[go: up one dir, main page]

CN114133389A - 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

Info

Publication number
CN114133389A
CN114133389A CN202111516401.9A CN202111516401A CN114133389A CN 114133389 A CN114133389 A CN 114133389A CN 202111516401 A CN202111516401 A CN 202111516401A CN 114133389 A CN114133389 A CN 114133389A
Authority
CN
China
Prior art keywords
formula
reaction
group
mixture
palladium catalyst
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202111516401.9A
Other languages
Chinese (zh)
Other versions
CN114133389B (en
Inventor
华瑞茂
汤宝鑫
粟骥
王恺之
欧阳赟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hefei Taili Zhulin New Materials Co.,Ltd.
Original Assignee
Hainan Fansheng Biotechnology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hainan Fansheng Biotechnology Co ltd filed Critical Hainan Fansheng Biotechnology Co ltd
Priority to CN202111516401.9A priority Critical patent/CN114133389B/en
Publication of CN114133389A publication Critical patent/CN114133389A/en
Application granted granted Critical
Publication of CN114133389B publication Critical patent/CN114133389B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D487/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

The invention discloses a method for preparing isoindoline-1-ketone ring-fused 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

Process for preparing isoindolin-1-one fused rings 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 may 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); chlortchalidone 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 MT3Potential 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); batracylin can act as an inhibitor of topoisomerase II (Guillamel, 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, such as lenoxamine and chilenine, which are alkaloids isolated from Berberis plants of Chilean (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 synthesis method of three isoindolin-1-one fused ring structures (Garcia, A.; Rodriguez, D.; et al tetrahedron Lett.2001,42,1903), which uses a condensation reaction of o-bromoaniline and acetaldehyde, followed by a reaction with o-iodobenzoyl chloride, and finally an intramolecular Heck reaction, and the method has high requirements for a substrate, requires bromine as a halogen atom in the ortho-position of aniline, requires an iodine atom as a halogen atom in the ortho-position of benzoyl chloride, and requires the addition of 20 mol% of a Pd catalyst. A subject group uses ortho-ester or ortho-carboxyl acetophenone, and an ortho-halophenylamine compound to perform condensation and intramolecular Heck cyclization reactions to synthesize three isoindolin-1-one fused ring structures (Kim, G.; Kim, J.H.; et al tetrahedron Lett.2003,44,8207), which are also synthesized in two steps and require the use of 10 mol% Pd catalyst. In addition, a method for synthesizing three isoindoline-1-ketone fused ring structures by means of 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 by means of two steps, 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: in the presence of a catalyst and alkali, reacting dihalogenated benzamide shown in a formula II with alkyne shown in a formula III in an inert atmosphere 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, R1And R2Each independently selected from hydrogen, alkyl, alkoxy, halogen, acyl or nitro, preferably an electron withdrawing group such as acyl, nitro, halogen; r3Selected from aryl, heteroaryl, hydrogen, trimethylsilyl, preferably aryl and trimethylsilyl; n is 0, 1, 2.
The alkyl group may be C1～C6A linear or branched alkyl group;
the alkoxy group may be C1～C6A linear or branched alkoxy group;
the halogen can be fluorine, chlorine, bromine or iodine;
the acyl group may be C1～C6Saturated or unsaturated acyl group of (a);
the aryl group may be C6～C12Aryl, 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(PPh3)2Cl2、Pd(dppf)2Cl2(ii) a The palladium catalyst is selected from at least one of the following: pd (OAc)2、PdCl2(ii) a The phosphine ligand is selected from any one of the following: triphenylphosphine, dppf, preferably Pd (PPh)3)2Cl2。
The base is potassium carbonate, triethylamine or DBU, preferably potassium carbonate.
The feeding mole usage 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, calculated by the feeding mole 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 that of the dihalobenzamide compound shown in the formula II.
The molar amount of the base to be charged is 1 to 3 equivalents, preferably 2 equivalents, of 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 ℃, and 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 preferred 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 carrying out reduced pressure concentration to remove the solvent to obtain the product-containing silica gel; filling 300-400 meshes of silica gel and petroleum ether containing triethylamine into a column, and loading the column by using a dry method, wherein the volume fraction of the triethylamine is 0.1%; eluting with a petroleum ether/ethyl acetate mixed solvent, wherein the proportion 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 generally: 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) is 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 high, the required addition amount is very small, and the product obtained by the reaction is a heterocyclic compound with high added value. (2) Is convenient. 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. (3) Is universally applicable. 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 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 (10mmol), 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, and 50mL of ethyl acetate, 1.0119g of triethylamine (10mmol) and 10mmol of an amine compound were added thereto and stirred for 6 hours. 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 shown in the formula II.
Example 1 Synthesis of 11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R1Is hydrogen, R2Is hydrogen, R3Is phenyl, X is bromine, n is 0)
