Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
  • C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
  • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
  • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
  • C07C403/14—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
  • C07C403/22—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

• the present invention relates to processes for preparing retinoid and carotenoid compounds. More specifically, the present invention relates to a practical synthetic method to provide retinol, retinal and ⁇ -carotene.
• Retinol generally known as vitamin A
• vitamin A is an essential nutrient which gives effects on growth and specialization of tissues, and prevention of oxidation, and it has been recently used as an important ingredient in cosmetics on the purpose of preventing wrinkles and skin aging.
• Retinal is well known as a compound having a key role in visual function, while ⁇ -carotene, as a precursor of vitamin A, is a very important substance that has been widely used as food coloring, stock feed, health tonics and the like.
• Representative processes for synthesizing retinoid and carotenoid compounds having conjugated polyene as the skeletal structure include three processes industrialized by Roche, BASF and Aventis (Pure & Appl. Chem. 1991, 63, 45-58; ibid. 1979, 51, 447-462). These processes have basic differences in the mode of forming double bond.
• the Roche process induces extension of chain and formation of double bond via addition of acetylide and partial hydrogenation thereof.
• cis-type double bond with low activity is dominantly obtained at the time of partial hydrogenation and dehydration.
• the process needs more synthetic stages with less efficiency, as compared with the other two processes described below.
• the process for preparing vitamin A and ⁇ -carotene by BASF which is characterized in that double bond is formed via Wittig reaction, consists of short and simple reaction stages, but the by-product phosphine oxide from Wittig reaction cannot be easily treated, and the compound having cis-type double bond with low activity is obtained in a substantial amount.
• the process by Aventis for synthesizing retinol that is most recently developed and more excellent process as compared to the two processes mentioned above, employs coupling and double bond formation by using sulfone compound developed by Julia. According to the process, the synthetic intermediate compound is stable and the coupling reaction is excellently carried out; trans-type product is dominantly obtained at the time of double bond formation; and the by-product can be easily treated.
• Reaction Scheme 1 illustrates the processes for synthesizing retinol, retinal and ⁇ -carotene by employing Julia's sulfone chemistry. These processes utilize C-15 sulfone compound, an important intermediate for the syntheses of retinoid and carotenoid compounds, by adding vinyl Grignard compound to ⁇ -ionone as the starting material to form vinyl ⁇ -ionol, and then reacting the obtained compound with sodium benzenesulfinate in acetic acid solvent. Coupling reaction ofthe C-15 sulfone compound with C-5 halo-acetate compound, dehydrosulfonation reaction, and hydrolysis of acetate provide retinol (Bull. Soc. Chim.
• the processes for synthesizing retinoid and carotenoid compounds by using the sulfone compound according to Reaction Scheme 1 are advantageous in that the processes employ relatively stable intermediates as described, trans-type compound are effectively produced at the time of double bond formation, and the by-product can be easily treated.
• Patent Application No. 2000-77567, PCT/KROl/02078) In the same patent, the inventors have suggested an efficient process for synthesizing retinoic acid by using the intermediate described above.
• the technical object of the present invention is to overcome the disadvantages in the preparation of the C-15 allylic sulfone compound which had been usefully employed in the syntheses of retinoid and carotenoid compounds, and to provide a process for practically and economically preparing retinol by employing C-15 allylic disulfone compound (Chemical Formula 1) that is prepared more efficiently and economically.
• Another technical object of the present invention is to provide a practical and economic process for preparing retinal by employing C-15 allylic disulfone compound (Chemical Formula 1) as described above.
• Still another technical object of the present invention is to provide a practical and economic process for preparing ⁇ -carotene by employing C-15 allylic disulfone compound (Chemical Formula 1) as described above.
• the first technical object of the present invention is achieved by a process for preparing retinol (Chemical Formula 2) which comprises the steps of (1) treating C-15 allylic disulfone compound of Chemical Formula 1 with 2 equivalents of base to deprotonate the compound, and reacting C-5 halo-acetate compound (A) [wherein, X is a halogen atom] therewith to synthesize compound (B) having 20-carbon skeleton which is needed for retinol synthesis; and (2) treating the C-20 compound (B) with excess amount (3 equivalents or more) of base to form double bonds by carrying out dehydrosulfonation and hydrolysis of acetate group at the same time (Reaction Scheme 2).
• Reaction Scheme 2 Reaction Scheme 2
• X is selected from the group consisting of-Cl, -Br and -I.
• step (1) deprotonation is carried out by adding 2 equivalents of base to the compound of Chemical Formula 1 at low temperatures, preferably at a temperature of 0 °C or lower.
• base r ⁇ -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, or the like can be used.
• C-5 halo-acetate (A) can be efficiently prepared by electrophilic halogen addition to isoprene in acetic acid solvent (J. Am. Chem. Soc. 1950, 72, 4608-4613;
• step (2) dehydrosulfonation is preferably carried out by treating 3 equivalents or more of base to compound (B) at the boiling temperature of alcoholic solvent.
• the base to be employed is selected from the group consisting of NaNH ) t-BuOK, CH 3 CH 2 OK, CH 3 OK, CH 3 CH 2 ONa and CH 3 ONa. This time, hydrolysis of acetate is simultaneously performed to directly provide retinol.
• the second technical object of the present invention is achieved by a process for preparing retinal (Chemical Formula 3) which comprises treating C-15 allylic disulfone compound of Chemical Formula 1 with excess amount (3 equivalents or more) of base to deprotonate the compound, and reacting C-5 halo-acetal compound (C) [wherein, X is a halogen atom] therewith to synthesize compound (D) having 20-carbon skeleton which is needed for retinal synthesis; wherein at the same time dehydrosulfonation is performed by excess amount of base existed to synthesize retinal acetal compound (E), and hydrolysis of the acetal is immediately performed without further purification (Reaction Scheme 3).
