Total synthesis of vitamin A and its derivatives, and their deuterated compounds

Abstract

The present invention discloses a method for the total synthesis of vitamin A and its derivatives and their deuterated compounds, which uses β-cyclic citral as a starting material to produce an alkenyl borate ester, and then the alkenyl borate ester (or alkenyl boronic acid after hydrolysis) undergoes a series of reactions to produce retinal or retinal having a substituent, which is then reduced to obtain vitamin A or vitamin A having a substituent; vitamin A or vitamin A having a substituent undergoes an esterification reaction to obtain vitamin A ester or vitamin A ester having a substituent; or the retinal or retinal having a substituent undergoes an oxidation reaction to obtain vitamin A acid or vitamin A acid having a substituent. By using deuterated arenol, deuterated vitamin A and its derivatives can be obtained. The present invention has the advantages of a short synthesis scheme, simple operation, easy availability of raw materials and reagents, modularity and diversification, and can synthesize deuterated vitamin A and its derivatives, which were difficult to synthesize in the prior art.

Description

[Technical field]

[0001] The present invention belongs to the technical field of chemical synthesis and relates to a method for the total synthesis of vitamin A and its derivatives, as well as their deuterated compounds. [Background technology]

[0002] Vitamin A (retinol) is a fat-soluble vitamin necessary for maintaining normal metabolism and function in the human body. It is an important nutrient with various physiological functions, such as promoting growth and reproduction, and maintaining vision and epithelial tissue. Important derivatives of vitamin A include retinal and retinoic acid, both of which have similar physiological functions and pharmacological activity. Vitamin A can also be extracted from animal tissues, but due to the complicated and expensive process, most of the vitamin A currently on the market is produced by chemical synthesis. As vitamin A is unstable, the main vitamin A products currently available are vitamin A acetate, vitamin A palmitate, etc. (Ref: (a) Parker, GL; Smith, LK; Baxendale, IR Tetrahedron 2016, 72, 1645-1652. (b) Eggersdorfer, M.; Laudert, D.; Letinois, U.; McClymont, T.; Medlock, J.; Netscher, T.; Bonrath, W. Angew. Chem. Int. Ed. 2012, 51, 12960-12990.)

[0003] Vitamin A is a capital- and technology-intensive product. Currently, there are two main schemes for industrially synthesizing vitamin A around the world (as shown in the following formula (B), in which only the important steps are shown): the Hoffmann-La Roche scheme (C14+C6) and the BASF scheme (C15+C5). [ka]

[0004] The key step of the Hoffmann-La Roche scheme is the Grignard reaction. This scheme is the main synthetic scheme adopted by vitamin A manufacturers around the world, and although the process is relatively mature, it has the disadvantages of involving many raw materials and auxiliary materials, a long scheme, and complex equipment. The key step of the BASF scheme is the Wittig reaction, which has few steps and a short scheme, but has high requirements for the process and equipment, especially the core step Wittig reaction, which has a complex by-product processing step. Although industrial production of vitamin A has a history of more than 70 years, each of these industrial synthetic schemes has its own shortcomings, and improvements and development of new schemes are necessary. At present, the technical barriers to vitamin A production are still high, and research into new synthetic methods is still actively underway.

[0005] Deuterated compounds are widely used in pharmaceutical research (Ref: Pirali, T.; Serafini, M.; Cargnin, S.; Genazzani, AAJ Med. Chem. 2019, 62, 5276-5297.), mechanistic studies (Ref: Gomez-Gallego, M.; Sierra, MA Chem. Rev. 2011, 111, 4857-4963.) and biochemistry research (Ref: Atzrodt, J.; Derdau, V.; Kerr, WJ; Reid, M. Angew. Chem. Int. Ed. 2018, 57, 1758-1784.). Since the first deuterated drug, Austedo (Ref: Schmidt, C. Nat. Biotechnol. 2017, 35, 493-494.), was approved by the U.S. Food and Drug Administration (FDA) and released in 2017, research on deuterated drugs has developed rapidly (Ref: (a) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. Angew. Chem. Int. Ed. 2007, 46, 7744-7765. (b) Atzrodt, J.; Derdau, V.; Kerr, WJ; Reid, M. Angew. Chem. Int. Ed. 2018, 57, 3022-3047. (c) Valero, M.; Derdau, VJ Label. Compd. Radiopharm. 2019, 1-15.). Among them, the deuterated drug ALK-001 (deuterated vitamin A acetate) is used to treat Stargardt disease and is currently in phase II clinical trials. At present, the synthesis of deuterated vitamin A and its derivatives is very complicated, and only a few structures of deuterated vitamin A and its derivatives have been reported. For the inactive methyl groups on the polyene structure of vitamin A and its derivatives, there is still no synthetic method that can flexibly control the number of deuterium atoms on the methyl group. Moreover, this controllable and divergent deuterium synthesis method is also a great challenge in the field of organic synthesis. Summary of the Invention

[0006] In order to solve the shortcomings of the prior art, the object of the present invention is to provide a simpler, easier to operate, and modularized total synthesis method for vitamin A and its derivatives and their deuterated compounds. By using deuterated raw materials, various deuterated vitamin A and its derivatives that are difficult to synthesize by existing technologies can be synthesized in a modular manner. The method of the present invention has the advantages of a short synthesis scheme, simple operation, easy availability of raw materials and reagents, modularization and diversification, and can synthesize various deuterated vitamin A and its derivatives that are difficult to synthesize by conventional technologies.

[0007] The present invention provides a method for the total synthesis of vitamin A and its derivatives and their deuterated compounds, comprising the following steps:

[0008] (1) β-cyclic citral represented by S1 and bis[(pinacol)boryl]methane are reacted with lithium tetramethylpiperidine in a first organic solvent to produce an alkenyl borate represented by S2; (2) An alkenyl borate ester represented by S2 and an arenol represented by 5 are reacted with a rhodium catalyst, a copper catalyst, an alkali, water, air (or oxygen) in a second organic solvent to produce a 2-alkenal represented by S4; or an alkenyl borate ester represented by S2 is hydrolyzed to an alkenyl boronic acid represented by S3, and then reacted with an arenol represented by 5 in a second organic solvent under the action of a rhodium catalyst, a copper catalyst, an alkali, air (or oxygen) to produce a 2-alkenal represented by S4; (3) 2-alkenal represented by S4 and bis[(pinacol)boryl]methane are reacted with lithium tetramethylpiperidine in a first organic solvent to produce an alkenyl borate represented by S5; (4) An alkenyl borate ester represented by S5 and an arenol represented by 5 are reacted with a rhodium catalyst, a copper catalyst, an alkali, water, air (or oxygen) in a second organic solvent to produce a retinal represented by 1 or a retinal having a substituent; (5) Retinal represented by formula 1 or retinal having a substituent is reduced to produce vitamin A represented by formula 2 or vitamin A having a substituent; (6) Vitamin A represented by formula (2) or vitamin A having a substituent is esterified to produce a vitamin A ester represented by formula (3) or a vitamin A ester having a substituent; (7) Retinal represented by formula 1 or retinal having a substituent is oxidized to produce vitamin A acid represented by formula 4 or vitamin A acid having a substituent; In the step (2) and / or step (4), when a hydrogen isotope-labeled arenol represented by 5 is used, a hydrogen isotope-labeled vitamin A or vitamin A derivative is finally obtained; The synthetic scheme of the total synthesis method is as shown in the following formula (A): [ka] Where: H a are hydrogen, deuterium, and tritium; R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H b are hydrogen, deuterium, and tritium; H c are hydrogen, deuterium, and tritium; R 2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H d are hydrogen, deuterium, and tritium; H e are hydrogen, deuterium, and tritium; R 3 is acyl; Here, the aryl is a phenyl having substituents at the ortho, meta and para positions, and the substituents include alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen and sulfur, and is an aliphatic ring, an aromatic ring or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy and cyano.

[0009] The total synthesis method of the present invention comprises the reaction shown in reaction scheme (a): [ka] In reaction scheme (a), bis[(pinacol)boryl]methane reacts with β-cyclic citral (S1) in a first organic solvent under the action of lithium 2,2,6,6-tetramethylpiperidine (LiTMP) as an alkali to produce compound S2; where lithium 2,2,6,6-tetramethylpiperidine can be prepared in situ using 2,2,6,6-tetramethylpiperidine and n-butyl lithium.

