METHOD OF PREPARING 4-CHLORO-3-METHYL-2-BUTENYL PHENYL SULFIDE, DI (4-CHLORO-3-METHYL-2-BUTENYL) SULFIDE AND DI (4- CHLORO-3-METHYL-2-BUTENYL) SULFONE FOR SYNTHESIS OF NATURAL CAROTENOID PRODUCTS TECHNICAL FIELD The present invention pertains to preparation methods of the intermediates required for synthesis of carotenoid products. More specifically, the present invention is directed to, upon synthesis of natural carotenoid products by the Julia reaction using sulfone compounds for the formation of double bonds, the preparation methods of 4- chloro-3-methyl-2-butenyl phenyl sulfide represented by the following Formula 1 as a C5-unit compound for lengthening an isoprenyl unit, and di (4-chloro-3-methyl-2- butenyl) sulfide represented by the following Formula 2 as a C10-unit compound for providing a central triene moiety, and di (4-chloro-3-methyl-2-butenyl) sulfone represented by the following Formula 3 as a selective oxide of di (4-chloro-3-methyl-2- butenyl) sulfide, and a preparation method of di (4-chloro-3-methyl-2-butenyl) sulfone: Formula 1 Formula 2 Formula 3

PRIOR ART Typically represented by beta-carotene, lycopene and astaxanthin, carotenoid compounds represented by the following Formula 4 act as a precursor of vitamin A importantly affecting differentiation and growth of living tissues: Formula 4 Further, such compounds are used as a food coloring material harmless to the human body, and have been used for promoting nutrition and supporting health due to the prophylaxis effects on cancers. Since the carotene compound is extracted in very small amounts from green-yellow vegetables, there has been research into the development of organic synthetic methods for carotenoid compounds. Such efforts have been made for quite a while.

Organic synthetic methods have been developed for several of important carotenoid compounds among hundreds of natural carotenoids. Representative syntheses are classified into three methods depending on the manner of forming double bonds, for instance, a Roche method using acetylide, a BASF AG method using the Wittig reaction, and the Julia reaction using sulfone compounds. Specifically, the Roche method forms double bonds by partial hydrogenation of triple bonds after a desired carbon backbone is obtained from acetylide. However, this method is disadvantageous in terms of many preparation steps, and formation of many cis double bonds having relatively low biochemical activity. Alternatively, the BASF AG

method produces carotenoid compounds having double bonds with the use of the Wittig reaction, and has advantages in terms of relatively simple and efficient preparation process. The above method, however, suffers from drawbacks, such as difficulties in the preparation of a Wittig salt containing polyene and in the treatment of reaction by- products. Finally, the Julia method of synthesizing carotenoid compounds through the formation of double bonds using sulfone compounds, developed by the present inventors, has advantages of utilizing relatively stable sulfone compounds as synthetic intermediates, a simple reaction process and easy treatment of by-products, and is recognized as an excellent synthetic method (J. Org. Chem. 1999,64, 8051-8053; Angew. Chem. Int. Ed. 2001,40, 3627-3629; Korean Patent Laid-open Publication 2002-59202).

The method of synthesizing carotenoid compounds by the Julia reaction using sulfone compound is characterized in that, as shown in the following Reaction Scheme 1, two molecules of C15 sulfone compounds are coupled with di (4-chloro-3-methyl-2- butenyl) sulfide as a C 10-unit represented by the above Formula 2 to form a fundamental carbon backbone required for the synthesis of a carotenoid compound, which is subjected to Ramberg-Ba cklund reaction to form a central triene moiety of the carbon backbone, which is then desulfonated while forming double bonds, thereby yielding a carotenoid compound:

Reaction Scheme 1 Suitable for use in the synthesis of lycopene following the above procedure, the C15 sulfone compound was afforded by the coupling reaction of easily producible geranyl sulfone as a CIO-unit compound with 4-halo-3-methyl-2-butenyl phenyl sulfide represented by the Formula 1 as a C5 isoprenyl unit, as shown in the following Reaction Scheme 2 (Angew. Chem. Int. Ed. 2001,40, 3627-3629; Korean Patent Laid- open Publication No. 2002-59202): Reaction Scheme 2 i) ! SOPh S02Ph Obi S02Ph ) i ! S02Ph W W + X 'SPh or S02Ph X = Halogen

As in the above Reaction Schemes 1 and 2, 4-chloro-3-methyl-2-butenyl phenyl sulfide (Formula 1) as a C5-unit and di (4-chloro-3-methyl-2-butenyl) sulfide (Formula 2) as a Cl0-unit, which are developed by the present inventors and efficiently used for the synthesis of carotenoid compounds, are afforded according to procedures of the following Reaction Scheme 3: Reaction Scheme 3 HOSPh-' CI v v'SPh <Formula 1 > W,\ cri Cl-t 0z,--, s o CI<S<CI « « °</S-s<° <Formula 2> In the Reaction Scheme 3, isoprene is oxidized to isoprene monoxide, which is reacted with benzenethiol (PhSH) in the presence of a Cu (I) catalyst to perform a ring- opening reaction, giving a hydroxy-sulfide compound, which is subjected to halogenation of the hydroxyl group, thereby yielding 4-chloro-3-methyl-2-butenyl phenyl sulfide (Formula 1) (langem. Chez. Int. Ed. 2001,40, 3627-3629).'Separately, isoprene monoxide is subjected to a ring-opening reaction using cupric chloride (CuCl2) to form chloroaldehyde, two molecules of which are coupled with sodium sulfide (Na2S) to obtain a C10 dialdehyde compound, which then forms the corresponding alcohol through aldehyde-reduction, after which the alcohol compound is subjected to chlorination, thereby giving di (4-chloro-3-methyl-2-butenyl) sulfide (Formula 2) as a C I O-unit compound (J Org. Chem. 1999,64, 8051-8053).

Large scale preparations of 4-chloro-3-methyl-2-butenyl phenyl sulfide (Formula 1) as the C5-unit compound and di (4-chloro-3-methyl-2-butenyl) sulfide (Formula 2) as the CIO-unit compound according to the procedures of the above Reaction Scheme 3, however, suffer from the following disadvantages: first, following the ring-opening reaction of isoprene monoxide using benzenethiol (PhSH), phenyldisulfide (PhS-SPh) which is an oxide of benzenethiol is produced in an appreciable amount, and silica gel column chromatography should be additionally performed to remove the above oxide; second, the chloroaldehyde compound resulting from the ring-opening reaction of isoprene monoxide using cupric chloride is produced in low yield, and the dechlorinated aldehyde compound is also produced as a side- product, and it is difficult to treat the reaction mixture and a by-product of cuprous chloride in the work-up process; third, chlorination of the alcohol obtained by reduction of Cl0 dialdehyde is problematic in treating the reaction mixture and removing the by- products.

With the aim of synthesizing carotenoid products using the compounds represented by the Formulas 1 and 2 on a large scale, it is required to develop easy and efficient synthetic methods of the compounds represented by the Formulas 1 and 2 while overcoming the above problems. In addition, upon synthesis of a carotenoid compound according to the Reaction Scheme 1, selective oxidation of the sulfide moiety at the center to the sulfone group is difficult to perform due to many double bonds present in the carbon backbone. Thus, the problems related to achieving oxidation should be resolved.

DISCLOSURE OF THE INVENTION It is, therefore, an object of the present invention to solve the problems encountered in the prior art and to provide a method of preparing 4-chloro-3-methyl-2- butenyl phenyl sulfide represented by the Formula 1 as a C5-unit compound.

It is another object of the present invention to provide a method of preparing di (4-chloro-3-methyl-2-butenyl) sulfide represented by the Formula 2 as a CIO-unit compound.

It is still another object of the present invention to provide di (4-chloro-3- methyl-2-butenyl) sulfone represented by the Formula 3 as a C l 0-unit compound.

