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CN114133389B - Process for preparing isoindolin-1-one fused rings and analogues thereof - Google Patents

Process for preparing isoindolin-1-one fused rings and analogues thereof Download PDF

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CN114133389B
CN114133389B CN202111516401.9A CN202111516401A CN114133389B CN 114133389 B CN114133389 B CN 114133389B CN 202111516401 A CN202111516401 A CN 202111516401A CN 114133389 B CN114133389 B CN 114133389B
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CN114133389A (en
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华瑞茂
汤宝鑫
粟骥
王恺之
欧阳赟
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Hefei Taili Zhulin New Materials Co.,Ltd.
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a method for preparing isoindoline-1-ketone ring derivatives shown in a formula I.The method uses dihalogenated benzamide compounds and terminal alkyne as substrates, and reacts in DMSO under the condition that palladium containing phosphine ligands and cuprous iodide are used as catalysts to obtain the isoindoline-1-ketone ring-fused derivative shown in the structural general formula I.

Description

Method for preparing isoindoline-1-keto-ring and analogues thereof
Technical Field
The invention belongs to the field of catalytic synthesis of fine chemical products, and relates to a method for preparing isoindoline-1-keto-cyclic derivatives.
Background
Isoindoline-1-ketone compounds are heterocyclic molecules widely existing in nature, often show specific physiological and biological activities, and are widely applied to the fields of medicine, dye and the like. For example, some isoindolin-1-ones can act as potential antagonists of hNK1 receptors in the central nervous system (Dinnell, K.; chicchi, G.G.; et al, bioorg. Med. Chem. Lett.2001,11,1237); chlorthalidone is a hypotensor (Davis, B.R.; cutler, J.A.; et al. Ann. Intern. Med.2002,137, 313); fumaridine is an alkaloid extracted from plants of the family Violaceae (Yao, T.L.; guo, Z.; et al.J.org.chem.2018,83,13370).
Many isoindolin-1-one fused ring structural compounds have received much attention due to their specific properties. For example, some 6H-isoindolo [2,1-a]Indole-6-ones as melatonin MT 3 Potential ligands (Boussard, M.F.; truche, S.; et al. Eur.J. Med. Chem.2006,41,306); has anticancer activity (Nallapatiti, S.B.; adepu, R.; et al.RSC.adv.2015,5,88686); batrachylin can be used as an inhibitor of topoisomerase II (Guillaumel, J.; leontce, S.; et al. Eur. J. Med. Chem.2006,41,379); in addition, many natural products also contain isoindolin-1-one fused ring structures, for example lenoxamine and chilenine are alkaloids isolated from Berberis plant, chilli (Valencia, E.; freyer, A.; et al. Tetrahedron Lett.2006,41,379);
the specific physiological activity of isoindoline-1-one fused ring structure attracts attention of many scholars, and a plurality of literatures report a synthesis method of the isoindoline-1-one fused ring structure, but only one synthesis method of the isoindoline-1-one fused ring structure is often reported in the literatures, and the literature that a plurality of isoindoline-1-one fused ring skeleton structures are synthesized by one synthesis method is less. There are reports of a two-step process for the synthesis of three isoindolin-1-one fused ring structures (Garcia, A.; rodriguez, D.; et al tetrahedron Lett.2001,42,1903), which uses a condensation reaction between an o-bromoaniline compound and acetaldehyde, followed by a reaction with o-iodobenzoyl chloride, and finally an intramolecular Heck reaction, and which has high substrate requirements, requires bromine as the halogen atom in the ortho position of aniline, iodine as the halogen atom in the ortho position of benzoyl chloride, and requires the addition of 20mol% Pd catalyst. There are problems in synthesizing three isoindoline-1-one fused ring structures (Kim, G.; kim, J.H.; et al tetrahedron Lett.2003,44,8207) by using o-ester group or o-carboxyacetophenone through condensation and intramolecular Heck cyclization reactions, which is also a two-step synthesis and requires the use of 10mol% Pd catalyst. In addition, a method for synthesizing three isoindoline-1-ketone fused ring structures through electro-reduction cyclization is reported in the literature (Kise, N.; isemoto, S.; et al, J. Org. Chem.2011,76,9856), the method is also synthesized through a two-step method, the structure of raw materials is complex, and a special instrument is required for the synthesis.
