Preparation method of vitamin A

Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a preparation method of vitamin A. According to the method, BETA-cyclocitral and a prepared intermediate phosphate ester are taken as key raw materials, and based on a Horner-Wadsworth-Emmons reaction, the vitamin A is synthesized through a series of reactions such as reduction, oxidation and the like. The invention provides a synthesis method which is good in reaction selectivity, relatively good in reproducibility, relatively high in yield, simple and convenient to operate and safe for vitamin A preparation.

Description

Technical Field

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

[0002] Vitamin A (VA) is a fat-soluble vitamin. The main sources of vitamin A intake include animal foods such as animal liver, seafood, meat, dairy products, eggs, and plant foods such as carrots, pumpkin, spinach, and tomatoes. It plays an important role in vision protection, immune system support, cell growth and differentiation, reproductive health and development, and antioxidant effects. Vitamin A deficiency can lead to anemia, decreased immunity, growth and development disorders, and a variety of skin and eye symptoms. Since the human body cannot synthesize vitamin A on its own, it needs to be obtained through food or supplements. However, the content of vitamin A in natural foods is limited and is affected by many factors such as region, season, storage and cooking methods. Artificial synthesis of vitamin A has become an important supplement.

[0003] Early methods of synthesizing vitamin A were to extract it from the liver of slow-caught fish. However, this method was difficult to meet large-scale demand due to limited fish resources and high costs. Currently, vitamin A is mainly obtained through chemical synthesis, such as the Kuhn-Morris synthesis method, from β -ionone, adding bromoacetate to obtain C15-skeleton, which is then converted into C15-aldehyde to obtain a key intermediate, which undergoes aldol condensation with pentenal in the presence of piperidine and acetic acid to generate retinal, which can be reduced to vitamin A by Meerwein-Ponndorf-Verley. The raw materials of this method are easy to obtain, but the reproducibility is poor; Patent US2676990A discloses a method from β -ionone synthesis of vitamin A process, the method has a high yield, but there is a problem of cumbersome operation. Therefore, it is of great significance to explore a vitamin A synthesis method with good reproducibility, simple operation and high yield. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides a method for preparing vitamin A. BETA-cyclocitral and the prepared intermediate phosphate are used as key raw materials, based on the Horner-Wadsworth-Emmons reaction, vitamin A is synthesized through a series of reactions such as reduction and oxidation. The present invention provides a synthetic method for preparing vitamin A with good reaction selectivity, good reproducibility, high yield, simple operation and safety.

[0005] In order to achieve the technical purpose of the present invention, on the one hand, the present invention provides a method for preparing vitamin A, and its synthetic route is as follows, which specifically comprises the following steps:

[0006] S1: Dissolve hydroxyacetone in the first solvent, then add tert-butyldimethylsilyl chloride and a catalyst, and then add triethylamine. Stir at room temperature for 5 to 10 hours. After the reaction is complete, add the second solvent, wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, and concentrate the organic phase to obtain a colorless oil (Compound I).

[0007] 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 volume ratio of hydroxyacetone to the first solvent is 1:1-1:30; The molar ratio of hydroxyacetone to tert-butyldimethylsilyl chloride is 1:1.1 to 1:1.5; The catalyst is any one of 4-dimethylaminopyridine (DMAP), pyridine, 2,6-lutidine, and 2-methylpyridine; the molar ratio of hydroxyacetone to the catalyst is 1:1.2 to 1:1.5; The molar ratio of hydroxyacetone to triethylamine is 1:1.2 to 1:1.5; The second 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 hydroxyacetone to the second solvent is 1:2-1:30; The weight-to-volume ratio of hydroxyacetone to saturated saline is 1:2 to 1:30; The weight ratio of hydroxyacetone to anhydrous sodium sulfate is 1:0.5~1:1.

[0008] S2: Add compound I prepared in S1 to the third 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 and stir 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 the organic phase, and purify it by column chromatography to obtain a colorless oil (Compound II).

[0009] 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 I to the third 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 I to the first strong base is 1:1~1:2; The first ester R 1 OEt, OMe, OBu; R2 is CO2CH3, CO2Et or CO2Pr; the molar ratio of compound I to the first ester is 1:1~1:3; The weak acid is any one of formic acid, acetic acid, phosphoric acid and hydrofluoric acid; the weight volume ratio of compound I to the weak acid is 1:3-1:30; 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.

