KR20020059202A - Allylic sulfones containing conjugated polyene moieties, preparation thereof, and a process for preparing lycopene by using the same compound as an intermediate - Google Patents

Abstract

PURPOSE: Provided are an allylic sulfone compound containing conjugated polyene, a preparation thereof, and a process for producing a carotene-based polyene chain structured compound, especially lycopene by using the allylic sulfone compound as an intermediate. CONSTITUTION: The allylic sulfone compound represented by the formula 1, especially the formula 1-2 is produced by treating a thio-sulfone compound with a base to obtain an allylic sulfide containing the conjugated polyene and then oxidizing the allylic sulfide selectively. And the lycopene is produced by a process comprising the steps of: treating the allylic sulfone compound represented by the formula 1-2 with a base for deprotonation and reacting the resultant and 1/2 equivalent(based on the compound of 1 equivalent) of a diallylic sulfide to obtain an allylic sulfide compound; oxidizing the allylic sulfide compound selectively to prepare an allylic sulfone compound; preparing di(phenyl sulfonyl)-triene compound from the allylic sulfone compound; reacting the di(phenyl sulfonyl)-triene compound with a base. In the formula, R1, R2, and R3 are each selected from the group consisting of hydrogen, C1-C30 alkyl, C1-C30 alkenyl, aryl, -CN, -COOR'(R' is C1-C10 alkyl), and -C(=O)H or R1, R2, and R3 form C5-C12 aliphatic ring capable of having a low alkyl substituent and a double bond in the ring together.

Description

Alily sulfones containing conjugated polyene moieties, preparations, and a process for preparing lycopene by using the same compound as an intermediate }

The present invention relates to a method for preparing a retinol and carotene-based polyene chain structure compounds, and more particularly, intermediate compounds (Formula 1) which can be usefully used in synthesizing retinol and carotene-based compounds, in particular, a new compound of Formula 1-2 A compound of the present invention and a method for preparing the same, and a method for preparing a polyene chain structure compound, in particular, lycopene, using the intermediate compound.

In said formula, R <_1> , R <_2> , R <_3> is respectively hydrogen, a C1-C30 alkyl group, a C1-C30 alkenyl group, an aryl group, -CN, -COOR '(R' is a C1-C10 alkyl group) R ₁ and R ₃ or R ₂ and R ₃ together may have a lower alkyl substituent and may have a double bond in the ring. An aliphatic ring having a carbon number of Provided that R ₂ is methyl and the aliphatic rings (including R ₂ ) formed by R ₁ and R ₃ are 2,6,6-trimethyl-1-cyclohexenyl.

Representative synthetic methods of retinol and carotene-based compounds represented by vitamin A and beta-carotene can be classified into three methods. The first method is chain expansion and partial hydrogenation using Roche's acetylide, and the Wittig reaction being used by BASF is second. It can be mentioned as. Third, the most important method is the method using sulfone compounds which are used by Aventis and developed by Julia ( Pure & Appl. Chem , 1979 , 51, 447-462; Pure & Appl Chem , 1991 , 63, 45-58). The method using the sulfone compound has the advantages that the intermediate products of the synthesis are very stable, the binding reaction is excellent, and the by-products are easily processed when the double bond is formed.

Scheme 1 is a method for synthesizing a polyene chain compound using a sulfone compound (Bent . Soc. Chim . France 1973 , 746-750) and a method for synthesizing beta-carotene developed by the present inventors, etc. Starting materials used in J. Org.Chem . 1999 , 64 , 8051-8053). These reactions commonly use C15 allyl sulfone compounds containing conjugated polyenes represented by Formula 1-1 as starting materials, which are intended for ease of synthesis and efficient formation of trans double bonds.

Scheme 1 also shows the synthesis of Chemical Formula 1-1 used in Aventis et al. In other words, using beta-ionone as a starting material for synthesis, a vinyl grignard reagent is added to form vinyl beta-ionol, which is benzenesulfinic acid (sodium salt) and acetic acid. It is a method of synthesizing the C-15 sulfone compound <Formula 1-1> by reacting with a solvent. This method uses the relatively expensive beta-ionone as a starting material for the synthesis, and also has the disadvantage of using an intractable and expensive vinyl grignard reagent. In addition, as reported, the addition reaction of vinyl Grignard to beta-ionone also proceeded in poor yield due to the basicity of vinyl Grignard reagent. Therefore, a more economical and practical synthesis of Formula 1-1 is required to overcome the above disadvantages.

On the other hand, a method for preparing lycopene has been developed by the present inventors comprising a reaction of a disulfone compound having a structure similar to the formula (1) with a base to diprotonate and bind it to a dihalo allyl sulfide compound (Korean Patent Application No. 2000-10376).

Here, 2 equivalents of n -butyl lithium is used as a strong base, and the reaction must be carried out at low temperature (-78 ° C) to suppress double-bond migration or sea-trans isomerization. To give sufficient reactivity the halogen of the dihaloallylic sulfide must be Br. (In the case of Cl, the reaction hardly proceeds, and the addition of NaI and substitution with I are not easy due to the reactivity of the base used.) Dibromo allyl sulfide is more difficult to prepare than dichloro allyl sulfide. Somewhat unstable, not only difficult to handle, but also expensive. Therefore, there is still a need for the development of a method using mild base under relatively mild reaction conditions and using stable, inexpensive and inexpensive reagents.

The technical problem to be solved by the present invention is to provide an allyl sulfone compound (Formula 1) containing the above-described conjugate polyene and a method for efficiently synthesizing them.

