrochloric acid, the aqueous phase is extracted with ethyl acetate and dried over anhydrous sodium sulfate. The weight ratio of Compound IV to the dilute hydrochloric acid is 1:3 to 1:30, the weight-to-volume ratio of Compound IV to the ethyl acetate used for each extraction is 1:2 to 1:30, and the weight ratio of Compound IV to anhydrous sodium sulfate is 1:0.5 to 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 Compound V to the dichloromethane used for each extraction is 1:2 to 1:30, and the weight ratio of Compound V to anhydrous sodium sulfate is 1:0.5 to 1:

1.

7. The preparation method according to claim 1, wherein The seventh solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; The weight-to-volume ratio of Compound VII to the seventh solvent is 1:2 to 1:30; The molar concentration of the solution of the second strong base is 1 - 2.5; The molar ratio of Compound VII to the second strong base is 1:1.1 to 1:3; The molar ratio of Compound VII to N,N-dimethylallylurea is 1:1.2 to 1:1.5; The molar ratio of Compound VII to 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-to-volume ratio of Compound VIII to the eighth solvent is 1:3 to 1:25; The molar ratio of Compound VIII to 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 Compound IX to the ninth solvent is 1:2 to 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-to-volume ratio of Compound X to the seventh solvent is 1:2 to 1:30; The molar ratio of Compound X to the second strong base is 1:1.1 to 1:3; The molar ratio of Compound X to N,N-dimethylallylurea is 1:1.2 to 1:1.5; The molar ratio of the compound Ⅹ to the compound Ⅶ is 1:1 to 1:2; The weight-to-volume ratio of the compound Ⅺ to the eighth solvent is 1:3 to 1:25; The molar ratio of the compound Ⅺ to the diisobutylaluminum hydride is 1:3 to 1:

6.

8. The preparation method according to claim 1, characterized in that, The reaction temperature of S8 is -5 to 8 °C, and the reaction time is 1 to 2 h; The reaction temperature of S9 is -5 to 5 °C, and the reaction time is 1 to 3 h; The heating reflux temperature of S10 is 50 to 80 °C, and the heating reflux time is 3 to 8 h; The reaction temperature for generating the compound Ⅺ in S11 is -5 to 8 °C, and the reaction time is 1 to 2 h; The reaction temperature for generating the deuterated vitamin A in S11 is -5 to 5 °C, and the reaction time is 1 to 3 h; After the reaction of S8 is completed, the reaction is quenched with a saturated aqueous ammonium chloride solution, the aqueous phase is extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The weight-to-volume ratio of the compound Ⅶ to the saturated aqueous ammonium chloride solution is 1:2 to 1:

30. The weight-to-volume ratio of the compound Ⅶ to the ethyl acetate used for each extraction is 1:2 to 1:

30. The weight ratio of the compound Ⅶ to the anhydrous sodium sulfate is 1:0.5 to 1:1; After the reaction of S9 is completed, the reaction is quenched with a saturated aqueous potassium sodium tartrate solution, the aqueous phase is extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The weight-to-volume ratio of the compound Ⅷ to the saturated aqueous potassium sodium tartrate solution is 1:2 to 1:

30. The weight-to-volume ratio of the compound Ⅷ to the ethyl acetate used for each extraction is 1:2 to 1:

30. The weight ratio of the compound Ⅷ to the anhydrous sodium sulfate is 1:0.5 to 1:1; After the reaction of S10 is completed, it is cooled to room temperature and filtered through diatomaceous earth. The weight ratio of the compound Ⅸ to the diatomaceous earth is 1:2 to 1:3; After the compound Ⅺ is generated in S11, the reaction is quenched with a saturated aqueous ammonium chloride solution, the aqueous phase is extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The weight-to-volume ratio of the compound Ⅹ to the saturated aqueous ammonium chloride solution is 1:2 to 1:

30. The weight-to-volume ratio of the compound Ⅹ to the ethyl acetate used for each extraction is 1:2 to 1:

30. The weight ratio of the compound Ⅹ to the anhydrous sodium sulfate is 1:0.5 to 1:1; After the deuterated vitamin A is generated in S11, the reaction is quenched with a saturated aqueous potassium sodium tartrate solution, the aqueous phase is extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The weight-to-volume ratio of the compound Ⅺ to the saturated aqueous potassium sodium tartrate solution is 1:2 to 1:

30. The weight-to-volume ratio of the compound Ⅺ to the ethyl acetate used for each extraction is 1:2 to 1:

30. The weight ratio of the compound Ⅺ to the anhydrous sodium sulfate is 1:0.5 to 1:

1.

9. Use of the preparation method according to any one of claims 1 to 8 in the preparation of deuterated vitamin A.

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