Although there are many reports on methods for synthesizing isoindolin-1-one fused ring structures, one method is less documented for synthesizing a variety of isoindolin-1-one fused ring structures and often requires a two-step synthesis. Efficient, one-pot synthesis of a variety of isoindolin-1-one fused ring structures is a significant effort. Alkyne is a commonly used synthon in organic synthesis, and has high unsaturation, high atom economy and high reaction activity, so that alkyne is a very important cyclization substrate in heterocyclic synthesis. The one-pot tandem reaction is a common synthetic strategy in heterocyclic synthesis, can form a plurality of chemical bonds at one time, and has high step economy. The method is significant work by carrying out inverse synthesis analysis on the isoindoline-1-ketone parallel-ring structure and designing a synthetic route which participates in alkyne and is based on a series reaction.
Disclosure of Invention
The invention aims to provide a method for preparing isoindoline-1-ketone ring derivatives.
The invention provides a preparation method of isoindoline-1-ketone ring derivative (namely compound shown in formula I), which comprises the following steps: reacting dihalogenated benzamide shown in a formula II with alkyne shown in a formula III in an inert atmosphere in the presence of a catalyst and alkali to obtain a compound shown in a formula I after the reaction is finished;
Figure BDA0003403561660000021
in the formula I, the formula II and the formula III, R 1 And R 2 Each independently selected from hydrogen, alkyl, alkoxy, halogen, acyl or nitro, preferably an electron withdrawing group such as acyl, nitro, halogen; r 3 Selected from aryl, heteroaryl, hydrogen, trimethylsilyl, preferably aryl and trimethylsilyl; n is 0,1,2.
The alkyl group may be C 1 ～C 6 A linear or branched alkyl group;
the alkoxy group may be C 1 ～C 6 A linear or branched alkoxy group;
the halogen can be fluorine, chlorine, bromine or iodine;
the acyl group may be C 1 ～C 6 Saturated or unsaturated acyl group of (a);
the aryl group may be C 6 ～C 12 Aryl, such as phenyl, substituted phenyl (e.g., p-methoxyphenyl, p-trifluoromethylphenyl), naphthyl;
the heteroaryl group can be a thiaheteroaryl group, an azaaryl group, such as thienyl, pyridyl.
The catalyst consists of cuprous iodide and a palladium catalyst containing a phosphine ligand; or cuprous iodide, a palladium catalyst and a phosphine ligand;
the palladium catalyst containing a phosphine ligand is selected from at least one of the following: pd (PPh) 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd(dppf) 2 Cl 2 (ii) a The palladium catalyst is selected from at least one of the following: pd (OAc) 2 、PdCl 2 (ii) a The phosphine ligand is selected from any one of the following: triphenylphosphine, dppf, preferably Pd (PPh) 3 ) 2 Cl 2 。
The base is potassium carbonate, triethylamine or DBU, preferably potassium carbonate.
The molar dosage of the palladium catalyst containing the phosphine ligand or the palladium catalyst is 1.0-5.0%, preferably 2.5% of that of the dihalobenzamide compound shown in the formula II based on the molar dosage of Pd.
The feeding molar amount of the phosphine ligand is 100-300%, preferably 200% of the palladium catalyst.
The feeding molar amount of the cuprous iodide is 1.0-10.0%, preferably 5.0% of the dihalogenated benzamide compound shown in the formula II.
The molar amount of the base to be charged is 1 to 3 equivalents, preferably 2 equivalents, to the dihalobenzamide compound represented by the formula II.
The reaction is carried out in a solvent; the solvent is DMF, DMSO or NMP (N-methylpyrrolidone), DMSO being preferred.