[0010] The reaction represented by the above reaction scheme (a) specifically includes the following steps: (1) Protect the reaction system with inert gas; put 2,2,6,6-tetramethylpiperidine and the first organic solvent into a dry reaction flask, add n-butyllithium reagent at -90~30°C, and then stir at -90~30°C for another 15 minutes to 3 hours, prepare lithium 2,2,6,6-tetramethylpiperidine solution in situ, preferably, the reaction temperature is -80~0°C, and the stirring time is 0.5~2 hours; (2) bis[(pinacol)boryl]methane is dissolved in a first organic solvent, and added to a lithium 2,2,6,6-tetramethylpiperidine solution at -90 to 30°C, and then stirred at -90 to 30°C for an additional 1 minute to 2 hours; preferably, added to a lithium 2,2,6,6-tetramethylpiperidine solution at -20 to 20°C, and then stirred at -20 to 20°C for an additional 1 to 30 minutes; (3) dissolving β-cyclic citral in a first organic solvent, adding it to the mixture produced in step (2) at -90 to 30°C, and then reacting with stirring at -90 to 30°C for 0.5 to 12 hours; preferably adding it to the mixture produced in step (2) at -80 to 0°C, and then reacting with stirring at -80 to 0°C for 0.5 to 6 hours; (4) After the reaction in step (3) is completed, the reaction is quenched, and compound S2 is obtained by extraction, concentration, and separation.

[0011] The first organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, ethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, toluene, and is preferably tetrahydrofuran.

[0012] The molar ratio of the β-cyclic citral (S1), lithium 2,2,6,6-tetramethylpiperidine, and bis[(pinacol)boryl]methane is 1:(1.0-2.0):(1.0-2.0), preferably 1:(1.1-1.6):(1.1-1.6); when the lithium 2,2,6,6-tetramethylpiperidine solution is prepared in situ, the molar ratio of the β-cyclic citral (S1), 2,2,6,6-tetramethylpiperidine, n-butyllithium, and bis[(pinacol)boryl]methane is 1:(1.0-2.0):(1.0-2.0):(1.0-2.0), preferably 1:(1.1-1.6):(1.1-1.6):(1.1-1.6).

[0013] The total synthesis method of the present invention comprises the reaction shown in reaction scheme (b): [ka] Where: H a are hydrogen, deuterium, and tritium; R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H b are hydrogen, deuterium, and tritium; Here, the aryl is a phenyl having substituents at the ortho, meta and para positions, and the substituents include alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen and sulfur, and is an aliphatic ring, an aromatic ring or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy and cyano.

[0014] Preferably, the R 1is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, The heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano.

[0015] In the reaction formula (b), the allenol 5 reacts with the compound S2 in a second organic solvent under the action of a rhodium catalyst, a copper catalyst, an alkali, water, air or oxygen to produce the compound S4.

[0016] The reaction represented by the above reaction scheme (b) specifically includes the following steps: (1) Put a rhodium catalyst, an alkali, a copper catalyst, compound S2, arenol 5, water and a second organic solvent into a dry reaction flask, plug the reaction flask with a rubber stopper, and then insert an air or oxygen bulb to keep the reaction flask in an air or oxygen gas atmosphere, and react at -20 to 60°C for 4 to 96 hours with stirring; (2) After completion of the reaction in step (1), the mixture in the reaction flask is filtered through a short column of silica gel (or diatomaceous earth), washed with a third organic solvent, and then concentrated and separated to obtain compound S4.

[0017] The second organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, methanol, ethanol, methylene chloride, ethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and the like; preferably tetrahydrofuran.

[0018] The amount of the second organic solvent used is based on the amount of arenol 5 used as shown in reaction formula (b), and the amount of the second organic solvent used is 1.0 to 20.0 mL / mmol; preferably 5.0 to 10.0 mL / mmol.

[0019] The third organic solvent is at least one of ethyl acetate, ethyl ether, methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, acetonitrile, and the like, and is preferably ethyl acetate; the amount of the third organic solvent used is based on the amount of arenol 5 used shown in reaction formula (b), and the amount of the third organic solvent used is 1.0 to 200 mL / mmol, and preferably 20 to 100 mL / mmol.

[0020] The rhodium catalyst is at least one of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium(III), rhodium(III) acetylacetonate, dichloropentaamminechlororhodium(III), tris(ethylenediamine)rhodium(III) trichloride, potassium pentachlororhodate(III), sodium hexachlororhodate(III), potassium hexachlororhodate(III), rhodium(III) chloride, rhodium(III) bromide, rhodium(III) iodide, rhodium(III) sulfate, rhodium(III) nitrate, and potassium hexanitrirhodium(III), and is preferably dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer.

[0021] The copper catalyst is at least one of copper acetate hydrate, copper acetate, copper sulfate hydrate, copper sulfate, copper nitrate hydrate, copper nitrate, copper chloride hydrate, copper chloride, copper bromide, and the like, and is preferably copper acetate monohydrate.

[0022] The alkali is at least one of sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, magnesium acetate, calcium acetate, and the like, and is preferably sodium acetate.

[0023] The molar ratio of the rhodium catalyst, copper catalyst, alkali, compound S2, arenol 5, and water is (0.005-0.10):(0.005-1.20):(0-0.60):(1.0-3.0):1.0:(0-20.0); preferably (0.010-0.025):(0.05-0.10):(0.20-0.30):(1.2-2.0):1.0:(2.0-5.0).

[0024] The total synthesis method of the present invention comprises the reaction shown in reaction scheme (c): [ka] In the above reaction formula (b), compound S2 undergoes a hydrolysis reaction to produce compound S3.

[0025] In the present invention, any hydrolysis reaction can be used to produce compound S3, and preferably, compound S2 is hydrolyzed in a mixed solvent of acetone and water under the action of sodium periodate and ammonium acetate at 0 to 40° C. to produce compound S3.

[0026] The total synthesis method of the present invention comprises the reaction shown in reaction scheme (d): [ka] Where: H a are hydrogen, deuterium, and tritium; R1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H b are hydrogen, deuterium, and tritium; Here, the aryl is a phenyl having substituents at the ortho, meta and para positions, and the substituents include alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen and sulfur, and is an aliphatic ring, an aromatic ring or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy and cyano.

[0027] Preferably, the R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, The heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano.

[0028] In the reaction formula (d), arenol 5 reacts with compound S3 in a second organic solvent under the action of rhodium catalyst, copper catalyst, alkali, air or oxygen to produce compound S4; compound S3 can be obtained by hydrolysis of compound S2.

[0029] The reaction represented by the reaction formula (d) specifically includes the following steps: (1) Put the rhodium catalyst, alkali, copper catalyst, compound S3, arenol 5 and the second organic solvent into a dry reaction flask, plug the reaction flask with a rubber stopper, and then insert an air or oxygen bulb to keep the reaction flask in an air or oxygen gas atmosphere, and react at -20 to 60°C for 4 to 96 hours with stirring; (2) After completion of the reaction in step (1), the mixture in the reaction flask is filtered through a short column of silica gel (or diatomaceous earth), washed with a third organic solvent, and then concentrated and separated to obtain compound S4.

[0030] The second organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, methanol, ethanol, methylene chloride, ethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and the like; preferably tetrahydrofuran.

[0031] The amount of the second organic solvent used is based on the amount of arenol 5 used as shown in reaction formula (d), and the amount of the second organic solvent used is 1.0 to 20.0 mL / mmol; preferably 5.0 to 10.0 mL / mmol.

[0032] The third organic solvent is at least one of ethyl acetate, ethyl ether, methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, acetonitrile, and the like, and is preferably ethyl acetate; the amount of the third organic solvent used is based on the amount of arenol 5 used shown in reaction formula (d), and the amount of the third organic solvent used is 1.0 to 200 mL / mmol, and preferably 20 to 100 mL / mmol.

[0033] The rhodium catalyst is at least one of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium(III), rhodium(III) acetylacetonate, dichloropentaamminechlororhodium(III), tris(ethylenediamine)rhodium(III) trichloride, potassium pentachlororhodate(III), sodium hexachlororhodate(III), potassium hexachlororhodate(III), rhodium(III) chloride, rhodium(III) bromide, rhodium(III) iodide, rhodium(III) sulfate, rhodium(III) nitrate, and potassium hexanitrirhodium(III), and is preferably dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer.

[0034] The copper catalyst is at least one of copper acetate hydrate, copper acetate, copper sulfate hydrate, copper sulfate, copper nitrate hydrate, copper nitrate, copper chloride hydrate, copper chloride, copper bromide, and the like, and is preferably copper acetate monohydrate.

[0035] The alkali is at least one of sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, magnesium acetate, calcium acetate, and the like, and is preferably sodium acetate.

[0036] The molar ratio of the rhodium catalyst, copper catalyst, alkali, compound S3, and arenol 5 is (0.005-0.10):(0.005-1.20):(0-0.60):(1.0-3.0):1.0; preferably, (0.010-0.025):(0.05-0.10):(0.20-0.30):(1.2-2.0):1.0.

