RU2739248C1 - Synthesis of semisynthetic esters of natural zeaxanthin - Google Patents

Synthesis of semisynthetic esters of natural zeaxanthin Download PDF

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RU2739248C1
RU2739248C1 RU2019139342A RU2019139342A RU2739248C1 RU 2739248 C1 RU2739248 C1 RU 2739248C1 RU 2019139342 A RU2019139342 A RU 2019139342A RU 2019139342 A RU2019139342 A RU 2019139342A RU 2739248 C1 RU2739248 C1 RU 2739248C1
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zeaxanthin
esters
synthesis
ketoprofen
ibuprofen
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Станислав Витальевич Печинский
Анна Гургеновна Курегян
Эдуард Тоникович Оганесян
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федеральное государственное бюджетное образовательное учреждение высшего образования "Волгоградский государственный медицинский университет" Министерства здравоохранения Российской Федерации
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    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/46—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid
    • C07C57/48—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings and other rings, e.g. cyclohexylphenylacetic acid having unsaturation outside the aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/127—Preparation from compounds containing pyridine rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

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Abstract

FIELD: medicine; pharmaceuticals.
SUBSTANCE: invention refers to pharmacy, particularly to the chemical-pharmaceutical industry, and concerns a method of producing novel semi-synthetic esters of zeaxanthin and can be used to produce medicinal preparations based on these compounds. Described is synthesis of semisynthetic esters of natural zeaxanthin and benzoic, n-methylbenzoic, phenylglycolic, nicotinic, salicylic acids, ibuprofen and ketoprofen. Method for synthesis of zeaxanthin esters enables to carry out esterification reactions with model acids (benzoic, phenylglycolic, n-methylbenzoic) and drugs (nicotinic and salicylic acids, ibuprofen, ketoprofen) in a non-aqueous medium, at temperature 40 °C, which is due to use of biocatalyst Amano Lipase PS.
EFFECT: disclosed method of synthesis of semi-synthetic derivatives of natural zeaxanthin enables to obtain esters thereof with model acids (benzoic, phenylglycolic, 4-methylbenzoic) and medicinal agents (nicotinic, salicylic, ibuprofen, ketoprofen), which can be used for development of new original domestic medicinal agents.
1 cl, 1 dwg, 1 ex

Description

Изобретение относится к фармации, в частности, к химико-фармацевтической отрасли и касается способа получения новых полусинтетических сложных эфиров зеаксантина и может использоваться для получения лекарственных препаратов на основе этих соединений.The invention relates to pharmacy, in particular, to the chemical-pharmaceutical industry and relates to a method for producing new semi-synthetic esters of zeaxanthin and can be used to obtain drugs based on these compounds.

В периодической научной литературе отсутствуют данные по получению полусинтетических производных зеаксантина.In the periodical scientific literature there are no data on the preparation of semi-synthetic derivatives of zeaxanthin.

Зеаксантин проявляет антиоксидантную активность, доказано его протективное действие в отношении ишемической болезни сердца, инсульта, катаракты и возрастной макулярной дегенерация (ВМД). Зеаксантин не обладает активностью провитамина A [Krinsky N. Carotenoids in health and disease. New York: Dekker, 2004. P. 503.]. Макулярные ксантофиллы - зеаксантин и лютеин избирательно накапливаются в сетчатке глаза, что объясняется участием в их транспорте специфичных лютеинсвязывающего (StARD3) и зеаксантинсвязывающего (GSTP1) белков [Horvath М.Р., George E.W., Tran Q.T., Baumgardner K., Zharov G., Lee S., Sharifzadeh H., Shihab S., Mattinson Т., Li В., Bernstein P.S./ Structure of the lutein-binding domain of human StARD3 at 1.74 A resolution and model of a complex with lutein // Struct. Biol. Commun. 2016. Vol. 72: N 8. P. 609-618., Jirayu Tanprasertsuk, Binxing Li, Paul S. Bernstein, Rohini Vishwanathan, Mary Ann Johnson, Leonard Poon, Elizabeth J. Johnson / Relationship between concentrations of lutein and StARD3among pediatric and geriatric human brain tissue // PLOS ONE. 2016. Vol.11. N 7. e0159877, Billsten, H.H.; Bhosale, P.; Yemelyanov, A.; Bernstein, P.S.; Polivka, T. / Photophysical properties of xanthophylls in carotenoproteins from human retina // Photochem. Photobiol. 2003. Vol. 78. N 2. P. 138-145, Ana Gabriela Murillo, Siqi Hu, Maria Luz Fernandez / Zeaxanthin: metabolism, properties, and antioxidant protection of eyes, heart, liver, and skin // Antioxidants 2019. Vol. 8. N 9. P. 390]. Следует подчеркнуть, что в периферической зоне сетчатки соотношение лютеин : зеаксантин составляет 2:1, а в макулярной зоне у 90% людей в возрасте от 3 до 95 лет зеаксантин является доминирующим макулярным каротиноидом [Mares J. / Lutein and zeaxanthin isomers in eye health and disease // Annu Rev Nutr. 2016. Jul 17. N 36. P. 571 - 602, Britton G. Carotenoids. Nutrition and Health. Basel; Boston; Berlin:

Figure 00000001
Verlag, 2009. Vol. 5. P. 464]. ВМД является одной из первопричин слепоты пожилых людей в развитых странах мира, например, согласно данным National Eye Institute [National Eye Institute USA: https://nei.nih.gov.] к 2050 году только в США число страдающих этой нозологией возрастет до 5,4 млн человек. Существует прямая взаимосвязь между высоким уровнем потребления макулярных ксантофиллов и снижением риска возникновения ВМД [Ong В.В., Ah-Fat F.G. / Age-related macular degeneration // Br. J. Hosp.Med. - (Lond.). - 2016. - Vol. 77, N 2. P. 18-21].Zeaxanthin exhibits antioxidant activity, its protective effect has been proven against coronary heart disease, stroke, cataracts and age-related macular degeneration (AMD). Zeaxanthin has no pro-vitamin A activity [Krinsky N. Carotenoids in health and disease. New York: Dekker, 2004. P. 503.]. Macular xanthophylls - zeaxanthin and lutein selectively accumulate in the retina, which is explained by the participation of specific lutein-binding (StARD3) and zeaxanthin-binding (GSTP1) proteins in their transport [Horvath MR, George EW, Tran QT, Baumharovgardner K., Z Lee S., Sharifzadeh H., Shihab S., Mattinson T., Li B., Bernstein PS / Structure of the lutein-binding domain of human StARD3 at 1.74 A resolution and model of a complex with lutein // Struct. Biol. Commun. 2016. Vol. 72: N 8.P. 609-618., Jirayu Tanprasertsuk, Binxing Li, Paul S. Bernstein, Rohini Vishwanathan, Mary Ann Johnson, Leonard Poon, Elizabeth J. Johnson / Relationship between concentrations of lutein and StARD3among pediatric and geriatric human brain tissue // PLOS ONE. 2016. Vol.11. No. 7.e0159877, Billsten, HH; Bhosale, P .; Yemelyanov, A .; Bernstein, PS; Polivka, T. / Photophysical properties of xanthophylls in carotenoproteins from human retina // Photochem. Photobiol. 2003. Vol. 78. N 2.P. 138-145, Ana Gabriela Murillo, Siqi Hu, Maria Luz Fernandez / Zeaxanthin: metabolism, properties, and antioxidant protection of eyes, heart, liver, and skin // Antioxidants 2019. Vol. 8. N 9. P. 390]. It should be emphasized that in the peripheral zone of the retina the ratio of lutein: zeaxanthin is 2: 1, and in the macular zone in 90% of people aged 3 to 95 years, zeaxanthin is the dominant macular carotenoid [Mares J. / Lutein and zeaxanthin isomers in eye health and disease // Annu Rev Nutr. 2016. Jul 17. N 36. P. 571-602, Britton G. Carotenoids. Nutrition and Health. Basel; Boston; Berlin:
Figure 00000001
Verlag, 2009. Vol. 5. P. 464]. AMD is one of the root causes of blindness in older people in developed countries, for example, according to the National Eye Institute [National Eye Institute USA: https://nei.nih.gov.] By 2050 in the United States alone, the number of people suffering from this nosology will increase to 5 , 4 million people. There is a direct relationship between a high level of consumption of macular xanthophylls and a reduced risk of AMD [Ong VV, Ah-Fat FG / Age-related macular degeneration // Br. J. Hosp.Med. - (Lond.). - 2016. - Vol. 77, No. 2. P. 18-21].

