RU2735661C1 - Method for combined production of 1-hydroxymethyl-substituted bicyclo[4_2_1]nona-2,4,7-trienes exhibiting antineoplastic activity - Google Patents

Method for combined production of 1-hydroxymethyl-substituted bicyclo[4_2_1]nona-2,4,7-trienes exhibiting antineoplastic activity Download PDF

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RU2735661C1
RU2735661C1 RU2019122540A RU2019122540A RU2735661C1 RU 2735661 C1 RU2735661 C1 RU 2735661C1 RU 2019122540 A RU2019122540 A RU 2019122540A RU 2019122540 A RU2019122540 A RU 2019122540A RU 2735661 C1 RU2735661 C1 RU 2735661C1
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nona
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Усеин Меметович Джемилев
Владимир Анатольевич Дьяконов
Гульнара Назифовна Кадикова
Лиля Усеиновна Джемилева
Рамиль Нурфаизович Насретдинов
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Федеральное государственное бюджетное научное учреждение Уфимский федеральный исследовательский центр Российской академии наук
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Abstract

FIELD: medicine; pharmaceuticals.
SUBSTANCE: invention relates to a method for combined production of 1-hydroxymethyl-substituted bicyclo[4.2.1]nona-2,4,7-trienes of general formula (1) and (2), where R=Bu, (CH2)3OH, (CH2)4OH, which consists in fact that 1,3,5-cycloheptatriene derivative used is 1,3,5-cycloheptatrienyl methanol, as a catalyst Co(acac)2(dppe)/Zn/ZnI2, reaction of 1,3,5-cycloheptatrienylmethanol (CGT) with terminal alkynes of general formula
Figure 00000011
(where R is specified above) is carried out at molar ratio alkyne: CGT: Co(acac)2(dppe) : Zn : ZnI2 = (1–1.5):1:(0.05–0.15):(0.15–0.45):(0.1–0.3), in ampoule at 20–80 °C, in 2,2,2-trifluoroethanol, for 20–48 hours.
Figure 00000012
EFFECT: technical result is obtaining novel compounds which can be used in medicine as biologically active substances possessing antitumour activity.
3 cl, 2 tbl, 9 ex

Description

Предлагаемое изобретение относится к области органической химии, конкретно, к способу совместного получения 1-гидроксиметил-замещенных бицикло[4.2.1]нона-2,4,7-триенов формулы (1) и (2):The present invention relates to the field of organic chemistry, in particular, to a method for the joint production of 1-hydroxymethyl-substituted bicyclo [4.2.1] nona-2,4,7-trienes of the formula (1) and (2):

Figure 00000001
Figure 00000001

Указанные соединения относятся к классу функционально-замещенных бицикло[4.2.1]нонатриенов, которые могут найти применение в качестве полупродуктов в синтезе современных медицинских препаратов, проявляющих противоопухолевую, противовирусную и другие виды активности (N.A. Petasis, М.А. Patane, Tetrahedron. 1992, 48, 5757; Z.-X. Yu, Y. Wang, Y. Wang. Chem. Asian J., 2010, 5, 1072). В свою очередь, бицикло[4.2.1]нонановый остов является ключевым структурным элементом важных терпеноидов и их метаболитов, таких как производные медитерранеолов А и В, лонгифолана, секо-лонгифолиндиола, обладающих выраженной противоопухолевой активностью (С. Francisco, В. Banaigs, R. Valls, L. Codomier. Tetrahedron Lett., 1985, 26(22), 2629; S.N. Suryawanshi, U.R. Nayak. Tetrahedron Lett., 1977, 18(30), 2619; C. Francisco, B. Banaigs, J. Teste, A. Cave. J. Org. Chem., 1986, 51 (7), 1115).These compounds belong to the class of functionally substituted bicyclo [4.2.1] nonatrienes, which can be used as intermediates in the synthesis of modern medicines exhibiting antitumor, antiviral and other types of activity (NA Petasis, MA Patane, Tetrahedron. 1992 , 48, 5757; Z.-X. Yu, Y. Wang, Y. Wang. Chem. Asian J., 2010, 5, 1072). In turn, the bicyclo [4.2.1] nonane backbone is a key structural element of important terpenoids and their metabolites, such as derivatives of mediterraneols A and B, longifolan, secolongifolindiol, which have a pronounced antitumor activity (C. Francisco, B. Banaigs, R Valls, L. Codomier, Tetrahedron Lett. 1985, 26 (22), 2629; SN Suryawanshi, UR Nayak. Tetrahedron Lett., 1977, 18 (30), 2619; C. Francisco, B. Banaigs, J. Teste , A. Cave J. Org. Chem. 1986, 51 (7), 1115).