[0010] S3: Add the fourth solvent to compound II, then add tetrabutylammonium fluoride, cool to -5~8°C, and continue stirring at this temperature for 2~4 hours. After the reaction is complete, quench the reaction with dilute hydrochloric acid, then extract the aqueous phase three times with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase, and purify it by column chromatography to obtain an oily substance (compound III).

[0011] The fourth solvent is any one of methanol, 1,2-dichloroethane, dichloromethane, ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; preferably, the fourth solvent is dichloromethane or tetrahydrofuran; the weight volume ratio of compound II to the fourth solvent is 1:3-1:30; The molar ratio of compound II to tetrabutylammonium fluoride is 1:2 to 1:10; The weight concentration of dilute hydrochloric acid is 2-15%, and the weight volume ratio of compound II to dilute hydrochloric acid is 1:3-1:30; The weight-volume ratio of compound II to ethyl acetate used in each extraction is 1:2-1:30; the weight ratio of compound II to anhydrous sodium sulfate is 1:0.5-1:1.

[0012] S4: Add compound III to the fifth solvent, then add triphenylphosphine and carbon tetrabromide, and stir at room temperature for 5-15 hours. After the reaction is complete, extract the aqueous phase three times with dichloromethane, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase, and purify it by column chromatography to obtain an oily substance (compound IV).

[0013] The fifth solvent is any one of 1,2-dichloroethane, dichloromethane, ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; preferably, the fifth solvent is 1,2-dichloroethane or dichloromethane; the weight volume ratio of compound III to the fifth solvent is 1:2 to 1:20; The molar ratio of compound III to triphenylphosphine is 1:1 to 1:1.2; The molar ratio of compound III to carbon tetrabromide is 1:1 to 1:1.2; The weight-volume ratio of compound III to dichloromethane 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.

[0014] S5: Add the second ester to compound IV, heat and reflux at 100-150°C for 2-4 hours. After the reaction is complete, concentrate the system and purify by column chromatography to obtain a colorless oil (compound V).

[0015] The second ester is R 3 2POEt, the second ester R 3 It is any one of OEt, OMe, and OBu; the molar ratio of compound IV to the second ester is 1:1.1~1:2.

[0016] S6: Add the sixth solvent to compound V at -5-8°C, add the second strong base solution, N,N -dimethylpropylene urea (DMPU) and BETA-cyclocitral are stirred at this temperature for 1-2 hours. After the reaction is complete, the system is quenched with a saturated aqueous solution of ammonium chloride, the aqueous phase is extracted three times with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate, and concentrated to obtain compound VI.

[0017] The sixth 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 V to the sixth solvent is 1:2-1:30; 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 which is 1 to 2.5, and the molar ratio of compound V to the second strong base is 1:1.1 to 1:3; Compound V N,N - The molar ratio of dimethyl propylene urea is 1:1.2 to 1:1.5; The molar ratio of compound V to BETA-cyclocitral is 1:1 to 1:2; The weight volume ratio of compound V to saturated ammonium chloride aqueous solution is 1:2 to 1:30; The weight-volume ratio of compound V to ethyl acetate 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.

[0018] S7: Add the seventh solvent to compound VI, 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 the organic phase, and purify it by column chromatography to obtain an oily substance (compound VII).

[0019] The seventh solvent is any one of 1,2-dichloroethane, dichloromethane, diethyl ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; preferably, the seventh solvent is 1,2-dichloroethane or diethyl ether; the weight volume ratio of compound VI to the seventh solvent is 1:3-1:20; The molar ratio of compound VI to DIBAL-H is 1:3 to 1:6; The weight-to-volume ratio of compound VI to a saturated aqueous solution of sodium potassium tartrate is 1:2 to 1:30; The weight-volume ratio of compound VI to ethyl acetate used in each extraction is 1:2-1:30; the weight ratio of compound VI to anhydrous sodium sulfate is 1:0.5-1:1.

[0020] S8: Add the eighth solvent to compound VII, then add the oxidant, heat to reflux for 3 to 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 VIII).

[0021] The eighth 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 eighth solvent is 1:2-1:40; The oxidant is any one of chromic acid, hydrogen peroxide, and manganese dioxide; the molar ratio of compound VII to the oxidant is 1:20 to 1:50; The weight ratio of compound VII to diatomaceous earth is 1:2~1:3.