[0037] The total synthesis method of the present invention comprises the reaction shown in reaction scheme (e): [ka] Where: H a are hydrogen, deuterium, and tritium; R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H b are hydrogen, deuterium, and tritium; Here, the aryl is a phenyl having substituents at the ortho, meta and para positions, and the substituents include alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen and sulfur, and is an aliphatic ring, an aromatic ring or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy and cyano.

[0038] Preferably, the R 1is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, The heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano.

[0039] In reaction scheme (e), bis[(pinacol)boryl]methane reacts with compound S4 in a first organic solvent under the action of lithium 2,2,6,6-tetramethylpiperidine (LiTMP) as an alkali to produce compound S5; where lithium 2,2,6,6-tetramethylpiperidine can be prepared in situ using 2,2,6,6-tetramethylpiperidine and n-butyl lithium.

[0040] The reaction represented by the above reaction formula (e) specifically includes the following steps: (1) Protect the reaction system with inert gas; put 2,2,6,6-tetramethylpiperidine and the first organic solvent into a dry reaction flask, add n-butyllithium reagent at -90~30°C, and then stir at -90~30°C for another 15 minutes to 3 hours, prepare lithium 2,2,6,6-tetramethylpiperidine solution in situ, preferably, the reaction temperature is -80~0°C, and the stirring time is 0.5~2 hours; (2) bis[(pinacol)boryl]methane is dissolved in a first organic solvent, and added to a lithium 2,2,6,6-tetramethylpiperidine solution at -90 to 30°C, and then stirred at -90 to 30°C for an additional 1 minute to 2 hours; preferably, added to a lithium 2,2,6,6-tetramethylpiperidine solution at -20 to 20°C, and then stirred at -20 to 20°C for an additional 1 to 30 minutes; (3) dissolving compound S4 in a first organic solvent, adding it to the mixture produced in step (2) at -90 to 30°C, and then reacting with stirring at -90 to 30°C for 0.5 to 12 hours; preferably adding it to the mixture produced in step (2) at -80 to 0°C, and then reacting with stirring at -80 to 0°C for 0.5 to 6 hours; (4) After the reaction in step (3) is completed, the reaction is quenched, and compound S5 is obtained by extraction, concentration, and separation.

[0041] The first organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, ethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, toluene, and is preferably tetrahydrofuran.

[0042] The molar ratio of S4 to lithium 2,2,6,6-tetramethylpiperidine to bis[(pinacol)boryl]methane is 1:(1.0-2.0):(1.0-2.0), preferably 1:(1.1-1.6):(1.1-1.6); when the lithium 2,2,6,6-tetramethylpiperidine solution is prepared in situ, the molar ratio of S4 to 2,2,6,6-tetramethylpiperidine to n-butyllithium to bis[(pinacol)boryl]methane is 1:(1.0-2.0):(1.0-2.0):(1.0-2.0), preferably 1:(1.1-1.6):(1.1-1.6):(1.1-1.6).

[0043] The total synthesis method of the present invention comprises the reaction shown in reaction scheme (f): [ka] Where: H a are hydrogen, deuterium, and tritium; R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H b are hydrogen, deuterium, and tritium; H c are hydrogen, deuterium, and tritium; R 2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H d are hydrogen, deuterium, and tritium; Here, the aryl is a phenyl having substituents at the ortho, meta and para positions, and the substituents include alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen and sulfur, and is an aliphatic ring, an aromatic ring or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy and cyano.

[0044] Preferably, R 1is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, carboxyl, cyano, amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen, or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; R 2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, The heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano.

[0045] In the reaction formula (f), arenol 5 reacts with compound S5 in a second organic solvent under the action of a rhodium catalyst, a copper catalyst, an alkali, water, air or oxygen to produce compound 1.

[0046] The reaction represented by the reaction formula (f) specifically includes the following steps: (1) Put a rhodium catalyst, an alkali, a copper catalyst, compound S5, Allenol 5, water and a second organic solvent into a dry reaction flask, plug the reaction flask with a rubber stopper, and then insert an air or oxygen bulb to keep the reaction flask in an air or oxygen gas atmosphere, and react at -20 to 60°C for 4 to 96 hours with stirring; (2) After completion of the reaction in step (1), the mixture in the reaction flask is filtered through a short column of silica gel (or diatomaceous earth), washed with a third organic solvent, and then concentrated and separated to obtain compound 1.

[0047] The second organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, methanol, ethanol, methylene chloride, ethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether; preferably tetrahydrofuran.

[0048] The amount of the second organic solvent used is based on the amount of arenol 5 used as shown in reaction formula (f), and the amount of the second organic solvent used is 1.0 to 20.0 mL / mmol; preferably 5.0 to 10.0 mL / mmol.

[0049] The third organic solvent is at least one of ethyl acetate, ethyl ether, methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, acetonitrile, and the like, and is preferably ethyl acetate; the amount of the third organic solvent used is based on the amount of arenol 5 used shown in reaction formula (b), and the amount of the third organic solvent used is 1.0 to 200 mL / mmol, and preferably 20 to 100 mL / mmol.

[0050] The rhodium catalyst is at least one of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium(III), rhodium(III) acetylacetonate, dichloropentaamminechlororhodium(III), tris(ethylenediamine)rhodium(III) trichloride, potassium pentachlororhodate(III), sodium hexachlororhodate(III), potassium hexachlororhodate(III), rhodium(III) chloride, rhodium(III) bromide, rhodium(III) iodide, rhodium(III) sulfate, rhodium(III) nitrate, and potassium hexanitrirhodium(III), and is preferably dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer.

[0051] The copper catalyst is at least one of copper acetate hydrate, copper acetate, copper sulfate hydrate, copper sulfate, copper nitrate hydrate, copper nitrate, copper chloride hydrate, copper chloride, copper bromide, and the like, and is preferably copper acetate monohydrate.

[0052] The alkali is at least one of sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, magnesium acetate, calcium acetate, and the like, and is preferably sodium acetate.

[0053] The molar ratio of the rhodium catalyst, copper catalyst, alkali, compound S5, arenol 5, and water is (0.005-0.10):(0.005-1.20):(0-0.60):(1.0-3.0):1.0:(0-20.0); preferably (0.010-0.025):(0.05-0.10):(0.20-0.30):(1.2-2.0):1.0:(2.0-5.0).

[0054] The total synthesis method of the present invention comprises the reaction shown in reaction scheme (g): [ka] Where: H a are hydrogen, deuterium, and tritium; R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H b are hydrogen, deuterium, and tritium; H c are hydrogen, deuterium, and tritium; R 2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H d are hydrogen, deuterium, and tritium; H e are hydrogen, deuterium, and tritium; Here, the aryl is a phenyl having substituents at the ortho, meta and para positions, and the substituents include alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen and sulfur, and is an aliphatic ring, an aromatic ring or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy and cyano.

[0055] Preferably, R 1is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, carboxyl, cyano, amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen, or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; R 2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, The heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano.

[0056] In the above reaction formula (g), compound 1 undergoes a reduction reaction to produce compound 2.

[0057] In the present invention, any reduction reaction can be used to produce compound 2, but preferably, compound 2 is produced by reducing compound 1 under the action of sodium borohydride at −20 to 40° C. using methanol or ethanol as a solvent.

[0058] The total synthesis method of the present invention comprises the reaction shown in reaction scheme (h): [ka] Where: H a are hydrogen, deuterium, and tritium; R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H b are hydrogen, deuterium, and tritium; H c are hydrogen, deuterium, and tritium; R 2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H d are hydrogen, deuterium, and tritium; H e are hydrogen, deuterium, and tritium; R 3 is acyl; Here, the aryl is a phenyl having substituents at the ortho, meta and para positions, and the substituents include alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen and sulfur, and is an aliphatic ring, an aromatic ring or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy and cyano.

[0059] Preferably, R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, carboxyl, cyano, amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen, or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; R 2is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, The heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano.

[0060] In the above reaction formula (h), compound 2 produces compound 3 by esterification reaction.

[0061] In the present invention, any esterification reaction can be used to produce compound 3, but preferably, compound 2 and acetic anhydride are esterified in the presence of triethylamine and DMAP (4-dimethylaminopyridine) using dichloromethane as a solvent at 0 to 60°C to produce compound 3.

[0062] The total synthesis process of the present invention comprises the reaction shown in scheme (i): [ka] Where: H a are hydrogen, deuterium, and tritium; R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; Hb are hydrogen, deuterium, and tritium; H c are hydrogen, deuterium, and tritium; R 2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H d are hydrogen, deuterium, and tritium; Here, the aryl is a phenyl having substituents at the ortho, meta and para positions, and the substituents include alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen and sulfur, and is an aliphatic ring, an aromatic ring or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy and cyano.

