KR100682347B1 - Synthesis of Aromatic 1-Azaspiro Compound Using Palladium Catalyst - Google Patents

Abstract

The present invention relates to a method for preparing an aromatic 1-azaspiro compound, which is a core structure of an erythrina alkaloid, comprising: (1) a keto ester compound having a halogen-substituted aromatic amine and a C4 to C7 ring; Condensation reaction step; (2) A method for producing an aromatic 1-azaspiro compound, comprising an intramolecular cyclization step of heating the precursor obtained in the above step and a palladium (Pd) transition metal catalyst in the presence of a base to obtain a 1-azaspiro structure. It is about. By further using a chiral phosphine ligand in the intramolecular cyclization step, a 1-azaspiro compound can be obtained in the form of a chiral compound.

Alkaloids, Spiro Structural Compounds, Palladium Transition Metals

Description

Synthesis of Aromatic 1-Azaspiro Compound Using Palladium Catalyst}

The present invention relates to a method for synthesizing an aromatic 1-azaspiro compound which is a core structure of an erythr or alkaloid.

Eritrina is a genus of Rosaceae legumes, which means red. Eritrina is a deciduous arborescent tree inhabiting a wide range of tropical and subtropical areas. Eritrina seeds and bark contain erythr or alkaloids and are widely used in folk medicine because they are known to have sedative effects, lower blood pressure, block nerve roots, and anesthetize. These effects are thought to be related to the 1-azaspirocyclic structure specific for the erythri or alkaloid compounds, and many have been interested in developing methods for the synthesis of this core structure. . Developing a method for economically synthesizing derivatives of 1-azaspirocyclic compounds will be of great help in the development of new drugs with new structures, and may also be applicable to the synthesis of chiral drug intermediates.

Erytris and alkaloids are generally classified into two types depending on the structure of the 1-azaspiro ring compound. That is, the D-ring shown in Scheme 1 can be divided into an aromatic compound and an unsaturated lactone compound, and erysotramidine and cocculolidine are examples.

The method for preparing the 1-azaspiro ring compound can be classified based on which ring is formed last. The methods for forming the A, B, C, and D rings at the end have all been developed, but one of the most widely used ones is the formation of the C ring at the end to prepare a 1-azaspir cyclic structure. As the method of forming the C ring at the end, the method of preparing a spiro compound through N-acyliminium ions using an acid catalyst is most commonly applied as shown in the following [Scheme 1] (J Org.Chem. 69 (24), 8209-8218, 2004; J. Chem. Soc., Perkin Trans. 1, 2001, 3029-3036). However, the intramolecular cyclic reaction using N-acyliminium ions as an intermediate has a limitation that a racemic mixture can be produced. If the spiro compound can be prepared in the form of a chiral compound existing in nature, it will help in the development of new drugs with higher efficacy and lower toxicity.

Scheme 1

It is therefore an object of the present invention to provide a new method for the efficient synthesis of aromatic 1-azaspiro compounds, which are the core structures of aromatic erythr or alkaloids.

Another object of the present invention is to provide a process for preparing the 1-aza spiro compound in the form of a chiral compound.

The present invention for achieving the above object relates to a method for producing an aromatic 1-azaspiro compound of the following [Formula 1], (1) a keto ester compound having a halogen-substituted aromatic amine and a C4 ~ C7 ring; Condensation reaction step; (2) a method for producing an aromatic 1-azaspiro compound, characterized in that the precursor obtained in the above step comprises an intramolecular cyclization step of obtaining a 1-azaspiro structure using a palladium (Pd) transition metal catalyst. .

[Formula 1]

X and Y and Z in the [Formula 1] may be the same or different, each of H, C1 ~ C4 alkoxy group or hydroxyl group. X and Y may also take the form of a ring of -OCH ₂ O-. N and m are each an integer selected from a range of 0 to 4, and may be the same as or different from each other.

If the manufacturing method of [Formula 1] is represented by the reaction scheme, it is the same as [Scheme 2].

Scheme 2

 Hereinafter, each reaction will be described in detail step by step.

(1) condensation reaction step

A condensation reaction is carried out by heating a keto ester compound having a halogen-substituted aromatic amine and a C4 to C7 ring. At this time, since the condensation reaction proceeds more efficiently when the generated water is removed, it is more preferable to remove the water produced during the reaction using the Dean-stark trap. As the solvent used in the reaction, it is preferable to use an organic solvent such as benzene, toluene, and xylene which are mainly used for dehydration because of high boiling point and low density, but is not limited thereto. The reaction is preferably carried out at 90 to 150 ° C. for 10 to 20 hours to facilitate the removal of water. Usually, the organic solvent used is refluxed to react. Since the reaction time depends on the reaction temperature, the properties of the reactants, the type of solvent, the use and type of the catalyst, and the like, it is preferable to confirm and control the progress of the reaction by an analytical method such as TLC or HPLC.