[0022] S9: Repeat S6 with the compound VIII obtained above to obtain compound IX. Repeat S7 with compound IX. After the reaction is complete, quench with a saturated aqueous solution of potassium sodium tartrate. Concentrate the organic phase to obtain a crude product. Purify it by silica gel column chromatography to obtain finished vitamin A (VA).

[0023] Specifically, the weight volume ratio of compound IX to the saturated aqueous solution of potassium sodium tartrate is 1:2 to 1:30.

[0024] Compared with the prior art, the technical solution provided by the present invention has at least the following beneficial effects or advantages: The present invention provides a method for preparing vitamin A, using BETA-cyclocitral and the prepared intermediate phosphate as key raw materials, based on the Horner-Wadsworth-Emmons reaction, and then synthesizing vitamin A through a series of reactions such as reduction and oxidation. The present invention provides a synthetic method for preparing vitamin A with good reaction selectivity, good reproducibility, high yield, simple operation and safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is the H NMR spectrum of compound Ⅰ.

[0026] Figure 2 This is the carbon NMR spectrum of compound Ⅰ.

[0027] Figure 3 This is the H NMR spectrum of compound II.

[0028] Figure 4 This is the carbon NMR spectrum of compound II.

[0029] Figure 5 This is the H NMR spectrum of compound III.

[0030] Figure 6 This is the carbon NMR spectrum of compound III.

[0031] Figure 7 This is the hydrogen NMR spectrum of compound IV.

[0032] Figure 8 This is the carbon NMR spectrum of compound IV.

[0033] Fig. 9 This is the hydrogen NMR spectrum of compound V.

[0034] Fig.10 This is the carbon NMR spectrum of compound V.

[0035] Fig.11 This is the hydrogen nuclear magnetic resonance spectrum of compound VI.

[0036] Fig.12 This is the hydrogen nuclear magnetic resonance spectrum of compound VIII.

[0037] Fig.13 This is the H NMR spectrum of compound IX.

[0038] Fig.14 This is the H NMR spectrum of VA. DETAILED DESCRIPTION

[0039] 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.

[0040] The unit of weight to volume ratio in the present invention is g:mL.

[0041] The synthetic route of vitamin A of the present invention is as follows.

[0042]