It is a further object of the present invention to provide a method of preparing di (4-chloro-3-methyl-2-butenyl) sulfone.

According to an embodiment of the present invention, there is provided a preparation method of 4-chloro-3-methyl-2-butenyl phenyl sulfide as a C5-unit compound (Formula 1) comprising the steps represented by the following Reaction Scheme 4, the method comprising (1) synthesizing 1-chloro-2-methyl-3-buten-2-ol (A) as a chlorohydrin compound from isoprene; (2) synthesizing 4-halo-l-chloro-2-methyl- 2-butene (B) by halogenation (bromination or iodination) involving allylic rearrangement of the allylic alcohol of 1-chloro-2-methyl-3-buten-2-ol (A); and (3) coupling 4-halo-l-chloro-2-methyl-2-butene (B) with benzenethiol (PhSH) in the presence of a base while selectively leaving X with higher reactivity than Cl:

Reaction Scheme 4 OH cl/ (A) C : sPh Cl"x Cl < SPh Cl ><~X <Formula 1> (B) Where X represents Br or I.

According to another embodiment of the present invention, there is provided a preparation method of di (4-clzloro-3-methyl-2-butenyl) sulfide as a C10-unit compound (Formula 2) comprising the steps represented by the following Reaction Scheme 5, the method comprising (1) synthesizing 1-chloro-2-methyl-3-buten-2-ol (A) as a chlorohydrin compound from isoprene; (2) synthesizing 4-halo-l-chloro-2-methyl-2- butene (B) by halogenation (bromination or iodination) involving allylic rearrangement of the allylic alcohol of 1-chloro-2-methyl-3-buten-2-ol (A); and (3') coupling two molecules of 4-halo-l-chloro-2-methyl-2-butene (B) with sodium sulfide (Na2S) while selectively leaving X with higher reactivity than Cl: Reaction Scheme 5 OH CI ci Clo S<CI < CX X <Formula 2> (B) Where X represents Br or I.

According to still another embodiment of the present invention, there is provided a di (4-chloro-3-methyl-2-butenyl) sulfone compound as a new C10-unit represented by the following Formula 3, as a selective oxide of the di (4-chloro-3- methyl-2-butenyl) sulfide as a C 1 0-unit represented by the above Formula 2: Formula 3 According to a further embodiment of the present invention, there is provided a preparation method of di (4-chloro-3-methyl-2-butenyl) sulfone represented by the Formula 3 as a C10-unit compound comprising the step represented by the following Reaction Scheme 6, the method comprising the selective oxidation of di (4-chloro-3- methyl-2-butenyl) sulfide represented by the Formula 2 using H202 as an oxidant in the presence of a metal oxide catalyst: Reaction Scheme 6 <Formula 2> <Formula 3> According to a further embodiment of the present invention, there is provided a preparation method of a C40 trisulfone compound (D) used for synthesis of carotenoid compounds comprising the steps represented by the following Reaction Scheme 7, the method comprising deprotonating a sulfone compound (C) as a C 15-unit and reacting the deprotonated sulfone compound with di (4-chloro-3-methyl-2-butenyl) sulfone of the Formula 3:

Reaction Scheme 7 S02Ph Ph02S \ \ CI \/CI +// /\ 0 0 (C) <Formula 3> (C) S02Ph I S02Ph O O 6 \6 o"b (D) R= e e BEST MODES FOR CARRYING OUT THE INVENTION Based on the present invention aiming at preparation of the intermediates required for synthesis of natural carotenoid products, there are provided more effective and practical preparation methods which have overcome the problems in conventional synthesis of 4-chloro-3-methyl-2-butenyl phenyl sulfide (Formula 1) as a C5-unit ..... compound and di (4-chloro-3-methyl-2-butenyl) sulfide (Formula 2) as a C10-unit compound, and di (4-chloro-3-methyl-2-butenyl) sulfone (Formula 3) newly proposed as a CIO-unit compound to solve the problems of selective oxidation of sulfides to sulfones in the presence of polyene, and a preparation method thereof.