In the condensation reaction of this step, an acid may be used as a catalyst in order to proceed the reaction more efficiently. As the acid, any of inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as p-toluenesulfonic acid (p-TsOH), trifluoroacetic acid (TFA) and Lewis acids may be used.

After the reaction is completed, the organic compound may be purified and used for the next reaction.

(2) cyclization step

An intramolecular cyclization step of reacting the precursor obtained in the above step with a palladium (Pd) transition metal catalyst in the presence of a base to obtain a 1-azaspiro structure. The base may be an organic base such as DBU (diazabicycloundecene) or diisopropyl ethylamine or an inorganic base such as K ₂ CO ₃ . Other organic solvents such as acetonitrile and N, N-dimethylformamide may be used together. At this time, the amount of the base is preferably 5 to 10 equivalents.

As the palladium catalyst, any palladium salt capable of forming palladium zero valent may be used. In the present embodiment, palladium acetate is used, but is not limited thereto. Other examples of palladium salts may be tetrakis triphenylphosphine palladium, palladium chloride, Pd ₂ (dba) ₂ .

When the mixture of the precursor, base and palladium catalyst obtained in step (1) is reacted at 100 to 150 ° C. for 10 to 20 hours, a 1-azaspiro compound of [Formula 1] is obtained. At this time, by adding a chiral phosphine ligand, the 1-azaspiro compound can be obtained in the form of a chiral compound. The chiral phosphine ligands include (R)-(+)-2,2'-Bis [di (3,5-xylyl) phosphino] -1,1'-binaphthyl ((R) -3,5-xylyl -BINAP), (S)-(-)-2,2'-Bis (di-p-tolyphosphino) -1,1'-binaphthyl ((S) -Tol-BINAP)), (+)-1,2 -Bis ((2R, 5R) -2,5-di-i-propylphospholano) benzene ((R, R) -i-Pr-DUPHOS)), (-)-2,3-o-isopropylidene-2,3 -dihydroxy-1,4-bis (denylphosphino) butane ((-)-DIOP, (R, R) -DIOP), (2S, 3S)-(-) -Bis (diphenylphosphino) butane ((S, S)- CHIRAPHOS), (+)-2,3-o-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane ((+)-DIOP, (S, S) -DIOP), (1S, 2S )-(+)-bis [(2-methoxyphenyl) phenylphosphino] ethane ((S, S) -DIPAMP), (R) -1-[(1S) -2- (Diphenylphosphino) ferrocenyl] ethyl di-tert-butyl phosphine, (R) -1-[(1S) -2- (Diphenylphosphino) ferrocenyl] ethyl dicyclohexyl phosphine ((R)-(S) -josiphos), (S) -1-[(1R) -2- (Diphenylphosphino ferrocenyl] ethyldicyclohexyl-phosphine ((S)-(R) -josiphos), R-(+)-6,6'-Bis (diphenylphosphino) -1,1'-biphenyl-2,2'-diylbis (acetate) ((R) -Methyl Soniphos), S-(-)-6,6'-Bis (diphenylphosphino) -1,1'-biphenyl-2,2'- di ylbis (acetate) ((S) -Methyl Soniphos), R-(+)-6,6'-Bis (diphenylphosphino) -1,1'-biphenyl-2,2'-diylbis (cyclohexylcarboxylate) ((R)- cyclohexyl Soniphos), R-(+)-2,2'-Bis (N-diphenylphosphinoamino) -5,5 ', 6,6', 7,7 ', 8,8'-octahydro-1,1'-binaphthyl (CTH- (R) -BINAM), S-(-)-2,2'-Bis (N-diphenylphosphinoamino) -5,5 ', 6,6', 7,7 ', 8,8'-octahydro- One of 1,1'-binaphthyl (CTH- (S) -BINAM) can be selected and used. It is preferable that the equivalent of a chiral phosphine ligand is 0.05-0.1 equivalent.

Hereinafter, the present invention will be described in detail through examples. However, these embodiments are for illustrative purposes only and the present invention is not limited thereto.

Example

Example 1:

In a 100 mL round bottom flask, 2-iodine-4,5-dimethoxyphenylamine (10.7g), ethyl 2-cyclohexanyl ylacetate (7.7g) and p-TsOH (1.3g) were added and dissolved in toluene solvent for 15 hours. Water generated while stirring with heat is removed using a Dean-stark trap. After cooling, the solvent was removed under reduced pressure, diluted with 300 mL of ethyl acetate solvent, washed with 3M aqueous NaOH solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The reaction product was purified by column chromatography (hexane: ethyl acetate 1: 2) to give 7 g (47%) of the product.

