KR20020079555A - Practical Synthetic Method of Retinoid and Carotenoid Compounds - Google Patents

Abstract

PURPOSE: Provided is a practical method for synthesizing retinol, retinal, and beta-carotene by using a C-15 allylic disulfone compound produced stably and economically. CONSTITUTION: The method for synthesizing the retinol(formula 2), the retinal(formula 3), and the beta-carotene(formula 4) comprises the steps of: performing a deprotonation of the C-15 allylic disulfone compound(formula 1) by using an excess base to obtain a carbon anion; performing a coupling reaction and a desulfonation of the carbon anion and a C-5 halo-acetate compound, a C-5 halo-acetal compound, and C-10 dihaloallylic sulfide compound.

Description

Practical Synthetic Method of Retinoid and Carotenoid Compounds

The present invention relates to a process for the preparation of retinol and carotene compounds, and more particularly to efficient and practical synthesis of retinol, retinal and beta-carotene. Retinol, well-known as vitamin A, is an essential nutrient that has effects on tissue growth, differentiation, and oxidation, and is recently used as a raw material for cosmetics for the purpose of preventing wrinkles and preventing skin aging. Retinal is well known as a compound that plays an important role in visual action, and beta-carotene is a very important substance widely used as food coloring, animal feed, and health supplements as a precursor of vitamin A.

Representative methods for synthesizing retinol and carotene-based compounds based on the structure of conjugate polyenes include three methods currently being industrialized by Roche, BASF, and Aventis. Pure & Appl. Chem. 1991 , 63 , 45-58; ibid. 1979 , 51 , 447-462). They have a fundamental difference in the way they form double bonds. First, Roche's method induces the expansion of chains and the formation of double bonds by the addition reaction of acetylide and its partial hydrogenation. This method is known to provide mainly cis-type double bonds, which are known to be less active in partial hydrogenation and dehydration reactions. It is thought to be.

Synthesis method of vitamin A and beta-carotene of BASF, characterized by the formation of double bonds by the Wittig reaction, is short and concise, but the phosphine oxide is a by-product produced after the Wittig reaction. It is not easy to treat phosphine oxide, and a considerable amount of compounds having a double bond of cis type having low activity is obtained.

Compared with the most recently developed and previously described methods, Aventis' retinol synthesis, a better method, utilizes coupling and double bond formation reactions with sulfone compounds developed by Julia. According to this method, it is known that the intermediate products of the synthesis are stable, the binding reaction is excellent, and when the double bond is produced, a trans structure is mainly obtained, and the by-products are easily processed.

Scheme 1 below describes the synthesis of vitamin A, retinal, and beta-carotene using Julia's sulfone chemistry. They use beta-ionone as a starting material for synthesis to form vinyl beta-ionol by the addition reaction of vinyl grignard, which is then dissolved in an acetic acid solvent. Reaction with benzenesulfinic acid (sodium salt) yields C-15 sulfone compounds, which are important intermediates in the synthesis of retinol and carotene compounds. The coupling reaction, desulfonation reaction and hydrolysis reaction of acetate with the C-15 sulfone compound and the C-5 halo-acetate compound resulted in the formation of vitamin A ( Bull. Soc. Chim. France 1973 , 746-750; Tetrahedron 1977 , 33 , 2799-2805). On the other hand, the coupling reaction between the C-15 sulfone compound and the C-5 halo-acetal compound, the desulfonation reaction, and the hydrolysis reaction of the acetal form retinal (US Patent 5,276,209). The coupling reaction between the -15 sulfone compound and the C-10 dihaloallylic sulfide compound, the oxidation of the central sulfide and the Lambberg-Backlund reaction, and the desulfonation reaction are beta-carotene. ( Journal of Organic Chemistry , 1999 , 64 , 8051-8053).

Synthesis method of the retinol and carotene compound using the sulfone compound according to Scheme 1 has the advantage of using a relatively stable intermediate, efficient formation of double bond-generating citrance structure, and easy processing of by-products. . However, several disadvantages can be pointed out in the preparation of C-15 sulfone compounds, which are important intermediates in these methods: first, the use of relatively expensive beta-ionone as a starting material for synthesis, and secondly, intractable and expensive. Vinyl grignard reagents should be used. Therefore, a more economical and practical method of synthesizing C-15 sulfone compounds or new sulfone compounds corresponding thereto and overcoming the above disadvantages has been required to develop a method for synthesizing retinol and carotene compounds.