[0063] Preferably, R 1is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, carboxyl, cyano, amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen, or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; R 2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, The heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano.

[0064] In the above reaction formula (i), compound 1 is oxidized to produce compound 4.

[0065] The present invention can use any oxidation reaction to produce compound 4.

[0066] The present invention also provides the application of the above process in the production of vitamin A and its derivatives, as well as deuterated compounds thereof.

[0067] The present invention also provides the application of the above-described preparation methods in the synthesis and modification of retinoid fragments.

[0068] The present invention also provides vitamin A and its derivatives, as well as deuterated compounds thereof, the molecular formula of which is as follows: [ka] Where: H a are hydrogen, deuterium, and tritium; R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H b are hydrogen, deuterium, and tritium; H c are hydrogen, deuterium, and tritium; R 2 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H d are hydrogen, deuterium, and tritium; H e are hydrogen, deuterium, and tritium; R 3 is acyl; Here, the aryl is a phenyl having substituents at the ortho, meta and para positions, and the substituents include alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen and sulfur, and is an aliphatic ring, an aromatic ring or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy and cyano.

[0069] Preferably, R 1 is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, carboxyl, cyano, amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen, or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; R 2is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, C1-C40 hydrocarbyl, or C1-C40 hydrocarbyl having a functional group; the aryl is a phenyl having a substituent at the ortho, meta, or para position, and the substituent is a C1-C40 alkyl, a C2-C40 alkenyl, a phenyl, a halogen, a trifluoromethyl, a C1-C40 alkoxy, a C1-C40 alkoxycarbonyl, an acyl, an acyloxy, an amido, a sulfonyl, a sulfonyloxy, a hydroxyl, a nitro, The heterocyclyl is a 3-10 membered heterocycle whose ring atoms are atoms such as carbon, nitrogen, oxygen or sulfur, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; in the C1-C40 hydrocarbyl having the functional group, the functional group includes acyl, hydroxyl, halogen, C1-C40 alkoxy, C1-C40 alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano.

[0070] The advantageous effect of the present invention is that the total synthesis method described in the present invention uses β-cyclic citral as starting material, and by repeating the combination of unit reactions, it is ingeniously realized to easily synthesize vitamin A and its derivatives in a modular manner, and compared with the existing synthesis scheme, the scheme is simple and efficient, the procedure is simple, and it has the potential for industrial application. Among them, the reaction between alkenyl boron reagent and arenol is a key step, and in this step, 1,4-hydrogen (or hydrogen isotope) transfer occurs, which reflects the site specificity, and overcomes the difficulty of introducing deuterium atom controllability in the synthesis of deuterated compounds, and finally obtains multiple hydrogen isotope-labeled vitamin A and its derivatives, which have been difficult to synthesize in the past.

[0071] Compared with conventional techniques, the total synthesis method provided by the present invention has the advantages of short steps, modularization, simple operation, flexible control of deuteration structure, specific stereoselectivity, and easy availability of raw materials and reagents; the present invention can solve the problem of the difficulty in synthesizing vitamin A and its derivatives; the modular synthetic operation provided by the present invention can be applied to the synthesis and modification of retinoid fragments, thus providing a powerful synthetic method for drug modification and research. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0072] The present invention will be described in more detail with reference to the following specific examples. The processes, conditions, experimental methods, etc. for carrying out the present invention are common knowledge or common general knowledge in the relevant field, except for the contents specifically described below, and the contents are not particularly limited to the present invention.

[0073] In the reaction schemes of the following examples, equiv stands for equivalents; mol stands for moles; mmol stands for millimole; mol% stands for the molar ratio calculated based on 1 equivalent of reactant; L stands for liters; mL stands for milliliters; M stands for mol / L; g stands for grams; mg stands for milligrams; min stands for minutes; h stands for hours; rt stands for room temperature; LiTMP stands for lithium 2,2,6,6-tetramethylpiperidine; THF stands for tetrahydrofuran; [Cp*RhCl2]2 stands for dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer; NaOAc stands for sodium acetate; Cu(OAc)2·H2O stands for copper acetate monohydrate; air stands for the reaction carried out under an air atmosphere; air Balloon means that the reaction is carried out in an air atmosphere by inserting an air balloon; Ar means that the reaction is carried out under an argon gas atmosphere; NaIO4 means sodium periodate; NHOAc means ammonium acetate; MeOH means methanol; NaBH4 means sodium borohydride; DCM means dichloromethane; Ac2O means acetic anhydride; Et3N means triethylamine; DMAP means 4-dimethylaminopyridine; NaClO2 means sodium chlorite; NaH2PO4 means sodium dihydrogen phosphate; t-BuOH means tert-butanol; the boiling point range of petroleum ether is 60-90°C; 300-400 mesh silica gel is used; NMR yield is 1 Determined by H NMR with dibromomethane as the internal standard; deuteration ratio was 1 Determined by 1 H NMR. EXAMPLES

[0074] [ka] Under the protection of argon gas atmosphere, 2,2,6,6-tetramethylpiperidine (11.8 mL, density 0.837 g / mL, 9.8766 g, 70 mmol) and THF (70 mL) were added to a dry reaction flask. The reaction flask was cooled to -78°C in a dry ice acetone bath, n-butyllithium (2.5 M in Hexane, 28.0 mL, 70 mmol) was added dropwise, and then stirred at 0°C in an ice water bath for 30 minutes (producing a lithium 2,2,6,6-tetramethylpiperidine solution). At 0°C, a solution of bis[(pinacol)boryl]methane (19.1414 g, 70 mmol) in THF (140 mL) was added to the reaction flask, and then stirred at 0°C for an additional 30 minutes. The reaction flask was cooled to -78°C in a dry ice acetone bath, and a solution of β-cyclocitral (S1, 8.0101g, 95% purity, 50mmol) in THF (50mL) was added. The reaction solution was stirred at -78°C for 3 hours, and then at room temperature for another 2 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (50mL), water (400mL) was added, and extracted with ethyl acetate (3x300mL). The organic phases were combined, washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Separation and purification were carried out by silica gel column chromatography (eluent: petroleum ether, then petroleum ether / ethyl acetate=30 / 1) to obtain product S2 (12.4276g, 86%) as a pale yellow liquid. 1 H NMR (400 MHz, CDCl3): δ = 7.01 (d, J = 18.4 Hz, 1 H, =CH), 5.42 (d, J = 18.4 Hz, 1 H, =CH), 2.00 (t, J = 6.2 Hz, 2 H, CH2), 1.71 (s, 3 H, CH3), 1.63-1.55 (m, 2 H, CH2), 1.47-1.41 (m, 2 H, CH2), 1.29 (s, 12 H, 4 x CH3), 1.04 (s, 6 H, 2 x CH3); 13C NMR (100 MHz, CDCl3): δ = 149.5, 139.2, 130.9, 82.9, 39.8, 33.7, 33.1, 28.8, 24.8, 21.6, 19.1; IR (neat): v = 2977, 2928, 2866, 2827, 1615, 1459, 1379, 1370, 1344, 1317, 1266, 1212, 1164, 1144, 1109, 1028 cm -1 ; MS (70 eV, EI) m / z (%): 276 (M + , 32.02), 161 (100). EXAMPLES

[0075] [ka] Compound S2 was dissolved in a mixture of acetone and water (100 mL, 2:1), and sodium periodate (12.8357 g, 60 mmol) and ammonium acetate (4.6306 g, 60 mmol) were added. The mixture was stirred at room temperature for 10 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (4×100 mL), and the organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product S3, which was used directly in the next step without purification. [Cp*RhCl2]2 (201.1 mg, 0.325 mmol), NaOAc (213.5 mg, 2.6 mmol), Cu(OAc)2·H2O (130.1 mg, 0.65 mmol), S3 (19.5 mmol, from the previous step), THF (50 mL), 5a (911.4 mg, 13 mmol), and THF (15 mL) were added sequentially to a dry reaction flask. The reaction flask was sealed with a rubber stopper and an air bulb was inserted to keep the reaction system in an air atmosphere, and the mixture was stirred at room temperature for 19 h. The reaction solution was filtered through a short column of silica gel, washed with ethyl acetate (300 mL), and the solvent was removed by rotary evaporation. Separation and purification were performed by silica gel column chromatography (eluent: petroleum ether, then petroleum ether / ethyl acetate = 40 / 1) to obtain the product S4a (1.1517 g, 41%) as a yellow liquid. 1 H NMR (400 MHz, CDCl3): δ = 10.13 (d, J = 8.4 Hz, 1 H, CHO), 6.74 (d, J = 16.0 Hz, 1 H, =CH), 6.21 (d, J = 16.0 Hz, 1 H, =CH), 5.94 (d, J = 8.4 Hz, 1 H, =CH), 2.31 (s, 3 H, CH3), 2.05 (t, J = 6.4 Hz, 2 H, CH2), 1.73 (s, 3 H, CH3), 1.69-1.59 (m, 2 H, CH2), 1.51-1.45 (m, 2 H, CH2), 1.05 (s, 6 H, 2 x CH3); 13 IR (neat): v = 2956, 2927, 2864, 2769, 2722, 1662, 1606, 1594, 1445, 1384, 1361, 1333, 1259, 1204, 1146, 1125, 1106, 1045, 1029 cm -1 ; MS (70 eV, EI) m / z (%): 218 (M+ , 30.48), 119 (100). EXAMPLES