[0043] Example 1 This embodiment provides a method for preparing vitamin A, which specifically comprises the following steps: S1: Dissolve 5g of hydroxyacetone in 60mL of dichloromethane, then add 12g of tert-butyldimethylsilyl chloride and 10.7g of 4-dimethylaminopyridine, and then add 9g of triethylamine, stir at room temperature for 7h, after the reaction is complete, add 60mL of ether, wash the organic phase with 50mL of saturated brine, dry with 4g of anhydrous sodium sulfate, and concentrate the organic phase to obtain a colorless oil (Compound I), with a yield of 78%. The H NMR spectrum of Compound I is as follows Figure 1 As shown, 1 H NMR (500 MHz, CDCl3):δ 4.13 (s, 2H),2.15 (s, 3H), 0.91 (s, 10H), 0.07 (s, 6H). The carbon NMR spectrum of compound Ⅰ is shown in Figure 2 As shown, 13 CNMR (126 MHz, CDCl3): δ 209.40, 69.66, 26.11, 25.87, 18.40, -5.41. S2: Add 1.76g of compound I 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 II) with a yield of 50%. The hydrogen nuclear magnetic resonance spectrum of compound II is as follows: Figure 3 As shown, 1 H NMR (500 MHz, CDCl3):δ 5.96(t, J = 1.6 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 4.08 (d, J = 2.0 Hz, 2H), 2.03(s, 3H), 1.26 (t, 3H), 0.90 (s, 9H), 0.06 (s, 6H). The carbon NMR spectrum of compound II is shown in Figure 2. Figure 4 As shown, 13 C NMR (126 MHz, CDCl3): δ 167.21, 157.30, 113.41, 67.19, 59.69, 25.98,18.48, 15.55, 14.47, -5.34. S3: Add 1.92g of compound II 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 three times with 20mL of ethyl acetate, dry the organic phase with 1.5g of anhydrous sodium sulfate, concentrate the organic phase, and purify it with silica gel column chromatography (volume ratio of petroleum ether to ethyl acetate is 30:1) to obtain an oil (compound III), with a yield of 70%. The hydrogen nuclear magnetic resonance spectrum of compound III is as follows Figure 5 As shown, 1 H NMR (500 MHz, CDCl3):δ 5.90 (d, J = 4.0 Hz, 1H),4.09 (q, 2H), 4.04 (s, 2H), 3.33 (s, 1H), 2.00 (s, 3H), 1.27 – 1.17 (m, 3H). The carbon NMR spectrum of compound ‌Ⅲ is shown in Figure 6 As shown, 13 C NMR (126 MHz, CDCl3): δ 167.22, 157.78,113.45, 66.78, 59.86, 15.58, 14.25. S4: Add 866 mg of compound ‌Ⅲ to 12 mL of dichloromethane, then add 1.77 g of triphenylphosphine and 2.23 g of carbon tetrabromide, and stir at room temperature for 7 hours; 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 with silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 200:1) to obtain an oil (compound ‌Ⅳ), with a yield of 60%. The hydrogen nuclear magnetic resonance spectrum of compound ‌Ⅳ is as follows Figure 7 As shown, 1 H NMR (500 MHz, CDCl3):δ 5.95(s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.94 (s, 2H), 2.27 (d, J = 1.4 Hz, 3H),1.28 (t, J = 7.1, 1.7 Hz, 3H). The carbon NMR spectrum of compound Ⅳ is shown in Figure 8 As shown, 13 C NMR (126MHz, CDCl3): δ 166.06, 152.47, 119.65, 60.25, 38.44, 17.33, 14.36. S5: Add 0.9 mL of triethyl phosphite to 1.05 g of compound Ⅳ, heat under reflux at 120°C and stir for 3 h. 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 Ⅴ) with a yield of 60%. The H NMR spectrum of compound Ⅴ is as follows Fig. 9 As shown, 1 H NMR (500 MHz, CDCl3):δ5.72 (d, J = 5.4 Hz, 1H), 4.17 – 3.97 (m, 6H), 2.62 (d, J = 23.4 Hz, 2H),2.27 – 2.21 (m, 3H), 1.26 (t, J = 7.1 Hz, 6H), 1.21 (t, J = 7.1 Hz, 3H). The carbon NMR spectrum of compound Ⅴ is shown in Figure 2. Fig.10 As shown, 13 C NMR (126 MHz, CDCl3): δ 166.04, 166.01,149.64, 149.56, 120.07, 119.97, 62.26, 62.21, 59.76, 39.08, 38.01, 20.04,20.02, 16.44, 16.39, 14.28. S6: 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 587mg BETA-cyclocitral) to obtain a reaction system, 936mg compound Ⅴ was added to 7mL ether, and then added to the above reaction system, stirred at -5°C for 2h, after the reaction was complete, the system was quenched with 10mL saturated ammonium chloride aqueous solution, the aqueous phase was extracted 3 times with 10mL ethyl acetate, the organic phase was dried with 1g anhydrous sodium sulfate, and concentrated to obtain the organic phase (compound Ⅵ), with a yield of 50%. The hydrogen nuclear magnetic resonance spectrum of compound Ⅵ is as follows Fig.11 As shown, 1H NMR (500MHz, CDCl3): δ 6.55 (d, J = 15.9 Hz, 1H), 6.08 (d, J = 16.1 Hz, 1H), 5.73 (s,1H), 4.22 – 4.11 (m, 2H), 2.33 (d, J = 1.1 Hz, 3H), 2.05 – 1.99 (m, 2H), 1.69 (s, 3H), 1.64 – 1.58 (m, 2H), 1.51 – 1.42 (m, 2H), 1.31 – 1.24 (m, 3H), 1.01 (s, 6H). S7: Add 796.23 mg of compound VI to 14 mL of dichloromethane, followed by 8 mL of DIBAL-H (1.5 M intoluene), and stir at -5 °C for 1 h. After the reaction is complete, quench the system with 20 mL of saturated aqueous potassium sodium tartrate solution, extract the aqueous phase three times with 20 mL of ethyl acetate, dry the organic phase with 0.6 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 VII), which is directly added to the next step.