As shown in the following Reaction Scheme 4,4-chloro-3-methyl-2-butenyl phenyl sulfide (Formula 1) is prepared by (1) synthesizing l-chloro-2-methyl-3-buten- 2-ol (A) by formation of chlorohydrin from isoprene, (2) synthesizing 4-halo-l-chloro- 2-methyl-2-butene (B) by halogenation (bromination or iodination) through allylic rearrangement of the allylic alcohol of l-chloro-2-methyl-3-buten-2-ol (A), and (3)

coupling 4-halo-l-chloro-2-methyl-2-butene (B) with benzenethiol (PhSH) in the presence of a base while selectively leaving X with higher reactivity than Cl: Reaction Scheme 4 OH A cl (A) Cl ><SPh Cl J+X <Formula 1 (B) Where, X represents Br or I.

As shown in the following Reaction Scheme 5, di (4-chloro-3-methyl-2- butenyl) sulfide (Formula 2) as a C I 0-unit compound is obtained by (1) synthesizing 1- chloro-2-methyl-3-buten-2-ol (A) by formation of chlorohydrin from isoprene, (2) synthesizing 4-halo-l-chloro-2-methyl-2-butene (B) by halogenation (bromination or iodination) through allylic rearrangement of the allylic alcohol of 1-chloro-2-methyl-3- buten-2-ol (A), and (3') coupling two molecules of 4-halo-l-chloro-2-methyl-2-butene (B) with sodium sulfide (Na2S) while selectively leaving X with higher reactivity than Cl: Reaction Scheme 5 OH CI\ ci (A) I CX S<Cl « Cl <X <Formula 2> (B)

Where, X represents Br or I.

At the step (1) in the above reactions, the formation procedure of the chlorohydrin compound (A) from isoprene is disclosed in British Patent No. 978,892 (1964) concerning a method of blowing C02 into an aqueous solution of NaOCI, and in Russian Patent No. 2,047, 591 (1995) regarding a method of reacting isoprene with NCS (N-chlorosuccinimide) using a polar solvent containing water at room temperature (20-25 °C). The former method is more economical due to the use of an inexpensive reagent, while the latter method is excellent in terms of high efficiency of reaction.

In the present invention, a polar solvent is not used, and a slight excess of isoprene (1.2 equivalents) is reacted with NCS (1 equivalent) in the presence of water at 30-100 °C, to obtain the chlorohydrin compound (A) having high yield and high purity to the extent of not requiring an additional purification procedure.

The halogenation involving allylic rearrangement of the step (2) in the above Reaction Schemes 4 and 5, may use PBr3, Br2/P, Br2/PPh3, NBS/PPh3, I2/PPh3, NIS/PPh3, etc. In particular, when 0.4 equivalents of PBr3 are used based on the chlorohydrin compound (A) in the presence of a copper (I) salt catalyst including Cul, CuBr, CuCl and CuCN, trans double bonds (8 : 1 or more) are mainly formed. Further, no halogenated compound without allylic rearrangement, that is to say, 2-brom-1- chloro-2-methyl-3-butene are produced at all in the presence of the copper (I) salt.

At the step (3) in the above Reaction Scheme 4, making use of a reactivity. difference between the two halogen substituents Cl and X (Br or I) of the allylic dihalo compound (B) obtained at the above step (2) toward a benzenethiol (PhSH) nucleophile, X is selectively left while inducing a coupling reaction of the dihalo compound (B) with the benzenethiol, to synthesize 4-chloro-3-methyl-2-butenyl phenyl sulfide as represented by the Formula 1. As such, it is preferred that 0.95 equivalents of

benzentiol as the nucleophile and 1 equivalent of triethylamine (Et3N) base are added . based on the compound (B), and this step is performed at a temperature of 0 °C or lower in order to increase selectivity of the reaction.