Известен способ [Achard M., Tenaglia A., Buono G. First cobalt(I)-catalyzed [6+2] cycloadditions of cycloheptatriene with alkynes // Organic Lett., 2005, V. 7, №12, 2353] получения бицикло[4.2.1]нона-2,4,7-триенов (3) реакцией [6π+2π]-циклоприсоединения терминальных алкинов к 1,3,5-циклогептатриену в присутствии каталитической системы CoI2(dppe)/Zn/ZnI2 при температуре 40°С в 1,2-дихлорэтане за 20 часов по схеме:The known method [Achard M., Tenaglia A., Buono G. First cobalt (I) -catalyzed [6 + 2] cycloadditions of cycloheptatriene with alkynes // Organic Lett., 2005, V. 7, No. 12, 2353] obtaining bicyclo [4.2.1] nona-2,4,7-trienes (3) by the reaction of [6π + 2π] -cycloaddition of terminal alkynes to 1,3,5-cycloheptatriene in the presence of the CoI 2 (dppe) / Zn / ZnI 2 catalytic system at temperature 40 ° С in 1,2-dichloroethane for 20 hours according to the scheme:

Figure 00000002
Figure 00000002

Известным способом не могут быть получены 1-гидроксиметил-замещенные бицикло[4.2.1]нона-2,4,7-триены формулы (1) и (2).The known method cannot be obtained 1-hydroxymethyl-substituted bicyclo [4.2.1] nona-2,4,7-trienes of the formula (1) and (2).

Известен способ [V.A. D'yakonov, G.N. Kadikova, D.L Kolokoltsev, I.R. Ramazanov, U.M. Dzhemilev. Titanium-Catalyzed [6π+2π]-Cycloaddition of Alkynes and Allenes to 7-Substituted 1,3,5-Cycloheptatrienes // Eur. J. Org. Chem., 2015, 4464] получения замещенных бицикло[4.2.1]нона-2,4,7-триенов (4) реакцией [6π+2π]-циклоприсоединения Si-, N-содержащих алкинов к 7-алкил(аллил,фенил)-1,3,5-циклогептатриенам в присутствии каталитической системы Ti(acac)2Cl2-Et2AlCl при температуре 80°С в бензоле за 8 часов по схеме:The known method [VA D'yakonov, GN Kadikova, DL Kolokoltsev, IR Ramazanov, UM Dzhemilev. Titanium-Catalyzed [6π + 2π] -Cycloaddition of Alkynes and Allenes to 7-Substituted 1,3,5-Cycloheptatrienes // Eur. J. Org. Chem., 2015, 4464] for the preparation of substituted bicyclo [4.2.1] nona-2,4,7-trienes (4) by the reaction of [6π + 2π] cycloaddition of Si-, N-containing alkynes to 7-alkyl (allyl, phenyl ) -1,3,5-cycloheptatrienes in the presence of the catalytic system Ti (acac) 2 Cl 2 -Et 2 AlCl at a temperature of 80 ° C in benzene for 8 hours according to the scheme:

Figure 00000003
Figure 00000003

Известным способом не могут быть получены 1-гидроксиметил-замещенные бицикло[4.2.1]нона-2,4,7-триены (1) и (2).The known method cannot be obtained 1-hydroxymethyl-substituted bicyclo [4.2.1] nona-2,4,7-trienes (1) and (2).