[0044] S8: Add 11 mL of tetrahydrofuran to 496 mg of compound Ⅶ, then add 3.86 g of manganese dioxide, heat and reflux at 65 ° C 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 (the volume ratio of petroleum ether to ethyl acetate is 50:1) to obtain an oil (compound Ⅷ). The yield of the above two steps S7 and S8 is 50%. The hydrogen nuclear magnetic resonance spectrum of compound Ⅷ is as follows Fig.12 As shown, 1 H NMR (500 MHz, CDCl3): δ 10.12 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 16.1 Hz, 1H), 6.20 (d, J = 16.1 Hz, 1H), 5.93 (d, J = 8.2Hz, 1H), 2.30 (s, 3H), 2.04 (t, J = 6.5 Hz, 2H), 1.72 (s, 3H), 1.64 – 1.58 (m, 2H), 1.49 – 1.45 (m, 2H), 1.03 (s, 6H). S9: Repeat S6 with 362 mg of compound Ⅷ to obtain compound IX, with a yield of 50%; repeat S7 with 225 mg of compound IX. After the reaction is complete, quench with 5 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 vitamin A (VA), with a yield of 50%. The H NMR spectrum of compound IX is as follows: Fig.13 As shown, 1 H NMR (500 MHz, CDCl3) δ 6.99 (dd, J = 15.1, 11.4 Hz, 1H), 6.29 (d, J = 5.7 Hz, 1H), 6.26 (d, J = 6.7 Hz, 1H), 6.15 (s, 1H), 6.12 (d, J = 6.0Hz, 1H), 5.77 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 2.02 (t, J =6.4 Hz, 2H), 2.00 (s, 3H), 1.71 (s, 3H), 1.64 – 1.58 (m, 2H), 1.48 – 1.45 (m, 2H), 1.29 (d, J = 7.2 Hz, 2H), 1.27 (d, J = 3.1 Hz, 2H), 1.02 (s, 6H). The H NMR spectrum of VA is as follows: Fig.14 As shown, 1 H NMR (500 MHz, CDCl3): δ 6.67 – 6.54 (m, 1H), 6.28 (d, J= 15.2 Hz, 1H), 6.18 – 6.03 (m, 3H), 5.69 (t, J = 6.9 Hz, 1H), 4.31 (d, J =6.9 Hz, 2H), 2.01 (t, J = 6.6 Hz, 3H), 1.95 (s, 3H), 1.86 (s, 2H), 1.70 (s,3H), 1.64 – 1.57 (m, 2H), 1.48 – 1.43 (m, 2H), 1.02 (s, 6H). Example 2 This embodiment provides a method for preparing vitamin A, which specifically comprises the following steps: S1: Dissolve 5 g of hydroxyacetone in 60 mL of tetrahydrofuran, then add 11.19 g of tert-butyldimethylsilyl chloride and 9.9 g of 4-dimethylaminopyridine, and then add 8.2 g of triethylamine. Stir at room temperature for 5 h. After the reaction is complete, add 10 mL of dimethyl ether. Wash the organic phase with 10 mL of saturated brine, dry with 2.5 g of anhydrous sodium sulfate, and concentrate the organic phase to obtain a colorless oil (Compound I) with a yield of 70%.

[0045] S2: Add 0.9 g of compound I to 1.8 mL of dimethyl ether, cool to -5°C, add 628.39 mg of sodium hydride (30% in mineral oil) to the system, then add 0.9 mL of diethyl methylphosphonoacetate, warm to room temperature and stir for 3 hours. After the reaction is complete, neutralize the system with 2.7 mL of formic acid, extract the aqueous phase three 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 it by silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 100:1) to obtain a colorless oil (compound II) with a yield of 40%.

[0046] S3: Add 1 g of compound II to 3 mL of dichloromethane, followed by 7.6 mL of tetrabutylammonium fluoride, cool to -7 °C, and continue stirring at this temperature for 2 h. After the reaction is complete, quench the reaction with 4 g of 5 wt% dilute hydrochloric acid, extract the aqueous phase three 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 it with silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 30:1) to obtain an oil (compound III) with a yield of 58%.

[0047] S4: Add 430 mg of compound ‌Ⅲ to 0.86 mL of tetrahydrofuran, followed by 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 three times with 0.85 mL of dichloromethane, dry the organic phase with 215 mg of anhydrous sodium sulfate, concentrate the organic phase, and purify it with silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 200:1) to obtain an oil (compound ‌Ⅳ) with a yield of 48%.

[0048] S5: Add 403.42 mg of dimethyl ethyl phosphite to 0.5 g of compound Ⅳ, heat under reflux at 100°C with stirring for 2 h. 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 Ⅴ) with a yield of 51%.