In order to meet this demand, the present inventors have overcome the problem of synthesizing the C-15 allylic sulfone compound containing the conjugate polyene described above (see Scheme 1), which has been used as an important intermediate for the synthesis of retinol and carotene family compounds. A new C-15 allylic disulfone compound (Formula 1) and a method for preparing the same, which are synthesized in a more efficient and economic manner, have already been developed (Korean Patent Application No. 2000-77567, PCT / KR01 / 02078). An efficient method for synthesizing retinoic acid using the intermediate has been presented.

The technical problem to be achieved by the present invention is to overcome the problems of the above-mentioned C-15 allylic sulfone compound which has been usefully used for synthesizing retinol and carotene compounds, C-15 allylic disulfone produced more efficiently and economically It is to provide a practical and economical method for producing retinol using the compound (Formula 1).

Another technical problem to be achieved by the present invention is to provide a practical and economical method for producing retinal using the above-mentioned C-15 allylic disulfone compound (Formula 1).

Another technical problem to be achieved by the present invention is to provide a practical and economical method for producing beta-carotene using the above-mentioned C-15 allylic disulfone compound (Formula 1).

The first technical problem of the present invention is (1) deprotonation by treating 2 equivalents of a base of C-15 allylic disulfone compound of Formula 1, and then adding C-5 halo-acetate compound (A ) (X is a halogen atom) to synthesize Compound (B) having 20 carbon skeletons required for synthesis of the retinol compound; And (2) treating the C-20 compound (B) with an excess (more than 3 equivalents) of base to form a double bond, performing a desulfonation reaction, and simultaneously performing hydrolysis of an acetate group. It is made by the manufacturing method of 2) (Scheme 2).

Wherein X is selected from the group consisting of -Cl, -Br, and -I.

In step (1), the deprotonation reaction of Chemical Formula 1 requires the addition of 2 equivalents of the base dropwise with respect to Chemical Formula 1 at low temperature, preferably at 0 ° C. or less, wherein n is the base. -BuLi, s -BuLi, phenyllithium, NaH, NaNH ₂ , lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, t- Use BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa, etc. On the other hand, it has been reported that C-5 halo-acetate (A) can be efficiently produced by the electrophilic addition of halogen to isoprene in acetic acid solvent ( J. Am. Chem. Soc. 1950 , 72 , 4608 -4613; Tetrahedron Lett. 1974 , 351-354; Tetrahedron Lett. 1976 , 239-242).

In the step (2), the desulfonation reaction is preferably added at least 3 equivalents of a base to the compound (B) in an alcoholic solvent to react at the boiling temperature of the solvent, the base used is NaNH ₂ , t -BuOK , CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa, etc., wherein the hydrolysis of the acetate group proceeds at the same time to obtain the retinol immediately.

According to a second technical problem of the present invention, a C-15 allyl disulfone compound of Formula 1 is treated with an excess (more than 3 equivalents) of base to be deprotonated, followed by C-5 halo-acetal compound ( Reacting C) (X is a halogen atom) to form a compound (D) having 20 carbon skeletons necessary for the synthesis of the retinal compound, and the desulfonation reaction proceeds simultaneously by the action of the excess base present, resulting in retinal acetal. Synthesis of compound (E), and by the method of producing a retinal (Formula 3) characterized in that it comprises the step of proceeding to hydrolysis of acetal immediately without a separate purification process (Scheme 3).

Wherein X is selected from the group consisting of -Cl, -Br, and -I.

In the reaction step, the deprotonation reaction of the formula (1) requires the addition of an excess of base (preferably 4 equivalents) to the formula (1) at a low temperature, preferably below 0 ℃, wherein the excess Since the base of is also used in the desulfonation reaction of the compound (D) formed by the coupling reaction between the formula (1) and C-5 halo-acetal, the following bases, namely NaNH ₂ , t- BuOK, CH ₃ CH ₂ OK, selected from the group consisting of such as _{CH 3 OK, CH 3 CH 2} ONa, CH 3 ONa is, that from it is preferable to use a metal alkoxide.