Another technical problem to be achieved by the present invention is to provide a method for producing a polyene chain structure compound, particularly lycopene, using an allyl sulfone compound containing the conjugated polyene.

The present invention provides a compound represented by the formula (1) to achieve the first technical problem of the present invention.

In said formula, R <_1> , R <_2> , R <_3> is respectively hydrogen, a C1-C30 alkyl group, a C1-C30 alkenyl group, an aryl group, -CN, -COOR '(R' is a C1-C10 alkyl group) R ₁ and R ₃ or R ₂ and R ₃ together may have a lower alkyl substituent and may have a double bond in the ring. An aliphatic ring having a carbon number of Provided that R ₂ is methyl and the aliphatic ring (including R ₂ ) formed by R ₁ and R ₃ is 2,6,6-trimethyl-1-cyclohexenyl.

In particular, the present invention is an intermediate useful for synthesizing lycopene among the compounds represented by the formula (1) as an anti-aging agent, antioxidant and cancer prevention agent, R ₁ is hydrogen, R ₂ is methyl, R _It provides a novel compound (Formula 1-2) that is _trivalent prenyl.

The second technical problem of the present invention is (a-1) deprotonation of the allylic sulfone compound (A), and then reacted with the haloallylic sulfide compound (B) to thio-sulfone ) Obtaining compound (C); (b-1) treating the thio-sulfone compound (C) with a base to form a double bond to remove the sulfone group, thereby obtaining allyl sulfide (D) containing the conjugate polyene; ; And (c-1) selectively oxidizing the allylic sulfide (D) to obtain a corresponding allylic sulfone, wherein the allyl sulfone containing the conjugate polyene represented by the formula (1) is included. Is made by.

In said formula, R <_1> , R <_2> , R <_3> is respectively hydrogen, a C1-C30 alkyl group, a C1-C30 alkenyl group, an aryl group, -CN, -COOR '(R' is a C1-C10 alkyl group) R ₁ and R ₃ or R ₂ and R ₃ together may have a lower alkyl substituent and may have a double bond in the ring. An aliphatic ring having a carbon number of -X, wherein X is -Cl, -Br, -I, -OSO ₂ CF ₃ , -OSO ₂ Ph, -OSO ₂ C ₆ H ₄ CH ₃ and -OSO ₂ CH ₃ Is selected from.

The allylic sulfone compound containing the conjugated polyene of Formula 1 according to the present invention can be used in the synthesis of retinol and its derivatives and carotene-based compounds in combination with various C5 or C10 halide compounds, and synthesized through the following reaction steps. do. First, diprotonation is carried out by treating a base or an allylic sulfone compound having a chain or ring structure, such as prenyl sulfone, geranyl sulfone, and cyclic-geranyl sulfone. deprotonation and reaction with haloallylic sulfide compound (B) to form thio-sulfone compound (C). The haloallylic sulfide (B) and the preparation method thereof used here have already been developed by the present inventors (Korean Patent Application 2000-10376).

That is, step (a-1) is performed by the same method as used in Korean Patent Application No. 2000-10376 and Korean Patent Application No. 2000-77567 presented by the present inventors. That is, the deprotonation reaction of the allylic sulfone compound (A) requires the addition of a base dropwise to the allylic sulfone compound (A) at a low temperature, preferably at 0 ° C. or lower, wherein Is n- BuLi, s- BuLi, t- BuLi, phenyllithium, NaH, NaNH ₂ , lithium diisopropylamide (LDA), lithium hexamethyldisilazide, sodium hexamethyldisilazide hexamethyldisilazide), t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa and the like. Alkyl lithium is preferably used as the base, and X in the haloallylic sulfide compound is preferably Br in terms of reactivity and yield.

Next, the thio-sulfone compound (C) is treated with a base to obtain an allylic sulfide compound (D) containing a conjugated polyene, in which the phenylthio group is maintained as it is. Only phenylsulfonyl groups are removed and form double bonds.

The base used in the conjugated polyene formation reaction of step (b-1) is not particularly limited. Specific examples include NaNH ₂ , t- BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa and the like, of which metal alkoxide is preferably used.

The allylic sulfide (D) is selectively oxidized to obtain an allylic sulfone compound containing the conjugate polyene represented by the formula (1). For the selective oxidation reaction, oxidation conditions to generally known sulfone compounds may be used, but appropriate reaction conditions are selected in consideration of side reactions, yields of reactions, and selectivity.

That is, the selective oxidation of step (c-1) may be performed at room temperature under hydrogen peroxide as a quantitative oxidant under a metal oxide catalyst such as lithium molybdenum-niobate (LiNbMoO ₆ ) or vanadium oxide (V ₂ O ₅ ). It is preferable that the solution is added dropwise to an allyl sulfide compound (D). When the oxidation reaction is carried out under these conditions, no side reactant in which the double bond is oxidized is produced, and thus the yield characteristics of the reaction are excellent.

The third technical problem of the present invention is (a-2) in the allylic sulfone compound containing the conjugate polyene represented by the formula (1), R ₁ is hydrogen, R ₂ is methyl, R ₃ is represented by prenyl (prenyl) Deprotonation by treating a base in Formula 1-2, and then based on the allylic sulfone compound (Formula 1-2), ½ equivalent of diallylic sulfide (E) Reacting to obtain an allylic sulfide compound (F); (b-2) selectively oxidizing the allylic sulfide compound (F) to prepare a corresponding allylic sulfone compound (G); (c-2) preparing a di (phenylsulfonyl) -triene compound (H) from the allyl sulfone compound (G) via a Lambberg-Barklund reaction; And (d-2) reacting the di (phenylsulfonyl) -triene compound (H) with a base.