0.3550g of 2-bromo-N- (2-bromophenyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) 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 is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution and 25mL of ethyl acetate for three times, extracting the mixture for three times, combining organic phases, adding silica gel, concentrating the mixture under reduced pressure until the solvent is drained, loading the mixture by a dry method, and carrying out column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.2483g of yellow solid, namely the target product 11-phenyl-6H-isoindolo [2,1-a ] of the product]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 obtained 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) -one (in formula I, R)1Is hydrogen, R2Is hydrogen, R3Is phenyl, X is bromine, n is 1)
0.3690g of 2-bromo-N- (2-bromophenylmethyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) were weighed in this order3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) 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 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, loading the sample by a dry method, and usingPetroleum ether-ethyl acetate (1: 5, v/v) as eluent for column separation to obtain 0.2635g of yellow solid and the target product 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)1Is hydrogen, R2Is hydrogen, R3Is phenyl, X is bromine, n is 2)
0.3831g of 2-bromo-N- (2-bromophenylethyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) 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 is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution and 25mL of ethyl acetate for three times, extracting the mixture for three times, combining organic phases, adding silica gel, concentrating the mixture under reduced pressure until the solvent is drained, loading the mixture by a dry method, and carrying out column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.1676g of white solid and the 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)1Is hydrogen, R2Is hydrogen, R3Is thienyl, X is bromo, n is 1)
0.3690g of 2-bromo-N- (2-bromophenylmethyl) benzamide (1mmol), 0.1298g of 2-ethynylthiophene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) 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 DEG CStirred for 24 hours. After the reaction is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution and 25mL of ethyl acetate for three times, extracting the mixture for three times, combining organic phases, adding silica gel, concentrating the mixture under reduced pressure until the solvent is drained, loading the mixture by a dry method, and carrying out column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.2142g of yellow solid, namely the target product 12- (thiophene-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)1Is hydrogen, R2Is hydrogen, R3Is p-methoxyphenyl, X is bromine, n is 2)
0.3831g of 2-bromo-N- (2-bromophenylethyl) benzamide (1mmol), 0.1586g of p-methoxyphenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) 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 is finished, the mixture is transferred to a separating funnel, 25mL of saturated saline solution and 25mL of ethyl acetate are added for three times, after three times of extraction, organic phases are combined, silica gel is added, the mixture is decompressed and concentrated until the solvent is drained, the mixture is loaded by a dry method, and the mixture is subjected to column separation by using petroleum ether-ethyl acetate (1: 4, v/v) as an eluent to obtain 0.1700g of white solid, namely the target product 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)1Is hydrogen, R2Is hydrogen, R3Is p-trifluoromethylphenyl, X is bromine, n is 2)
0.3831g of 2-bromo-N- (2-bromophenylethyl) benzamide (1mmol), 0.2042g of p-trifluoromethylphenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) 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 is finished, the mixture is transferred to a separating funnel, 25mL of saturated saline solution and 25mL of ethyl acetate are added for three times, after three times of extraction, organic phases are combined, silica gel is added, the mixture is decompressed and concentrated until the solvent is drained, the mixture is loaded by a dry method, and the mixture is subjected to column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.2552g of white solid, namely the target product 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, R1Is hydrogen, R2Is methyl, R3Is phenyl, X is bromine, n is 0)
0.3690g of 2-bromo-N- (2-bromo-4-methylphenyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in this order3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) 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 is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution and 25mL of ethyl acetate for three times, extracting the mixture for three times, combining organic phases, adding silica gel, concentrating the mixture under reduced pressure until the solvent is drained, loading the mixture by a dry method, and carrying out column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.2286g of yellow solid and 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, R1Is hydrogen, R2Is chlorine, R3Is phenyl, X is bromine, n is 0)
0.3895g of 2-bromo-N- (2-bromo-4-chlorophenyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in this order3)2Cl2(0.025mmol) and 0.0095g cuprous iodide(0.05mmol) and 0.2764g potassium carbonate (2eq.) 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 is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution and 25mL of ethyl acetate for three times, extracting the mixture for three times, combining organic phases, adding silica gel, concentrating the mixture under reduced pressure until the solvent is drained, loading the mixture by a dry method, and carrying out column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.2782g of yellow solid, namely 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) -one (in formula I, R)1Is methoxy, R2Is hydrogen, R3Is phenyl, X is bromine, n is 1)