The reaction conditions of the reaction are as follows: the reaction temperature is 100-140 ℃, preferably 120 ℃; the reaction time is 12 to 36 hours, preferably 24 hours. The reaction time varies depending on the reactants of formula II. The completion of the reaction can be monitored by thin layer chromatography or gas chromatography.
After the reaction is finished, the reaction system can be separated and purified according to a conventional method, and the preferable separation mode is as follows: the stock solution after the reaction was transferred to a separatory funnel, 25mL of ethyl acetate was added to wash the reaction tube during the transfer to reduce the loss, and 25mL of saturated saline was added to the separatory funnel and extracted three times, and each organic phase was 25mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate and filtered; adding a certain amount of 100-200 meshes of silica gel, and removing the solvent by vacuum concentration to obtain the product-containing silica gel; silica gel of 300-400 meshes and petroleum ether containing triethylamine are used for loading into a column, and a dry method is used for loading into the column, wherein the volume fraction of the triethylamine is 0.1%; eluting with mixed solvent of petroleum ether and ethyl acetate, wherein the ratio of petroleum ether to ethyl acetate is different according to the polarity of reactants and products, and the volume fraction of ethyl acetate is generally 10-30% by estimating through a result of thin layer chromatography; the solution containing the reaction product I was collected, concentrated under reduced pressure to remove the solvent and dried under vacuum, weighed and the yield was calculated. For solid products, higher purity can be achieved by recrystallization, which is typically: adding a certain amount of dichloromethane into a sample, completely dissolving, concentrating under reduced pressure on a rotary evaporator, adding a poor solvent n-hexane into the mixture after a small amount of solid appears, and slowly volatilizing to obtain the product, namely the single crystal.
The method for synthesizing the isoindoline-1-ketone ring-fused derivative has the following characteristics: (1) economical. The synthesis of reaction raw materials is very simple, the solvent used in the reaction is very cheap and easy to obtain, the used catalyst is a common catalyst, the price is not expensive, the required addition amount is very small, and the product obtained by the reaction is a heterocyclic compound with high added value. And (2) convenience and rapidness are realized. The experimental operation is simple, the final product can be obtained in one step of reaction, the post-treatment only needs extraction and column chromatography separation, and the separation process is very simple because the reaction is a single product. And (3) universal adaptation. The reaction is applicable to various substrates, including various aryl, heteroaryl, electron donating group or electron withdrawing group substrates, so that the system can obtain the isoindoline-1-ketone ring compound with diversified substituent groups.
Drawings
FIG. 1 is the NMR spectrum of the objective product obtained in example 1.
FIG. 2 is the NMR spectrum of the objective product obtained in example 1.
FIG. 3 is the NMR spectrum of the objective product obtained in example 2.
FIG. 4 is the NMR spectrum of the objective product obtained in example 2.
FIG. 5 is the NMR spectrum of the objective product obtained in example 3.
FIG. 6 is the NMR spectrum of the objective product obtained in example 3.
FIG. 7 is the NMR spectrum of the objective product obtained in example 4.
FIG. 8 is the NMR carbon spectrum of the objective product obtained in example 4.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The materials are commercially available from the open literature unless otherwise specified.
A method of making a structure according to formula II: a100 mL round-bottomed flask was charged with 50mL of methylene chloride, 0.5mL of N, N-dimethylformamide, a magnetic stirrer, and 1.523g of oxalyl chloride (10 mmol), and after stirring for 5 minutes, 10mmol of an o-bromobenzoic acid compound was added and the mixture was stirred until no bubble appeared in the solution. The mixture was concentrated under reduced pressure until the solvent was drained, 50mL of ethyl acetate, 1.0119g of triethylamine (10 mmol) and 10mmol of an amine compound were added, and the mixture was stirred for 6 hours. And after the reaction is finished, transferring the mixture to a separating funnel, adding 50mL of saturated saline solution and 50mL of ethyl acetate twice, extracting for three times, combining organic phases, and concentrating under reduced pressure until the solvent is drained to obtain a solid with the structure of the formula II.
