阅读说明：本技术 一种异喹啉类化合物的制备方法 (Preparation method of isoquinoline compounds ) 是由 黄志斌 史达清 赵应声 戴晨阳 于 2020-07-10 设计创作，主要内容包括：本发明公开了一种异喹啉类化合物的制备方法,以草酰胺保护的苄胺和醋酸烯丙酯为原料,通过C-H键官能团化和水解的串联反应,两步“一锅”合成得到一系列异喹啉类化合物,其所用的原料简单、易得,反应条件温和、后处理简单。(The invention discloses a preparation method of isoquinoline compounds, which takes benzylamine and allyl acetate protected by oxamide as raw materials, and synthesizes a series of isoquinoline compounds by two steps of one pot through a series reaction of C-H bond functionalization and hydrolysis.)

1. A preparation method of isoquinoline compounds is characterized by comprising the following steps: using benzylamine (formula I) protected by oxamide and allyl acetate (formula II) as raw materials, palladium acetate as a catalyst, silver carbonate as an oxidant, any one of dibutyl phosphate, diphenyl phosphate, diethyl phosphate or dibenzyl phosphate as an additive, any one of 1, 2-dichloroethane, 1, 4-dioxane, chlorobenzene, toluene, ethanol, tert-butanol or tert-amyl alcohol as a solvent, carrying out C-H functional group reaction, then carrying out hydrolysis by using sodium hydroxide to synthesize an isoquinoline derivative (formula III),

the reaction formula is shown as (formula IV):

2. the method for preparing isoquinoline compounds according to claim 1, wherein: the benzylamine is selected from any one of benzylamine, o-methylbenzylamine, o-methoxybenzylamine, o-chlorobenzylamine, o-bromobenzylamine, o-ethoxybenzylamine, m-methylbenzylamine, m-methoxybenzylamine, p-methylbenzylamine, p-methoxybenzylamine, p-isopropylbenzylamine, p-tert-butylbenzylamine, p-ethoxybenzylamine, 2, 3-dimethylbenzylamine, 2, 5-dimethylbenzylamine or 3, 4-dimethylbenzylamine.

3. The method for preparing isoquinoline compounds according to claim 1, wherein: the mol ratio of the oxamide-protected benzylamine to the allyl acetate is 1:1-1:2, the dosage of the catalyst is 5 mol% of the dosage of the oxamide-protected benzylamine, and the mol ratio of the oxidant to the oxamide-protected benzylamine is 2: 1.

4. The method for preparing isoquinoline compounds according to claim 1, wherein: the molar ratio of the additive to the oxamide-protected benzylamine was 1.5: 1.

5. The method for preparing isoquinoline compounds according to claim 1, wherein: the amount of solvent required per mmol of starting material was 3 mL.

6. The method for preparing isoquinoline compounds according to claim 1, wherein: the amount of sodium hydroxide used was 25 equivalents.

7. The method for preparing isoquinoline compounds according to claim 1, wherein: the reaction time of the C-H functionalization reaction is 36 hours, and the reaction temperature is 120 ℃.

8. The method for preparing isoquinoline compounds according to claim 1, wherein: the reaction time of the hydrolysis was 24 hours, and the reaction temperature was 80 ℃.

9. The method for preparing isoquinoline compounds according to claim 1, wherein: the method comprises the following steps of taking oxamide-protected benzylamine and allyl acetate as raw materials, wherein the molar ratio of the oxamide-protected benzylamine to the allyl acetate is 1:2, taking 5 mol% of palladium acetate as a catalyst, 2 equivalents of silver carbonate as an oxidant, 1.5 equivalents of dibutyl phosphate as an additive, 1, 2-dichloroethane as a solvent, carrying out C-H functional group reaction at 120 ℃ for 36 hours, and then carrying out hydrolysis with sodium hydroxide at 80 ℃ for 24 hours to synthesize the isoquinoline derivative.

Technical Field

The invention belongs to the field of organic synthesis, and relates to a preparation method of isoquinoline compounds.