Likewise, at the step (3') in the above Reaction Scheme 5, making use of a reactivity difference between the two halogen substituents Cl and X (Br or I) of the allylic dihalo compound (B) obtained at the step (2) toward a Na2S nucleophile, X is selectively left while inducing a coupling reaction of the dihalo compound (B) with S2-, to synthesize di (4-chloro-3-methyl-2-butenyl) sulfide as represented by the Formula 2.

As such, 2 equivalents of the compound (B) should be used on the basis of 1 equivalent of Na2S nucleophile. As for the two double bonds of the C10-unit compound, a ratio of a trans-trans form to a trans-cis form is 4: 1 or more. It is preferred that the reaction is performed at a low temperature (0 °C or lower) in order to increase selectivity of the reaction, and THF or lower alcohol is used as a reaction solvent.

As shown in the following Reaction Scheme 6, diallylic sulfide represented by the Formula 2 is subjected to selective oxidation, to afford a diallylic sulfone compound represented by the Formula 3: Reaction Scheme 6 <Formula 2> <Formula 3> When carotenoid compounds are typically synthesized using the diallylic sulfide of the Formula 2 (Reaction Scheme 1), undesired non-selective oxidation of a sulfide group occurs due to many conjugated double bonds present in the coupled C40 sulfide compound. Therefore, for solving the non-selective oxidation of the sulfide, there is newly proposed the diallylic sulfone compound of the Formula 3, which is obtained by selective oxidation of the sulfide compound represented by the Formula 2

comprising a simple structure. As for selective oxidation from the sulfide to the sulfone, preferably, a metal oxide such as V205, LiNbMo06 and NaVO3 is used as a catalyst, and H202 as an oxidant is used in an amount of 2 equivalents or more based on the compound of the Formula 2.

As such, double bonds and allylic chloride in the compound of the Formula 2 are stable to oxidation conditions. Further, different from the diallylic sulfide compound of the Formula 2, in the case of the diallylic sulfone of the Formula 3, a compound having trans double bonds may be isolated by recrystallization. Thereby, when the carotenoid compound is synthesized using di (4-chloro-3-methyl-2-butenyl) sulfone as the C10-unit compound represented by the Formula 3, the problematic oxidation may be avoided.

Further, as shown in the following Reaction Scheme 7, the C15 sulfone compound (C) is deprotonated and then reacted with 1/2 equivalents of the diallylic sulfone compound of the Formula 3 based on the sulfone compound (C), yielding a C40 tri-sulfone compound (D) that has been used in synthesis of carotenoid compounds: Reaction Scheme 7 S02Ph Ph02S RiJ + CG Sv CI + <R orb (C) <Formula 3> (C) S02Ph S02Ph R \ \ S R R R Ouzo 0 (D) R v C, I

Deprotonation of the C15 sulfone compound (C) is performed by function of a base, for example, NaH, NaNH2, n-BuLi, s-BuLi, t-BuLi, Ph-Li, LDA (lithium diisopropylamide), EtONa, MeONa, EtOK, MeOK, t-BuOK, etc. The coupling of the sulfone compound (C) with the compound of the Formula 3 is performed at low temperatures, preferably, at-90-0 °C, using DMF or THF solvent, to give the C40 trisulfone compound (D). If the temperature is above 0 °C, the yield may be decreased due to dehydrochlorination of the compound of the Formula 3 by function of the base.

Syntheses of beta-carotene and lycopene as the carotenoid compounds from the compound (D) have been reported by the present inventors (J. Org. Chem. 1999, 64, 8051-8053 ; Korean Patent Laid-open Publication No. 2002-59202).

Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.

EXAMPLE 1 Synthesis of l-Chloro-2-methyl-3-buten-2-ol (A) To a mixture of isoprene (24ml, 0. 24mol) and water (100ml) was added NCS (N- chlorosuccinimide, 26. 7g, 0. 20mol), after which the reaction mixture was maintained at 60 °C for 24 hours and cooled to room temperature. A resultant material was extracted with diethyl ether, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, to give 1-chloro-2-methyl-3-buten-2-ol (18.8g, 0. 156mol, 78%) which was pure to the extent of not requiring further purification.