On the other hand, the synthesis of C-5 halo-acetal (C) is followed by the method of Liebigs Ann. Chem. 1976 , 2194-2205, or C-5 halo-acetate (A) as shown in Scheme 4 below. Hydrolysis of acetate from to form alcohols ( Tetrahedron Letters , 1976 , 239-242), and the oxidation of alcohols to form aldehydes, which can then be synthesized according to the method of forming acetal with neopentylglycol.

Wherein X is selected from the group consisting of -Cl, -Br, and -I.

The third technical problem of the present invention is to (1) deprotonation by treating 2 equivalents of a base of C-15 allyl disulfone compound of Formula 1, and then adding the C-15 allyl disulfone compound ( Allyl sulfide compound (G) having 40 carbon skeletons required for beta-carotene synthesis by reacting up to 1/2 equivalent dihaloallylic sulfide (F) (X is a halogen atom) based on formula (1) Synthesizing; (2) selectively oxidizing the allylic sulfide compound (G) to produce an allylic sulfone compound (H); (3) preparing tetra (benzenesulfonyl) -triene compound (I) from the sulfone compound (G) via a Lambberg-Backlund reaction; And (4) reacting the tetra (benzenesulfonyl) -triene compound (I) with a base to form a double bond and proceeding a desulfonation reaction of the beta-carotene (Formula 4) By the preparation method (Scheme 5).

Wherein X is selected from the group consisting of -Cl, -Br, and -I.

In step (1), the deprotonation reaction of Chemical Formula 1 requires the addition of 2 equivalents of the base dropwise with respect to Chemical Formula 1 at low temperature, preferably at 0 ° C. or less, wherein n is the base. -BuLi, s -BuLi, phenyllithium, NaH, NaNH ₂ , lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, t -BuOK , CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa and so on. On the other hand, C-10 dihaloallylic sulfide compound (F) can be synthesized from isoprene as a compound developed by the inventors for the efficient synthesis of carotene compounds ( Journal of Organic Chemistry , 1999 , 64 , 8051-8053) Recently, the method for synthesizing this compound has been improved (Korean Patent Application 2001-0067305).

The selective oxidation of step (2) is hydrogen peroxide in sulfide compound (G) under a metal oxide catalyst represented by lithium molybdenate-niobate (LiNbMoO ₆ ) or vanadium oxide (V ₂ O ₅ ) at room temperature. It is preferable to make it by adding 2 equivalents or more of solutions dropwise. Under these reaction conditions, the double bond of allyl sulfide (G) is not oxidized, and only sulfide is oxidized to sulfone to selectively obtain compound (H).

The Lambberg-Backlund reaction of step (3) is a reaction for obtaining compound (I) by removing SO ₂ at the center of the structure of the allyl sulfone compound (H) and simultaneously forming a double bond. It is preferable to carry out in the condition which removed oxygen in air, ie, nitrogen or argon atmosphere.

In the desulfonation reaction of step (4), an excess of a base is added dropwise to the compound (I) in an alcoholic solvent, and the reaction is carried out at a boiling temperature of the solvent. The bases used are NaNH ₂ , t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa and the like. Under these conditions, beta-carotene of formula 4 is synthesized by forming a double bond from compound (I) and removing four benzenesulfonyl groups.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited only to the following Examples.

Synthesis Example 1 Vitamin A (Retinol, Formula 2)

(1) coupling reaction

5.00 g (10.27 mmol) of 1,5-di (benzenesulfonyl) -3-methyl-5- (2,6,6-trimethyl-1-cyclohexenyl) -2-pentene (Formula 1) was dissolved in anhydrous tetrahydro Dissolve in 30 ml of furan (THF) and add 2.54 g (22.59 mmol) of t- BuOK at 0 ° C. The reaction mixture was stirred at the same temperature for 20 minutes, then 2.55 g (12.32 mmol) of bromo-acetate compound (A) having a ratio of trans and seed structure of 4: 1 was added by dissolving in 10 ml THF, and this was carried out for 3 hours. After vigorously stirring, 30 ml of 1 M aqueous HCl solution is slowly added to terminate the reaction. The reaction mixture was extracted with Ether, washed with water, filtered off with anhydrous sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was evaporated under reduced pressure to yield 7.53 g of concentrated product, which was used in the next desulfonation reaction without further purification.