0.3991g of 2-bromo-N- (2-bromophenylmethyl) -4-methoxybenzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) were weighed in this order3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) 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 is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution and 25mL of ethyl acetate for three times, extracting the mixture for three times, combining organic phases, adding silica gel, concentrating the mixture under reduced pressure until the solvent is drained, loading the mixture by a dry method, and carrying out column separation by using petroleum ether-ethyl acetate (1: 4, v/v) as an eluent to obtain 0.2869g of yellow solid, namely 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)1Is fluorine, R2Is hydrogen, R3Is phenyl, X is bromine, n is 1)
0.3870g of 2-bromo-N- (2-bromophenylmethyl) -4-fluorobenzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) were weighed in this order3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate(2eq.) to 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 is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution and 25mL of ethyl acetate for three times, extracting the mixture for three times, combining organic phases, adding silica gel, concentrating the mixture under reduced pressure until the solvent is drained, loading the mixture by a dry method, and carrying out column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.2873g of yellow solid, namely 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, R1Is hydrogen, R2Is hydrogen, R3Is phenyl, X is bromine, n is 0)
0.3550g of 2-bromo-N- (2-bromophenyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) 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. The mixture was stirred in an oil bath at 100 ℃ for 24 hours. After the reaction is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution 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, loading the mixture by a dry method, and carrying out column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.1502g of yellow solid, wherein the target product is synthesized into 11-phenyl-6H-isoindolo [2,1-a ] of the target product]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, R1Is hydrogen, R2Is hydrogen, R3Is phenyl, X is bromine, n is 0)
0.3550g of 2-bromo-N- (2-bromophenyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) in a 25mL stopcock containing a magnetic stirrer, 2.0mL of DMSO was added; after vacuum pumping, nitrogen is filled inRepeat the operation 15 times. The mixture was stirred in an oil bath at 140 ℃ for 24 hours. After the reaction is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution 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, loading the mixture by a dry method, and carrying out column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.1184g of yellow solid, wherein the target product is synthesized into 11-phenyl-6H-isoindolo [2,1-a ] of the target product]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, R1Is hydrogen, R2Is hydrogen, R3Is phenyl, X is bromine, n is 0)
0.3550g of 2-bromo-N- (2-bromophenyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) in a 25mL lock tube with a magnetic stirrer, 2.0mL of DMF 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 is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution 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, loading the mixture by a dry method, and carrying out column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.2103g of yellow solid, wherein the target product is synthesized into 11-phenyl-6H-isoindolo [2,1-a ] of the target product]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, R1Is hydrogen, R2Is hydrogen, R3Is phenyl, X is bromine, n is 0)
0.3550g of 2-bromo-N- (2-bromophenyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.2764g potassium carbonate (2eq.) 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 reaction mixture was transferred to liquid separationAdding 25mL of saturated saline water and 25mL of ethyl acetate for three times into a funnel, extracting for three times, combining organic phases, adding silica gel, concentrating under reduced pressure until the solvent is drained, loading the mixture by a dry method, carrying out column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.1450g of yellow solid, and synthesizing the target product into 11-phenyl-6H-isoindolo [2,1-a ] of the target product]The isolated yield of indol-6-one was 49%.
Example 15 Synthesis of 11-phenyl-6H-isoindolo [2,1-a]Indol-6-ones (formula I, R1Is hydrogen, R2Is hydrogen, R3Is phenyl, X is bromine, n is 0)
0.3550g of 2-bromo-N- (2-bromophenyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.4567g DBU (3eq.) 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 solution and 25mL of ethyl acetate were added for three times, after extraction, the organic phases were combined, silica gel was added, the mixture was concentrated under reduced pressure until the solvent was drained, the mixture was loaded by a dry method, and column separation was performed using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.0817g of a yellow solid, and 11-phenyl-6H-isoindolo [2,1-a ] was synthesized]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, R1Is hydrogen, R2Is hydrogen, R3Is phenyl, X is bromine, n is 0)
0.3550g of 2-bromo-N- (2-bromophenyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol), 0.0095g cuprous iodide (0.05mmol) and 0.3036g triethylamine (3eq.) 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, and silica gel was addedConcentrating under reduced pressure to dry the solvent, loading by dry method, separating with petroleum ether-ethyl acetate (1: 5, v/v) as eluent to obtain yellow solid 0.0501g, and synthesizing the target product 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, R1Is hydrogen, R2Is hydrogen, R3Is phenyl, X is bromine, n is 0)
0.3550g of 2-bromo-N- (2-bromophenyl) benzamide (1mmol), 0.1226g of phenylacetylene (1.2mmol) and 0.0175g of Pd (PPh) are weighed in sequence3)2Cl2(0.025mmol) and 0.2764g potassium carbonate (2eq.) 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 is finished, transferring the mixture to a separating funnel, adding 25mL of saturated saline solution 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, loading the mixture by a dry method, and performing column separation by using petroleum ether-ethyl acetate (1: 5, v/v) as an eluent to obtain 0.0820g of yellow solid, wherein the target product is synthesized into 11-phenyl-6H-isoindolo [2,1-a ] indole [2]The isolated yield of indol-6-one is 28%.