'HNMR 8 1.38 (3H, s), 2.17 (1H, br s), 3.53 (1H, d of A of ABq, Jd= 11.0, JAB = 12. 1 Hz), 3.57 (1H, d of B of ABq, Jd = 11.0, JAB = 12.1 Hz), 5.21 (1H, dd, J= 10.7, 1.0 Hz), 5. 38 (in, dd, J= 17.3, 1.0 Hz), 5.92 (1H, dd, J= 17.3, 10.7 Hz) ppm.

13C NMR b 25. 3, 54.0, 72.5, 114.7, 141.9 ppm EXAMPLE 2 Synthesis of 4-Bromo-1-chloro-2-methyl-2-butene (B) 1-Chloro-2-methyl-3-buten-2-ol (23. 5g, 0.195 mol) obtained in the above example 1 was dissolved in anhydrous diethyl ether (100ml), to which CuBr (559mg, 3.9mmol) was added, and PBr3 (6. 5ml, 78. 1mmol) was cautiously further added at 0 °C.

The reaction mixture was stirred at room temperature for 2 hours, diluted with 100ml of diethyl ether, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, to give 4-bromo-1-chloro-2-methyl-2-butene (28.2g, 0. 146mol, 75%). As such, a ratio of trans to cis double bonds was 8: 1 or more.

Further, 2-bromo-1-chloro-2-methyl-3-butene by bromination without allylic rearrangement was not produced at all. trans : 1H NMR 5 1. 85 (3H, s), 3. 98 (2H, dd, J= 8.3, 0.9Hz), 4.03 (2H, s), 5.87 (1 H, dt, Jd = 0. 9, Jt = 8.3 Hz) ppm 13C NMR 8 14.1, 27.3, 50. 6,125. 3, 137. 8 ppm cis :'H NMR 8 1.92 (3H, s), 4.00 (2H, dd, J= 8.3, 0.7Hz), 4.10 (2H, s), 5.73 (1H, dt, Jd = 0. 7, Jt = 8. 3Hz) ppm

EXAMPLE 3 Synthesis of 4-Chloro-3-methyl-2-butenyl Phenyl Sulfide Represented By Formula 1 4-Bromo-l-chloro-2-methyl-2-butene (10.7g, 55.4mmol) obtained in the above example 2 was dissolved in tetrahydrofuran (100ml), to which benzenethiol (5. 9ml, 52.6mmol) and triethylamine (7. 9ml, 55.4mmol) were successively added at 0 °C. The reaction mixture was stirred at 0 °C for 6 hours, added with water, extracted with diethyl ether and washed with 1M HC1 and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. A crude product was purified by silica gel chromatography, to give 4-chloro-3-methyl-2-butenyl phenyl sulfide (9.92g, 46. 5mmol, 84%). As such, a ratio of trans to cis double bonds was 8: 1. trans : lH NMR 5 1.62 (3H, s), 3.52 (2H, d, J= 7.7Hz), 3. 97 (2H, s), 5.64 (1H, t, J= 7.7 Hz), 7. 18-7. 40 (5H, m) ppm cis :'H NMR 8 1.83 (3H, s), 3.56 (2H, d, J= 7. 7 Hz), 3.87 (2H, s), 5.52 (1H, t, J= 7.7 Hz), 7.18-7. 40 (5H, m) ppm EXAMPLE 4 Synthesis of Di (4-chloro-3-methyl-2-butenyl) Sulfide Represented By Formula 2 4-Bromo-l-chloro-2-methyl-2-butene (15.6g, 80. 7mmol) obtained in the above example 2 was dissolved in tetrahydrofuran (100ml), to which Na2S (6.76g, 40. 3mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 6 hours, added with water, extracted with diethyl ether, washed with water, dried over anhydrous sodium