[0076] [ka] [Cp*RhCl2]2 (7.7 mg, 0.0125 mmol), NaOAc (8.2 mg, 0.1 mmol), Cu(OAc)2·H2O (5.0 mg, 0.025 mmol), S2 (206.7 mg, 0.75 mmol), THF (1.0 mL), 5a (35.1 mg, 0.5 mmol), THF (1.5 mL), and H2O (27 μL, 27.0 mg, 1.5 mmol) were added sequentially to a dry reaction flask. The reaction flask was sealed with a rubber stopper and an air bulb was inserted to keep the reaction system in an air atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction solution was filtered through a short column of silica gel, washed with ethyl acetate (20 mL), and the solvent was removed by rotary evaporation. Separation and purification were carried out by silica gel column chromatography (eluent: petroleum ether, then petroleum ether / ethyl acetate=50 / 1) to obtain product S4a (54.4 mg, 50%) as a yellow liquid. 1 H NMR (400 MHz, CDCl3): δ = 10.13 (d, J = 8.0 Hz, 1 H, CHO), 6.74 (d, J = 16.0 Hz, 1 H, =CH), 6.21 (d, J = 16.4 Hz, 1 H, =CH), 5.94 (d, J = 8.0 Hz, 1 H, =CH), 2.32 (s, 3 H, CH3), 2.05 (t, J = 6.2 Hz, 2 H, CH2), 1.73 (s, 3 H, CH3), 1.68-1.59 (m, 2 H, CH2), 1.52-1.45 (m, 2 H, CH2), 1.05 (s, 6 H, 2 x CH3); 13IR (neat): v = 2956, 2928, 2864, 2769, 2723, 1661, 1606, 1594, 1445, 1384, 1361, 1333, 1259, 1204, 1146, 1125, 1106, 1045, 1029 cm -1 ; MS (70 eV, EI) m / z (%): 218 (M + , 28.07), 119 (100). EXAMPLES

[0077] [ka] The procedure was the same as in Example 3. [Cp*RhCl2]2 (7.7 mg, 0.0125 mmol), NaOAc (8.2 mg, 0.1 mmol), Cu(OAc)2·H2O (5.0 mg, 0.025 mmol), S2 (207.4 mg, 0.75 mmol), THF (1.0 mL), 5b (36.0 mg, 0.5 mmol), THF (1.5 mL), H2O (27 μL, 27.0 mg, 1.5 mmol), and reacted for 46 h to obtain the product S4b (50.5 mg, 46%) as a yellow liquid (eluent: petroleum ether / ethyl acetate = 40 / 1). 11H NMR (400 MHz, CDCl3): δ = 10.13 (d, J = 8.0 Hz, 1 H, CHO), 6.74 (d, J = 16.0 Hz, 1 H, =CH), 6.21 (d, J = 16.4 Hz, 1 H, =CH), 5.94 (d, J = 8.0 Hz, 1 H, =CH), 2.28 (s, 1 H, CD2H), 2.05 (t, J = 6.2 Hz, 2 H, CH2), 1.73 (s, 3 H, CH3), 1.68 - 1.59 (m, 2 H, CH2), 1.52 - 1.45 (m, 2 H, CH2), 1.05 (s, 6 H, 2 x CH3); 13 13C NMR (100 MHz, CDCl3): δ = 191.3, 155.0, 137.0, 135.6, 135.5, 132.7, 128.7, 39.5, 34.2, 33.2, 28.9, 21.7, 19.0, 12.4 (quint, J = 20.3 Hz); IR (neat): v = 2959, 2928, 2864, 2774, 2735, 1661, 1605, 1585, 1456, 1360, 1258, 1194, 1146, 1125, 1101, 1043, 1026 cm -1 ; MS (70 eV, EI) m / z (%): 220 (M + , 26.80), 121 (100); HRMS calcd m / z for C 15 H 20 D2O [M + : 220.1791, found 220.1790.

Example

[0078]

Chemical

Example

[0079]

change

Example

[0080]

change

[0081] [ka] The procedure was the same as in Example 7. [Cp*RhCl2]2 (3.2 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc)2·H2O (2.0 mg, 0.01 mmol), S5a (THF solution, 0.5 M, 600 μL, 0.3 mmol), 5b (14.4 mg, 0.2 mmol), THF (1 mL), and H2O (11 μL, 11.0 mg, 0.6 mmol) were reacted for 43 hours to obtain the orange liquid product 1ab (22.9 mg, 40%) (silica gel separation plate was alkalized with petroleum ether containing 5% by volume of triethylamine 5) (eluent: petroleum ether / ethyl acetate = 20 / 1). 11H NMR (400 MHz, CDCl3): δ = 10.10 (d, J = 8.0 Hz, 1 H, CHO), 7.14 (dd, J1 = 14.8 Hz, J2 = 11.6 Hz, 1 H, =CH), 6.43 - 6.29 (m, 2 H, 2 x =CH), 6.22 - 6.11 (m, 2 H, 2 x =CH), 5.97 (d, J = 8.0 Hz, 1 H, =CH), 2.29 (s, 1 H, CD2H), 2.09 - 1.99 (m, 5 H, CH3 and CH2), 1.72 (s, 3 H, CH3), 1.66 - 1.58 (m, 2 H, CH2), 1.51 - 1.44 (m, 2 H, CH2), 1.04 (s, 6 H, 2 x CH3); 13 13C NMR (100 MHz, CDCl3): δ = 191.1, 154.8, 141.3, 137.6, 137.1, 134.5, 132.5, 130.5, 129.7, 129.4, 129.0, 39.6, 34.2, 33.1, 28.9, 21.7, 19.2, 13.0, 12.4 (quint, J = 19.4 Hz); IR (neat): v = 2956, 2925, 2861, 1655, 1569, 1447, 1375, 1353, 1265, 1194, 1161, 1107 cm -1 ; MS (70 eV, EI) m / z (%): 286 (M + , 100); HRMS calcd m / z for C 20 H 26 D2O [M + : 286.2260, found 286.2259.

Example

[0082]

Chem.

[0083] [ka] The procedure was the same as in Example 7. [Cp*RhCl2]2 (3.1 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc)2·H2O (2.0 mg, 0.01 mmol), S5a (THF solution, 0.5 M, 600 μL, 0.3 mmol), 5d (40.4 mg, 0.2 mmol), THF (1 mL), and H2O (11 μL, 11.0 mg, 0.6 mmol) were reacted for 48 hours to obtain the orange liquid product 1ad (31.7 mg, 38%) (silica gel separation plate was alkalized with petroleum ether containing 5 vol.% triethylamine) (eluent: petroleum ether / ethyl acetate = 20 / 1). 1 H NMR (400 MHz, CDCl3): δ = 10.11 (d, J = 8.0 Hz, 1 H, CHO), 7.35-7.30 (m, 2 H, Ar-H), 7.21-7.12 (m, 3 H, =CH and Ar-H), 6.37-6.27 (m, 2 H, 2 x =CH), 6.17-6.08 (m, 3 H, 3 x =CH), 4.13 (s, 2 H, CH2), 2.02 (t, J = 6.0 Hz, 2 H, CH2), 1.90 (s, 3 H, CH3), 1.69 (s, 3 H, CH3), 1.66-1.58 (m, 2 H, CH2), 1.49-1.42 (m, 2 H, CH2), 1.30 (s, 9 H, 3 x CH3), 1.01 (s, 6 H, 2 x CH3); 13C NMR (100 MHz, CDCl3): δ = 191.4, 156.7, 149.6, 141.5, 137.6, 137.0, 135.3, 133.9, 133.2, 130.5, 129.9, 129.5, 129.2, 127.5, IR (neat): v = 2957, 2924, 2864, 2737, 1657, 1572, 1458, 1362, 1346, 1267, 1159, 1099 cm -1 ; MS (70 eV, EI) m / z (%): 416 (M + , 58.4), 147 (100); HRMS calcd m / z for C 30 H 40 O [M + ]: 416.3074, found 416.3075. EXAMPLES