Wherein X is selected from the group consisting of -Cl, -Br, -I, -OSO ₂ CF ₃ , -OSO ₂ Ph, -OSO ₂ C ₆ H ₄ CH ₃ and -OSO ₂ CH ₃ .

This method is based on the method for synthesizing beta-carotene developed by the inventor using C15 allyl sulfone of the formula 1-1 ( J. Org. Chem. 1999 , 64 , 8051-8053). That is, instead of the cyclic allylic sulfone of Formula 1-1, the chain structure C15 allylic sulfone of Formula 1-2 was used to first deprotonate the base, and then based on the allylic sulfone, Coupling with the dihalo allyl sulfide compound (E) forms compound (F) with the carbon backbone necessary for lycopene synthesis.

In the step (a-2), the deprotonation reaction of Chemical Formula 1-2 requires the addition of a base to Chemical Formula 1-2 at a low temperature, preferably at 0 ° C. or lower, wherein Is n- BuLi, s- BuLi, t- BuLi, phenyllithium, NaH, NaNH 2 , lithium diisopropylamide (LDA), lithium hexamethyldisilazide, sodium hexamethyldisilazide hexamethyldisilazide), t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa and the like. The equivalent ratio of the allylic sulfone compound and the dihaloallylic sulfide is used in a 2: 1 ratio, and it is preferable that the allylic sulfone compound is used slightly above the equivalent ratio.

In addition, when X of the dihaloallylic sulfide compound (E) is Cl, it is preferable in terms of reactivity to add a stoichiometric amount of sodium iodide to proceed with the coupling reaction.

According to the step (a-2), by using the compound of formula 1-2 (new compound of the present invention), it should be carried out at a low temperature (-78 ℃) using two equivalents of strong base ( n -BuLi) It overcomes the shortcomings of the conventional method in which the halogen of dihalo allyl sulfide had to be bromine, ie Korean Patent No. 2000-10376, which makes dichloro allyllic at 0 ° C. or room temperature much easier under mild conditions (using 1 equivalent of NaH). Reaction may proceed.

Next, a sulfone compound (G) is synthesized by a selective oxidation reaction of elemental sulfur in the center of the compound (F). The selective oxidation reaction of the step (b-2) is performed at low temperature, preferably 0. It is preferably made by dropwise addition of a mixture of urea-hydrogen peroxide (UHP) and phthalic anhydride to the allylic sulfide compound (F) below &lt; RTI ID = 0.0 &gt;

Subsequently, a Lamberberg-Backrunt reaction is applied to the allylic sulfone compound (G) to remove the central SO ₂ to form a compound (H) containing the conjugate triene. At this time, it is preferable to use reaction conditions improved by Meyers ( J. Am. Chem. Soc. 1969 , 91 , 7510-7512).

The Lambberg-Backrunt reaction of step (c-2) is preferably carried out under the condition of excluding oxygen in the air, that is, under nitrogen or argon gas atmosphere, in terms of yield to prevent side reaction with oxygen.

Finally, the compound (H) can be desulfonated by heating under the basic conditions such as an alcohol solvent and a metal alkoxide to synthesize lycopene.

The base of the step (d-2) is not particularly limited, specific examples include NaNH ₂ , t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa, CH ₃ ONa, etc. Preference is given to using metal alkoxides.

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. Phenyl 3-methyl-5- (phenylsulfonyl) -5- (2,6,6-trimethyl-1-cyclohexenyl) -2-pentenyl sulfide (C-1)

The title compound was prepared in the same manner as in Synthesis Example 1 of Korean Patent Application No. 2000-77567.

2.06 g (7.40 mmol) of phenyl (2,6,6-trimethyl-1-cyclohexenyl) methyl sulfone (cyclo-geranyl sulfone) was dissolved in 30 mL THF and cooled to -78 ° C under argon atmosphere, followed by 1.6 M 5.1 ml (8.14 mmol) of n- BuLi hexane solution are slowly added. After vigorously stirring at this temperature for about 30 minutes, 2.31 g (9.00 mmol, 4: 1 trans: cis) of phenyl 4-bromo-3-methyl-2-butenyl sulfide (B) was added to a small amount of THF, and The temperature of the reaction mixture is gradually raised to room temperature. After about 14 hours, the reaction mixture was diluted with Ether, washed three times with 10 ml of 1M-HCl, and then dried with 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 phenyl 3-methyl-5- (phenylsulfonyl) -5- (2,6,6-trimethyl-1-cyclohexenyl) -2-pentenyl 3.14 g (6.90 mmol) of sulfide (C-1) was obtained (yield: 93%). ^{According to 1} H NMR and GC analysis, the ratio of the trans and seas double bond (carbon 2) structure was 4: 1 or more.

(Trans C-1) ¹ H-NMR: δ 0.81 (3H, s), 1.05 (3H, s), 1.24 (3H, s), 1.33-1.77 (4H, m), 1.90-2.20 (2H, m) , 2.00 (3H, s), 2.62 (1H, d of ABq, J _AB = 14.5, J _d = 6.4 Hz), 3.00 (1H, d of ABq, J _AB = 14.5, J _d = 6.6 Hz), 3.40 ( 2H, dd, J = 7.6, 2.7 Hz), 3.90 (1H, dd. J = 6.6, 6.4 Hz), 5.35 (1H, t, J = 7.6 Hz), 7.15-7.73 (m, 5H), 7.43-7.65 (3H, m), 7.80-7.96 (2H, m).

