WO2019147015A1 - Procédé de synthèse efficace de bis(phosphonate) de polyène en c20 et composé de carotène l'utilisant - Google Patents

Procédé de synthèse efficace de bis(phosphonate) de polyène en c20 et composé de carotène l'utilisant Download PDF

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WO2019147015A1
WO2019147015A1 PCT/KR2019/000964 KR2019000964W WO2019147015A1 WO 2019147015 A1 WO2019147015 A1 WO 2019147015A1 KR 2019000964 W KR2019000964 W KR 2019000964W WO 2019147015 A1 WO2019147015 A1 WO 2019147015A1
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structural formula
compound represented
formula
carotene
phosphonate
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PCT/KR2019/000964
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English (en)
Korean (ko)
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구상호
김다혜
김윤지
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명지대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4015—Esters of acyclic unsaturated acids
    • 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
    • C07C403/02—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 containing only carbon and hydrogen 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
    • C07C403/04—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 halogen 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
    • C07C403/06—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
    • C07C403/10—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 etherified 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
    • C07C403/18—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 nitrogen 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • C07F9/6541—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention is an antioxidant or a functional food as food coloring, medicines, and carotene compounds of novel represented by the following structural formula 1, which can be used as cosmetic ingredients, for efficiently synthesized in this appropriate formula 2 novel C 20 polyenes service represented by (Phosphonate) compound, a method for synthesizing the same, and a method for easily synthesizing the carotene compound by reacting it with various aldehyde compounds.
  • novel C 20 polyenes service represented by (Phosphonate) compound
  • R may be selected from the group consisting of alkyl, aryl, aralkyl, and heteroaryl having 5 to 20 carbon atoms.
  • Natural carotene compounds such as lycopene, zeaxanthin, canthaxanthin, and astaxanthin, as well as beta-carotene, commonly contain the polyene chain structure represented by Structural Formula (1). They are known to have an antioxidative effect by reacting with active oxygen in living organisms and efficiently removing it, and it plays an important role in photosynthesis in absorbing light and transferring energy together with chlorophyll. Since carotene compounds have various industrial uses such as livestock feeds, food additives, health supplements, medicines, and cosmetic raw materials, studies on efficient synthesis of these carotene compounds are continuing.
  • an alpha, beta-unsaturated ketone compound [structural formula B] is synthesized by reacting an aldehyde compound [structural formula A] with acetone as shown in the following figure, (HX) and triphenylphosphine (PPh 3 ) are sequentially reacted to synthesize the compound [structural formula C], and then the biotite salt represented by the structural formula 3 is produced.
  • the above method utilizes a C 10 dialdehyde compound of the structural formula 4 that is efficiently used in the synthesis of a carotene compound.
  • a C 10 dialdehyde compound of the structural formula 4 that is efficiently used in the synthesis of a carotene compound.
  • the C 10 dialdehyde compound with the aldehyde compound [structural formula A] . That is, in order to prepare the various carotene compounds represented by the structural formula 1, it is necessary to prepare various biotite salts represented by the structural formula 3 through various steps of reaction from the respective aldehyde compounds [structural formula A].
  • R may be selected from the group consisting of alkyl, aryl, aralkyl and heteroaryl having between 5 and 20 carbon atoms.
  • the various carotene compounds of formula 1 can be prepared in a single step reaction, so that the reaction proceeds efficiently and economically, And can be manufactured easily and quickly.
  • R may be selected from the group consisting of alkyl, aryl, aralkyl, and heteroaryl having 5 to 20 carbon atoms.