Учитывая то, что организм человека не способен синтезировать зеаксантин, а потребность в нем может восполняться только с продуктами питания или лекарственными средствами [Krinsky N. Carotenoids in health and disease. New York: Dekker, 2004. P. 503.], то, что природный этерифицированный зеаксантин имеет более высокую биодоступность, чем его свободная форма [Breithaupt, D.E.; Weller, P.; Wolters, M.; Hahn, A. / Comparison of plasma responses in human subjects after the ingestion of 3R,3R'-zeaxanthin dipalmitate from wolfberry (Lycium barbarum) and non-esterified 3R,3R'-zeaxanthin using chiral high-performance liquid chromatography // Br. J. Nutr. 2004. Vol. 91. N 5. P. 707-713] и то, что зеаксантин имеет высокую специфичность локализации в организме человека [Mares J. / Lutein and zeaxanthin isomers in eye health and disease // Annu Rev Nutr. 2016. Jul 17. N 36. P. 571-602], мы сочли целесообразным получить полусинтетические эфиры природного зеаксантина.Considering the fact that the human body is not able to synthesize zeaxanthin, and the need for it can be met only with food or drugs [Krinsky N. Carotenoids in health and disease. New York: Dekker, 2004. P. 503.], that naturally occurring esterified zeaxanthin has a higher bioavailability than its free form [Breithaupt, D.E .; Weller, P .; Wolters, M .; Hahn, A. / Comparison of plasma responses in human subjects after the ingestion of 3R, 3R'-zeaxanthin dipalmitate from wolfberry (Lycium barbarum) and non-esterified 3R, 3R'-zeaxanthin using chiral high-performance liquid chromatography // Br. J. Nutr. 2004. Vol. 91. N 5. P. 707-713] and the fact that zeaxanthin has a high specificity of localization in the human body [J. Mares / Lutein and zeaxanthin isomers in eye health and disease // Annu Rev Nutr. 2016. Jul 17. N 36. P. 571-602], we considered it expedient to obtain semi-synthetic esters of natural zeaxanthin.

Нами предлагается использовать в качестве кислот не только модельные соединения - бензойную, 4-метилбензойную (n-толуиловая), фенилгликолевую и никотиновую кислоты [Патент РФ 2702005 Синтез полусинтетических производных природных лютеина и атаксантина / Печинский С.В., Курегян А.Г., Степанова Э.Ф. опубликовано 03.10.2019, Бюл. №28. - 2 с., Печинский С.В., Курегян А.Г., Оганесян Э.Т., Степанова Э.Ф. // Журн. общ. Химии. 2019. Т. 89 (5). С. 721-725], но и лекарственные средства - салициловую кислоту, ибупрофен, кетопрофен.We propose to use as acids not only model compounds - benzoic, 4-methylbenzoic (n-toluic), phenylglycolic and nicotinic acids [RF Patent 2702005 Synthesis of semi-synthetic derivatives of natural lutein and ataxanthin / Pechinsky S.V., Kuregyan A.G., Stepanova E.F. published on 03.10.2019, Bul. No. 28. - 2 p., Pechinsky S.V., Kuregyan A.G., Oganesyan E.T., Stepanova E.F. // Journal. total Chemistry. 2019.Vol. 89 (5). S. 721-725], but also drugs - salicylic acid, ibuprofen, ketoprofen.

Классическими условиями проведения реакции этерификации являются: водная среда, присутствие в реакционной среде металлов и сильных кислот, нагревание свыше 50°С Особенности структуры ксантофиллов, в частности, зеаксантина не позволяют проводить его этерификацию при таких параметрах синтеза. Решить это противоречие можно используя в качестве катализаторов энзимы.The classical conditions for carrying out the esterification reaction are: an aqueous medium, the presence of metals and strong acids in the reaction medium, heating over 50 ° C. Features of the structure of xanthophylls, in particular, zeaxanthin, do not allow its esterification with such synthesis parameters. This contradiction can be solved by using enzymes as catalysts.