¹³ C-NMR: δ 15.4, 18.9, 23.3, 28.4, 29.1, 31.9, 34.5, 35.9, 39.6, 40.9, 65.4, 123.8, 126.1, 128.3, 128.7, 128.7, 129.5, 130.0, 130.5, 133.0, 134.9, 137.9, 141,9.

Synthesis Example 2. 5-phenylsulfonyl-1-phenylthio-3,7,11-trimethyl-2,6,10-dodecatriene (C-2)

The title compound was synthesized in the same manner as in Synthesis Example 3-1 of Korean Patent Application No. 2000-10376.

After dissolving 28.7 g (103 mmol) of geranyl sulfone in 150 mL of THF, 64 mL (103 mmol) of n- BuLi (1.6 M nucleic acid solution) were slowly added thereto at 0 ° C. and stirred for 20 minutes, followed by stirring into the reaction mixture. 29.1 g (113 mmol, 4: 1 trans: cis) of 4-bromo-3-methyl-2-butenyl phenyl sulfide were added. Then, the temperature was gradually raised and stirred at room temperature for about 11 hours.

100 mL of ether was added to the reaction mixture, and the resultant was washed sequentially using 1M aqueous solution of H-Cl (20 mL × 2) and distilled water (30 mL). The reaction mixture was then dehydrated using anhydrous sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and then subjected to silica gel chromatography to 43.6 g of 5-phenylsulfonyl-1-phenylthio-3,7,11-trimethyl-2,6,10-dodecatriene (C-2). (96 mmol) was obtained (yield: 93%). ^{According to 1} H NMR and GC analysis, the ratio of the trans and seas double bond (carbon 2) structure was 4: 1 or more.

(Trans C-2) ¹ H-NMR: δ 1.13 (s, 3H), 1.53 (s, 3H), 1.59 (s, 3H), 1.68 (s, 3H), 1.92 (br s, 4H), 2.31 ( dd, 1H, J = 13.2, 11.4 Hz), 2.90 (dd, 1H, J = 13.2, 3.0 Hz), 3.48 (d, 2H, J = 7.5 Hz), 3.87 (ddd, 1H, J = 11.4, 10.3, 3.0 Hz), 4.88 (d, 1H, J = 10.3 Hz), 5.01 (br s, 1H), 5.32 (t, 1H, J = 7.5 Hz), 7.15 to 7.38 (m, 5H), 7.40 to 7.58 (m , 2H), 7.58 to 7.70 (m, 1H), 7.75 to 7.90 (m, 2H).

¹³ C-NMR: δ 16.0, 16.4, 17.7, 25.7, 26.2, 31.8, 37.1, 39.6, 63.2, 116.8, 123.0, 123.6, 126.1, 128.7, 128.8, 129.3, 129.5, 131.9, 133.5, 134.6, 136.5, 137.6, 145.6.

Synthesis Example 3. Phenyl 3-methyl-5- (2,6,6-trimethyl-1-cyclohexenyl) -2,4-pentadienylsulfide (D-1)

Dissolve 1.19 g (51.7 mmol) of Na in 30 ml of anhydrous ethanol, heat it to the boiling point of the solution for 1 hour, and then cool it to room temperature. Here, 2.35 g (5.17 mmol) of phenyl 3-methyl-5- (phenylsulfonyl) -5- (2,6,6-trimethyl-1-cyclohexenyl) -2-pentenyl sulfide (C-1) After dissolving in 5 ml of anhydrous ethanol (EtOH), the mixture was further refluxed with stirring for 10 hours. After cooling the reaction mixture to room temperature, distilled water (30 ml) was slowly added, followed by extraction with hexanes (50 ml × 2). ), And dried over 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 phenyl 3-methyl-5- (2,6,6-trimethyl-1-cyclohexenyl) -2,4-penta of formula (D-1). Dienyl sulfide 1.30 g (4.15 mmol) was obtained (yield: 80%). According to ¹ H NMR analysis, the ratio of the trans and the Cs double bond (carbon 2) structure was about 2: 1, and the two structures could not be separated by chromatography, and after oxidation with sulfone of Example 5 It could be separated from the formula (1-1).

¹ H-NMR: trans δ 0.99 (6H, s), 1.42-1.48 (2H, m), 1.56-1.64 (2H, m), 1.67 (3H, s), 1.70 (3H, s), 1.99 (2H, t, J = 5.7 Hz), 3.68 (2H, d, J = 7.9 Hz), 5.53 (1H, t, J = 7.9 Hz), 6.02 (2H, br s), 7.13-7.27 (3H, m), 7.27 ˜7.38 (2H, m); Seas δ 1.01 (6H, s), 1.42-1.48 (2H, m), 1.56-1.64 (2H, m), 1.69 (3H, s), 1.88 (3H, s), 1.99 (2H, t, J = 5.7 Hz), 3.71 (2H, d, J = 8.0 Hz), 5.44 (1H, t, J = 8.0 Hz), 6.27 (1H, A of ABq, J = 16.2 Hz), 6.37 (1H, B of ABq, J = 16.2 Hz), 7.13 to 7.27 (3H, m), 7.27 to 7.38 (2H, m).

¹³ C-NMR: trans δ 12.1, 19.2, 19.8, 21.6, 28.9, 32.8, 32.9, 34.2, 39.5, 112.9, 124.5, 126.3, 126.5, 128.7, 129.3, 130.4, 136.9, 137.5, 137.6; Seas δ 12.5, 19.2, 19.8, 21.7, 28.9, 31.3, 32.9, 34.1, 39.5, 117.8, 125.9, 126.2, 126.4, 128.9, 129.1, 130.4, 136.2, 137.9, 139.0.