Claims (10)

1. A process for the preparation of a compound of formula I, comprising the steps of: in the presence of a catalyst and alkali, reacting a compound shown as a formula II with a compound shown as a formula III in an inert atmosphere to obtain a compound shown as a formula I after the reaction is finished;
Figure FDA0003403561650000011
wherein, in the formula I, the formula II and the formula III, R1And R2Are each independently selected from hydrogen, alkyl, alkoxy, halogen, acyl, or nitro; r3Selected from aryl, heteroaryl, hydrogen or trimethylsilyl; n is 0, 1 or 2.
2. The method of claim 1, wherein:
the R is1And R2Are all independently selected from acyl, nitro, halogen; r3Selected from aryl and trimethylsilyl;
the alkyl group is C1～C6A linear or branched alkyl group;
the alkoxy is C1～C6A linear or branched alkoxy group;
the halogen is fluorine, chlorine, bromine or iodine;
the acyl group is C1～C6Saturated or unsaturated acyl group of (a);
said aryl group is C6～C12An aryl group;
the heteroaryl group is a thiaheteroaryl group or an azaaryl group.
3. The production method according to claim 1 or 2, characterized in that:
the catalyst consists of cuprous iodide and a palladium catalyst containing a phosphine ligand; or cuprous iodide, a palladium catalyst and a phosphine ligand.
4. The production method according to claim 3, characterized in that:
the palladium catalyst containing a phosphine ligand is selected from at least one of the following: pd (PPh)3)4、Pd(PPh3)2Cl2、Pd(dppf)2Cl2；
The palladium catalyst is selected from at least one of the following: pd (OAc)2、PdCl2；
The phosphine ligand is selected from any one of the following: triphenylphosphine, dppf, preferably Pd (PPh)3)2Cl2。
5. The production method according to any one of claims 1 to 4, characterized in that: the base is potassium carbonate, triethylamine or DBU, preferably potassium carbonate.
6. The production method according to any one of claims 1 to 5, characterized in that:
the feeding mole amount of the palladium catalyst containing the phosphine ligand or the palladium catalyst is 1.0-5.0%, preferably 2.5% of that of the compound shown in the formula II calculated by the feeding mole amount 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 that of the compound shown in the formula II.
7. The production method according to any one of claims 1 to 6, characterized in that: the molar amount of the base to be fed is 1 to 3 equivalents, preferably 2 equivalents, of the compound represented by the formula II.
8. The production method according to any one of claims 1 to 7, characterized in that: the reaction is carried out in a solvent; the solvent is DMF, DMSO or NMP, preferably DMSO.
9. The production method according to any one of claims 1 to 8, characterized in that: in the reaction step, the temperature is 100-140 ℃, and preferably 120 ℃; the time is 12 to 36 hours, preferably 24 hours.
10. The method according to any one of claims 1 to 9, wherein: in the reaction step, the reaction apparatus is a closed reaction apparatus or a reaction vessel with a reflux apparatus, preferably a closed reaction apparatus, and more preferably a glass-sealed tube.
CN202111516401.9A 2021-12-10 2021-12-10 Process for preparing isoindolin-1-one fused rings and analogues thereof Active CN114133389B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202111516401.9A CN114133389B (en) 2021-12-10 2021-12-10 Process for preparing isoindolin-1-one fused rings and analogues thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111516401.9A CN114133389B (en) 2021-12-10 2021-12-10 Process for preparing isoindolin-1-one fused rings and analogues thereof

Publications (2)

Publication Number Publication Date
CN114133389A true CN114133389A (en) 2022-03-04
CN114133389B CN114133389B (en) 2023-03-21

Family

ID=80385880

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111516401.9A Active CN114133389B (en) 2021-12-10 2021-12-10 Process for preparing isoindolin-1-one fused rings and analogues thereof