Example 1 Synthesis of 11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R 1 Is hydrogen, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 0)
0.3550g 2-bromo-N- (2-bromophenyl) benzamide (1 mmol), 0.1226g phenylacetylene (1.2 mmol) and 0.0175g Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL lock containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline solution and 25mL of ethyl acetate were added three times, and after extraction three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained off, and then the sample was loaded by a dry method, and eluted with petroleum ether-ethyl acetate (1, v/v)Column separation is carried out on the agent to obtain 0.2483g of yellow solid and a target product 11-phenyl-6H-isoindolo [2,1-a]The isolated yield of indol-6-one is 84%. FIG. 1 and FIG. 2 show the NMR spectrum and the carbon spectrum of the product prepared in this example, respectively, and it can be seen that the compound has a correct structure.
Example 2 Synthesis of 12-phenylisoindolo [2,1-b]Isoquinolin-7 (5H) -ones (in formula I, R) 1 Is hydrogen, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 1)
0.3690g of 2-bromo-N- (2-bromophenylmethyl) benzamide (1 mmol), 0.1226g of phenylacetylene (1.2 mmol) and 0.0175g of Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL stopcock containing a magnetic stirrer, 2.0mL DMSO was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added for three times, and after extraction for three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.2635g of a yellow solid and 12-phenylisoindolo [2,1-b]The isolated yield of isoquinolin-7 (5H) -one was 85%. FIG. 3 and FIG. 4 are the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Example 3 Synthesis of 13-phenyl-7,8-dihydro-5H-benzo [4,5]Azacyclo [2,1-a]Isoindol-5-ones (in formula I, R) 1 Is hydrogen, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 2)
0.3831g of 2-bromo-N- (2-bromophenylethyl) benzamide (1 mmol), 0.1226g of phenylacetylene (1.2 mmol) and 0.0175g of Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL stopcock containing a magnetic stirrer, 2.0mL DMSO was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, and 25mL of saturated saline solution and III were addedAfter 25mL of ethyl acetate are extracted for three times, organic phases are combined, silica gel is added, the mixture is concentrated under reduced pressure until the solvent is drained, the mixture is loaded by a dry method, and petroleum ether-ethyl acetate (1, 5, v/v) is used as an eluent for column separation to obtain 0.1676g of white solid and a target product 13-phenyl-7,8-dihydro-5H-benzo [4,5]Azacyclo [2,1-a]The isolated yield of isoindol-5-one was 52%. FIGS. 5 and 6 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Example 4 Synthesis of 12- (thien-2-yl) isoindolo [2,1-b]Isoquinolin-7 (5H) -one (in formula I, R) 1 Is hydrogen, R 2 Is hydrogen, R 3 Is thienyl, X is bromo, n is 1)
0.3690g of 2-bromo-N- (2-bromophenylmethyl) benzamide (1 mmol), 0.1298g of 2-ethynylthiophene (1.2 mmol) and 0.0175g of Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL lock containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added three times, and after extraction three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.2142g of a yellow solid, and the target product 12- (thiophen-2-yl) isoindolo [2,1-b]The isolated yield of isoquinolin-7 (5H) -one was 68%. FIGS. 7 and 8 show the NMR spectrum and the carbon spectrum of the product obtained in this example, respectively, and it can be seen that the compound has a correct structure.
Example 5 Synthesis of 13- (4-methoxyphenyl) -7,8-dihydro-5H-benzo [4,5]Azacyclo [2,1-a]Isoindol-5-ones (in formula I, R) 1 Is hydrogen, R 2 Is hydrogen, R 3 Is p-methoxyphenyl, X is bromine, n is 2)
0.3831g of 2-bromo-N- (2-bromophenylethyl) benzamide (1 mmol), 0.1586g of p-methoxyphenylacetylene (1.2 mmol) and 0.0175g of Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g iodinationCuprous (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) were added to a 25mL stopcock containing a magnetic stirrer, 2.0mL DMSO; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added three times, and after extraction three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 4, v/v) as an eluent to obtain 0.1700g of a white solid, and 13- (4-methoxyphenyl) -7,8-dihydro-5H-benzo [4,5]Azacyclo [2,1-a]The isolated yield of isoindol-5-one was 48%.