В периодической литературе опубликованы результаты применения биокатализаторов в реакциях этерификации, гидролиза и синтеза лекарственных средств [Enzymatic esterification of oleic acid and propanol by Novozym 435 /Sawittree Mulaleea, Karnjana Senab, and Muenduen Phisalaphong // Applied Mechanics and Materials, 2015. - Vol. 705. - P. 29-33; Основные аспекты использования липаз для получения биодизеля (обзор) / А.В. Гарабаджиу, В.А. Галынкин, М.М. Карасев, Г.В. Козлов, Т.Б. Лисицкая // Известия Санкт-Петербургского государственного технологического института (технического университета), 2010. - №7 (33). - С. 63-67, Solvent free lipase catalyzed synthesis of butyl caprylate / Meera T Sose, Sneha R Bansode, Virendra K Rathod // J. Chem. Sci., 2017. - Vol. 129. - №11. - P. 1755-1760; High Enantioselective Novozym 435-Catalyzed Esterification of (R,S)-Flurbiprofen Monitored with a Chiral Stationary Phase / Tomasz

Figure 00000002
Debby Mangelings, Yvan Vander Heyden, Marta Ziegler-Borowska, Michal Piotr Marsza // Appl Biochem Biotechnol, 2015. - Vol. 175. - P. 2769-2785, Липазы в реакциях катализа в органическом синтезе (Обзор) / А.М. Безбородов, Н.А. Загустина // Прикладная биохимия и микробиология, 2014, том 50, №4, с. 347-373].The results of the use of biocatalysts in the reactions of esterification, hydrolysis and synthesis of drugs [Enzymatic esterification of oleic acid and propanol by Novozym 435 / Sawittree Mulaleea, Karnjana Senab, and Muenduen Phisalaphong // Applied Mechanics and Materials, 2015. - Vol. 705 P. 29-33; The main aspects of using lipases for biodiesel production (review) / A.V. Garabaghiu, V.A. Galynkin, M.M. Karasev, G.V. Kozlov, T.B. Lisitskaya // Bulletin of the St. Petersburg State Technological Institute (Technical University), 2010. - №7 (33). - S. 63-67, Solvent free lipase catalyzed synthesis of butyl caprylate / Meera T Sose, Sneha R Bansode, Virendra K Rathod // J. Chem. Sci., 2017. - Vol. 129. - No. 11. - P. 1755-1760; High Enantioselective Novozym 435-Catalyzed Esterification of (R, S) -Flurbiprofen Monitored with a Chiral Stationary Phase / Tomasz
Figure 00000002
Debby Mangelings, Yvan Vander Heyden, Marta Ziegler-Borowska, Michal Piotr Marsza // Appl Biochem Biotechnol, 2015. - Vol. 175. - P. 2769-2785, Lipases in catalysis reactions in organic synthesis (Review) / A.M. Bezborodov, N.A. Zagustina // Applied Biochemistry and Microbiology, 2014, volume 50, no. 4, p. 347-373].

За прототип был принят способ получения сложных эфиров лютеина и астаксантина [Патент РФ 2702005 Синтез полусинтетических производных природных лютеина и атаксантина / Печинский С.В., Курегян А.Г., Степанова Э.Ф. опубликовано 03.10.2019, Бюл. №28. - 2 с., Печинский С.В., Курегян А.Г., Оганесян Э.Т., Степанова Э.Ф. // Журн. общ. Химии. 2019. Т. 89 (5). С. 721-725]. Согласно описанию сложные эфиры лютеина и астаксантина получали, используя в качестве растворителя толуол. Температура реакционной среды не должна превышать 37°С Время протекания реакции от 6 часов. В качестве ферментного катализатора авторы использовали липазу Novozyme 435 в количестве 1,0 г. Реакционную среду перемешивали в течение 6 часов при скорости вращения мешалки 30 об/мин, смену направления перемешивания осуществляли через 10 мин. Высушивание полученных соединений проводили при комнатной температуре над безводным сульфатом натрия, предохраняя от действия света. Анализ полученных сложных эфиров проводили методом ВЭЖХ.For the prototype was adopted a method for producing esters of lutein and astaxanthin [RF Patent 2702005 Synthesis of semi-synthetic derivatives of natural lutein and ataxanthin / Pechinsky SV, Kuregyan AG, Stepanova EF. published on 03.10.2019, Bul. No. 28. - 2 p., Pechinsky S.V., Kuregyan A.G., Oganesyan E.T., Stepanova E.F. // Journal. total Chemistry. 2019.Vol. 89 (5). S. 721-725]. As described, esters of lutein and astaxanthin were prepared using toluene as solvent. The temperature of the reaction medium should not exceed 37 ° C. The reaction time is from 6 hours. As an enzyme catalyst, the authors used Novozyme 435 lipase in an amount of 1.0 g. The reaction medium was stirred for 6 hours at a stirrer speed of 30 rpm, the direction of stirring was changed after 10 minutes. The resulting compounds were dried at room temperature over anhydrous sodium sulfate, protected from light. The obtained esters were analyzed by HPLC.