Таким образом, в литературе отсутствуют сведения по синтезу 1-гидроксиметил-замещенных бицикло[4.2.1]нона-2,4,7-триенов формулы (1) и (2).Thus, there is no information in the literature on the synthesis of 1-hydroxymethyl-substituted bicyclo [4.2.1] nona-2,4,7-trienes of formulas (1) and (2).

Предлагается новый способ синтеза 1-гидроксиметил-замещенных бицикло[4.2.1]нона-2,4,7-триенов формулы (1) и (2).A new method for the synthesis of 1-hydroxymethyl-substituted bicyclo [4.2.1] nona-2,4,7-trienes of formulas (1) and (2) is proposed.

Сущность способа заключается во взаимодействии терминальных алкинов общей формулы (5) с 1,3,5-циклогептатриенилметанолом (ЦГТ) в присутствии каталитической системы Co(acac)2(dppe)/Zn/ZnI2, при мольном соотношении алкин : ЦГТ : Co(acac)2(dppe) : Zn : ZnI2=(1-1.5):1:(0.05-0.15):(0.15-0.45):(0.1-0.3), предпочтительно 1:1:0.1:0.3:0.2. Реакцию проводят в ампуле при 20-80°С. Время реакции 20-48 ч, выход целевого продукта 40-85%. В качестве растворителя необходимо использовать 2,2,2-трифторэтанол.The essence of the method lies in the interaction of terminal alkynes of general formula (5) with 1,3,5-cycloheptatrienylmethanol (CGT) in the presence of the Co (acac) 2 (dppe) / Zn / ZnI 2 catalytic system, at a molar ratio of alkyne: CGT: Co ( acac) 2 (dppe): Zn: ZnI 2 = (1-1.5): 1: (0.05-0.15) :( 0.15-0.45) :( 0.1-0.3), preferably 1: 1: 0.1: 0.3: 0.2. The reaction is carried out in an ampoule at 20-80 ° C. The reaction time is 20-48 hours, the yield of the target product is 40-85%. 2,2,2-trifluoroethanol must be used as a solvent.

Реакция протекает по схеме:The reaction proceeds according to the scheme:

Figure 00000004
Figure 00000004

Целевые продукты (1) и (2) образуются только лишь с участием терминальных алкинов, 1,3,5-циклогептатриенилметанола и каталитической системы Co(acac)2(dppe)/Zn/ZnI2. В присутствии других комплексов переходных металлов (например, Cp2ZrCl2, Cp2TiCl2, Zr(acac)4, Pd(acac)2, Ni(acac)2, Fe(acac)3) целевые продукты (1) и (2) не образуются.The target products (1) and (2) are formed only with the participation of terminal alkynes, 1,3,5-cycloheptatrienylmethanol, and the Co (acac) 2 (dppe) / Zn / ZnI 2 catalytic system. In the presence of other complexes of transition metals (for example, Cp 2 ZrCl 2 , Cp 2 TiCl 2 , Zr (acac) 4 , Pd (acac) 2 , Ni (acac) 2 , Fe (acac) 3 ), the target products (1) and ( 2) are not formed.

Проведение реакции в присутствии катализатора Co(acac)2(dppe) больше 0.1 ммоль на 1 ммоль 1,3,5-циклогептатриенилметанола не приводит к существенному увеличению выхода целевых продуктов (1) и (2). Использование в реакции катализатора Co(acac)2(dppe) менее 0.1 ммоль на 1 ммоль 1,3,5-циклогептатриенилметанола снижает выход аддуктов (1) и (2), что связано с уменьшением каталитически активных центров в реакционной массе. Опыты проводили при 20-80°С. При более высокой температуре (например, 100°С) происходит уменьшение выхода содимеров, вероятно, вследствие побочных процессов разложения и полимеризации. При меньшей температуре (например, 20°С) снижается скорость реакции.Carrying out the reaction in the presence of a Co (acac) 2 (dppe) catalyst greater than 0.1 mmol per 1 mmol of 1,3,5-cycloheptatrienylmethanol does not lead to a significant increase in the yield of the target products (1) and (2). The use of Co (acac) 2 (dppe) catalyst in the reaction of less than 0.1 mmol per 1 mmol of 1,3,5-cycloheptatrienylmethanol decreases the yield of adducts (1) and (2), which is associated with a decrease in catalytically active sites in the reaction mass. The experiments were carried out at 20-80 ° C. At a higher temperature (for example, 100 ° C), a decrease in the yield of codimers occurs, probably due to side processes of decomposition and polymerization. At lower temperatures (for example, 20 ° C), the reaction rate decreases.