(2) desulfonation reaction

4.72 g (0.205 mol) of sodium is finely chopped and slowly and carefully added to 80 ml 99.5% ethanol (EtOH), followed by stirring under reflux for 1 hour to the boiling point of the solvent. After the reaction was cooled to room temperature, 7.53 g of the concentrated resultant prepared in advance was dissolved in 20 ml of 99.5% EtOH. The reaction mixture is again refluxed to the boiling point of the solvent, stirred for 15 hours and cooled to room temperature. Water and 1M HCl aqueous solution were carefully added sequentially to the reaction product, which was extracted with chloroform (CHCl ₃ ), followed by removal of water using anhydrous sodium sulfate (Na ₂ SO ₄ ), followed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the resulting product was purified by silica gel chromatography to obtain 1.77 g (6.16 mmol) of Vitamin A (retinol) of Chemical Formula 2 (yield 60%). Vitamin A obtained at this time was obtained in a ratio of 1: 3 of the compound having a cs and trans structure in carbon 13, they could be separated.

(Trans-vitamin A) ¹ H NMR: δ 1.02 (6H, s), 1.36-1,53 (2H, m), 1.53-1.67 (2H, m), 1.71 (3H, s), 1.87 (3H, s ), 1.96 (3H, s), 2.01 (2H, t, J = 6.0 Hz), 4.31 (2H, d, J = 6.8 Hz), 5.69 (1H, t, J = 6.8 Hz), 6.11 (1H, d , J = 10.8 Hz), 6.12 (1H, A of ABq, J = 15.9 Hz), 6.17 (1H, B of ABq, J = 15.9 Hz), 6.30 (1H, d, J = 15.0 Hz), 6.63 (1H , dd, J = 15.0, 10.8 Hz) ppm.

¹³ C NMR: δ 12.5, 12.6, 19.2, 21.7, 28.9, 28.9, 33.0, 34.1, 39.5, 59.3, 125.0, 126.6, 129.2, 130.0, 130.1, 136.0, 136.3, 136.6, 137.6, 137.7 ppm.

(C-13 Seas-Vitamin A) ¹ H NMR: δ 1.03 (6H, s), 1.36-1.52 (2H, m), 1.52-1.65 (2H, m), 1.71 (3H, s), 1.94 (3H, s), 1.97 (3H, s), 1.96-2.09 (2H, m), 4.33 (2H, d, J = 7.1 Hz), 5.57 (1H, t, J = 7.1 Hz), 6.13 (1H, A of ABq , J = 16.0 Hz), 6.15 (1H, d, J = 9.7 Hz), 6.20 (1H, B of ABq, J = 16.0 Hz), 6.63 (1H, A of ABq, J _AB = 15.1 Hz), 6.69 ( 1 H, d of B of ABq, J _AB = 15.1, J _d = 9.7 Hz) ppm.

¹³ C NMR δ 12.8, 19.2, 20.5, 21.7, 28.9, 28.9, 33.0, 34.2, 39.5, 58.5, 127.2, 127.2, 128.1, 128.2, 129.5, 130.1, 136.0, 137.1, 137.5, 137.7 ppm.

It was confirmed that the ¹ H NMR data of the trans-vitamin A and C-13 Sea-vitamin A exactly match the data of the authentic samples.

Synthesis Example 2 Retinal (Formula 3)

(1) 2- (3-bromo-2-methyl-1-butenyl) -5,5-dimethyl- [1,3] -dioxane {2- (3-bromo-2-methyl-1-butenyl ) -5,5-dimethyl- [1,3] -dioxane} (C) (see Scheme 4)