Заявляемое изобретение ставит своей целью синтез полусинтетических производных природного каротиноида-ксантофилла - зеаксантина, в частности, его сложных эфиров:The claimed invention aims to synthesize semi-synthetic derivatives of the natural carotenoid-xanthophyll-zeaxanthin, in particular, its esters:

зеаксантина и бензойной кислоты,zeaxanthin and benzoic acid,

зеаксантина и n-метилбензойной кислоты (n-толуиловой кислоты),zeaxanthin and n-methylbenzoic acid (n-toluic acid),

зеаксантина и фенилгликолевой кислоты,zeaxanthin and phenylglycolic acid,

зеаксантина и никотиновой кислоты,zeaxanthin and nicotinic acid,

зеаксантина и салициловой кислоты,zeaxanthin and salicylic acid,

зеаксантина и ибупрофенаZeaxanthin and Ibuprofen

зеаксантина и кетопрофена (рисунок 1).zeaxanthin and ketoprofen (Figure 1).

Существенными отличительными признаками изобретения являются следующие особенности:The essential distinguishing features of the invention are the following features:

сложные эфиры получены на основе природного ксантофилла зеаксантина, который использован как спиртосоставляющая сложных эфиров;esters are obtained on the basis of the natural xanthophyll zeaxanthin, which is used as the alcohol component of esters;

сложные эфиры получены с салициловой кислотами, ибупрофеном, кетопрофеном;esters obtained with salicylic acids, ibuprofen, ketoprofen;

растворитель - смесь толуола и метанола (50:3);solvent - a mixture of toluene and methanol (50: 3);

температура процесса - 40°С;process temperature - 40 ° С;

катализатор - или Новозим 435 (Novozyme 435), или Amano Lipase PS в количестве 0,2 г;catalyst - either Novozyme 435 (Novozyme 435), or Amano Lipase PS in an amount of 0.2 g;

высушивание полученных соединений проводится в течение 2 ч в вакууме (20-25 мм рт. ст.);drying of the obtained compounds is carried out for 2 hours in a vacuum (20-25 mm Hg);

подтверждение структуры полученных эфиров зеаксантина проведено - методом масс-спектрометрии:confirmation of the structure of the obtained zeaxanthin esters was carried out by mass spectrometry:

масс-спектр соединения 1, m/z: 777.4853 [М+Н]+. С54Н64O4Н+. Мвыч. 777.4877;mass spectrum of compound 1, m / z: 777.4853 [M + H] + . C 54 H 64 O 4 H + . M deducted 777.4877;

масс-спектр соединения 2, m/z: 779.4766 [М+Н]+. С52Н62N2O4Н+. Мвыч. 779.4782;mass spectrum of compound 2, m / z: 779.4766 [M + H] + . C 52 H 62 N 2 O 4 H + . M deducted 779.4782;

масс-спектр соединения 3, m/z: 805.4769 [М+Н]+. С56Н68O4Н+. Мвыч. 809.4776,mass spectrum of compound 3, m / z: 805.4769 [M + H] + . C 56 H 68 O 4 H + . M deducted 809.4776,

масс-спектр соединения 4, m/z: 805.5182 [М+Н]+. C56H68O4H+. Мвыч. 805.5190;mass spectrum of compound 4, m / z: 805.5182 [M + H] + . C 56 H 68 O 4 H + . M deducted 805.5190;

масс-спектр соединения 5, m/z: 837.5062 [М+Н]+. С56Н68O6Н+. Мвыч. 837.5089;mass spectrum of compound 5, m / z: 837.5062 [M + H] + . C 56 H 68 O 6 H + . M deducted 837.5089;

масс-спектр соединения 6, m/z: 945.6776 [М+Н]+. С66Н88O4Н+. Мвыч. 945.6755;mass spectrum of compound 6, m / z: 945.6776 [M + H] + . C 66 H 88 O 4 H + . M deducted 945.6755;

масс-спектр соединения 7, m/z: 1041.6005 [М+Н]+. С66Н88O4Н+. Мвыч. 1041.6028).mass spectrum of compound 7, m / z: 1041.6005 [M + H] + . C 66 H 88 O 4 H + . M deducted 1041.6028).

