CN110128422B

CN110128422B - Synthesis method of 5-methoxy-7-azaindole

Info

Publication number: CN110128422B
Application number: CN201910006524.4A
Authority: CN
Inventors: 孔飞; 宋桐集; 王永灿; 杨海龙
Original assignee: Jinkai Liaoning Life Technology Co ltd
Current assignee: Jinkai Liaoning Life Technology Co ltd
Priority date: 2019-01-04
Filing date: 2019-01-04
Publication date: 2022-03-18
Anticipated expiration: 2039-01-04
Also published as: CN110128422A

Abstract

The invention relates to a synthesis method of 5-methoxy-7-azaindole. The invention provides a synthesis method of 5-methoxy-7-azaindole, which comprises the following steps: step a): preparing a compound 2 by taking the compound 1 as a raw material; step b): the 5-methoxy-7-azaindole is prepared by the compound 2. Compared with the prior art, the synthesis method greatly shortens the synthesis route, effectively avoids byproducts in the prior art, and improves the total yield.

Description

Synthesis method of 5-methoxy-7-azaindole

Technical Field

The invention relates to the field of drug intermediates, in particular to a synthesis method of 5-methoxy-7-azaindole.

Background

Azaindole can be regarded as a biological electron isostere of indole, an indole molecular unit plays a great role in the life process, and a plurality of drug molecules contain the indole unit, so that the azaindole compound plays an important role in the design and synthesis of drug active molecules. Azaindoles and derivatives thereof have activity in inhibiting a variety of proteases. For example, a compound containing a 7-azaindole structure in a natural product is an important alkaloid and has physiological activities of resisting cancer, resisting diabetes and the like. Due to the special physicochemical properties and pharmacological activity of the compounds, chemists usually use compounds with 7-azaindole structures as lead compounds for structural modification. 5-methoxy-7-azaindole is currently predominantly prepared from 5-bromo-7-azaindole as a key intermediate for the preparation of active pharmaceutical ingredients.

The preparation method comprises the following steps:

and 5-bromo-7 azaindole as a raw material is not easy to obtain, and the preparation cost is high. The current preparation methods of 5-bromo-7 azaindole mainly comprise the following steps:

US20100204214, US20070049615, hecocecle, 2003,60(4):865-877, JACS, 2006,128(45):14426-14437 and chemmedchem,2007,2(7):1071-1075 all disclose the preparation of 5-bromo-7 azaindole which is prepared by brominating, eliminating, reducing and oxidizing 7-azaindole, and has the following reaction formula:

the method has long steps, needs a large amount of bromine to take part in the reaction and finally eliminates the bromine, generates a large amount of waste liquid, and has complex operation and low total yield.

WO2003064413, WO2004078757 and WO2007135398 both disclose that 7-azaindole is used as a raw material, and 5-bromo-7-azaindole is obtained by hydrogenation reduction, bromination and dehydrogenation, and the reaction route is as follows:

the method has the disadvantages that bromine is excessively used in the bromination step, a large amount of waste liquid is generated, and the pollution is serious; in the dehydrogenation step, manganese dioxide is adopted, so that a large amount of manganese-containing waste residues are generated, and pollution is caused.

2049-bromo-2-aminopyridine is used as a raw material, and the raw material is subjected to iodination, Sonogashira cross-coupling, hydrolysis in strong alkali and cyclization to obtain the 5-bromo-7-azaindole, wherein the reaction route of the synthesis 2008 (13) is as follows:

the route uses various metal catalysts, the cross-coupling by-products are not well purified, the conditions are harsh, and the industrial cost is high.

Chinese patent application No. CN201210025316 provides a preparation method of 5-bromo-7-azaindole, which takes 7-azaindole as a raw material and mainly comprises the following steps: reacting 7-azaindole with sodium bisulfite to generate dihydro-7-azaindole-2-sulfonic acid sodium salt; brominating dihydro-7-azaindole-2-sulfonic acid sodium salt to generate dihydro-5-bromo-7-azaindole-2-sulfonic acid sodium salt; the 5-bromo-7-azaindole-2-sulfonic acid sodium salt is subjected to sodium desulfonation under the alkaline condition to generate the 5-bromo-7-azaindole, and the reaction route is as follows:

the preparation method has the problems of high bromine consumption, more cross-coupling byproducts in the bromination process, large amount of waste liquid and complicated operation.