  • a carotene compound having various structures represented by the structural formula 1 is prepared by using 2,7-dimethyl-2,4,6-octatrienediar represented by the structural formula 4 according to the conventional method using the Biathyer reaction
  • a novel polyene compound which is required for the production of a carotene compound having various structures represented by the structural formula 1 by a single step reaction with various aldehyde compounds [structural formula A], a method for producing the same, We propose a simple and efficient method for synthesizing the compounds.
  • the present invention provides a novel C 20 polyenbis represented by the structural formula 2 required for the simple and efficient synthesis of various carotene compounds from various aldehyde compounds (structural formula A) Nate) compound, a method for producing the same, and various carotene compounds represented by the structural formula 1 using the same, and a method for efficiently synthesizing the same.
  • the first technical object of the present invention is to provide a novel tetraethyl (2,6,11,15-tetramethylhexadeca-2,4,6,8,10,12,14-heptaene -1, 16-diyl) bis (phosphonate).
  • a second technical objective of the present invention is to provide a process for the preparation of tetraethyl (2,6,11,15-tetramethylhexadeca-2,4,6,8,10,12,14-heptaen-1,16 (Benzo [ d ] thiazol-2-ylsulfonyl) -2-methyl-2-buten-l-yl) -bis (phosphonate) To provide a phosphonate.
  • a third technical object of the present invention is to provide a novel diethyl (4- (benzo [ d ] thiazole-2-ylsulfonyl) -2-methyl- And to provide a method for producing a phenate.
  • the method comprises: (a) preparing a chlorohydrin compound represented by formula D from isoprene;
  • the chlorohydrin formation reaction of isoprene in the step (a) can be carried out using N-chlorosuccinimide (NCS) in an aqueous solution, and it is preferable to mix a polar organic solvent such as DMF at a volume ratio of about 10%.
  • NCS N-chlorosuccinimide
  • the bromination reaction of the allylic alcohol proceeds at 0 ° C to room temperature using PBr 3 , and copper (Cu-X) is preferably added as a catalyst for the allylic rearrangement reaction.
  • the nucleophilic substitution reaction of the allylic bromide and the 2-mercaptobenzothiazole of the compound represented by the structural formula E is preferable in terms of the position-selective reaction of K 2 CO 3 as a base in an acetone solvent.
  • step (c) the allylic halide compound represented by the structural formula E and the 2-mercaptobenzothiazole may be reacted in an equivalent ratio of 1: 1. Wherein the 2-mercaptobenzothiazole can react with an allylic bromide group.
  • the oxidation of the sulfide group to sulfone in step (d) can be carried out using H 2 O 2 and various metal catalysts or by using an organic oxidizing agent such as peracetic acid, MCPBA (meta-chloroperbenzoic acid) or mono perphthalic acid have.
  • an organic oxidizing agent such as peracetic acid, MCPBA (meta-chloroperbenzoic acid) or mono perphthalic acid have.
  • the Arbuzov reaction is preferably carried out by activating allylic chloride with allylic iodide in a Finkelstein reaction (NaI, acetone) and reacting with triethylphosphite.
  • a fourth technical object of the present invention is to provide a process for producing a diethyl (4- (benzo [ d ] thiazole-2-ylsulfonyl) -2-methyl- (2,6,11,15-tetramethylhexadeca-2,4-dione represented by the structural formula 2) by reacting 2,7-dimethyl-2,4,6- 6,8,10,12,14-heptaen-1,16-diyl) bis (phosphonate).
  • the reaction is preferably carried out at a low temperature of -78 ° C to 0 ° C using a base such as NaHMDS or KHMDS in an aprotic solvent such as THF or DME.
  • a fifth technical objective of the present invention is to provide a process for preparing various carotene compounds of formula 1 by reacting a C 20 polyenes (phosphonate) compound of formula 2 with various aldehyde compounds [formula A].
  • R may be selected from the group consisting of alkyl, aryl, aralkyl, and heteroaryl having 5 to 20 carbon atoms.
  • alkyl, aryl or aralkyl, and heteroaryl may have a substituent.
  • R is , , , ,
  • the above process is preferably carried out by heating the mixture at a temperature of 100 ° C or higher using a metal alkoxide base in a mixed solvent of alcohol and toluene.
  • the diethyl (4- (benzo [ d ] thiazol-2-ylsulfonyl) -2-methyl-2-buten-1-yl) phosphonate of the newly prepared formula 5 has the structure 2, (2,6,11,15-tetramethylhexadec-2-ene) represented by the above structural formula 2 which can be used in the synthesis of a carotene compound by a single step reaction with 7-dimethyl- , 4,6,8,10,12,14-heptaen-1,16-diyl) bis (phosphonate) efficiently and easily.