Предлагаемый способ включает следующие стадии:The proposed method includes the following stages:

1) эквимолярные навески зеаксантина и кислоты (или бензойной, или n-метилбензойной, или фенилгликолиевой, или никотиновой, или салициловой, или ибурофена, или кетопрофена) растворяют в 50 мл толуола и 3 мл метанола;1) equimolar portions of zeaxanthin and acid (or benzoic, or n-methylbenzoic, or phenylglycolic, or nicotinic, or salicylic, or iburofen, or ketoprofen) are dissolved in 50 ml of toluene and 3 ml of methanol;

2) полученные растворы помещают в химический реактор, предварительно защищенный от воздействия света (оборачивание черной бумагой или другое);2) the resulting solutions are placed in a chemical reactor, previously protected from light (wrapped in black paper or otherwise);

3) в реакционную среду вносят катализатор или Новозим 435 (Novozyme 435) (кат. №L4777 Sigma-Aldrich), или Amano Lipase PS (кат. №708011-10G Sigma-Aldrich) в количестве 0,2 г;3) a catalyst or Novozyme 435 (Novozyme 435) (cat. No. L4777 Sigma-Aldrich) or Amano Lipase PS (cat. No. 708011-10G Sigma-Aldrich) in an amount of 0.2 g is added to the reaction medium;

4) реакционную среду нагревают до 40°С;4) the reaction medium is heated to 40 ° C;

5) время протекания реакции 6 часов, скорость перемешивания 30 об/мин;5) the reaction time is 6 hours, the stirring speed is 30 rpm;

6) по истечении 6 часов раствор фильтруют через мембранный фильтр с диаметром пор 0,45 мкм и анализируют методом ВЭЖХ, определяя количественное содержание продуктов реакции и остаточное содержание исходных компонентов;6) after 6 hours, the solution is filtered through a membrane filter with a pore diameter of 0.45 μm and analyzed by HPLC, determining the quantitative content of the reaction products and the residual content of the starting components;

7) полученную смесь охлаждают до 20°С;7) the resulting mixture is cooled to 20 ° C;

8) промывают 95%-нным этиловым спиртом;8) washed with 95% ethyl alcohol;

9) высушивают 2 ч в вакууме (20-25 мм рт. ст.) при 40°С9) dried for 2 h in a vacuum (20-25 mm Hg) at 40 ° C

10) полученные вещества запаивают в ампулы темного стекла.10) the obtained substances are sealed in dark glass ampoules.

Пример получения сложного эфира зеаксантина с салициловой кислотой: 0,57 г зеаксантина (около 0,001 моль), 0,28 г (около 0,002 моль) салициловой кислоты (кат. №247588 Sigma-Aldrich), 50 мл толуола, 0,2 г Amano Lipase PS (кат. №708011-10G Sigma-Aldrich) помещали в реактор, предварительно обернув его черной бумагой, для предотвращения попадания света и продували азотом. Температура реакционной среды - 40°С, время протекания реакции - 6 часов, скорость перемешивания 30 об/мин. Полученный раствор фильтровали через мембранный фильтр с диаметром пор 0,45 мкм и анализировали методом ВЭЖХ в следующих условиях: колонка Develosil С30 150 мм × 4,6 мм, подвижная фаза: ацетонитрил - хлороформ - метанол (80:18:2), детектирование 445 нм. Установлено, что при использовании катализатора Amano Lipase PS образуется эфир зеаксантина в количестве 60%, дальнейшее проведение реакции свыше 6 часов не приводило к значимому увеличению продукта.An example of the preparation of an ester of zeaxanthin with salicylic acid: 0.57 g of zeaxanthin (about 0.001 mol), 0.28 g (about 0.002 mol) of salicylic acid (cat. No. 247588 Sigma-Aldrich), 50 ml of toluene, 0.2 g of Amano Lipase PS (Cat. # 708011-10G Sigma-Aldrich) was placed in the reactor, previously wrapped in black paper to prevent light from entering, and purged with nitrogen. The temperature of the reaction medium is 40 ° C, the reaction time is 6 hours, the stirring speed is 30 rpm. The resulting solution was filtered through a membrane filter with a pore diameter of 0.45 μm and analyzed by HPLC under the following conditions: Develosil C30 column 150 mm × 4.6 mm, mobile phase: acetonitrile - chloroform - methanol (80: 18: 2), detection 445 nm. It was found that when using the Amano Lipase PS catalyst, a zeaxanthin ester was formed in an amount of 60%; further reaction over 6 hours did not lead to a significant increase in the product.