sulfate, filtered and concentrated under reduced pressure. A crude product was purified by silica gel chromatography, to give di (4-chloro-3-methyl-2-butenyl) sulfide (7.83g, 32.7mmol, 81%). As such, in a double bond structure, a ratio of a trans-trans compound to a trans-cis compound was 4: 1 or more. trans-trans :'H NMR 8 1.78 (3H, s), 3.10 (2H, d, J= 7.6 Hz), 4.03 (2H, s), 5.62 (1 H, t, J = 7. 6 Hz) ppm trans-cis : lH NMR 8 1.83 (3H, s), 3.12 (2H, d, J= 8.1 Hz), 4.01 (2H, s), 5.44 (1H, t, J= 8. 1 Hz) ppm EXAMPLE 5 Synthesis of Di (4-chloro-3-methyl-2-butenyl) Sulfone Represented By Formula 3 The di (4-chloro-3-methyl-2-butenyl) sulfide (170. 86g, purity 70%, 0. 5mol) of the Formula 2 obtained in the above example 4 and 200 ml of methanol were placed into a 1L round-bottom flask, and added with NaV03 (0. 61g, 5mmol) with stirring. While a reaction temperature was maintained at 30 °C, an aqueous solution of 30% hydrogen peroxide (226.73g, 2mol) was slowly added dropwise to the reaction mixture for 5 hours.

After completion of reaction confirmed by liquid chromatography, the reaction mixture was added with 500ml of dichloromethane and 200ml of water and stirred, followed by separating an organic layer from a water layer. The organic layer was washed twice with 200ml of water and dried over Na2S04, and dichloromethane was distilled off using a stirred evaporator, to quantitatively obtain di (4-chloro-3-methyl-2-butenyl) sulfone (134g, purity 70%, yield 100%). A trans structure of di (4-chloro-3-methyl-2-butenyl) sulfone (40.2g, purity 95%, yield 30%) was afforded by crystallization using 400ml of methanol at-5°C.

trans-trans : 1H NMR 5 1.87 (3H, s), 3.74 (2H, d, J= 7.7 Hz), 4. 08 (2H, s), 5.69 (1H, t, J= 7. 7 Hz) ppm 13C NMR å 15.1, 50. 2,51. 9,115. 3, 141.5 ppm trans-cis : 1H NMR 8 1.74 (3H, s), 3.71 (2H, d, J= 8.6 Hz), 4.08 (2H, s), 5.29 (1H, t, J= 8. 1 Hz) ppm EXAMPLE 6 Synthesis of Di (l l-benzensulfonyl-11, 12-dihydroretinyl) Sulfone (D-1) Into a 500ml round-bottom flask, 100ml of DMF and t-BuOK (12. 99g, 0. 1 lmol) were introduced and stirred at 25°C. Then, a solution of 3-methyl-5- (2, 6, 6-trimethyl-1- cyclohexen-l-yl)-2, 4-pentadienyl phenyl sulfone as a C15 sulfone compound (C-1) (35. 15g, 0. lmol in 100ml DMF) was slowly added dropwise into the flask at 25°C for 30 minutes, and stirred at 25°C for 1 hour and cooled to-10°C. Thereafter, the C10 sulfone solution of the Formula 3 (18.08g, 0. 06mol in 100ml DMF) was further slowly added dropwise into the flask at-10°C for 2 hours. After 1 hour, whether the reaction was completed was confirmed by liquid chromatography. Then, the temperature in the flask was increased to 25°C and 300ml of water was introduced into the flask, followed by stirring the flask for 10 minutes. As such, a crystallized product obtained by filtration was added to 300ml of 1M aqueous HCl solution and stirred for 10 minutes to obtain an acidified reaction mixture. Thereafter, a filtered crystalline product was added to 300ml of methanol and stirred for 10 minutes, followed by filtering a crystalline

product. A washing procedure using methanol was repeated twice, to finally give C40 tri-sulfone (D-1) (37.71g) in 85% yield.