Существенные отличия предлагаемого способа:Significant differences of the proposed method:

Предлагаемый способ базируется на использовании в качестве исходных реагентов 1,3,5-циклогептатриенилметанола и терминальных алкинов в присутствии каталитической системы Co(acac)2(dppe)/Zn/ZnI2. В известных способах:The proposed method is based on the use of 1,3,5-cycloheptatrienylmethanol and terminal alkynes as starting reagents in the presence of a Co (acac) 2 (dppe) / Zn / ZnI 2 catalytic system. In known ways:

1. аддукт (3) получен с использованием 1,3,5-циклогептатриена и терминальных алкинов в присутствии CoI2(dppe)/Zn/ZnI2;1. adduct (3) was obtained using 1,3,5-cycloheptatriene and terminal alkynes in the presence of CoI 2 (dppe) / Zn / ZnI 2 ;

2. аддукт (4) получен при использовании в качестве исходных соединений Si-, N-содержащих алкинов к 7-алкил(аллил,фенил)-1,3,5-циклогептатриенам под действием каталитической системы Ti(acac)2Cl2-Et2AlCl.2.adduct (4) was obtained using Si-, N-containing alkynes to 7-alkyl (allyl, phenyl) -1,3,5-cycloheptatrienes as starting compounds under the action of the catalytic system Ti (acac) 2 Cl 2 -Et 2 AlCl.

Предлагаемый способ обладает следующими преимуществами:The proposed method has the following advantages:

1. Способ позволяет получать с высокими выходами 1-гидроксиметил-замещенные бицикло[4.2.1]нона-2,4,7-триены (1) и (2), синтез которых в литературе не описан.1. The method allows to obtain in high yields 1-hydroxymethyl-substituted bicyclo [4.2.1] nona-2,4,7-trienes (1) and (2), the synthesis of which is not described in the literature.

Способ поясняется следующими примерами:The method is illustrated by the following examples:

ПРИМЕР 1. В стеклянную ампулу в атмосфере сухого аргона загружали 0.066 г (0.1 ммоль) Co(acac)2(dppe), и 0.020 г (0.3 ммоль) цинкового порошка в 1.5 мл 2,2,2-трифторэтанола. Смесь перемешивалась при комнатной температуре 2 минуты. Затем были добавлены 0.122 г (1 ммоль) 1,3,5-циклогептатриенилметанола, 0.082 г (1 ммоль) гексина-1, 1.5 мл 2,2,2-трифторэтанола и 0.064 г (0.2 ммоль) ZnI2. После нагревания при 60°С в течение 20 ч, ампулу вскрывали, содержимое отфильтровывали, легкие растворители удаляли под вакуумом, остаток хроматографировали на колонке SiO2 элюент (100% петролейный эфир). Получали (8-бутилбицикло[4.2.1]нона-2,4,7-триен-1-ил)метанол (1): и (7-бутилбицикло[4.2.1]нона-2,4,7-триен-1-ил)метанол (2) с общим выходом 82%.EXAMPLE 1. 0.066 g (0.1 mmol) Co (acac) 2 (dppe), and 0.020 g (0.3 mmol) zinc powder in 1.5 ml of 2,2,2-trifluoroethanol were loaded into a glass ampoule in an atmosphere of dry argon. The mixture was stirred at room temperature for 2 minutes. Then 0.122 g (1 mmol) of 1,3,5-cycloheptatrienylmethanol, 0.082 g (1 mmol) of hexin-1, 1.5 ml of 2,2,2-trifluoroethanol, and 0.064 g (0.2 mmol) of ZnI 2 were added. After heating at 60 ° C for 20 hours, the ampoule was opened, the contents were filtered, the solvents were removed under a light vacuum, the residue is chromatographed on SiO 2 eluting with (100% ether). Received (8-butylbicyclo [4.2.1] nona-2,4,7-trien-1-yl) methanol (1): and (7-butylbicyclo [4.2.1] nona-2,4,7-triene-1 -yl) methanol (2) in 82% overall yield.