  • novel carotene compounds of the structural formulas 1-1 to 1-9 prepared according to the present invention exhibit antioxidative ability by reacting with active oxygen and radicals and can be used for a variety of purposes including livestock feeds, food additives, health supplements, medicines, It is a substance that is used for industrial purposes.
  • N-chlorosuccinimide 26.7 g, 0.20 mol
  • the reaction product was cooled to room temperature, extracted with diethyl ether, dried over anhydrous Na 2 SO 4 , filtered through filter paper, and the filtrate was concentrated under reduced pressure to obtain a colorless liquid chlorohydrin [formula D] (18.8 g, 0.16 mol) Was obtained in a yield of 78%.
  • Acetonitrile 150 mL is added to Urea-H 2 O 2 (44.35 g, 0.47 mmol) and anhydrous phthalic acid (38.90 g, 0.236 mol) under an argon atmosphere. The mixture was stirred at room temperature for 1.5 hours to obtain a colorless mono-phthalic acid solution.
  • 4-Chloroallyl sulfide [formula F] 21.20 g, 78.57 mmol
  • CH 2 Cl 2 10 mL
  • the white solid was diluted with CH 2 Cl 2 and filtered with a filter paper.
  • Example 5 A compound represented by the structural formula 5
  • the mixture is stirred at -78 < 0 > C for 1.5 h, stirred at 0 < 0 > C for 3.5 h and then quenched with 10% ammonium chloride solution.
  • the reaction mixture is extracted with ethyl acetate, washed with brine, dried over anhydrous potassium carbonate, filtered and the filtrate is concentrated under reduced pressure to give 1.52 g of a red liquid.
  • Tetraethyl bis (phosphonate) (83 mg, 0.15 mmol) and p -tolualdehyde (92 mg, 0.77 mmol) of the structural formula 2 were dissolved in methanol (30 mL) and toluene (30 mL) 3.84 mmol). The mixture is refluxed for 12 hours at a temperature of 110 < 0 > C under an argon atmosphere and then allowed to cool to room temperature. Most of the solvent is removed under reduced pressure, diluted with diethyl ether and washed with 10% ammonium chloride solution.
  • Tetraethyl bis (phosphonate) (176 mg, 0.33 mmol) and 3,5-dimethylbenzaldehyde (218 mg, 1.63 mmol) in the same manner as in Example 7 were dissolved in methanol (30 mL) and toluene (30 mL) mL) and KOMe (570 mg, 8.13 mmol) is added. The mixture was reacted at 110 ° C. for 12 hours under an argon atmosphere and then purified by recrystallization using methanol to obtain a carotene compound represented by the structural formula 1-3 of red solid (81 mg, 0.162 mmol, all- ( E )) Was obtained in a yield of 50%.
  • Example 10 A compound represented by the structural formula 1-4
  • Tetraethylbis (phosphonate) (423 mg, 0.78 mmol) and 1,2,3,4-tetramethoxy-5-methylbenzaldehyde (940 mg, 3.91 mmol) in a similar manner to Example 7, Is dissolved in methanol (30 mL) and toluene (30 mL), followed by KOMe (1.37 g, 19.55 mmol). The mixture was reacted at 110 ° C for 24 hours under an argon atmosphere, and then purified by recrystallization using methanol to obtain 134 mg of a carotene compound represented by Structural Formula 1-4 (134 mg, 0.187 mmol, all- ( E )) was obtained in a yield of 24%.
  • Structural Formula 1-4 134 mg, 0.187 mmol, all- ( E )
  • Example 11 A compound represented by the structural formula 1-5
  • Example 13 A compound represented by the structural formula 1-7
  • Example 14 A compound represented by the structural formula 1-8
  • Example 15 A compound represented by the structural formula 1-9
  • Example 16 A compound represented by the formula [1-10]
  • Example 7 (300 mg, 0.27 mmol) and p -anisylaldehyde (180 mg, 1.32 mmol) in the same manner as in Example 7 were dissolved in methanol (30 mL) and toluene (30 mL) Followed by KOMe (464 mg, 6.61 mmol). The mixture was reacted at 110 ° C for 24 hours under an argon atmosphere, and then purified by recrystallization using methanol to obtain a carotene compound (39 mg, 0.77 mmol, 9- ( Z )) Was obtained in a yield of 29%.
  • Example 17 A compound represented by the structural formula 1-11
  • Tetraethyl bis (phosphonate) (155 mg, 0.287 mmol) and benzaldehyde (152 mg, 1.43 mmol) in the same manner as in Example 7 were dissolved in methanol (30 mL) and toluene (30 mL) Add KOMe (503 g, 7.18 mmol). The mixture was reacted at 110 DEG C for 12 hours under an argon atmosphere, and then purified by recrystallization using methanol to obtain a carotene compound (68 mg, 0.152 mmol) represented by the structural formula 1-11 as red solid in 53% Yield.
  • Example 18 A compound represented by the formula [1-12]
  • Example 20 A compound represented by the formula [1-14]