[0084] [ka] The procedure was the same as in Example 7. [Cp*RhCl2]2 (3.1 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc)2·H2O (2.0 mg, 0.01 mmol), S5b (THF solution, 0.5 M, 600 μL, 0.3 mmol), 5a (14.0 mg, 0.2 mmol), THF (1 mL), and H2O (11 μL, 11.0 mg, 0.6 mmol) were reacted for 57 hours to obtain the orange liquid product 1ba (23.1 mg, 40%) (silica gel separation plate was alkalized with petroleum ether containing 5% by volume of triethylamine) (eluent: petroleum ether / ethyl acetate = 20 / 1). 11H NMR (400 MHz, CDCl3): δ = 10.11 (d, J = 8.0 Hz, 1 H, CHO), 7.14 (dd, J1 = 14.8 Hz, J2 = 11.6 Hz, 1 H, =CH), 6.44 - 6.29 (m, 2 H, 2 x =CH), 6.22 - 6.10 (m, 2 H, 2 x =CH), 5.97 (d, J = 8.0 Hz, 1 H, =CH), 2.33 (s, 3 H, CH3), 2.07 - 1.97 (m, 3 H, CD2H and CH2), 1.72 (s, 3 H, CH3), 1.66 - 1.58 (m, 2 H, CH2), 1.50 - 1.43 (m, 2 H, CH2), 1.04 (s, 6 H, 2 x CH3); 13 13C NMR (100 MHz, CDCl3): δ = 191.1, 154.8, 141.3, 137.6, 137.1, 134.5, 132.5, 130.5, 129.7, 129.4, 129.0, 39.6, 34.3, 33.1, 28.9, 21.7, 19.2, 13.1, 12.5 (quint, J = 19.2 Hz); IR (neat): v = 2959, 2924, 2862, 2762, 1655, 1574, 1447, 1385, 1159, 1132, 1109, 1043 cm -1 ; MS (70 eV, EI) m / z (%): 286 (M + , 100); HRMS calcd m / z for C 20 H 26 D2O [M + : 286.2260, found 286.2263.

Example

[0085]

Chemical formula

[0086] [ka] The procedure was the same as in Example 7. [Cp*RhCl2]2 (3.1 mg, 0.005 mmol), NaOAc (3.3 mg, 0.04 mmol), Cu(OAc)2·H2O (2.0 mg, 0.01 mmol), S5b (THF solution, 0.5 M, 600 μL, 0.3 mmol), 5c (14.8 mg, 0.2 mmol), THF (1 mL), and H2O (11 μL, 11.0 mg, 0.6 mmol) were reacted for 57 hours to obtain product 1bc (23.7 mg, 41%) as an orange liquid (silica gel separation plate was alkalized with petroleum ether containing 5% by volume of triethylamine) (eluent: petroleum ether / ethyl acetate = 20 / 1). 1 H NMR (400 MHz, CDCl3): δ = 7.13 (dd, J1= 14.8 Hz, J2= 11.6 Hz, 1 H, =CH), 6.45-6.29 (m, 2 H, 2 x =CH), 6.25-6.11 (m, 2 H, 2 x =CH), 5.97 (s, 1 H, =CH), 2.08-1.96 (m, 3 H, CD2H and CH2), 1.72 (s, 3 H, CH3), 1.68-1.59 (m, 2 H, CH2), 1.51-1.44 (m, 2 H, CH2), 1.04 (s, 6 H, 2 x CH3); 13C NMR (100 MHz, CDCl3): δ = 190.8 (t, J = 26.1 Hz), 154.8, 141.2, 137.6, 137.0, 134.5, 132.5, 130.5, 129.7, 129.4, 129.0, 39.6, IR (neat): v = 2959, 2926, 2862, 2824, 2093, 1647, 1566, 1551, 1456, 1358, 1186, 1165, 1043 cm -1 ; MS (70 eV, EI) m / z (%): 290 (M + , 100); HRMS calcd m / z for C 20 H 22 D6O [M + ]: 290.2511, found 290.2511. EXAMPLES

[0087] [ka] Retinal (1aa, 57.0 mg, 0.2 mmol) and methanol (1 mL) were added to a dry reaction tube, and sodium borohydride (15.2 mg, 0.4 mmol) was added with stirring. The mixture was stirred at room temperature in the dark for 15 minutes. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (4×5 mL). The organic phases were combined, washed twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the solvent was removed on a rotary evaporator to give vitamin A (2aa, 57.1 mg, 99%) as a yellow liquid. 11H NMR (400 MHz, CDCl3): δ = 6.61 (dd, J1 = 15.0 Hz, J2 = 11.4 Hz, 1 H, =CH), 6.29 (d, J = 14.8 Hz, 1 H, =CH), 6.21 - 6.07 (m, 3 H, 3 x =CH), 5.69 (t, J = 6.8 Hz, 1 H, =CH), 4.31 (d, J = 7.2 Hz, 2 H, OCH2), 2.01 (t, J = 6.2 Hz, 2 H, CH2), 1.96 (s, 3 H, CH3), 1.86 (s, 3 H, CH3), 1.71 (s, 3 H, CH3), 1.65 - 1.57 (m, 2 H, CH2), 1.49 - 1.43 (m, 2 H, CH2), 1.02 (s, 6 H, 2 x CH3); 13 13C NMR (100 MHz, CDCl3): δ = 137.8, 137.6, 136.9, 136.3, 136.2, 130.05, 129.95, 129.3, 126.7, 125.2, 59.5, 39.6, 34.2, 33.0, 28.9, 21.7, 19.2, 12.7, 12.6; IR (neat): v = 3384, 3039, 2926, 2863, 1662, 1629, 1572, 1444, 1376, 1359, 1266, 1203, 1079, 1006 cm -1 ; MS (70 eV, EI) m / z (%): 286 (M + , 97.12), 91 (100).

Example

[0088]

Chem.

[0089] The crude product of vitamin A (2aa) was dissolved in dichloromethane (3 mL) and triethylamine (151.6 mg, 1.5 mmol), dichloromethane (1 mL), 4-dimethylaminopyridine (DMAP, 3.1 mg, 0.025 mmol), acetic anhydride (127.6 mg, 1.25 mmol), and dichloromethane (1 mL) were added sequentially with stirring at room temperature. The mixture was stirred at room temperature in the dark for 11 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate (10 mL), followed by dichloromethane (10 mL), washing, and separating the layers. The organic phase was further washed once with saturated aqueous sodium bicarbonate (15 mL), once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the solvent was removed on a rotary evaporator to give the crude product of vitamin A acetate (3aa). The NMR yield was 50% (2 steps). EXAMPLES

[0090] [ka] Retinal (1aa, 57.0 mg, 0.2 mmol), tert-butanol (4 mL), and 2-methyl-2-butene (1.2 mL, density 0.662 g / mL, 794.4 mg, purity 90%, 10 mmol) were added sequentially to a dry reaction tube. NaClO2 (163.2 mg, 1.8 mmol) and NaH2PO4 (167.9 mg, 1.4 mmol) were dissolved in water (2 mL), and this aqueous solution was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hours, then low boiling components were removed by rotary evaporation, water (10 mL) was added, the pH was adjusted to 3 with 1 M aqueous hydrochloric acid, extracted with ether (4 x 10 mL), washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain the crude product of vitamin A acid (4aa). The NMR yield was 38%.

[0091] The protection of the present invention is not limited to the above embodiments. All modifications and advantages that can be imagined by those skilled in the art without departing from the spirit and scope of the concept of the present invention are included in the present invention and are protected by the appended claims.