Спектральные характеристики (8-бутилбицикло[4.2.1]нона-2,4,7-триен-1-ил)метанола (1):Spectral characteristics of (8-butylbicyclo [4.2.1] nona-2,4,7-trien-1-yl) methanol (1):

Спектр ЯМР 1Н (500 МГц, CDCl3, δ, м.д.): 6.24 (дд, J=10.9 Гц, J=7.4 Гц, 1H), 5.86-5.92 (м, 1Н), 5.77-5.86 (м, 2Н), 5.11 (с, 1H), 3.88 (д, J=10.7 Гц, 1H), 3.82 (д, J=10.6 Гц, 1H), 3.02 (тд, J=7.2 Гц, J=2.2 Гц, 1Н), 1.89-2.21 (м, 3Н), 1.20-1.52 (м, 5Н), 0.84-0.98 (м, 3Н). 13С ЯМР (125 MHz, CDCl3, δ, м.д.): 140.44, 140.20, 139.78, 124.36, 123.06, 119.81, 66.89, 55.71, 41.13, 33.61, 31.11, 26.00, 22.50, 13.96. 1 H NMR spectrum (500 MHz, CDCl 3 , δ, ppm): 6.24 (dd, J = 10.9 Hz, J = 7.4 Hz, 1H), 5.86-5.92 (m, 1H), 5.77-5.86 (m , 2H), 5.11 (s, 1H), 3.88 (d, J = 10.7 Hz, 1H), 3.82 (d, J = 10.6 Hz, 1H), 3.02 (td, J = 7.2 Hz, J = 2.2 Hz, 1H ), 1.89-2.21 (m, 3H), 1.20-1.52 (m, 5H), 0.84-0.98 (m, 3H). 13 С NMR (125 MHz, CDCl 3 , δ, ppm): 140.44, 140.20, 139.78, 124.36, 123.06, 119.81, 66.89, 55.71, 41.13, 33.61, 31.11, 26.00, 22.50, 13.96.

Спектральные характеристики (7-бутилбицикло[4.2.1]нона-2,4,7-триен-1-ил)метанола (2):Spectral characteristics of (7-butylbicyclo [4.2.1] nona-2,4,7-trien-1-yl) methanol (2):

Спектр ЯМР 1Н (500 МГц, CDCl3, δ, м.д.): 6.14-6.20 (м, 1Н), 5.97 (д, J=11.6 Гц, 1Н), 5.86-5.92 (м, 1H), 5.77-5.86 (м, 1Н), 4.89 (с, 1Н), 3.57-3.74 (м, 2Н), 3.23 (т, J=7.1 Гц, 1H), 1.89-2.21 (м, 3Н), 1.20-1.52 (м, 5Н), 0.84-0.98 (м, 3Н). 13С ЯМР (125 MHz, CDCl3, δ, м.д.): 141.91, 140.27, 139.48, 124.11, 123.31, 120.08, 68.66, 54.16, 46.29, 33.68, 29.96, 27.98, 22.50, 13.96. 1 H NMR spectrum (500 MHz, CDCl 3 , δ, ppm): 6.14-6.20 (m, 1H), 5.97 (d, J = 11.6 Hz, 1H), 5.86-5.92 (m, 1H), 5.77 -5.86 (m, 1H), 4.89 (s, 1H), 3.57-3.74 (m, 2H), 3.23 (t, J = 7.1 Hz, 1H), 1.89-2.21 (m, 3H), 1.20-1.52 (m , 5H), 0.84-0.98 (m, 3H). 13 С NMR (125 MHz, CDCl 3 , δ, ppm): 141.91, 140.27, 139.48, 124.11, 123.31, 120.08, 68.66, 54.16, 46.29, 33.68, 29.96, 27.98, 22.50, 13.96.