WO2011110479 and WO2011109932 both disclose that 5-bromo-3-methyl-2-aminopyridine is used as a raw material, an intermediate is generated under the action of tetrahydropyrrole and N, N-dimethylformamide dimethyl acetal (DMF-DMA), and then the intermediate is cyclized by LDA (N, N-lithium diisopropylamide) to obtain 5-bromo-7-azaindole, wherein the reaction route is as follows:

although the method shortens the synthetic route, the total yield is lower.

Chinese patent application No. CN201410596601.3 discloses that 2-amino-3-methyl-5-bromopyridine is used as a raw material, 2-nitro-3-methyl-5-bromopyridine is generated under the oxidation action of caronic acid, then an intermediate is generated under the action of pyrrolidine and N, N-dimethylformamide dimethyl acetal (DMF-DMA), and finally ring closure is reduced under the action of raney nickel/85% hydrazine hydrate system or other low-valence metals to form 5-bromo-7-azaindole, wherein the reaction route is as follows:

the method produces a large amount of waste acid, the pressure of three wastes is high, and the industrial cost is high.

Moreover, the processes for preparing 5-bromo-7-azaindole reported so far mainly have the following disadvantages:

1. the raw materials or reagents involved are expensive.

2. The method comprises some oxidation-reduction processes which are dangerous for production, and is not beneficial to industrialization.

3. More by-products and loss of yield in the purification process, resulting in low overall yield.

Disclosure of Invention

Therefore, the technical problem solved by the invention is as follows: in the prior art, 5-bromo-7-azaindole is adopted to prepare 5-methoxy-7-azaindole, but 5-bromo-7-azaindole is not easy to obtain, the production cost is high, and the yield is low.

The invention aims to provide a synthesis method of 5-methoxy-7-azaindole, which is simple in process, low in requirements on production conditions, easy in product purification and high in yield compared with the existing method for preparing 5-methoxy-7-azaindole, and remarkably improves the production efficiency and product quality of 5-methoxy-7-azaindole.

The invention provides a 5-methoxy-7-azaindole, which comprises the following procedures:

step a): preparing a compound 2 by taking the compound 1 as a raw material;

step b): the 5-methoxy-7-azaindole is prepared by the compound 2.

Specifically, the present invention proposes the following technical solutions.

The invention provides a method for synthesizing 5-methoxy-7-azaindole, which comprises the following steps:

step a): preparing a compound 2 by taking the compound 1 as a raw material;

step b): the 5-methoxy-7-azaindole is prepared by the compound 2.

Preferably, in the above synthesis method, in the step b), the compound 2 is dissolved in a third organic solvent, then a base is added for reaction, then N, N-dimethylformamide is added to form an aldehyde intermediate, and finally the aldehyde intermediate is cyclized under an acidic condition and crystallized to obtain a product; among them, it is preferable to deprotonate the methyl group by adding a base; more preferably, the cyclization under acidic conditions is carried out by quenching and cyclization under acidic quenching agent conditions.

Preferably, in the above synthesis method, in the step b), the base is one selected from the group consisting of n-butyllithium, diisopropylaminolithium, lithium bis (trimethylsilyl) amide and sodium bis (trimethylsilyl) amide, and n-butyllithium is preferable.

Preferably, in the above synthesis method, in the step b), the third organic solvent is one selected from tetrahydrofuran, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, methyl propyl ether, n-butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, anisole, methyl tert-butyl ether, 1, 2-dichloroethane, benzene, toluene, p-xylene, hexane, heptane and octane, and is preferably tetrahydrofuran; preferably, the mass ratio of the compound 2 to the third organic solvent is 1:2 to 100, preferably 1:5 to 80, more preferably 1: 8-15.

Preferably, in the above synthesis method, in the step b), the acid quencher is one selected from concentrated hydrochloric acid, sulfuric acid, nitric acid, acetic acid and citric acid, preferably concentrated hydrochloric acid; preferably, the mass ratio of the compound 2 to the acidic quenching agent is 1: 2-10, preferably 1: 2-5, more preferably 1: 2.5 to 3.

Preferably, in the above synthesis method, in the step b), the molar ratio of the compound 2 to the base is 1:2.0 to 6.0, preferably 1:2.0 to 2.5; preferably, the molar ratio of the compound 2 to the N, N-dimethylformamide is 1: 1.0-10.0, preferably 1: 1.0-5, and more preferably 1: 1.0-1.5.

Preferably, in the above synthesis method, the temperature of the alkali added in the step b) is-40 to 30 ℃, preferably-20 to 0 ℃; preferably, the reaction time is 2 to 12 hours; preferably, the temperature for adding the N, N-dimethylformamide is-40-25 ℃, and preferably-20 ℃; preferably, the reaction time is 2 to 12 hours, preferably 4 to 6 hours.