Example 6 Synthesis of 13- (4-trifluoromethylphenyl) -7,8-dihydro-5H-benzo [4,5]Azacyclo [2,1-a]Isoindol-5-ones (in formula I, R) 1 Is hydrogen, R 2 Is hydrogen, R 3 Is p-trifluoromethylphenyl, X is bromine, n is 2)
0.3831g of 2-bromo-N- (2-bromophenylethyl) benzamide (1 mmol), 0.2042g of p-trifluoromethylphenylacetylene (1.2 mmol) and 0.0175g of Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL lock containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added three times, and after extraction three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.2552g of a white solid, and 13- (4-trifluoromethylphenyl) -7,8-dihydro-5H-benzo [4,5]Azacyclo [2,1-a]The isolated yield of isoindol-5-one was 65%.
Example 7 Synthesis of 2-methyl-11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R 1 Is hydrogen, R 2 Is methyl, R 3 Is phenyl, X is bromine, n is 0)
0.3690g of 2-bromo-N- (2-bromo-4-methylphenyl) benzamide (1 mmol), 0.1226g of phenylacetylene (1.2 mmol) and 0.0175g of Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL lock containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuumizing, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline solution and 25mL of ethyl acetate were added three times, and after extraction three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.2286g of a yellow solid, the target product 2-methyl-11-phenyl-6H-isoindolo [2,1-a]The isolated yield of indol-6-one is 74%.
Example 8 Synthesis of 2-chloro-11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R 1 Is hydrogen, R 2 Is chlorine, R 3 Is phenyl, X is bromine, n is 0)
0.3895g 2-bromo-N- (2-bromo-4-chlorophenyl) benzamide (1 mmol), 0.1226g phenylacetylene (1.2 mmol), 0.0175g Pd (PPh) were weighed in this order 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL lock containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added for three times, and after extraction for three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.2782g of a yellow solid, and the target product, 2-chloro-11-phenyl-6H-isoindolo [2,1-a]The isolated yield of indol-6-one is 84%.
Example 9 Synthesis of 10-methoxy-12-phenylisoindolo [2,1-b]Isoquinolin-7 (5H) -ones (in formula I, R) 1 Is methoxy, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 1)
0.3991g 2-bromo-N- (2-bromophenyl methyl) -4-methoxybenzamide (1 mmol), 0.1226g phenylacetylene (1.2 mmol) and 0.0175g Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025mmol)、0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL stopcock containing a magnetic stirrer, 2.0mL DMSO was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added for three times, and after extraction for three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 4, v/v) as an eluent to obtain 0.2869g of a yellow solid, and the target product 10-methoxy-12-phenylisoindolo [2,1-b]The isolated yield of isoquinolin-7 (5H) -one was 72%.
Example 10 Synthesis of 10-fluoro-12-phenylisoindolo [2,1-b]Isoquinolin-7 (5H) -one (in formula I, R) 1 Is fluorine, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 1)
0.3870g of 2-bromo-N- (2-bromophenylmethyl) -4-fluorobenzamide (1 mmol), 0.1226g of phenylacetylene (1.2 mmol) and 0.0175g of Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL lock containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added for three times, and after extraction for three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and the mixture was subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.2873g of a yellow solid and the target product 10-fluoro-12-phenylisoindolo [2,1-b]The isolated yield of isoquinolin-7 (5H) -one was 88%.