Другие примеры, подтверждающие способ, приведены в таблице 1.Other examples confirming the method are shown in Table 1.

Figure 00000005
Figure 00000005

ПРИМЕР 2. Оценка противоопухолевой активности заявленных соединений общей формулы (1) и (2) осуществлена методом проточной цитофлуориметрии, по отношению к четырем клеточным линиям: Jurkat, K562, U937 и HL60.EXAMPLE 2. Evaluation of the antitumor activity of the claimed compounds of general formula (1) and (2) was carried out by flow cytometry in relation to four cell lines: Jurkat, K562, U937 and HL60.

Figure 00000006
Figure 00000006

Значения ингибирующей концентрации CC50, полученные в результате экспозиции исследуемых соединений (1) и (2) на упомянутых выше клеточных линиях с последующим окрашиванием клеток красителем 7AAD варьируются в зависимости от клеточной культуры в интервале 287.19±4.51-757.34±6.24 μM/L.Inhibitory concentration values of CC 50 resulting from the exposure of the test compounds (1) and (2) at the above-mentioned cell lines, followed by 7AAD staining of cells vary according to the cell culture in the range of 287.19 ± 4.51-757.34 ± 6.24 μM / L .

Claims (5)

1. 1-гидроксиметил-замещенные бицикло[4.2.1]нона-2,4,7-триены общей формулы (1) и (2):1. 1-hydroxymethyl-substituted bicyclo [4.2.1] nona-2,4,7-trienes of general formula (1) and (2):
Figure 00000007
Figure 00000007
 2. Способ совместного получения 1-гидроксиметил-замещенных бицикло[4.2.1]нона-2,4,7-триенов общей формулы (1) и (2) по п.1: 2. A method of joint preparation of 1-hydroxymethyl-substituted bicyclo [4.2.1] nona-2,4,7-trienes of general formula (1) and (2) according to claim 1: каталитическим взаимодействием производных 1,3,5-циклогептатриена с терминальными алкинами, отличающийся тем, что в качестве производного 1,3,5-циклогептатриена используют 1,3,5-циклогептатриенилметанол, в качестве катализатора Co(acac)2(dppe)/Zn/ZnI2, реакцию 1,3,5-циклогептатриенилметанола (ЦГТ) с терминальными алкинами общей формулы
Figure 00000008
(где R = Вu, (CH2)3OH, (CH2)4OH) проводят при мольном соотношении алкин : ЦГТ : Co(acac)2(dppe) : Zn : ZnI2 = (1-1.5):1:(0.05-0.15):(0.15-0.45):(0.1-0.3), в ампуле при 20-80°С, в 2,2,2-трифторэтаноле, в течение 20-48 ч.catalytic interaction of 1,3,5-cycloheptatriene derivatives with terminal alkynes, characterized in that 1,3,5-cycloheptatrienylmethanol is used as 1,3,5-cycloheptatriene derivative, Co (acac) 2 (dppe) / Zn as catalyst / ZnI 2 , the reaction of 1,3,5-cycloheptatrienylmethanol (CHT) with terminal alkynes of the general formula
Figure 00000008
(where R = Bu, (CH 2 ) 3 OH, (CH 2 ) 4 OH) is carried out at a molar ratio of alkyne: CHT: Co (acac) 2 (dppe): Zn: ZnI 2 = (1-1.5): 1: (0.05-0.15) :( 0.15-0.45) :( 0.1-0.3), in an ampoule at 20-80 ° C, in 2,2,2-trifluoroethanol, for 20-48 hours. 3. Применение 1-гидроксиметил-замещенных бицикло[4.2.1]нона-2,4,7-триенов (1) и (2) по п.1 в качестве средств с противоопухолевой активностью.3. The use of 1-hydroxymethyl-substituted bicyclo [4.2.1] nona-2,4,7-trienes (1) and (2) according to claim 1 as agents with antitumor activity.
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