Preferably, in the above synthesis method, in the step b), the quenching reaction temperature is-10 to 30 ℃, preferably 0 to 5 ℃; preferably, the cyclization reaction temperature is 0-45 ℃, and preferably 40-45 ℃; preferably, the reaction time for the cyclization is 1 to 6 hours.

Preferably, in the above synthesis method, the step a) includes the following steps (1) and (2):

(1) synthesis of 2-amino-3-methyl-5-methoxypyridine: dissolving a compound 1 in a first organic solvent, and reacting the compound 1 with methoxide under the action of a first catalyst to obtain a compound 2-amino-3-methyl-5-methoxypyridine;

(2) synthesis of Compound 2: reacting the compound 2-amino-3-methyl-5-methoxypyridine with an amino protective agent to obtain a compound 2.

Preferably, in the above synthesis method, in the step (2), the compound 2-amino-3-methyl-5-methoxypyridine is dissolved in a second organic solvent, and then reacted with an amino protecting agent and a base in the presence of a second catalyst to obtain the amino protected compound 2, wherein in the compound 2, R is an amino protecting group; preferably, after the reaction with the amino protecting agent and the base, a quenching agent is further added for quenching, and recrystallization is carried out to obtain the amino protected compound 2.

Preferably, in the above synthesis method, in the step (1), the first organic solvent is one or more selected from methanol, ethanol, ethylene glycol, propanol, isopropanol, glycerol, methyl glycol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, methyl glycerol, 2-methylpropanol, and dimethyl glycol, and is preferably methanol; preferably, the mass ratio of the compound 1 to the first organic solvent is 1: 0.5-50, preferably 1: 3-10.

Preferably, in the above synthesis method, in step (1), the first catalyst is selected from one of metallic copper, cuprous salt or copper salt; preferably, the first catalyst is selected from one of copper powder, cuprous bromide, cuprous oxide, cupric oxide or cupric sulfate.

Preferably, in the above synthesis method, in the step (1), the molar ratio of the compound 1 to the first catalyst is 1:0.05 to 2, preferably 1:0.1 to 1.5, more preferably 1:0.1 to 0.5; preferably, the methoxide is selected from one of sodium methoxide, potassium methoxide and lithium methoxide, and is preferably sodium methoxide; preferably, the molar ratio of the compound 1 to the methoxide is 1: 0.8-20, preferably 1: 1-15, and preferably 1: 1.5-3.0.

Preferably, in the synthesis method, in the step (1), the reaction temperature is 80 to 150 ℃, preferably 100 to 130 ℃, and more preferably 120 to 130 ℃; preferably, the reaction time is 1 to 20 hours, preferably 1 to 15 hours, and more preferably 3 to 8 hours.

Preferably, in the above synthesis method, in the step (2), the second organic solvent is one or more selected from tetrahydrofuran, acetonitrile, methanol, ethanol, ethylene glycol, propanol, isopropanol, glycerol, methyl glycol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, methyl glycerol, 2-methyl glycerol, dimethyl glycol and tert-butanol, preferably tert-butanol; preferably, the mass ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the second organic solvent is 1: 0.5-30.0, preferably 1: 1-20, and more preferably 1: 1.0-5.0.

Preferably, in the above synthesis method, in the step (2), the second catalyst is one or more selected from pyridine, N-diisopropylethylamine, tetramethylethylenediamine, tripropylamine, 4-dimethylaminopyridine, triethylenediamine, tetrabutylammonium hydroxide, γ -chloropropylmethyldimethoxysilane, N-methylmorpholine and triethylamine, preferably 4-dimethylaminopyridine; preferably, the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the second catalyst is 1:0.01 to 1.0, preferably 1:0.02 to 0.2, and more preferably 1:0.02 to 0.05.

Preferably, in the above synthesis method, in the step (2), the amino group protecting agent is di-tert-butyl dicarbonate; preferably, during the reaction, the amino protective agent is dropwise added in a form of being melted into a liquid state or being dissolved in a fourth organic solvent to form a solution; preferably, the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the amino protective agent is 1: 1-10, preferably 1: 1.1-5, and more preferably 1: 2.1-2.5; preferably, the fourth organic solvent is one or more selected from tetrahydrofuran, acetonitrile, methanol, ethanol, ethylene glycol, propanol, isopropanol, glycerol, methyl glycol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, methyl glycerol, 2-methyl glycerol, dimethyl glycol and tert-butanol, preferably tert-butanol; preferably, the mass ratio of the amino protective agent to the fourth organic solvent is 1: 0.5-30, preferably 1: 1-20, and more preferably 1: 0.5-4.