4-acetoxy-1-bromo-2-methyl-2-butene with a 4: 1 double bond ratio of trans and seas structure (A) 2.23 g (10.76 mmol) was dissolved in 40 ml of methyl alcohol and 14 ml of water, and 4.46 g (32.3 mmol, 3 equivalents) of anhydrous K ₂ CO ₃ was added thereto while maintaining the temperature at 0 ° C., followed by stirring for 2 hours. Neutralized and extracted with CH ₂ Cl ₂ . The extracted mixture was dried using anhydrous sodium sulfate (Na ₂ SO ₄ ) to remove moisture, and then filtered. To the filtrate (40 ml), 4.05 g (10.76 mmol) of pyridinium dichromate (PDC) was added, followed by 5 hours at room temperature. After stirring, the reaction mixture was diluted with CH ₂ Cl ₂ and washed well with water, and then water was removed using anhydrous sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resultant was dissolved in 35 ml of benzene, 0.11 g (0.54 mmol) of p- TsOH and 1.12 g (10.76 mmol) of neopentyl glycol were added, followed by a Dean-Stark column and a condenser. (condensor) was installed and refluxed to the boiling point of the solvent and stirred for 12 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether and washed well with 1M aqueous NaOH solution and water, and water was removed using anhydrous K ₂ CO ₃ and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resulting product was purified by silica gel chromatography to obtain 1.39 g (5.58 mmol) of compound (C) (yield 52%). The double bond of the compound (C) obtained at this time was obtained with the ratio of a 2: 1 trans and seed structure.

(Trans (C)) ¹ H NMR: δ 0.65 (3H, s), 1.12 (3H, s), 1.78 (3H, s), 3.41 (2H, A of ABq, J = 10.7 Hz), 3.55 (2H, B of ABq, J = 10.7 Hz), 3.83 (2H, s), 4.97 (1H, d, J = 6.1 Hz), 5.58 (1H, d, J = 6.1 Hz) ppm.

¹³ C NMR δ 15.6, 21.9, 22.9, 30.0, 39.1, 77.1, 77.1, 98.2, 127.1, 138.0 ppm.

IR (KBr) 1471, 1395, 1158, 1126, 750 cm ^-1 .

(SEC (C)) ¹ H NMR: δ 0.87 (3H, s), 1.32 (3H, s), 1.80 (3H, s), 3.41 (2H, A of ABq, J = 10.7 Hz), 3.55 (2H, B of ABq, J = 10.7 Hz), 3.93 (2H, s), 5.01 (1H, d, J = 5.7 Hz), 5.39 (1H, d, J = 5.7 Hz) ppm.

(2) coupling and desulfonation reactions; Hydrolysis reaction

1.00 g (2.05 mmol) of 1,5-di (benzenesulfonyl) -3-methyl-5- (2,6,6-trimethyl-1-cyclohexenyl) -2-pentene (Formula 1) was dissolved in anhydrous tetrahydro Dissolve in 30 ml of furan (THF) and add 0.92 g (8.2 mmol, 4 equivalents) of t- BuOK at -20 ° C. The reaction mixture was stirred at the same temperature for 1 hour, and then 0.61 g (2.46 mmol, 1.2 equiv) of bromo-acetal compound (C) having a ratio of trans and sheath structure of 2: 1 was added to 10 ml THF, After vigorously stirring for 2 hours, the reaction temperature was raised to 4 ° C. and further stirred for 4 hours, 20 ml of 1M HCl aqueous solution was slowly added, followed by stirring for 1 hour. Under these conditions, hydrolysis of acetal proceeds, and the reaction mixture is extracted with diethyl ether and washed with water, followed by removal of water using anhydrous sodium sulfate (Na ₂ SO ₄ ), followed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the resulting product was purified by silica gel chromatography to obtain 0.45 g (1.59 mmol) of retinal of the formula (3) (yield 78%). Retinal obtained at this time obtained a compound having a cs and trans structure in carbon 13 in a ratio of 1: 4, and they could be separated.

(Trans-Retinal) ¹ H NMR: δ 1.04 (6H, s), 1.44-1,50 (2H, m), 1.51-1.54 (2H, m), 1.72 (3H, s), 1.97-2.09 (2H , m), 2.03 (3H, s), 2.33 (3H, s), 5.97 (1H, d, J = 8.2 Hz), 6.18 (1H, A of ABq, J = 16.2 Hz), 6.19 (1H, d, J = 11.6 Hz), 6.35 (1H, B of ABq, J = 16.2 Hz), 6.37 (1H, d, J = 15.0 Hz), 7.14 (1H, dd, J = 15.0, 11.6 Hz), 10.10 (1H, d, J = 8.2 Hz) ppm.