'H NMR : 8 0. 91 (s, 6H), 0.96 (s, 6H), 1.22 (s, 6H), 1.37-1. 49 (m, 4H), 1. 55-1. 67 (m, 4H), 1.62 (s, 6H), 1.65 (s, 6H), 1.99 (t, 4H, J= 5.9 Hz), 2.47 (dd, 2H, J= 13.0, 11.3 Hz), 3.05 (d, 2H, J= 13.0 Hz), 3.47 (d, 4H, J = 4.5 Hz), 4.06 (dt, 2H, Jd = 3.1 Hz, Jt= 10.8 Hz), 5.07 (d, 2H, J= 10.5 Hz), 5.24 (t, 2H, J= 7.4 Hz), 5.92 (A of ABq, 2H, J = 16.4 Hz), 5.97 (B of ABq, 2H, J= 16.4 Hz), 7.40-7. 55 (m, 4H), 7.55-7. 70 (m, 2H), 7.75- 7.90 (m, 4H) ppm 13C NMR : 8 12.3, 17.0, 19.1, 21.5, 28.7, 28.8, 32.8, 34.0, 37.3, 39.3, 51.0, 63.4, 114.1, 121.0, 128.8, 129.0, 129.3, 129.7, 133. 7, 135. 5, 137. 1, 137. 2,140. 8,142. 8 ppm EXAMPLE 7 Synthesis of Di (5-benzenesulfonyl-3, 7, 11, 15-tetramethyl-2,6, 8,10, 14- hexadecapentaenyl) Sulfone (D-2) Into a 1000ml round-bottom flask, 500ml of THF and t-BuOK (34.33g, 0. 306mol) were added and stirred at 25°C until t-BuOK was completely dissolved. The flask was cooled to-78°C, after which a solution of 3,7, 11-trimethyl-2, 4,6, 10- dodecatetraenyl phenyl sulfone as a C15 sulfone compound (C-2) (90. 0g, purity 90%, 0. 235mol in 100ml THF) was slowly added dropwise into the flask for 30 minutes, and stirred at-78°C for 1 hour. Thereafter, the C10 sulfone solution of the Formula 3 (37.46g, 0. 118mol in 100ml THF) was further slowly added dropwise into the flask at-

78°C for 2 hours. After 1 hour, whether the reaction was completed was confirmed by liquid chromatography. Then, 1000ml of an aqueous solution of 1M HC1 and 700ml of ethyl acetate as an extracting solvent were added to the reaction and stirred for a predetermined time, to increase the temperature in the flask to room temperature.. An organic solvent layer was recovered, washed once with 1000ml of a saturated aqueous solution of NaHC03 and further washed once with 1000ml of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. A crude product was purified by silica gel chromatography, to finally give C40 trisulfone (D-2) (88.79g, purity 96%) in 85% yield.

'H NMR: 8 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) ppm 13C NMR: 8 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 ppm INDUSTRIAL APPLICABILITY As described above, in the synthesis of natural carotenoid products using sulfone compounds, the inventive preparation method of 4-chloro-3-methyl-2-butenyl phenyl sulfide represented by the Formula 1 as a C5-unit compound, and di (4-chloro-3- methyl-2-butenyl) sulfide represented by the Formula 2 as a C10-unit compound is advantageous in terms of high preparation efficiency due to a relatively simple process,

and suitability for large scale preparation, while solving the problems in conventional synthetic methods. Additionally, in order to solve non-selective oxidation of a sulfide group which may cause problems in the C40 diallylic sulfide compound resulting from coupling of two C15 sulfones (C) with the compound of Formula 2, there is provided di (4-chloro-3-methyl-2-butenyl) sulfone as a new C10-unit compound containing a sulfone group, and further a preparation method thereof. Thereby, through the methods of the present invention, various carotenoid products can be efficiently and economically prepared.

The present invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation. Many modifications and variations of the present invention are possible in light of the above teachings. Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.