Country Status (1)

Country Link
CN (1) CN114133389B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104892614A (en) * 2015-05-27 2015-09-09 福建师范大学 Synthesis method of 6H-isoindolo[2, 1-alpha]indol-6-one derivative
CN109912492A (en) * 2019-03-29 2019-06-21 大连理工大学 A kind of synthetic method of 3-benzylidene isoindolin-1-one derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104892614A (en) * 2015-05-27 2015-09-09 福建师范大学 Synthesis method of 6H-isoindolo[2, 1-alpha]indol-6-one derivative
CN109912492A (en) * 2019-03-29 2019-06-21 大连理工大学 A kind of synthetic method of 3-benzylidene isoindolin-1-one derivative

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BOK-JIN LEE 等: "Sequential Heck–Heck reactions for the dibenz[a ,f]indolizine skeleton: synthetic application to decumbenine B", 《TETRAHEDRON LETTERS》 *
HITESH K. SAINI 等: "Copper and palladium-catalyzed sequential reactions: One-pot synthesis of isoindolo[2,1-b]isoquinolin-7(5H)-ones", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 *
REN-XIAO LIANG 等: "A Pd-catalyzed domino Larock annulation/dearomative Heck reaction", 《CHEMCOMM》 *

Also Published As

Publication number Publication date
CN114133389B (en) 2023-03-21

Similar Documents

Publication Publication Date Title
CN111205279B (en) Polysubstituted benzodihydrofuran heterocyclic compound and preparation method and application thereof
CN108640917B (en) A kind of synthetic method of indolo[2,1-a]isoquinoline compounds
Wang et al. Efficient construction of polycyclic chromans through 4-methylbenzenesulfonic acid mediated domino 1, 6-addition/oxa-Mannich reaction of ortho-hydroxyphenyl substituted para-quinone methides and cyclic enamides
CN105949152A (en) Benzofuran derivative and preparation method thereof
CN114014805B (en) Preparation method of trifluoromethylated 2,4-quinolinedione compounds
CN113845550B (en) Flexible large-steric-hindrance N-heterocyclic carbene palladium complex containing halogenated benzene ring, preparation method and application thereof
CN111978237B (en) A kind of preparation method of 3-morpholinyl-4-arylselenyl maleimide compound
CN106188044A (en) A kind of synthetic method of 3 arylthio imidazos [1,5 a] the N heterocyclic compound of catalysis of iodine
CN109651385A (en) A kind of preparation method of pyrans [3,2-a] carbazole compound
CN114133389B (en) Process for preparing isoindolin-1-one fused rings and analogues thereof
CN113735752B (en) Method for preparing isothiourea compound based on substituted iodobenzene
CN107629049B (en) Synthesis method of pyridine [2,1-a ] isoindole compound
CN113912609B (en) Preparation method of natural alkaloid tryptanthrin and derivatives thereof
CN111662147B (en) Process for preparing diynes and analogues thereof
CN112898202B (en) Heterocyclyl cyclopropane compound and synthesis method thereof
CN110437277B (en) A kind of synthetic method of phosphoenyl ester compound
CN112778317A (en) Synthetic method of [1,2,4] triazolo [1,5-a ] pyrimidine compound
CN109265403B (en) A kind of synthetic method of benzimidazole and derivative thereof
CN109678862B (en) Preparation method of polysubstituted distyryl indole derivative
Li et al. One-pot formal [3+ 2] annulation of 2-pyridinyl-substituted p-quinone methides and arynes for the synthesis of 3-aryl pyrido [1, 2-a] indoles
CN117003682B (en) Preparation method of polysubstituted 3-dihydropyrrole compound
CN116041126B (en) Method for synthesizing naphthalene compound
CN119039293A (en) Synthesis method of 6-substituted 5, 6-dihydropyrido bisindole compound
CN114181182A (en) A kind of synthetic method of multi-substituted 4H-pyran compounds
CN105017279A (en) A kind of bisthienopyridine derivative and its preparation method

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20240808

Address after: Room 311, Office Building, No. 24 Hongfeng Road, High tech Zone, Hefei City, Anhui Province, China 230000

Patentee after: Hefei Taili Zhulin New Materials Co.,Ltd.

Country or region after: China

Address before: 570203 maker space, building 2, building B, industry university research building, middle section of Haitao Avenue, Guilin Yang University District, Meilan District, Haikou City, Hainan Province

Patentee before: Hainan Fansheng Biotechnology Co.,Ltd.

Country or region before: China

TR01 Transfer of patent right