¹³ C NMR: δ 13.0, 13.1, 19.2, 21.7, 29.0, 29.0, 33.1, 34.3, 39.6, 129.0, 129.4, 129.7, 130.5, 132.5, 134.5, 137.1, 137.6, 141.3, 154.8, 191.1 ppm.

(C-13 Sea-Retinal) ¹ H NMR: δ 1.04 (6H, s), 1.43-1.53 (2H, m), 1.58-1.67 (2H, m), 1.73 (3H, s), 1.93-2.09 ( 2H, m), 2.03 (3H, s), 2.15 (3H, s), 5.84 (1H, d, J = 7.8 Hz), 6.19 (1H, A of ABq, J = 16.0 Hz), 6.23 (1H, d , J = 11.3 Hz), 6.36 (1H, B of ABq, J = 16.0 Hz), 7.05 (1H, dd, J = 14.9, 11.3 Hz), 7.30 (1H, d, J = 14.9 Hz), 10.20 (1H , d, J = 7.8 Hz) ppm.

¹³ C NMR δ 13.0, 19.2, 21.2, 21.7, 29.0, 29.0, 33.1, 34.3, 39.6, 126.3, 127.7, 129.4, 129.7, 130.5, 133.4, 137.0, 137.6, 141.5, 154.6, 189.9 ppm.

Synthesis Example 3 Beta-carotene (β)

(1) coupling reaction: compound (G)

4.00 g (8.21 mmol) of 1,5-di (benzenesulfonyl) -3-methyl-5- (2,6,6-trimethyl-1-cyclohexenyl) -2-pentene (Formula 1) was dissolved in anhydrous tetrahydro Dissolve in 50 ml of furan (THF) and add 11.3 ml (18.1 mmol, 2.2 equiv) of 1.6 M concentration n- BuLi nucleic acid solution at 0 ° C. The reaction mixture was stirred at the same temperature for 20 minutes, then 1.18 g (4.11 mmol, 0.5 equivalents) of dichloroallylic sulfide (F) was dissolved in 15 ml of THF, slowly added thereto, and stirred at 0 ° C. for 1 hour, followed by 1 M HCl. The reaction is terminated by careful addition of an aqueous solution. The reaction mixture was extracted with diethyl ether and then washed well with water, water was removed using anhydrous sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resultant was subjected to silica gel chromatography to obtain 3.85 g (6.75 mmol) of a coupling compound (G) consisting of 40 carbon chains (yield 82%). The compound has a stereocenter at the carbon to which the benzenesulfonyl group is linked, and thus contains stereoisomers. They could not be separated, of which the main product data are as follows.

¹ H NMR: δ 0.77 (3H, s), 0.82 (3H, s), 1.16 (3H, s), 1.23-1.43 (2H, m), 1.43-1.52 (2H, m), 1.50 (3H, s) , 1.86-2.12 (2H, m), 1.97 (3H, s), 2.03-2.32 (1H, m), 2.44-3.00 (3H, m), 2.90-3.20 (2H, m), 3.72-3.99 (2H, m), 4.83-5.00 (1H, m), 5.12-5.27 (1H, m), 7.43-7.68 (6H, m), 7.74-7.95 (4H, m) ppm.

¹³ C NMR δ 15.8, 18.7, 23.2, 28.5, 28.7, 34.4, 35.5, 35.7, 38.4, 39.4, 40.9, 41.4, 62.6, 65.4, 120.7, 124.3, 124.9, 128.6, 128.9, 129.0, 129.0, 131.3, 133.4, 133.7, 137.4, 137.7, 140.9, 141.8 ppm.

IR (KBr) 2931, 1447, 1304, 1144 cm <^-1> .

HRMS (FAB ⁺ ) calcd for C ₆₄ H ₈₂ S ₅ O ₈ -{(C ₆ H ₆ SO ₂ ) x 2} + H ⁺ = C ₅₂ H ₇₁ S ₃ O ₄ 855.4514, found 855.4511.