Claims

1. A method for the total synthesis of Vitamin A and its derivatives and their deuterated compounds, said method comprising the steps of: (1) β-cyclic citral represented by S1 and bis[(pinacol)boryl]methane are reacted with lithium tetramethylpiperidine in a first organic solvent to produce an alkenyl borate represented by S2; (2) The alkenyl borate ester represented by S2 produced in the step (1) and the arenol represented by 5 are reacted with a rhodium catalyst, a copper catalyst, an alkali, water, air or oxygen in a second organic solvent to produce a 2-alkenal represented by S4; or the alkenyl borate ester represented by S2 is hydrolyzed to an alkenyl boronic acid represented by S3, and then reacted with the arenol represented by 5 in a second organic solvent under the action of a rhodium catalyst, a copper catalyst, an alkali, air or oxygen to produce a 2-alkenal represented by S4; (3) the 2-alkenal represented by S4 produced in the step (2) and bis[(pinacol)boryl]methane are reacted with lithium tetramethylpiperidine in a first organic solvent to produce an alkenyl borate represented by S5; (4) The alkenyl borate ester represented by S5 and the arenol represented by 5 produced in the step (3) are reacted with a rhodium catalyst, a copper catalyst, an alkali, water, air or oxygen in a second organic solvent to produce a retinal represented by 1 or a retinal having a substituent; (5) The retinal represented by 1 or the retinal having a substituent produced in the step (4) is reduced to produce vitamin A represented by 2 or vitamin A having a substituent; (6) The vitamin A represented by 2 or the vitamin A having a substituent produced in the above step is esterified to produce a vitamin A ester represented by 3 or a vitamin A ester having a substituent; (7) The retinal represented by 1 or the retinal having a substituent produced in the step (4) is oxidized to produce vitamin A acid represented by 4 or vitamin A acid having a substituent; In the step (2) and / or the step (4), when a hydrogen isotope-labeled arenol represented by 5 is used, a hydrogen isotope-labeled vitamin A or vitamin A derivative is finally obtained; The synthesis scheme of the total synthesis method is as shown in formula (A) below: 【Chemical 29】 Where: The H ａ is hydrogen, deuterium, tritium; R １ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｂ is hydrogen, deuterium, tritium; H ｃ is hydrogen, deuterium, tritium; R ２ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｄ is hydrogen, deuterium, tritium; H ｅ is hydrogen, deuterium, tritium; R ３ is acyl; wherein the aryl is phenyl having substituents at the ortho, meta and para positions, and the substituents include alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are carbon, nitrogen, oxygen or sulfur atoms, and is an aliphatic ring, an aromatic ring or a ring formed by bonding two or more monocycles; and the functional group-containing hydrocarbyl is an acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy and cyano.

2. The total synthesis method includes the reaction shown in reaction scheme (a): 【Chemistry 30】 In the reaction formula (a), bis[(pinacol)boryl]methane reacts with β-cyclic citral represented by S1 in a first organic solvent under the action of lithium 2,2,6,6-tetramethylpiperidine (LiTMP) as an alkali to produce compound S2; where the lithium 2,2,6,6-tetramethylpiperidine is prepared using 2,2,6,6-tetramethylpiperidine and n-butyl lithium; The reaction represented by the reaction formula (a) specifically includes the following steps: (1) Protect the reaction system with inert gas; put 2,2,6,6-tetramethylpiperidine and a first organic solvent into a dry reaction flask, add n-butyllithium reagent at -90 to 30°C, and then stir at -90 to 30°C for another 15 minutes to 3 hours to prepare lithium 2,2,6,6-tetramethylpiperidine solution in situ; (2) dissolving bis[(pinacol)boryl]methane in the first organic solvent, adding it to the lithium 2,2,6,6-tetramethylpiperidine solution prepared in step (1) at −90 to 30° C., and then stirring at −90 to 30° C. for an additional 1 minute to 2 hours; (3) dissolving β-cyclic citral in the first organic solvent, adding it to the mixture produced in step (2) at −90 to 30° C., and then reacting with stirring at −90 to 30° C. for 0.5 to 12 hours; (4) After the reaction of step (3) is completed, the reaction is quenched, and compound S2 is obtained by extraction, concentration, and separation; The first organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, ethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, toluene; 2. The method of claim 1, wherein the molar ratio of the β-cyclic citral S1 to lithium 2,2,6,6-tetramethylpiperidine to bis[(pinacol)boryl]methane is 1:(1.0-2.0):(1.0-2.0); when the lithium 2,2,6,6-tetramethylpiperidine solution is prepared in situ, the molar ratio of the β-cyclic citral S1 to 2,2,6,6-tetramethylpiperidine to n-butyllithium to bis[(pinacol)boryl]methane is 1:(1.0-2.0):(1.0-2.0):(1.0-2.0).

3. The total synthesis method includes the reaction shown in reaction scheme (b): 【Chemistry 31】 Where: H ａ is hydrogen, deuterium, tritium; R １ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｂ is hydrogen, deuterium, tritium; wherein the aryl is a phenyl having a substituent at the ortho, meta, or para position, the substituents including alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano, and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are carbon, nitrogen, oxygen, or sulfur atoms, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; In the reaction formula (b), the allenol 5 reacts with the compound S2 in a second organic solvent under the action of a rhodium catalyst, a copper catalyst, an alkali, water, air or oxygen to produce the compound S4; The reaction represented by the reaction formula (b) specifically includes the following steps: (1) Put a rhodium catalyst, an alkali, a copper catalyst, compound S2, Allenol 5, water and a second organic solvent into a dry reaction flask, plug the reaction flask with a rubber stopper, and then insert an air or oxygen ball to keep the reaction flask in an air or oxygen gas atmosphere, and react at −20 to 60° C. for 4 to 96 hours with stirring; (2) After the reaction of step (1) is completed, the mixture in the reaction flask is filtered through a short column of silica gel or diatomaceous earth, washed with a third organic solvent, and then concentrated and separated to obtain compound S4; The second organic solvent is at least one of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, methanol, ethanol, methylene chloride, ethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether; the amount of the second organic solvent used is based on the amount of arenol 5 used in reaction formula (b), and the amount of the second organic solvent used is 1.0 to 20.0 mL / mmol; the third organic solvent is at least one of ethyl acetate, ethyl ether, methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, and acetonitrile; the amount of the third organic solvent used is based on the amount of arenol 5 used in reaction formula (b), and the amount of the third organic solvent used is 1.0 to 200 mL / mmol; The rhodium catalyst is at least one of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium(III), rhodium(III) acetylacetonate, dichloropentaamminechlororhodium(III), tris(ethylenediamine)rhodium(III) trichloride, potassium pentachlororhodate(III), sodium hexachlororhodate(III), potassium hexachlororhodate(III), rhodium(III) chloride, rhodium(III) bromide, rhodium(III) iodide, rhodium(III) sulfate, rhodium(III) nitrate, and potassium hexanitrirhodium(III); The copper catalyst is at least one of copper acetate hydrate, copper acetate, copper sulfate hydrate, copper sulfate, copper nitrate hydrate, copper nitrate, copper chloride hydrate, copper chloride, and copper bromide; The alkali is at least one of sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, magnesium acetate, and calcium acetate; The total synthesis method according to claim 1, characterized in that the molar ratio of the rhodium catalyst, the copper catalyst, the alkali, the compound S2, the arenol 5, and the water is (0.005-0.10):(0.005-1.20):(0-0.60):(1.0-3.0):1.0:(0-20.0).

4. The total synthesis method includes the reaction shown in the following reaction formula (c): 【Chemistry 32】 2. The total synthesis method according to claim 1, wherein in the reaction represented by reaction formula (c), compound S2 is hydrolyzed to produce compound S3.

5. The total synthesis method includes the reaction shown in reaction scheme (d): 【Chemical 33】 Where: H ａ is hydrogen, deuterium, tritium; R １ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｂ is hydrogen, deuterium, tritium; wherein the aryl is a phenyl having a substituent at the ortho, meta, or para position, the substituents including alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano, and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are carbon, nitrogen, oxygen, or sulfur atoms, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; In the reaction formula (d), the allenol 5 reacts with the compound S3 in a second organic solvent under the action of a rhodium catalyst, a copper catalyst, an alkali, air or oxygen to produce the compound S4; the compound S3 is obtained by hydrolyzing the compound S2; The reaction represented by the reaction formula (d) specifically includes the following steps: (1) Put the rhodium catalyst, the alkali, the copper catalyst, the compound S3, the allenol 5 and the second organic solvent into a dry reaction flask, plug the reaction flask with a rubber stopper, and then insert an air or oxygen ball to keep the reaction flask in an air or oxygen gas atmosphere, and react at −20 to 60° C. for 4 to 96 hours with stirring; (2) After the reaction of step (1) is completed, the mixture in the reaction flask is filtered through a short column of silica gel or diatomaceous earth, washed with a third organic solvent, and then concentrated and separated to obtain compound S4; The second organic solvent is at least one of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, methanol, ethanol, methylene chloride, ethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether; the amount of the second organic solvent used is based on the amount of arenol 5 used as shown in reaction formula (d), and the amount of the second organic solvent used is 1.0 to 20.0 mL / mmol; the third organic solvent is one or more of ethyl acetate, ethyl ether, methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, and acetonitrile; the amount of the third organic solvent used is based on the amount of arenol 5 used shown in reaction formula (d), and the amount of the third organic solvent used is 1.0 to 200 mL / mmol; The rhodium catalyst is at least one of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium(III), rhodium(III) acetylacetonate, dichloropentaamminechlororhodium(III), tris(ethylenediamine)rhodium(III) trichloride, potassium pentachlororhodate(III), sodium hexachlororhodate(III), potassium hexachlororhodate(III), rhodium(III) chloride, rhodium(III) bromide, rhodium(III) iodide, rhodium(III) sulfate, rhodium(III) nitrate, and potassium hexanitrirhodium(III); The copper catalyst is at least one of copper acetate hydrate, copper acetate, copper sulfate hydrate, copper sulfate, copper nitrate hydrate, copper nitrate, copper chloride hydrate, copper chloride, and copper bromide; The alkali is at least one of sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, magnesium acetate, and calcium acetate; The total synthesis method according to claim 1, characterized in that the molar ratio of the rhodium catalyst, the copper catalyst, the alkali, the compound S3 and the allenol 5 is (0.005-0.10):(0.005-1.20):(0-0.60):(1.0.0-3.0):1.