[0049] S6: At -7°C, slowly drop 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) to obtain a reaction system, 460mg of compound Ⅴ was added to 4mL tetrahydrofuran, and then added to the above reaction system, stirred at -7°C for 1h. After the reaction was complete, the system was quenched with 0.92mL saturated aqueous ammonium chloride solution, the aqueous phase was extracted 3 times with 0.92mL ethyl acetate, and the organic phase was dried with 230mg anhydrous sodium sulfate and concentrated to obtain the organic phase (compound Ⅵ) with a yield of 43%.

[0050] S7: Add 399 mg of compound VI to 1.197 mL of 1,2-dichloroethane, and then add 4 mL of DIBAL-H (1.5 Min toluene), stir at -7 °C for 2 h. After the reaction is complete, quench the system with 0.798 mL of saturated aqueous potassium sodium tartrate, extract the aqueous phase three times with 0.798 mL of ethyl acetate, dry the organic phase with 0.2 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 VII), which is directly added to the next step.

[0051] S8: Add 0.5 mL of methyl tert-butyl ether to 250 mg of compound Ⅶ, followed by 761 mg of hydrogen peroxide, and heat under reflux at 50 °C for 3 h. After the reaction is complete, cool the system to room temperature, filter with 0.5 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 Ⅷ). The yield of the above two steps S7 and S8 is 43%.

[0052] S9: Repeat S6 with 181 mg of compound Ⅷ to obtain compound IX, with a yield of 48%; repeat S7 with 108 mg of compound IX. After the reaction is complete, quench with 0.2 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 120 mg of finished vitamin A (VA), with a yield of 41%.

[0053] Example 3 This embodiment provides a method for preparing vitamin A, which specifically comprises the following steps: S1: Dissolve 5 g of hydroxyacetone in 60 mL of ether, then add 15.3 g of tert-butyldimethylsilyl chloride and 12.37 g of 4-dimethylaminopyridine, and then add 10.24 g of triethylamine. Stir at room temperature for 10 h. After the reaction is complete, add 150 mL of methyl tert-butyl ether. Wash the organic phase with 150 mL of saturated brine, dry over 5 g of anhydrous sodium sulfate, and concentrate the organic phase to obtain a colorless oil (Compound I) with a yield of 76%.

[0054] S2: Add 1.76 g of compound I to 52.8 mL of methyl tert-butyl ether, cool to 6°C, add 736 mg of sodium hydride to the system, then add 4.75 mL of triethyl phosphonoacetate, warm to room temperature and stir for 6 hours. After the reaction is complete, neutralize the system with 52.8 mL of acetic acid, extract the aqueous phase three times with 52.8 mL of ethyl acetate, dry the organic phase with 1.76 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 100:1) to obtain a colorless oil (compound II) with a yield of 49%.

[0055] S3: Add 1.92 g of compound II to 57.6 mL of toluene, then add 73.44 mL of tetrabutylammonium fluoride, cool to 8 ° C, and continue stirring at this temperature for 4 hours. After the reaction is complete, quench the reaction with 57.6 g of 15 wt% dilute hydrochloric acid, and then extract the aqueous phase three times with 57.6 mL of ethyl acetate. Dry the organic phase with 1.92 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 30:1) to obtain an oil (compound III) with a yield of 70%.

[0056] S4: Add 866 mg of compound ‌Ⅲ to 17.32 mL of 1,2-dichloroethane, followed by 1.85 g of triphenylphosphine and 2.34 g of carbon tetrabromide, and stir at room temperature for 15 h. After the reaction is complete, extract the aqueous phase three times with 25.98 mL of dichloromethane, dry the organic phase with 0.866 g of anhydrous sodium sulfate, concentrate the organic phase, and purify it with silica gel column chromatography (the volume ratio of petroleum ether to ethyl acetate is 200:1) to obtain an oil (compound ‌Ⅳ) with a yield of 58%.

[0057] S5: Add 1.2 mL of triethyl phosphite to 1.05 g of compound Ⅳ, heat under reflux at 150°C with stirring for 4 h. 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 Ⅴ) with a yield of 61%.

[0058] S6: At 8°C, slowly drop 4.20 mL of n-butyl lithium (2.5 M in hexane) into 0.63 mL N,N -dimethylpropylene urea (DMPU) and 4 mL of dimethyl ether (containing 1.07 mg of BETA-cyclocitral) were added to obtain a reaction system, 936 mg of compound Ⅴ was added to 28.05 mL of tetrahydrofuran, and then added to the above reaction system, stirred at 8°C for 2 h. After the reaction was complete, the system was quenched with 28.08 mL of saturated aqueous ammonium chloride solution, the aqueous phase was extracted 3 times with 28.08 mL of ethyl acetate, and the organic phase was dried with 0.936 g of anhydrous sodium sulfate and concentrated to obtain the organic phase (compound Ⅵ) with a yield of 52%.