(2) Oxidation reaction: Compound (H)

1.61 g (1.41 mmol) of the C-40 coupling compound (G) was dissolved in 20 ml of acetonitrile (CH ₃ CN), and 20 mg (0.07 mmol, 0.05 equivalent) of LiNbMoO ₆ and 0.55% aqueous solution of 35% H ₂ O ₂ at 0 ° C. g (5.64 mmol, 4 equivalents) was added dropwise, followed by stirring at the same temperature for 1 hour, followed by stirring at room temperature for 12 hours. The reaction mixture was extracted with CH ₂ Cl ₂ , washed with 1M aqueous HCl solution and water, and dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resulting product was purified by silica gel chromatography to obtain 1.36 g (1.13 mmol) of sulfone compound (H) (yield 80%). The compound has a stereocenter at the carbon to which the benzenesulfonyl group is linked, and thus contains stereoisomers. They could not be separated, of which the main product data are as follows.

¹ H NMR: δ 0.67 (3H, s), 0.79 (3H, s), 1.28 (3H, s), 1.23-1.54 (4H, m), 1.67 (3H, s), 1.93-2.03 (2H, m) , 2.00 (3H, s), 2.05-2.66 (2H, m), 2.71-2.92 (1H, m), 2.98-3.32 (1H, m), 3.42-3.70 (2H, m), 3.74-4.02 (2H, m), 4.86-5.10 (1H, m), 5.13-55.4 (1H, m), 7.45-7.69 (6H, m), 7.72-7.7.9 (4H, m) ppm.

¹³ C NMR δ 15.8, 18.9, 23.4, 28.4, 28.7, 34.6, 35.7, 36.1, 38.4, 39.5, 41.5, 51.7, 62.3, 65.4, 113.8, 114.5, 120.4, 128.6, 129.0, 129.0, 129.2, 131.1, 133.5, 133.8, 137.2, 137.8, 140.8, 142.2 ppm.

IR (KBr) 2931, 1447, 1305, 1144 cm <^-1> .

HRMS (FAB ⁺ ) calcd for C ₆₄ H ₈₂ S ₅ O ₁₀ − {(C ₆ H ₆ SO ₂ ) x 3} + H ⁺ = C ₄₆ H ₆₅ S ₂ O ₄ 745.4324, found 745.4333.

(3) Lambberg-Backklund reaction: compound (I)

0.98 g (0.84 mmol) of C-40 sulfone compound (H) was dissolved in 15 ml of CCl ₄ and 10 ml of t- BuOH, and 0.47 g (8.36 mmol, 10 equivalents) of KOH finely ground in an argon atmosphere at 0 ° C. was added dropwise. . The mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 10 hours. Water was carefully added to the reaction mixture, neutralized with 1M aqueous HCl solution, extracted with CH ₂ Cl ₂ , water was removed using anhydrous sodium sulfate (Na ₂ SO ₄ ), and filtered. The filtrate was concentrated by evaporation under reduced pressure to give 1.15 g of the reaction product (I), which was used for the next reaction without further purification because this compound was unstable.

(4) desulfonation reaction: beta-carotene (Formula 4)

1.2 g (52.14 mmol) of sodium (Na) was added to 50 ml of ethyl alcohol (99.9%), and the mixture was stirred under reflux for 1 hour, cooled to room temperature, and 1.15 g of the reaction product (I) was added to 20 ml of ethyl alcohol under an argon atmosphere. Melt and add dropwise. The mixture was stirred under reflux at 12 ° C. for 12 hours with light blocking, cooled to room temperature, and most of the solvent was removed under reduced pressure. Water was carefully added thereto, extracted with CHCl ₃ , washed with 1M aqueous HCl solution and water, and then dried using anhydrous sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated by evaporation under reduced pressure, and the resultant was subjected to silica gel chromatography to obtain 0.32 g (0.60 mmol) of beta-carotene of the formula (4) (yield 71%).

¹ H NMR: δ 1.03 (12H, s), 1.44-1.49 (4H, m), 1.55-1.67 (4H, m), 1.72 (6H, s), 1.98 (12H, s), 2.03 (4H, t, J = 6.3 Hz), 6.15 (2H, A of ABq, J = 16.5 Hz), 6.16 (2H, d, J = 11.4 Hz), 6.18 (2H, B of ABq, J = 16.5 Hz), 6.26 (2H, m), 6.37 (2H, A of ABq, J = 14.9 Hz), 6.64 (2H, m), 6.66 (2H, d of B of ABq, J _d = 11.4, J _AB = 14.9 Hz) ppm.