Example 11 Synthesis of 11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R 1 Is hydrogen, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 0)
0.3550g 2-bromo-N- (2-bromophenyl) benzamide (1 mmol), 0.1226g phenylacetylene (1.2 mmol) and 0.0175g Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a solution containing magnetAdding 2.0mL of DMSO into a 25mL sealed tube of a sexual stirring rod; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. The mixture was stirred in an oil bath at 100 ℃ for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added for three times, after extraction three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and the mixture was subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.1502g of a yellow solid, and the target product was synthesized into 11-phenyl-6H-isoindolo [2,1-a]The isolated yield of indol-6-one is 51%.
Example 12 Synthesis of 11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R 1 Is hydrogen, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 0)
0.3550g 2-bromo-N- (2-bromophenyl) benzamide (1 mmol), 0.1226g phenylacetylene (1.2 mmol) and 0.0175g Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL lock containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuumizing, nitrogen gas is filled in, and the operation is repeated for 15 times. The mixture was stirred in an oil bath at 140 ℃ for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added for three times, after extraction three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and the mixture was subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.1184g of a yellow solid, and the target product was synthesized into 11-phenyl-6H-isoindolo [2,1-a]The isolated yield of indol-6-one is 40%.
Example 13 Synthesis of 11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R 1 Is hydrogen, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 0)
0.3550g of 2-bromo-N- (2-bromophenyl) benzamide (1 mmol), 0.1226g of phenylacetylene (1.2 mmol) and 0.0175g of Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL lock containing a magnetic stirrer, 2.0mL of DMF was added; after evacuation, fill nitrogen, repeat operation 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added for three times, after extraction three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and the mixture was subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.2103g of a yellow solid, and the target product was synthesized into 11-phenyl-6H-isoindolo [2,1-a]The isolated yield of indol-6-one is 71%.
Example 14 Synthesis of 11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R 1 Is hydrogen, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 0)
0.3550g 2-bromo-N- (2-bromophenyl) benzamide (1 mmol), 0.1226g phenylacetylene (1.2 mmol) and 0.0175g Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol), and 0.2764g potassium carbonate (2 eq.) in a 25mL stopcock containing a magnetic stirrer, 2.0mL of NMP was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added three times, and after extraction three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and the mixture was subjected to dry-method sampling, column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.1450g of a yellow solid, and the target product was synthesized to 11-phenyl-6H-isoindolo [2,1-a]The isolated yield of indol-6-one was 49%.
Example 15 Synthesis of 11-phenyl-6H-isoindolo [2,1-a]Indol-6-one (formula I, R) 1 Is hydrogen, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 0)
0.3550g 2-bromo-N- (2-bromophenyl) benzamide (1 mmol), 0.1226g phenylacetylene (1.2 mmol) and 0.0175g Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol), and 0.4567g DBU (3 eq.) in a 25mL stopcock containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel and 25mL of the mixture was addedAnd saline solution, ethyl acetate 25mL for three times, after extraction three times, the organic phases are combined, silica gel is added, the mixture is concentrated under reduced pressure until the solvent is drained, dry-method loading is carried out, and column separation is carried out by using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent, so as to obtain 0.0817g of yellow solid, and 11-phenyl-6H-isoindolo [2,1-a]The isolated yield of indol-6-one is 28%.
Example 16 Synthesis of 11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R 1 Is hydrogen, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 0)
0.3550g 2-bromo-N- (2-bromophenyl) benzamide (1 mmol), 0.1226g phenylacetylene (1.2 mmol) and 0.0175g Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol), 0.0095g cuprous iodide (0.05 mmol) and 0.3036g triethylamine (3 eq.) in a 25mL lock containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuum pumping, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction, the mixture was transferred to a separatory funnel, 25mL of saturated saline and 25mL of ethyl acetate were added for three times, after extraction three times, the organic phases were combined, silica gel was added, and the mixture was concentrated under reduced pressure until the solvent was drained, and the mixture was subjected to dry-method sampling and column separation using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.0501g of a yellow solid, and the target product was synthesized into 11-phenyl-6H-isoindolo [2,1-a]The isolated yield of indol-6-one is 17%.