Synthesis Example 4 Phenyl 3,7,11-trimethyl-2,4,6,10-dodecatetraenyl sulfide (D-2)

15.5 g (0.673 mol) of Na was slowly added to 160 ml of anhydrous ethanol at 0 ° C., which was then heated to the boiling point of the solution for 2 hours and cooled to room temperature. Here, 15.3 g (33.7 mmol) of phenyl 5- (phenylsulfonyl) -3,7,11-trimethyl-2,6,10-dodecattrienyl sulfide (C-2) was added to 30 ml of anhydrous ethanol (EtOH). After dissolving and adding, the mixture was further refluxed with stirring for 6 hours. After the reaction mixture was cooled to room temperature, distilled water (100 mL) was slowly added, followed by extraction with nucleic acid (hexanes) (80 mL × 5), 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 resultant was purified by silica gel chromatography to obtain 7.92 g (25.3 mmol) of phenyl 3,7,11-trimethyl-2,4,6,10-dodecatetraenyl sulfide of the formula (D-2). Obtained (yield: 75%). According to ¹ H NMR analysis, the ratio of trans and seed double bond (carbon 2) structures was about 2.5: 1, and the two structures could not be separated by chromatography, and after oxidation to sulfone of Example 6 Could be isolated in formula 1-2.

¹ H-NMR: trans δ 1.60 (3H, 3), 1.68 (3H, s), 1.71 (3H, s), 1.78 (3H, s), 2.09 (4H, br s), 3.67 (2H, d, J = 8.0 Hz), 5.10 (1H, br s), 5.57 (1H, t, J = 8.0 Hz), 5.89 (1H, d, J = 11.0 Hz), 6.16 (1H, d, J = 15.2 Hz), 6.40 (1H, doublet of doublets, J = 15.2, 11.0 Hz), 7.12-7.44 (5H, m); Seeds δ 1.60 (3H, s), 1.68 (3H, s), 1.79 (3H, s), 1.88 (3H, s), 2.10 (4H, br s), 3.73 (2H, d, J = 7.9 Hz), 5.10 (1H, br s), 5.44 (1H, t, J = 7.9 Hz), 5.93 (1H, d, J = 11.5 Hz), 6.16 (1H, d, J = 15.2 Hz), 6.47 (1H, dd, J = 15.2, 11.0 Hz), 7.12-7.44 (5H, m).

¹³ C-NMR: trans δ 12.3, 16.8, 17.7, 25.7, 26.6, 32.8, 40.1, 123.9, 124.7, 125.1, 125.4, 126.3, 128.8, 129.4, 130.3, 131.7, 134.4, 137.5, 139.4, Sea δ 12.3, 16.9 , 20.4, 25.7, 26.6, 31.3, 40.1, 123.1, 123.9, 126.0, 126.3, 127.1, 128.8, 129.4, 130.3, 131.8, 136.2, 136.3, 140.5.

Synthesis Example 5 Phenyl 3-methyl-5- (2,6,6-trimethyl-1-cyclohexenyl) -2,4-pentadienylsulfone <Formula 1-1>

1.30 g (4.15 mmol) of phenyl 3-methyl-5- (2,6,6-trimethyl-1-cyclohexenyl) -2,4-pentadienylsulfide (D-1) was dissolved in 10 ml of methanol and 5 ml of benzene. After dissolving in, 26.3 mg (0.09 mmol) of LiNbMoO ₆ and 2.78 g (8.58 mmol) of an aqueous 30% H ₂ O ₂ solution are added sequentially at 0 ° C. The reaction mixture is stirred for 12 hours while slowly raising the temperature to 25 ° C. and most of the solvent is concentrated off. 50 ml of CHCl ₃ was added thereto, followed by washing with distilled water, removing water with anhydrous sodium sulfate, and filtering. The obtained filtrate was concentrated under reduced pressure, and then subjected to silica gel chromatography to obtain phenyl 3-methyl-5- (2,6,6-trimethyl-1-cyclohexenyl) -2,4-pentadienylsulfone. 1> 1.32 g (3.84 mmol) were obtained (yield: 93%). At this time, the trans and seed structures that could not be separated in the sulfide (D-1) state could be separated by chromatography.

¹ H-NMR: δ 0.98 (6H, s), 1.42 (3H, s), 1.40-1.48 (2H, m), 1.54-1.63 (2H, m), 1.66 (3H, s ), 1.99 (2H, t, J = 5.8 Hz), 3.96 (2H, d, J = 8.2 Hz), 5.38 (1H, t, J = 8.2 Hz), 6.01 (1H, d of A of ABq, J _AB = 16.4, J _d = 2.1 Hz), 6.06 (1H, B of ABq, J _AB = 16.4 Hz), 7.46-7.55 (2H, m), 7.58-7.62 (1H, m), 7.82-7.89 (1H, m ).

¹³ C-NHR: δ 12.0, 19.1, 21.5, 28.7, 32.7, 34.0, 39.3, 41.8, 56.4, 114.7, 128.3, 128.5, 128.9, 129.3, 133.5, 136.0, 137.1, 138.5, 142.6.

<SEC Formula 1-1> ¹ H-NMR: δ 0.92 (6H, s), 1.39 to 1.46 (2H, m), 1.53 (3H, s), 1.55 to 1.63 (2H, m), 1.89 (3H, s ), 1.97 (2H, t, J = 5.9 Hz), 3.97 (2H, d, J = 8.1 Hz), 5.31 (1H, t, J = 8.1 Hz), 6.01 (1H, A of ABq, J _AB = 16.1 Hz), 6.17 (1H, B of ABq, J _AB = 16.1 Hz), 7.46-7.55 (2H, m), 7.55-7.63 (1H, m), 7.83-7.90 (2H, m).