[0059] S7: Add 780 mg of compound VI to 15.6 mL of tetrahydrofuran, and then add 11.73 mL of DIBAL-H (1.5 Min 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, extract the aqueous phase three 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 VII), which is directly added to the next step.

[0060] S8: 19.2 mL of ether was added to 480 mg of compound Ⅶ, followed by 9.34 g of manganese dioxide. The mixture was heated under reflux at 80 °C for 8 h. After the reaction was complete, the system was cooled to room temperature and filtered with 1.44 g of diatomaceous earth. The organic phase was concentrated and chromatographed on a silica gel column (the volume ratio of petroleum ether to ethyl acetate was 50:1) to obtain an oil (compound Ⅷ). The yield of the above two steps S7 and S8 was 47%.

[0061] S9: Repeat S6 with 350 mg of compound Ⅷ to obtain compound IX, with a yield of 51%; repeat S7 with 221.88 g of compound IX. After the reaction is complete, quench with 6.66 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 finished vitamin A (VA), with a yield of 48%.

[0062] 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 vitamin A, characterized in that: The following synthetic routes are included: ； Using BETA-cyclocitral and the compound V as raw materials to prepare the vitamin A; R of the compound V 2 Any one of CO2CH3, CO2Et, and CO2Pr; R of the compound V 3 It is any one of OEt, OMe and OBu.

2. The preparation method according to claim 1, characterized in that: include: S1: dissolving hydroxyacetone in a first solvent, adding tert-butyldimethylsilyl chloride and a catalyst, and adding a second solvent after the reaction with triethylamine is complete to generate compound I; S2: adding the compound I into a third solvent to generate compound II under the action of a first strong base and a first ester; S3: adding a fourth solvent to the compound II, and adding tetrabutylammonium fluoride to react to generate a compound III; S4: adding the compound III to a fifth solvent to generate a compound IV under the action of triphenylphosphine and carbon tetrabromide; S5: Add the second ester to the compound IV, and heat under reflux to generate the compound V.

3. The preparation method according to claim 2, characterized in that: The reaction temperature of S1 is room temperature, and the reaction time is 5 to 10 hours; The reaction temperature of S2 is -5~6°C, and the reaction time is 3~6h; The reaction temperature of S3 is -5~8°C, and the reaction time is 2~4h; The reaction temperature of S4 is room temperature, and the reaction time is 5 to 15 hours; The heating reflux temperature of S5 is 100-150° C., and the heating reflux time 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 catalyst is any one of 4-dimethylaminopyridine, pyridine, 2,6-dimethylpyridine, and 2-methylpyridine; The second solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; The third 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 OEt, OMe, OBu; R 2 is CO2CH3, CO2Et or CO2Pr; The fourth solvent is any one of methanol, 1,2-dichloroethane, dichloromethane, ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; The fifth solvent is any one of 1,2-dichloroethane, dichloromethane, diethyl 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 2, characterized in that: The molar ratio of the hydroxyacetone to the tert-butyldimethylsilyl chloride is 1:1.1 to 1:1.5; The molar ratio of the hydroxyacetone to the catalyst is 1:1.2 to 1:1.5; The molar ratio of the hydroxyacetone to the triethylamine is 1:1.2 to 1:1.5; The weight volume ratio of the hydroxyacetone to the second solvent is 1:2 to 1:30; The weight volume ratio of the compound I to the third solvent is 1:2-1:30; The molar ratio of the compound I to the first strong base is 1:1 to 1:2; The molar ratio of the compound I to the first ester is 1:1 to 1:3; The weight volume ratio of the compound II to the fourth solvent is 1:3 to 1:30; The molar ratio of the compound II to the tetrabutylammonium fluoride is 1:2 to 1:10; The weight volume ratio of the compound III to the fifth solvent is 1:2 to 1:20; The molar ratio of the compound III to the triphenylphosphine is 1:1 to 1:1:2; The molar ratio of the compound III to the carbon tetrabromide is 1:1 to 1:1:2; The molar ratio of the compound IV to the second ester is 1:1.1-1:

2.