Example 17 Synthesis of 11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R 1 Is hydrogen, R 2 Is hydrogen, R 3 Is phenyl, X is bromine, n is 0)
0.3550g of 2-bromo-N- (2-bromophenyl) benzamide (1 mmol), 0.1226g of phenylacetylene (1.2 mmol) and 0.0175g of Pd (PPh) are weighed in sequence 3 ) 2 Cl 2 (0.025 mmol) and 0.2764g potassium carbonate (2 eq.) in a 25mL lock tube containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuumizing, nitrogen gas is filled in, and the operation is repeated for 15 times. Put into an oil bath at 120 ℃ and stirred for 24 hours. After the reaction is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline and 25mL of ethyl acetate for three times, extracting for three times, combining organic phases, adding silica gel, concentrating under reduced pressure until the solvent is drained, and loading the sample by a dry methodColumn separation was performed using petroleum ether-ethyl acetate (1, 5, v/v) as an eluent to obtain 0.0820g of a yellow solid, and the target product was synthesized as 11-phenyl-6H-isoindolo [2,1-a]The isolated yield of indol-6-one is 28%.

Claims (8)

1. A process for the preparation of a compound of formula I, comprising the steps of: reacting a compound shown in a formula II with a compound shown in a formula III in an inert atmosphere in the presence of a catalyst and alkali to obtain a compound shown in a formula I after the reaction is finished;
Figure FDA0004007242330000011
wherein, in the formula I, the formula II and the formula III, R 1 And R 2 Are each independently selected from hydrogen, alkyl, alkoxy, halogen, acyl, or nitro; r is 3 Selected from aryl, heteroaryl, hydrogen or trimethylsilyl; n is 0,1 or 2; x is bromine;
the alkyl group is C 1 ～C 6 A linear or branched alkyl group;
the alkoxy is C 1 ～C 6 A linear or branched alkoxy group;
the halogen is fluorine, chlorine, bromine or iodine;
the acyl group is C 1 ～C 6 Saturated or unsaturated acyl group of (4);
said aryl group is C 6 ～C 12 An aryl group;
the heteroaryl is a thiaheteroaryl or an azaaryl;
the catalyst consists of cuprous iodide and a palladium catalyst containing a phosphine ligand;
the palladium catalyst containing the phosphine ligand is Pd (PPh) 3 ) 2 Cl 2 ；
The alkali is potassium carbonate;
the reaction is carried out in a solvent; the solvent is DMSO;
the feeding mole amount of the palladium catalyst containing the phosphine ligand is 1.0-5.0% of that of the compound shown in the formula II calculated by the feeding mole amount of Pd;
the feeding molar amount of the cuprous iodide is 1.0-10.0% of the compound shown in the formula II;
the feeding molar amount of the alkali is 1-3 equivalents of the compound shown in the formula II;
in the reaction step, the temperature is 100-140 ℃; the time is 12 to 36 hours.
2. The production method according to claim 1, characterized in that: the R is 1 And R 2 Are each independently selected from acyl, nitro or halogen; r 3 Selected from aryl or trimethylsilyl.
3. The method of claim 1, wherein: the feeding mole amount of the palladium catalyst containing the phosphine ligand is 2.5 percent of that of the compound shown in the formula II calculated by the feeding mole amount of Pd;
the feeding molar amount of the cuprous iodide is 5.0 percent of that of the compound shown in the formula II.
4. The method of claim 1, wherein: the molar amount of the base to be fed is 2 equivalents of the compound represented by the formula II.
5. The production method according to claim 1, characterized in that: in the reaction step, the temperature is 120 ℃; the time period required was 24 hours.
6. The method according to claim 1 or 2, characterized in that: in the reaction step, the reaction device is a closed reaction device or a reaction container with an additional reflux device.
7. The method of claim 6, wherein: the reaction device is a closed reaction device.
8. The method of claim 7, wherein: the reaction device is a glass sealed tube.
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