Preferably, in the above synthesis method, in the step (2), the base is selected from one of hydroxides of alkali metals or alkaline earth metals, carbonates of alkali metals or alkaline earth metals, alkyl salts of alkali metals, di-isopropylated salts of alkali metals or bis-trimethylsilyl amide, preferably one of sodium hydroxide, potassium hydroxide, n-butyllithium, sec-butyllithium, iso-butyllithium, tert-butyllithium or bis-trimethylsilyl amide sodium; preferably, the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the base is 1: 1.0-5.0, preferably 1: 1.5-2.5.

Preferably, in the synthesis method, in the step (2), the reaction temperature is-40 to 85 ℃, preferably 60 to 85 ℃; preferably, the reaction time after the amino protective agent is added is 1-40 hours, preferably 6-8 hours; preferably, the reaction time after the addition of the alkali is 1 to 40 hours, preferably 6 to 10 hours.

Preferably, in the above synthesis method, the quenching agent is selected from one of hydrochloric acid, sulfuric acid, nitric acid, water, formic acid, acetic acid and citric acid.

The beneficial effects obtained by the invention are as follows:

compared with the currently reported synthesis method, the preparation method greatly shortens the synthesis route; the raw material is 2-amino-3-methyl-5-bromopyridine, and compared with the 5-bromo-7-azaindole in the prior art, the raw material is cheap and easy to obtain; the scheme effectively avoids byproducts in the prior art, improves the total yield, obtains products with higher purity, uses cheap and easily-obtained raw materials and reagents, has low requirement on equipment, and is very easy to realize industrialization.

Drawings

FIG. 1 is a GC spectrum of the compound obtained in step (1) of the example.

FIG. 2 is a GC-MS spectrum of the compound obtained in the step (1) of the example.

FIG. 3 is an HPLC chromatogram of Compound 2 obtained in example one.

FIG. 4 is the LC-MS spectrum of Compound 2 obtained in example one

FIG. 5 shows Compound 2 obtained in example one¹H NMR spectrum.

FIG. 6 is an HPLC chromatogram of the product obtained in example one.

FIG. 7 is the LC-MS spectrum of the product obtained in example one

FIG. 8 shows the product obtained in the first example¹H NMR spectrum.

Detailed Description

As described above, the present invention provides a method for synthesizing 5-methoxy-7-azaindole, which comprises the following steps:

step a): preparing a compound 2 by taking the compound 1 as a raw material;

step b): the 5-methoxy-7-azaindole is prepared by the compound 2.

In a preferred embodiment of the present invention, in the step b), the compound 2 is dissolved in a third organic solvent, then a base is added to react, then N, N-dimethylformamide is added to form an aldehyde-based intermediate, and finally the aldehyde-based intermediate is cyclized under an acidic condition and crystallized to obtain a product; among them, it is preferable to deprotonate the methyl group by adding a base; more preferably, the cyclization under acidic conditions is carried out by quenching and cyclization under acidic quenching agent conditions.

In a preferred embodiment of the present invention, in the step b), the base is selected from one of n-butyl lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, and sodium bis (trimethylsilyl) amide; n-butyllithium is preferred.

In a preferred embodiment of the present invention, in the step b), the third organic solvent is one selected from tetrahydrofuran, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, methyl propyl ether, n-butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, anisole, methyl tert-butyl ether, 1, 2-dichloroethane, benzene, toluene, p-xylene, hexane, heptane and octane, preferably tetrahydrofuran; preferably, the mass ratio of the compound 2 to the third organic solvent is 1:2 to 100, preferably 1:5 to 80, more preferably 1: 8-15.

In a preferred embodiment of the present invention, wherein the acid quenching agent is selected from one of concentrated hydrochloric acid, sulfuric acid, nitric acid, acetic acid or citric acid, preferably concentrated hydrochloric acid; preferably, the mass ratio of the compound 2 to the acidic quenching agent is 1: 2-10, preferably 1: 2-5, more preferably 1: 2.5 to 3; preferably, the concentrated hydrochloric acid is 25-35% by mass.

In a preferred embodiment of the present invention, in the step b), the molar ratio of the compound 2 to the base is 1:2.0 to 6.0, preferably 1:2.0 to 2.5; preferably, the molar ratio of the compound 2 to the N, N-dimethylformamide is 1: 1.0-10.0, preferably 1: 1.0-5, and more preferably 1: 1.0-1.5.