0.

6. The total synthesis method includes the reaction shown in reaction scheme (e): 【Chemical 34】 Where: H ａ is hydrogen, deuterium, tritium; R １ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｂ is hydrogen, deuterium, tritium; wherein the aryl is a phenyl having a substituent at the ortho, meta, or para position, the substituents including alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano, and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are carbon, nitrogen, oxygen, or sulfur atoms, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; In the reaction shown in reaction formula (e), bis[(pinacol)boryl]methane reacts with compound S4 in a first organic solvent under the action of lithium 2,2,6,6-tetramethylpiperidine LiTMP as an alkali to produce compound S5; wherein the lithium 2,2,6,6-tetramethylpiperidine is prepared in situ using 2,2,6,6-tetramethylpiperidine and n-butyl lithium; The reaction scheme (e) specifically includes the following steps: (1) Protect the reaction system with inert gas; put 2,2,6,6-tetramethylpiperidine and a first organic solvent into a dry reaction flask, add n-butyllithium reagent at -90 to 30°C, and then stir at -90 to 30°C for another 15 minutes to 3 hours to prepare lithium 2,2,6,6-tetramethylpiperidine solution in situ; (2) dissolving bis[(pinacol)boryl]methane in the first organic solvent and adding it to the lithium 2,2,6,6-tetramethylpiperidine solution at −90 to 30° C., followed by stirring at −90 to 30° C. for an additional 1 minute to 2 hours; (3) dissolving compound S4 in the first organic solvent, adding the resultant mixture produced in step (2) at −90 to 30° C., and then reacting the resultant mixture with stirring at −90 to 30° C. for 0.5 to 12 hours; (4) After the reaction of step (3) is completed, the reaction is quenched, and compound S5 is obtained by extraction, concentration, and separation; The first organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, ethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, toluene; 2. The method of claim 1, wherein the molar ratio of S4 to lithium 2,2,6,6-tetramethylpiperidine to bis[(pinacol)boryl]methane is 1:(1.0-2.0):(1.0-2.0); and when the lithium 2,2,6,6-tetramethylpiperidine solution is prepared in situ, the molar ratio of S4 to 2,2,6,6-tetramethylpiperidine to n-butyllithium to bis[(pinacol)boryl]methane is 1:(1.0-2.0):(1.0-2.0):(1.0-2.0).

7. The total synthesis method includes the reaction shown in reaction scheme (f): 【Chemistry 35】 Where: H ａ is hydrogen, deuterium, tritium; R １ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｂ is hydrogen, deuterium, tritium; H ｃ is hydrogen, deuterium, tritium; R ２ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｄ is hydrogen, deuterium, tritium; wherein the aryl is a phenyl having a substituent at the ortho, meta, or para position, the substituents including alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano, and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are carbon, nitrogen, oxygen, or sulfur atoms, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; In the reaction formula (f), the allenol 5 reacts with the compound S5 in a second organic solvent under the action of a rhodium catalyst, a copper catalyst, an alkali, water, air or oxygen to produce the compound 1; The reaction represented by the reaction formula (f) specifically includes the following steps: (1) Put a rhodium catalyst, an alkali, a copper catalyst, compound S5, Allenol 5, water and a second organic solvent into a dry reaction flask, plug the reaction flask with a rubber stopper, and then insert an air or oxygen ball to keep the reaction flask in an air or oxygen gas atmosphere, and react at −20 to 60° C. for 4 to 96 hours with stirring; (2) After the reaction of step (1) is completed, the mixture in the reaction flask is filtered through a short column of silica gel or diatomaceous earth, washed with a third organic solvent, and then concentrated and separated to obtain compound 1; The second organic solvent is at least one of tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, methanol, ethanol, methylene chloride, ethyl ether, anisole, methyl tert-butyl ether, ethylene glycol dimethyl ether, and ethylene glycol diethyl ether; the amount of the second organic solvent used is based on the amount of arenol 5 used as shown in reaction formula (f), and the amount of the second organic solvent used is 1.0 to 20.0 mL / mmol; the third organic solvent is one or more of ethyl acetate, ethyl ether, methanol, ethanol, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetone, and acetonitrile; the amount of the third organic solvent used is based on the amount of arenol 5 used shown in reaction formula (f), and the amount of the third organic solvent used is 1.0 to 200 mL / mmol; The rhodium catalyst is at least one of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium(III), rhodium(III) acetylacetonate, dichloropentaamminechlororhodium(III), tris(ethylenediamine)rhodium(III) trichloride, potassium pentachlororhodate(III), sodium hexachlororhodate(III), potassium hexachlororhodate(III), rhodium(III) chloride, rhodium(III) bromide, rhodium(III) iodide, rhodium(III) sulfate, rhodium(III) nitrate, and potassium hexanitrirhodium(III); The copper catalyst is at least one of copper acetate hydrate, copper acetate, copper sulfate hydrate, copper sulfate, copper nitrate hydrate, copper nitrate, copper chloride hydrate, copper chloride, and copper bromide; The alkali is at least one of sodium acetate, sodium carbonate, sodium bicarbonate, potassium acetate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium carbonate, magnesium acetate, and calcium acetate; The total synthesis method according to claim 1, characterized in that the molar ratio of the rhodium catalyst, the copper catalyst, the alkali, the compound S5, the arenol 5, and the water is (0.005-0.10):(0.005-1.20):(0-0.60):(1.0-3.0):1.0:(0-20.0).

8. The total synthesis method includes the reaction shown in reaction scheme (g): 【Chemical 36】 Where: H ａ is hydrogen, deuterium, tritium; R １ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｂ is hydrogen, deuterium, tritium; H ｃ is hydrogen, deuterium, tritium; R ２ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｄ is hydrogen, deuterium, tritium; H ｅ is hydrogen, deuterium, tritium; wherein the aryl is a phenyl having a substituent at the ortho, meta, or para position, the substituents including alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano, and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are carbon, nitrogen, oxygen, or sulfur atoms, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; 2. The method according to claim 1, wherein in the reaction formula (g), compound 1 is reduced to produce compound 2.

9. The total synthesis method includes the reaction shown in reaction scheme (h): 【Chemical 37】 Where: H ａ is hydrogen, deuterium, tritium; R １ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｂ is hydrogen, deuterium, tritium; H ｃ is hydrogen, deuterium, tritium; R ２ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｄ is hydrogen, deuterium, tritium; H ｅ is hydrogen, deuterium, tritium; R ３ is acyl; wherein the aryl is a phenyl having a substituent at the ortho, meta, or para position, the substituents including alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano, and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are carbon, nitrogen, oxygen, or sulfur atoms, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; 2. The method according to claim 1, wherein in reaction formula (h), compound 2 is esterified to produce compound 3.

10. The total synthesis method includes the reaction shown in reaction scheme (i): 【Chemical Formula 38】 Where: H ａ is hydrogen, deuterium, tritium; R １ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｂ is hydrogen, deuterium, tritium; H ｃ is hydrogen, deuterium, tritium; R ２ is hydrogen, deuterium, tritium, phenyl, aryl, heterocyclyl, hydrocarbyl, or functionalized hydrocarbyl; H ｄ is hydrogen, deuterium, tritium; wherein the aryl is a phenyl having a substituent at the ortho, meta, or para position, the substituents including alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxyl, cyano, and amino; the heterocyclyl is a 3-10 membered heterocycle whose ring atoms are carbon, nitrogen, oxygen, or sulfur atoms, and is an aliphatic ring, an aromatic ring, or a ring formed by bonding two or more monocycles; and in the hydrocarbyl having a functional group, the functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano; 2. The method according to claim 1, wherein in reaction formula (i), compound 1 is oxidized to produce compound 4.

11. Use of the method according to any one of claims 1 to 10 in the preparation of vitamin A and its derivatives and deuterated compounds thereof.

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