Background

Isoquinoline, a kind of heterocyclic compound, is widely present in natural products, bioactive molecules and drugs (Joule, j.a.; Mills, k.heterocyclic Chemistry. john Wiley & Sons,2008.), and has also been widely used in recent years in the fields of organic functional molecules and optoelectronic materials, etc. (Eicher, t.; hauttmann, s.; specificher, a.the Chemistry of Heterocycles: Structures, interactions, Synthesis, and applications,3rd.john Wiley & Sons, 2013.). The isoquinoline backbone is widely present in alkaloids, the largest of the known alkaloids, such as papaverine, liriodenine, morphinans, protoberberine and aporphine, which are also derived from isoquinoline (Chrzanowska, m.; rozwawska, m.d. chem.rev.,2004,104,3341.Delcey, m.c.; criisy, a.; Carrez, d.; hue, c.; Chiaroni, a.; ducreot, p.; Bisagni, e.; Jin, l.; lecercq, g.bioorg. med. chem.,2000,8, 2629.). Isoquinoline derivatives exhibit excellent biological activity, e.g., potassium channel inhibitors (Trotter, B.W.; Nanda, K.K.; Kett, N.R.; Dinsmore, C.J.J.Med.Chem, 2006,49,6954.), anti-cancer activity (Zaman, K.; Rahima, F.; Tahab, M.; Wadodec, A.Shah, S.A.A.; Gollapallif, M.; Ullahg, F.; Ahmedh, A.bioorg.Chem, 2019,89,102999.Khadka, D.B.; Wo, H.; Yang, S.H.; ZHao, C.; Jin, Y.; Lew.N.; Keon Y.; Y., Cho W.J.r.2015, K.K.; U.K. Ka U.A.K.; Wal U.K., U.A.K.; Wal gold, U.2015 U.A.K.; U.A.K. K.; gold pacif U.A.K., Palal K., Ka 2015 K., Ka, U.K., Ka K., Ka, K., Ka K. Ka, K. Ka K. Ka, K. Ka K. Ka, K. Ka, K. Ka, K. Ka, K. Ka, K. Ka, K. Ka, K. Ka K. Ka, K., h; van Galen, p.j.m.; noach, a.b.j.; van Dinther, t.g.; hood, a.m.m.; jenneboer, a.j.s.m.; van Boeckel, c.a.a.bioorg.med.chem.lett.,1999,9,685.), antimalarial (pari, m.k.; panda, g.; srivastava, k.; puri, s.k.bioorg.med.chem.lett.,2008,18,776.), a topoisomerase I catalytic inhibitor (khaddka, d.b.; park, s.; jin, y.; han, J.; kwon, y.; cho, w.j.eur.j.med.chem.,2018,143,200). Isoquinoline is also widely used as a ligand due to its excellent coordination capacity (Chen, c.; Li, x.d.; Schreiber, s.l.j.am.chem.soc.,2003,125,10174.Chen, z.f.; Liu, y.c.; Liu, l.m.; Wang, h.s.; Qin, s.h.; Wang, b.l.; Bian, h.d.; Yang, b.; Fun, h.k.; Liu, h.g.; Liang, h.; orig, c.dalton trans.,2009,262.), and it can also be used to prepare OLEDs (Su, y.j.; Huang, h.l.; Li, c.l.; Chen, c.h.; Tao, y.t.; ch.p.t.; datu, s.884, matr.; s.e., ador., s.d.;).

The traditional synthetic methods are mostly mild in reaction conditions, generally need substrates with higher activity for reaction, and synthesized heterocycles can only bring certain specific substituents at a few sites. Therefore, the search for a simple and convenient method for synthesizing isoquinoline becomes the focus of attention.