¹³ C-NMR: δ 19.1, 20.6, 21.7, 28.8, 32.8, 33.9, 39.3, 41,9, 55.5, 112.8, 128.0, 128.2, 128.9, 129.9, 131.1, 133.6, 137.3, 138.7, 142.1.

Synthesis Example 6 Phenyl 3,7,11-trimethyl-2,4,6,10-dodecatetraenyl sulfone

16.1 g (51.5 mmol) of phenyl 3,7,11-trimethyl-2,4,6,10-dodecatetraenyl sulfide (D-2) was dissolved in 30 ml of benzene and 70 ml of methanol, followed by 301 mg of LiNbMoO _6. 1.03 mmol) and 12.5 g (0.129 mol) of 35% H ₂ O ₂ aqueous solution are added sequentially at 0 ° C. The reaction mixture is then stirred at 25 ° C. for 6 hours and most of the solvent is concentrated off. 50 ml of CHCl ₃ was added thereto, followed by washing with distilled water, removing water with anhydrous sodium sulfate, and filtering. The resulting filtrate was concentrated under reduced pressure, and then subjected to silica gel chromatography to give 13.7 g (39.8 mmol) of benzene 3,7,11-trimethyl-2,4,6,10-dodecatetraenyl sulfone. Was obtained (yield 77%). At this time, the trans and seed structures that could not be separated in the sulfide (D-2) state could be separated by chromatography.

<Trans chemical formula 1-2> ¹ H-NMR: δ 1.46 (3H, s), 1.61 (3H, s), 1.68 (3H, s), 1.77 (3H, s), 2.10 (4H, br s), 3.94 (2H, d, J = 8.2 Hz), 5.09 (1H, br s), 5.39 (1H, t, J = 8.2 Hz), 5.88 (1H, d, J = 10.8 Hz), 6.13 (1H, d, J = 15.2 Hz), 6.40 (1H, dd, J = 15.2, 10.8 Hz), 7.47-7.58 (2H, m), 7.59-7.62 (1H, m), 7.82-7.88 (2H, m).

¹³ C-NMR: δ 12.2, 16.8, 17.5, 25.5, 26.4, 39.9, 56.5, 114.7, 123.6, 124.7, 126.4, 128.3, 128.9, 131.6, 133.1, 133.5, 138.5, 140.9, 142.7.

<SEC Formula 1-2> ¹ H-NMR: δ 1.62 (3H, s), 1.70 (3H, s), 1.76 (3H, s), 1.87 (3H, s), 2.09 (4H, br s), 3.96 (2H, d, J = 8.2 Hz), 5.09 (1H, br s), 5.25 (1H, t, J = 8.2 Hz), 5.74 (1H, d, J = 11.0 Hz), 5.98 (1H, d, J = 15.0 Hz), 6.44 (1H, dd, J = 15.0, 11.0 Hz), 7.46-7.74 (m, 3H), 7.82-7.74 (m, 2H).

¹³ C-NMR: δ 16.9, 17.7, 20.6, 25.7, 26.5, 40.1, 55.5, 112.8, 123.7, 124.9, 125.1, 128.4, 128.9, 129.2, 131.7, 133.6, 138.6, 141.4, 141.6.

Synthesis Example 7 Di (5- (phenylsulfonyl) -3,7,11,15-tetramethyl-2,6,8,10,14-hexadecapentaenyl) sulfide (F)

Phenyl 3,7,11-trimethyl-2,4,6,10-dodecatetraenyl sulfone 7.29 g (21.2 mmol) was dissolved in 50 ml of THF and then 60% 1.02 g (25.4 mmol) of NaH was added and stirred for 15 minutes. Di (4-chloro-3-methyl-2-butenyl) sulfide (E) 2.53 g (10.6 mmol) and NaI 3.81 g (25.4 mmol) were sequentially added to the reaction mixture, followed by stirring at room temperature for about 15 hours. It was.

100 mL of ether was added to the reaction mixture, and the resultant was washed sequentially using 1M aqueous solution of H-Cl (20 mL × 2) and distilled water (30 mL). The reaction mixture was then dehydrated using sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and then subjected to silica gel chromatography to di (5- (phenylsulfonyl) -3,7,11,15-tetramethyl-2,6,8,10,14-hexadecapenta. Nil) sulfide (F) 8.15 g (9.53 mmol) was obtained (yield: 90%).

¹ H-NMR: δ 1.29 (6H, s), 1.50 (6H, s), 1.61 (6H, s), 1.69 (6H, s), 1.76 (6H, s), 2.10 (8H, br s), 2.34 (2H, dd, J = 13.0, 11.7 Hz), 2.91 (4H, d, J = 7.5 Hz), 2.75-3.18 (2H, m), 4.00 (2H, dd, J = 10.3, 9.2 Hz), 5.09 ( 4H, br s), 5.19 (2H, t, J = 7.5 Hz), 5.85 (2H, d, J = 10.6 Hz), 6.06 (2H, d, J = 15.2 Hz), 6.30 (2H, dd, J = 15.2, 10.6 Hz), 7.43-7.75 (4H, m), 7.55-77.6 (2H, m), 7.73-7.86 (4H, m).

¹³ C-NMR: δ 12.5, 15.9, 16.9, 17.7, 25.7, 26.5, 28,1, 37.5, 40.1, 63.8, 110.0, 121.8, 123.8, 124.7, 124.8, 126,2, 128.8, 129.1, 131.7, 133.2, 133.5, 137.7, 140.9, 142.2.