• X is selected from the group consisting of-Cl, -Br and -I.
• Formula 1 should be performed by adding an excess amount of base (preferably 4 equivalents) at a temperature of 0 °C or lower. Since the excess amount of base is also employed in the dehydrosulfonation of compound (D) that is formed by coupling of the compound of Chemical Formula 1 with C-5 halo-acetal, 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 and CH 3 ONa. Among them, metal alkoxide can be most preferably used.
• C-5 halo-acetal can be synthesized according to a known art (Liebigs Ann. Chem. 1976, 2194-2205); or by hydrolyzing C-5 halo-acetate (A) to form an alcohol (Tetrahedron Letters, 1976, 239-242), oxidizing the alcohol to prepare an aldehyde, and reacting the aldehyde with neopentyl glycol to form an acetal (Reaction Scheme 4).
• X is selected from the group consisting of-Cl, -Br and -I.
• the third technical object of the present invention is achieved by a process for preparing ⁇ -carotene (Chemical Formula 4) which comprises the steps of (1) treating C-15 allylic disulfone compound of Chemical Formula 1 with 2 equivalents of base to deprotonate the compound, and reacting not more than 0.5 equivalent of dihaloallylic sulfide (F) [wherein, X is a halogen atom] on the basis of compound of Chemical Formula 1 to synthesize allylic sulfide compound (G) having 40-carbon skeleton which is needed for ⁇ -carotene synthesis; (2) selectively oxidizing the allylic sulfide compound (G) to prepare allylic sulfone compound (H); (3) subjecting the sulfone compound (H) to Ramberg-Backlund reaction to give tetra(benzenesulfonyl)-triene compound (I); and (4) treating the tetra(benzenesulfonyl)-triene
• X is selected from the group consisting of -CI, -Br and -I.
• step (1) deprotonation is carried out by adding 2 equivalents of base to the compound of Chemical Formula 1 at low temperatures, preferably at a temperature of 0 °C or lower.
• base r ⁇ -BuLi, s-BuLi, phenylhthium, 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, or the like can be used.
• the C-10 dihaloallylic sulfide compound (F) which was developed by the present inventors for efficient synthesis of ⁇ -carotene, can be synthesized starting from isoprene (Journal of Organic Chemistry, 1999, 64, 8051-8053). The process for preparing the compound has been recently improved (Korean Patent Application No. 2001-0067305).
• the selective oxidation in step (2) can be preferably performed by adding not less than 2 equivalents of hydrogen peroxide solution to the sulfide compound in the presence of metallic oxide catalyst such as lithium molibdenate-niobate (LiNbMoO 6 ) or vanadium oxide (V 2 O 5 ) at ambient temperature. Under such reaction condition, only sulfide is oxidized into sulfone but double bonds of the allylic sulfide (G) are not oxidized, to selectively provide compound (H).
• metallic oxide catalyst such as lithium molibdenate-niobate (LiNbMoO 6 ) or vanadium oxide (V 2 O 5 ) at ambient temperature.
• the Rarnberg-Backlund reaction in step (3) gives compound (I) by removing SO at the center ofthe allylic sulfone compound (H) and forming a double bond at the same time.
• the reaction is preferably performed under a condition excluding oxygen from the air, that is, under nitrogen or argon atmosphere.
• step (4) dehydrosulfonation is preferably carried out by treating excess amount of base to compound (I) at the boiling temperature of alcoholic solvent.
• the base to be employed 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. Under such condition, four benzenesulfonyl groups are eliminated from compound (I) with forming double bonds to provide ⁇ -carotene of Chemical Formula 4.
• pyridinium dichiOmate (PDC) (4.05 g, 10.76 mmol) was added, and the mixture was stirred at ambient temperature for 5 h.
• the reaction mixture was diluted with CH 2 C1 , thoroughly washed with water, dried over anhydrous sodium sulfate, and filtered. After concentrating the filtrate by evaporating under reduced pressure, the resultant substance was dissolved in benzene (35 mL), and />-TsOH (0.11 g, 0.54 mmol) and neopentyl glycol (1.12 g, 10.76 mmol) were added thereto.
• reaction mixture was extracted with dichloromethane, washed with 1 M aqueous
• reaction product (I) In a mixture of CC1 (15 mL) and t-BuOH (10 mL), dissolved was the C-40 sulfone compound (H) (0.98 g, 0.84 mmol), and well pulverized KOH (0.47 g, 8.36 mmol, 10 equivalents) was added in small portions to the mixture at 0 °C under argon atmosphere. After stirring at the same temperature for 1 h, and at room temperature for further 10 h, water was carefully added to the reaction mixture. The reaction mixture was neutralized with 1 M aqueous HCI solution, extracted with methylene chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 1.15 g of reaction product (I), which was so unstable that it was directly used for the next step without further purification.
• the present invention provides efficient and economic processes for retinol, retinal and ⁇ -carotene via coupling of C-15 disulfone compound (Chemical Formula 1), that can be prepared by a more economic and practical process as compared to that ofthe conventional C-15 allylic sulfone compound containing conjugated polyene, with C-5 halo-acetate compound (A), C-5 halo-acetal compound (C) and C-10 dihaloallylic sulfide (F), respectively, and double bond formation.
• C-15 disulfone compound Chemical Formula 1
• A C-5 halo-acetate compound
• C C-5 halo-acetal compound
• F dihaloallylic sulfide

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• 2002
  • 2002-04-10 KR KR10-2002-0019371A patent/KR100477899B1/ko not_active IP Right Cessation
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