C-H bond functionalization is an important research content in organic synthesis, and is a method for constructing various chemical bonds such as C-C, C-O, C-N through C-H bonds. The advent of transition metal catalysts has greatly facilitated the study of C-H bond functionalization. In recent years, many important research advances have been made using transition metal catalyzed C — H bond activation reactions (Ackerman, l.chem.rev.,2011,111,1315.He, j.; Wasa, m.; Chan, k.s.l.; Shao, q.; Yu, j.q.chem.rev.,2017,117,8754.). With the continuous and deep research on C-H bond functionalization, more and more organic synthesizers use C-H bond functionalization reaction to construct isoquinoline frameworks, and some new methods for synthesizing isoquinoline derivatives are developed.

Disclosure of Invention

The invention aims to provide an isoquinoline derivative which is synthesized by using benzylamine and allyl acetate protected by oxamide as raw materials, utilizing a palladium acetate catalyzed C-H bond functionalization reaction and a hydrolysis tandem reaction and adopting a two-step one-pot method based on wide biological and pharmacological activities of the isoquinoline derivative.

The technical scheme of the invention is as follows:

a preparation method of isoquinoline compounds is characterized by comprising the following steps: using benzylamine (formula I) protected by oxamide and allyl acetate (formula II) as raw materials, palladium acetate as a catalyst, silver carbonate as an oxidant, any one of dibutyl phosphate, diphenyl phosphate, diethyl phosphate or dibenzyl phosphate as an additive, any one of 1, 2-dichloroethane, 1, 4-dioxane, chlorobenzene, toluene, ethanol, tert-butanol or tert-amyl alcohol as a solvent, carrying out C-H functional group reaction, then carrying out hydrolysis by using sodium hydroxide to synthesize an isoquinoline derivative (formula III),

the reaction formula is shown as (formula IV):

further, the benzylamine is selected from any one of benzylamine, o-methylbenzylamine, o-methoxybenzylamine, o-chlorobenzylamine, o-bromobenzylamine, o-ethoxybenzylamine, m-methylbenzylamine, m-methoxybenzylamine, p-methylbenzylamine, p-methoxybenzylamine, p-cymylbenzylamine, p-tert-butylbenzylamine, p-ethoxybenzylamine, 2, 3-dimethylbenzylamine, 2, 5-dimethylbenzylamine, or 3, 4-dimethylbenzylamine.

Further, the molar ratio of the oxamide-protected benzylamine to allyl acetate is 1:1-1:2, the amount of the catalyst is 5 mol% of the amount of the oxamide-protected benzylamine, and the molar ratio of the oxidant to the oxamide-protected benzylamine is 2: 1.

Further, the molar ratio of the additive to the oxamide-protected benzylamine is 1.5: 1.

Further, the amount of the solvent required per mmol of the raw material was 3 mL.

Further, the amount of the sodium hydroxide is 25 equivalents.

Further, the reaction time of the C-H functionalization reaction is 36 hours, and the reaction temperature is 120 ℃.

Further, the reaction time of the hydrolysis is 24 hours, and the reaction temperature is 80 ℃.

Further, oxamide-protected benzylamine and allyl acetate are used as raw materials, the molar ratio of the oxamide-protected benzylamine to the allyl acetate is 1:2, 5 mol% palladium acetate is used as a catalyst, 2 equivalents of silver carbonate is used as an oxidant, 1.5 equivalents of dibutyl phosphate is used as an additive, 1, 2-dichloroethane is used as a solvent, a C-H functionalization reaction is carried out at the temperature of 120 ℃ for 36 hours, and then hydrolysis is carried out with sodium hydroxide at the temperature of 80 ℃ for 24 hours to synthesize the isoquinoline derivative.

The invention provides a preparation method of isoquinoline compounds, which takes benzylamine and allyl acetate protected by oxamide as raw materials, and obtains a series of isoquinoline compounds through two-step one-pot synthesis by a series of reactions of C-H bond functionalization and hydrolysis, and has the advantages that: the used raw materials are simple and easy to obtain, the reaction condition is mild, and the post-treatment is simple.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in detail below. The invention is not limited to the embodiments listed but also comprises any other known variations within the scope of the invention as claimed.

Reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic may be included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.