Synthesis Example 8 di (5- (phenylsulfonyl) -3,7,11,15-tetramethyl-, 2,6,8,10,14-hexadecapentaenyl) sulfone (G)

50 ml of acetonitrile were added to 3.42 g (36.4 mmol) of UHP and 2.70 g (18.2 mmol) of phthalic anhydride and vigorously stirred at room temperature for 1 hour to obtain a clear solution. The solution was transferred to a dropping funnel, and then the solution was diluted with di (5- (phenylsulfonyl) -3,7,11,15-tetramethyl-2,6,8,10,14-hexadeca. 6.23 g (7.28 mmol) of pentaenyl) sulfide (F) was added dropwise to the solution of 50 ml of acetonitrile over 3 hours. At this time, the temperature of the reaction mixture was adjusted to be maintained at 0 ° C.

After completion of the dropwise addition, the reaction mixture was stirred at 0 ° C. for 2 hours. Then 1M-HCl aqueous solution (30 mL) was added to the reaction mixture. The reaction mixture was then extracted using ethyl acetate (50 mL × 2), and the combined organic layers were dried over sodium sulfate. The resulting filtrate was then filtered and the resulting filtrate was concentrated under reduced pressure to form a white solid. The white solid obtained was dissolved in chloroform, and then the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and then subjected to silica gel chromatography to obtain di (5- (phenylsulfonyl) -3,7,11,15-tetramethyl-2,6,8,10,14-hexadecapentaenyl) 2.58 g (2.91 mmol) of sulfone (G) was obtained (yield: 40%).

¹ H-NMR: δ 1.29 (6H, s), 1.61 (6H, s), 1.62 (6H, s), 1.69 (6H, s), 1.75 (6H, s), 2.09 (8H, br s), 2.43 (2H, dd, J = 13.5, 11.2 Hz), 3.02 (2H, br d, J = 13.5 Hz), 3.48 (4H, d, J = 7.4 Hz), 4.04 (2H, ddd, J = 11.2, 9.7, 3.1 Hz), 5.08 (2H, d, J = 9.7 Hz), 5.10 (2H, br s), 5.23 (2H, t, J = 7.4 Hz), 5.85 (2H, d, J = 10.9 Hz), 6.05 ( 2H, d, J = 15.2 Hz), 6.33 (2H, dd, J = 15.2, 10.9 Hz), 7.45-7.57 (4H, m), 7.57-7.68 (2H, m), 7.74-7.85 (4H, m) .

¹³ C-NMR: δ 12.5, 16.9, 17.0, 17.7, 25.7, 26.6, 37.7, 40.1, 51.3, 63.5, 114.1, 121.2, 123.7, 124.7, 126.8, 128.9, 129.2, 131.9, 132.8, 133.7, 137.3, 140.9, 141.5, 142.7.

Synthesis Example 9. 11,11'-di (phenylsulfonyl) -11,11 ', 12,12'-tetrahydrolycopene (H)

Di (5- (phenylsulfonyl) -3,7,11,15-tetramethyl-2,6,8,10,14-hexadecapentaenyl) sulfone (G) 627 mg (0.71 mmol) in t-butanol After dissolving in 15 mL and 15 mL of CCl ₄ , 793 mg (14.1 mmol) of well ground KOH under argon gas atmosphere were added at room temperature. After the reaction mixture was stirred vigorously for 7 hours to complete the reaction, 50 ml of methylene chloride was added to the resultant to dissolve, and then washed with 20 ml of 1M-HCl. The combined methylene chloride layers were dried over anhydrous sodium sulfate and then filtered. The resultant was concentrated under reduced pressure, and then subjected to silica gel chromatography to obtain 367 mg (0.48 mmol) of 11,11'-di (phenylsulfonyl) -11,11 ', 12,12'-tetrahydrolycopene (H). (Yield 63%).

¹ H-NMR: δ 1.28 (6H, s), 1.60 (6H, s), 1.65 (6H, s), 1.68 (6H, s), 1.74 (6H, s), 2.08 (8H, br s), 2.41 (2H, dd, J = 13.2, 11.8 Hz), 3.03 (2H, d, J = 13.2 Hz), 4.04 (2H, ddd, J = 11.8, 9.0, 2.1 Hz), 5.10 (4H, br s), 5.87 (4H, br s), 6.07 (2H, d, J = 15.0 Hz), 6.20 (2H, m), 6.31 (2H, dd, J = 15.0, 10.1 Hz), 7.40-7.70 (6H, m), 7.73 -7.88 (4H, m).

¹³ C-NMR: δ 12.4, 16.8, 17.1, 17.6, 25.6, 26.5, 38.1, 40.0, 63.9, 121.7, 123.7, 124.8, 126.1, 127.8, 128.4, 128.8, 129.1, 131.7, 133.0, 133.3, 133.5, 137.6, 140.9, 142.1.

Synthesis Example 10 Lycopene

Dissolve 414 mg (18 mol) of Na in 20 ml of anhydrous ethanol, heat it to the boiling point of the solution for 1 hour, and cool it to room temperature. Here, 367 mg (0.45 mmol) of 11,11'-di (phenylsulfonyl) -11,11 ', 12,12'-tetrahydrolycopene (H) was dissolved in 10 ml of benzene, and then stirred for another 12 hours. It was refluxed. After the reaction mixture was cooled to room temperature, distilled water (30 mL) was slowly added, followed by extraction with benzene (30 mL × 2), 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 give 188 mg (0.35 mmol) of lycopene (yield: 78%).