Example 2:

1,4,5,6,7,7a-hexahydro-1- [2- (2-iodine-4,5-dimethoxyphenyl) ethyl] -2H-indol-2-one (1.0 in 50 mL Pyrex glass tube) g) and palladium acetate (30 mg) were stirred for 16 hours while heating to 140 ° C. under DBU 10 mL solvent. After cooling, the mixture was diluted with 50 mL of chloroform solvent, washed with 1N HCl aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction product was purified by column chromatography (hexane: ethyl acetate 1: 2) to obtain 0.40 g (57%) of the product.

Example 3:

1,4,5,6,7,7a-hexahydro-1- [2- (2-iodine-4,5-dimethoxyphenyl) ethyl] -2H-indol-2-one (1.5 in 50 mL Pyrex glass tube g), palladium acetate (80 mg) and (R) -BINAP (650 mg) were stirred for 16 hours while heating to 140 ° C. under a 20 mL solvent of diazabicycloundecene (DBU). After cooling, the mixture was diluted with 70 mL of chloroform solvent, washed with 1N HCl aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The reaction product was purified by column chromatography (hexane: ethyl acetate 1: 2) to give 0.60 g (57%) of the product (e.e. 38%).

According to the method of the present invention, an aromatic 1-azaspiro compound, which is a core structure of an aromatic erythr or alkaloid, can be efficiently synthesized by a two-step reaction by a cyclization reaction using a metal catalyst.

In addition, according to the method of the present invention, since the 1-aza spiro compound can be prepared in the form of a chiral compound, it can be applied to the synthesis process of a pharmaceutical intermediate.

Claims (3)

Regarding the preparation method of the aromatic 1-azaspiro compound of the formula 1 according to Scheme 2, (A) condensation reaction step by dehydration reaction of halogen-substituted aromatic amine (2) with keto ester compound (3) having C4 ~ C7 ring; And (B) an intramolecular cyclization step of obtaining the aromatic 1-azaspiro compound (1) by heating the precursor (4) and the palladium (Pd) transition metal catalyst obtained in the condensation step in the presence of a base; A process for producing an aromatic 1-azaspiro compound of formula (I) comprising: [Formula 1]

Scheme 2

In Formula 1 and Scheme 2, X, Y and Z are each an H, C1 ~ C4 alkoxy group or X and Y are -OCH2O- ring form; R = Me or Et n and M are integers each selected from 0 to 2. The method of claim 1, A method for producing an aromatic 1-azaspiro compound of formula (I), characterized in that further adding a chiral phosphine ligand to the intramolecular cyclization step. The method of claim 2, The chiral phosphine ligand is (R)-(+)-2,2'-Bis [di (3,5-xylyl) phosphino] -1,1'-binaphthyl ((R) -3,5-xylyl-BINAP ), (S)-(-)-2,2'-Bis (di-p-tolyphosphino) -1,1'-binaphthyl ((S) -Tol-BINAP)), (+)-1,2-Bis ((2R, 5R) -2,5-di-i-propylphospholano) benzene ((R, R) -i-Pr-DUPHOS)), (-)-2,3-o-isopropylidene-2,3-dihydroxy -1,4-bis (denylphosphino) butane ((-)-DIOP, (R, R) -DIOP), (2S, 3S)-(-)-Bis (diphenylphosphino) butane ((S, S) -CHIRAPHOS) , (+)-2,3-o-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane ((+)-DIOP, (S, S) -DIOP), (1S, 2S)- (+)-bis [(2-methoxyphenyl) phenylphosphino] ethane ((S, S) -DIPAMP), (R) -1-[(1S) -2- (Diphenylphosphino) ferrocenyl] ethyl di-tert-butyl phosphine, (R) -1-[(1S) -2- (Diphenylphosphino) ferrocenyl] ethyl dicyclohexyl phosphine ((R)-(S) -josiphos), (S) -1-[(1R) -2- (Diphenylphosphino) ferrocenyl ] ethyldicyclohexyl-phosphine ((S)-(R) -josiphos), R-(+)-6,6'-Bis (diphenylphosphino) -1,1'-biphenyl-2,2'-diylbis (acetate) (( R) -Methyl Soniphos), S-(-)-6,6'-Bis (diphenylphosphino) -1,1'-biphenyl-2,2'-diylbis (a cetate) ((S) -Methyl Soniphos), R-(+)-6,6'-Bis (diphenylphosphino) -1,1'-biphenyl-2,2'-diylbis (cyclohexylcarboxylate) ((R) -cyclohexyl Soniphos ), R-(+)-2,2'-Bis (N-diphenylphosphinoamino) -5,5 ', 6,6', 7,7 ', 8,8'-octahydro-1,1'-binaphthyl (CTH -(R) -BINAM), S-(-)-2,2'-Bis (N-diphenylphosphinoamino) -5,5 ', 6,6', 7,7 ', 8,8'-octahydro-1, 1'-binaphthyl (CTH- (S) -BINAM) A method for producing a 1-azaspiro compound of formula (I), characterized in that selected from the group consisting of.