The double bonds of the beta-carotene all have a trans structure, and it was confirmed that the ¹ H NMR data exactly matched the data of the authentic sample.

As described above, according to the present invention, in place of the C-15 allylic sulfone compound containing the conjugate polyene used in the synthesis of the retinol and carotene compound, Formula 1 prepared by a more economical and practical method C-5 halo-acetate compound (A), C-5 halo-acetal compound (C), and C-10 dihaloallylic sulfide (F), respectively, using the C-15 allyl disulfone compound represented by Coupling with and double bond formation reactions enables efficient and economic synthesis of retinol, retinal and beta-carotene.

Claims (10)

(1) C-15 allylic disulfone compound of Formula 1 is treated with a base to deprotonation, and then reacted with C-5 halo-acetate compound (A) to prepare vitamin A. Obtaining a disulfone compound (B) having a C-20 carbon skeleton; And (2) a method of preparing vitamin A of formula (2), wherein the C-20 disulfone compound (B) is treated with a base to perform desulfonation reaction and double bond formation and hydrolyze the acetate group at the same time. . Wherein X is selected from the group consisting of -Cl, -Br, and -I. The method of claim 1, wherein the base of step (1) is n- BuLi, s- BuLi, phenyllithium, NaH, NaNH ₂ , lithium diisopropylamide, lithium hexamethyldisalazide , Sodium hexamethyldisilazide, t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa, and selected from the group consisting of Used in an amount of 2 equivalents. According to claim 1, wherein the base of step (2) is selected from the group consisting of NaNH ₂ , t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa, The amount is 3 equivalent or more based on the compound (B). 20 carbon skeletons required for the synthesis of retinal compound by deprotonation by treating an excess of base with C-15 allylic disulfone compound of Formula 1 and then reacting with C-5 halo-acetal compound (C) Desulfonation reaction proceeds simultaneously by synthesizing the compound (D) having the presence of an excess of base, thereby synthesizing the retinal acetal compound (E), and hydrolyzing the acetal by adding an acid without further purification. Method for producing a retinal, characterized in that it comprises a step of. Wherein X is selected from the group consisting of -Cl, -Br, and -I. The base according to claim 4, wherein the base is selected from the group consisting of NaNH ₂ , t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa, and the amount of base is 3 relative to Formula 1 The method characterized by the above equivalent. (1) Deprotonation by treating a C-15 allyl disulfone compound of Formula 1 with a base, and then adding thereto 1/2 equivalents based on the C-15 allyl disulfone compound (Formula 1) Reacting the following dihaloallylic sulfide (F) to synthesize allyl sulfide compound (G) having 40 carbon skeletons required for beta-carotene synthesis; (2) selectively oxidizing the allylic sulfide compound (G) to produce an allylic sulfone compound (H); (3) preparing tetra (benzenesulfonyl) -triene compound (I) from the sulfone compound (G) via a Lambberg-Backlund reaction; And (4) preparing beta-carotene (Formula 4), comprising the step of reacting the tetra (benzenesulfonyl) -triene compound (I) with a base to form a double bond and proceeding to a desulfonation reaction. Way. Wherein X is selected from the group consisting of -Cl, -Br, and -I. The method of claim 6, wherein the base of step (1) is n- BuLi, s- BuLi, phenyllithium, NaH, NaNH ₂ , lithium diisopropylamide, lithium hexamethyldisalazide (lithium hexamethyldisilazide) , Sodium hexamethyldisalazide, t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa and selected from the group consisting of 2 Characterized in that it is used in equivalent amounts. The method according to claim 6, wherein the selective oxidation of step (2) is performed at least 2 equivalents of hydrogen peroxide under a lithium molybdenate-niobate (LiNbMoO ₆ ) or vanadium oxide (V ₂ O ₅ ) metal oxide catalyst. A method characterized by the addition of a drop. 7. The method of claim 6, wherein the Lambberg-Backlund reaction of step (3) is carried out under conditions excluding oxygen in the air, that is, under nitrogen or argon atmosphere. The base of the desulfonation reaction of step (4) is selected from the group of NaNH ₂ , t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa, and the like. And adding an excess of the base dropwise to react at the boiling temperature of the alcohol solvent.