¹ H-NMR: δ 1.61 (s, 6H), 1.68 (s, 6H), 1.82 (s, 6H), 1.96 (s, 12H), 2.11 (br s, 8H), 5.11 (br s, 2H), 5.95 (d, 2H, J = 10.8 Hz), 6.18 (d, 2H, J = 12.1 Hz), 6.24 (d, 2H, J = 14.9 Hz), 6.20-6.30 (m, 2H), 6.35 (d, 2H , J = 14.8 Hz), 6.49 (dd, 2H, J = 14.9, 10.8 Hz), 6.63 (dd, 2H, J = 14.8, 12.1 Hz), 6.55-6.70 (m, 2H).

¹³ C-NMR: δ 12.8, 12.9, 17.0, 17.7, 25.7, 26.7, 40.2, 123.9, 124.8, 125.1, 125.7, 130.1, 131.5, 131.8, 132.6, 135.4, 136.2, 136.5, 137.3, 139.5.

It was found that the lycopene data was consistent with the previously reported NMR data of trans-lycopene ( Helvetica Chimica Acta 1992 , 75 , 1848-1865).

As described above, when preparing a sulfonate compound required for synthesizing a carotene compound represented by lycopene and other carotene-based and retinol-based compounds including the compound according to Synthesis Examples 1 to 10, the manufacturing process is By using a simple, stable intermediate, the synthesis method is easy and efficient, as well as by-products such as phosphine oxide can be prevented. In addition, it has the advantage that it is easy to form a polyene chain structure having a structure of a trans double bond.

Claims (11)

Allyl sulfone containing the conjugate polyene represented by following formula (1). In said formula, R <_1> , R <_2> , R <_3> is respectively hydrogen, a C1-C30 alkyl group, a C1-C30 alkenyl group, an aryl group, -CN, -COOR '(R' is a C1-C10 alkyl group) R ₁ and R ₃ or R ₂ and R ₃ together may have a lower alkyl substituent and may have a double bond in the ring. An aliphatic ring having a carbon number of Provided that R ₂ is methyl and the aliphatic rings (including R ₂ ) formed by R ₁ and R ₃ are 2,6,6-trimethyl-1-cyclohexenyl. The compound of formula 1-2 according to claim 1, wherein R ₁ is hydrogen, R ₂ is methyl, and R ₃ is prenyl. (1) treating thio-sulfone compounds represented by the following formula (C) with a base to obtain allyl sulfide (D) containing the conjugate polyene; And (2) selectively oxidizing the allylic sulfide (D) to obtain a corresponding allylic sulfone. In said formula, R <_1> , R <_2> , R <_3> is respectively hydrogen, a C1-C30 alkyl group, a C1-C30 alkenyl group, an aryl group, -CN, -COOR '(R' is a C1-C10 alkyl group) R ₁ and R ₃ or R ₂ and R ₃ together may have a lower alkyl substituent and may have a double bond in the ring. An aliphatic ring having a carbon number of The method of claim 3, wherein the base used in step (1) is selected from the group consisting of NaNH ₂ , t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa and CH ₃ ONa. How to. The method of claim 3, wherein the selective oxidation reaction of step (2) is carried out at room temperature under hydrogen peroxide as a quantitative oxidant under a metal oxide catalyst such as lithium molybdenum-niobate (LiNbMoO ₆ ) or vanadium oxide (V ₂ O ₅ ). hydrogen peroxide) solution. (a-2) Deprotonation of a compound represented by the following Chemical Formula 1-2 by treatment with a base, followed by 1/2 equivalent of diallylic sulfide based on 1 equivalent of the compound Reacting (E) to obtain an allylic sulfide compound (F); (b-2) selectively oxidizing the allylic sulfide compound (F) to prepare a corresponding allylic sulfone compound (G); (c-2) preparing a di (phenylsulfonyl) -triene compound (H) from the allyl sulfone compound (G) via a Lambberg-Barklund reaction; And (d-2) reacting the di (phenylsulfonyl) -triene compound (H) with a base. Wherein X is selected from the group consisting of -Cl, -Br, -I, -OSO ₂ CF ₃ , -OSO ₂ Ph, -OSO ₂ C ₆ H ₄ CH ₃ and -OSO ₂ CH ₃ . The deprotonation reaction according to claim 6, wherein the deprotonation reaction of Chemical Formula 1-2 is carried out at below 0 ° C., n- BuLi, s- BuLi, t- BuLi, phenyllithium, NaH, NaNH ₂ , lithium diisopropylamide (LDA). ), Lithium hexamethyldisilazide, sodium hexamethyldisilazide, t -BuOK, CH ₃ CH ₂ OK, CH ₃ OK, CH ₃ CH ₂ ONa and CH ₃ ONa Characterized in that it is carried out using a base selected from. The process of claim 6 or 7, wherein in the step (a-2), when X of the dihaloallylic sulfide compound (E) is Cl, a stoichiometric amount of sodium iodide is added to proceed with the coupling reaction. Way. The method of claim 6 or 7, wherein the selective oxidation of step (b-2) is carried out at a temperature of 0 ° C. or lower, wherein the mixture of urea-hydrogen peroxide (UHP) and phthalic anhydride is allyl sulfide compound ( F) is carried out by dropwise addition. 8. The process according to claim 6 or 7, wherein the Lambert-Barkbrunn reaction of step (c-2) is carried out in a nitrogen or argon gas atmosphere. 8. The method of claim 6 or 7, wherein the base of step (d-2) is selected from metal alkoxides.