6. The preparation method according to claim 2, characterized in that: After the reaction of S1 is completed, the organic phase is washed with saturated brine and dried over anhydrous sodium sulfate, the weight volume ratio of the hydroxyacetone to the saturated brine is 1:2-1:30, and the weight ratio of the hydroxyacetone to the anhydrous sodium sulfate is 1:0.5-1:1; After the reaction of S2 is completed, a weak acid neutralization system is used, the aqueous phase is extracted with ethyl acetate, and dried with anhydrous sodium sulfate, the weak acid is any one of formic acid, acetic acid, phosphoric acid, and hydrofluoric acid, the weight volume ratio of the compound I to the weak acid is 1:3-1:30, the weight volume ratio of the compound I to the ethyl acetate used for 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 reaction of S3 is completed, dilute hydrochloric acid is used to quench the reaction, the aqueous phase is extracted with ethyl acetate, and the phase is dried over anhydrous sodium sulfate. The weight concentration of the dilute hydrochloric acid is 2-15%, the weight volume ratio of the compound II to the dilute hydrochloric acid is 1:3-1:30, the weight volume ratio of the compound II to the ethyl acetate used for each extraction 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 S4 reaction is completed, the aqueous phase is extracted with dichloromethane and dried with anhydrous sodium sulfate. The weight-to-volume ratio of the compound III to the dichloromethane used in each extraction is 1:2-1:30, and the weight ratio of the compound III to the anhydrous sodium sulfate is 1:0.5-1:

1.

7. The preparation method according to claim 2, characterized in that: The preparation of vitamin A using BETA-cyclocitral and compound V as raw materials comprises: S6: Add the sixth solvent to the compound V, in the solution of the second strong base, N,N -dimethylpropylene urea and BETA-cyclocitral to generate compound VI; S7: adding a seventh solvent to the compound VI to generate a compound VII under the action of diisobutylaluminum hydride; S8: adding an eighth solvent to the compound VII, heating under reflux under the action of an oxidant to generate a compound VIII; S9: Repeat S6 with the compound VIII to generate compound IX, and repeat S9 with the compound IX to generate vitamin A.

8. The preparation method according to claim 7, characterized in that: The reaction temperature of S6 is -5~8°C, and the reaction time is 1~2h; The reaction temperature of S7 is -5~5°C, and the reaction time is 1~3h; The heating reflux temperature of S8 is 50-80°C, and the heating reflux time is 3-8h; The sixth solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; 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 seventh solvent is any one of 1,2-dichloroethane, dichloromethane, diethyl ether, toluene, methyl tert-butyl ether, and tetrahydrofuran; The eighth solvent is any one of diethyl ether, methyl tert-butyl ether, dimethyl ether, and tetrahydrofuran; The oxidant is any one of chromic acid, hydrogen peroxide and manganese dioxide.

9. The preparation method according to claim 7, characterized in that: The weight volume ratio of the compound V to the sixth solvent is 1:2-1:30; The molar ratio of the compound V to the second strong base is 1:1.1 to 1:3; The compound V 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 V to the BETA-cyclocitral is 1:1 to 1:2; The weight volume ratio of the compound VI to the seventh solvent is 1:3 to 1:20; The molar ratio of the compound VI to the DIBAL-H is 1:3 to 1:6; The weight volume ratio of the compound VII to the eighth solvent is 1:2 to 1:40; The molar ratio of the compound VII to the oxidant is 1:20 to 1:

50.

10. The preparation method according to claim 7, characterized in that: After the reaction of S6 is completed, a saturated aqueous solution of ammonium chloride 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 V to the saturated aqueous solution of ammonium chloride is 1:2-1:30, the weight-volume ratio of the compound V to the ethyl acetate 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; After the reaction of S7 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 VI to the saturated aqueous solution of potassium sodium tartrate is 1:2-1:30, the weight volume ratio of the compound VI to the ethyl acetate used in each extraction is 1:2-1:30, and the weight ratio of the compound VI to the anhydrous sodium sulfate is 1:0.5-1:1; After the reaction of S8 is completed, the mixture is cooled to room temperature and filtered using diatomaceous earth, wherein the weight ratio of the compound VII to the diatomaceous earth is 1:2 to 1:3; After the reaction of S9 is completed, the reaction is quenched with a saturated aqueous solution of potassium sodium tartrate, and the weight volume ratio of the compound IX to the saturated aqueous solution of potassium sodium tartrate is 1:2-1:30.

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