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)

Abstract

La présente invention concerne un intermédiaire nécessaire pour produire un composé de carotène ayant une excellente activité antioxydante avec divers composés d'aldéhyde dans une réaction en une seule étape, un procédé de synthèse de celui-ci, et un procédé de synthèse de divers composés de carotène l'utilisant. L'invention concerne en particulier, un nouveau tétraéthyle (2,6,11,15-tétraméthylhexadéca-2,4,6,8,10,12,14-heptaen-1,16-diyl)bis(phosphonate) représenté par la formule structurale 2 et le diéthyl(4-(benzo[d]thiazole-2-ylsulfonyle)-2-méthyl-2-butèn-1-yl) phosphonate de formule structurale 5, ainsi qu'un procédé de synthèse efficace de celui-ci. L'invention permet l'utilisation du bis(phosphonate) de polyène en C20 de formule structurale 2, pour produire un composé de carotène de différentes structures par une réaction en une seule étape avec divers composés d'aldéhyde ; la réaction étant efficace et simple.
PCT/KR2019/000964 2018-01-26 2019-01-23 Procédé de synthèse efficace de bis(phosphonate) de polyène en c20 et composé de carotène l'utilisant WO2019147015A1 (fr)

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KR1020180010221A KR102092655B1 (ko) 2018-01-26 2018-01-26 C20 폴리엔 비스(포스포네이트)와 이를 이용한 카로틴 화합물의 효율적인 합성법

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112321421A (zh) * 2020-09-29 2021-02-05 宿迁科思化学有限公司 一种1-乙酰氧基-4-氯-3-甲基-2-丁烯的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2551914A1 (de) * 1975-11-19 1977-06-02 Hoechst Ag Verfahren zur darstellung symmetrischer carotinoide
KR20050077504A (ko) * 2001-10-31 2005-08-02 구상호 카로틴계 천연물 합성에 필요한디(4-클로로-3-메틸-2-부테닐) 설폰의 제조방법
KR100733023B1 (ko) * 2006-06-05 2007-06-28 구상호 디알데하이드 화합물, 이의 제조 방법, 및 이를 이용한카로틴 화합물의 합성 방법

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2551914A1 (de) * 1975-11-19 1977-06-02 Hoechst Ag Verfahren zur darstellung symmetrischer carotinoide
KR20050077504A (ko) * 2001-10-31 2005-08-02 구상호 카로틴계 천연물 합성에 필요한디(4-클로로-3-메틸-2-부테닐) 설폰의 제조방법
KR100733023B1 (ko) * 2006-06-05 2007-06-28 구상호 디알데하이드 화합물, 이의 제조 방법, 및 이를 이용한카로틴 화합물의 합성 방법

Non-Patent Citations (3)

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Title
EFFENBERGER, F.: "Synthesen endständig substituierter, konjugierter Polyene", SYNTHESIS, vol. 11, 1990, pages 1085 - 1094, XP055628935 *
KIM, D.: "Fast Assembly and High-Throughput Screening of Structure and Antioxidant Relationship of Carotenoids", ORGANIC LETTERS, vol. 21, no. 3, 16 January 2019 (2019-01-16), pages 714 - 718, XP055628938 *
KIM, M.: "Role of Ring Ortho Substituents on the Configuration of Carotenoid Polyene Chains", ORGANIC LETTERS, vol. 20, no. 2, 10 January 2018 (2018-01-10), pages 493 - 496, XP055628937 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112321421A (zh) * 2020-09-29 2021-02-05 宿迁科思化学有限公司 一种1-乙酰氧基-4-氯-3-甲基-2-丁烯的制备方法

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