Полученную смесь охлаждали до 20°С, промывали 95%-нным этиловым спиртом, высушивали 2 ч в вакууме (20-25 мм рт. ст.) при 40°С. Полученные вещества запаивали в ампулы темного стекла.The resulting mixture was cooled to 20 ° C, washed with 95% ethyl alcohol, and dried for 2 h in a vacuum (20-25 mm Hg) at 40 ° C. The resulting substances were sealed in dark glass ampoules.

Предлагаемый способ синтеза полусинтетических производных природного зеаксантина позволяет получать его сложные эфиры с модельными кислотами (бензойной, фенил гиколиевой, 4-метилбензойной) и лекарственными средствами (никотиновой, салициловой, ибупрофеном, кетопрофеном). Полученные сложные эфиры могут в дальнейшем быть использованы для разработки новых оригинальных отечественных лекарственных средств.The proposed method for the synthesis of semisynthetic derivatives of natural zeaxanthin makes it possible to obtain its esters with model acids (benzoic, phenylhycolic, 4-methylbenzoic) and drugs (nicotinic, salicylic, ibuprofen, ketoprofen). The resulting esters can be used in the future to develop new original domestic medicines.

Claims (1)

Синтез полусинтетических сложных эфиров ксантофилла в присутствии биокатализатора Amano Lipase PS в количестве 0,2 г, при эквимолярном соотношении спирт : кислота - 0,001:0,002, где в спиртосоставляющей сложных эфиров является природный ксантофилл - зеаксантин, в качестве кислот используют или бензойную, или n-метилбензойную кислоту, или фенилгликолиевую кислоту, или никотиновую кислоту, или салициловую кислоту, или ибупрофен, или кетопрофен, которые растворяют в 50 мл толуола, реакционную среду помещают в реактор, защищенный от воздействия света и воздуха, реакционную среду нагревают до 40°С, перемешивают в течение 6 часов при скорости вращения мешалки 30 об/мин, процесс синтеза контролируют методом ВЭЖХ, по окончании синтеза полученную смесь фильтруют, охлаждают до 20°С, промывают 95%-ным этиловым спиртом, высушивают 2 часа в вакууме (20-25 мм рт. ст.) при 40°С, полученные полусинтетические сложные эфиры хранят в ампулах темного стекла.Synthesis of semi-synthetic esters of xanthophyll in the presence of the biocatalyst Amano Lipase PS in an amount of 0.2 g, at an equimolar ratio of alcohol: acid - 0.001: 0.002, where natural xanthophyll - zeaxanthin is used in the alcohol component of the esters; either benzoic acid or n- methyl benzoic acid, or phenyl glycolic acid, or nicotinic acid, or salicylic acid, or ibuprofen, or ketoprofen, which are dissolved in 50 ml of toluene, the reaction medium is placed in a reactor, protected from light and air, the reaction medium is heated to 40 ° C, stirred for 6 hours at a stirrer speed of 30 rpm, the synthesis process is controlled by HPLC, at the end of the synthesis the resulting mixture is filtered, cooled to 20 ° C, washed with 95% ethyl alcohol, dried for 2 hours in a vacuum (20-25 mm Hg) at 40 ° C, the obtained semi-synthetic esters are stored in dark glass ampoules.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
US3673239A (en) * 1969-12-16 1972-06-27 Daicel Ltd Process for manufacturing 3,3,5-trimethylcyclohexyl mandelate
US7566795B2 (en) * 2006-10-06 2009-07-28 Eastman Chemical Company Preparation of retinyl esters

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3673239A (en) * 1969-12-16 1972-06-27 Daicel Ltd Process for manufacturing 3,3,5-trimethylcyclohexyl mandelate
US7566795B2 (en) * 2006-10-06 2009-07-28 Eastman Chemical Company Preparation of retinyl esters

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Печинский С.В. и др. Создание новых катализаторов для получения молекулярного водорода на основе производных акридина, иммобилизованных на углеродных материалах. Журнал общей химии, 2019, т. 89(5), с.721-725. *

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