In a preferred embodiment of the invention, in the step b), the temperature of the added alkali is-40 to 30 ℃, preferably-20 to 0 ℃; preferably, the reaction time is 2 to 12 hours; preferably, the temperature for adding the N, N-dimethylformamide is-40-25 ℃, and preferably-20 ℃; preferably, the reaction time is 2 to 12 hours, preferably 4 to 6 hours.

In a preferred embodiment of the present invention, in the step b), the quenching reaction temperature is-10 to 30 ℃, preferably 0 to 5 ℃; preferably, the cyclization reaction temperature is 0-45 ℃, and preferably 40-45 ℃; preferably, the reaction time for the cyclization is 1 to 6 hours.

In a preferred embodiment of the present invention, the step a) comprises the following steps (1) and (2):

In a preferred embodiment of the present invention, in the step (2), the compound 2-amino-3-methyl-5-methoxypyridine is dissolved in a second organic solvent, and then reacted with an amino protecting agent and a base in the presence of a second catalyst to obtain the amino protected compound 2, wherein in the compound 2, R is an amino protecting group; preferably, after the reaction with the amino protective agent and the alkali, a quenching agent is further added for quenching, and the amino-protected compound 2 is obtained by recrystallization; preferably, the compound 2-amino-3-methyl-5-methoxypyridine may be reacted with the amino protecting agent and then with the base to obtain the compound 2, or the compound 2-amino-3-methyl-5-methoxypyridine may be reacted with the base and then with the amino protecting agent to obtain the compound 2.

In a preferred embodiment of the present invention, in step (1), the first organic solvent is selected from one or more of methanol, ethanol, ethylene glycol, propanol, isopropanol, glycerol, methyl glycol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, methyl glycerol, 2-methyl glycerol and dimethyl glycol, preferably methanol; preferably, the mass ratio of the compound 1 to the first organic solvent is 1: 0.5-50, preferably 1: 3-10.

In a preferred embodiment of the present invention, wherein, in step (1), the first catalyst is selected from one of metallic copper, cuprous salt or copper salt; preferably, the first catalyst is selected from one of copper powder, cuprous bromide, cuprous oxide, cupric oxide or cupric sulfate; preferably, the molar ratio of the compound 1 to the first catalyst is 1: 0.05-2.0, preferably 1: 0.1-1.5, and more preferably 1: 0.1-0.5; preferably, the methoxide is selected from one of sodium methoxide, potassium methoxide and lithium methoxide, and is preferably sodium methoxide; preferably, the molar ratio of the compound 1 to the methoxide is 1: 0.8-20, preferably 1: 1-15, and more preferably 1: 1.5-3.0.

In a preferred embodiment of the present invention, in step (1), the reaction temperature is 80 to 150 ℃, preferably 100 to 130 ℃, and more preferably 120 to 130 ℃; preferably, the reaction time is 1 to 20 hours, preferably 1 to 15 hours, and more preferably 3 to 8 hours.

In a preferred embodiment of the present invention, wherein, in the step (2), the second organic solvent is one or more selected from tetrahydrofuran, acetonitrile, methanol, ethanol, ethylene glycol, propanol, isopropanol, glycerol, methyl glycol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, methyl glycerol, 2-methyl glycerol, dimethyl ethylene glycol and tert-butanol, preferably tert-butanol; preferably, the mass ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the second organic solvent is 1: 0.5-30.0, preferably 1: 1-20, and more preferably 1: 1.0-5.0.

In a preferred embodiment of the present invention, wherein, in the step (2), the second catalyst is selected from one or more of pyridine, N-diisopropylethylamine, tetramethylethylenediamine, tripropylamine, 4-dimethylaminopyridine, triethylenediamine, tetrabutylammonium hydroxide, γ -chloropropylmethyldimethoxysilane, N-methylmorpholine and triethylamine, preferably 4-dimethylaminopyridine; preferably, the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the second catalyst is 1:0.01 to 1:1.0, preferably 1:0.02 to 0.2, and more preferably 1:0.02 to 0.05.

In a preferred embodiment of the present invention, wherein, in step (2), the amino protecting agent is di-tert-butyl dicarbonate; preferably, during the reaction, the amino protective agent is added dropwise in a form of melting into a liquid state or dissolving in a fourth organic solvent; preferably, the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the amino protective agent is 1: 1-10, preferably 1: 1.1-5, and more preferably 1: 2.1-2.5; preferably, the fourth organic solvent is one or more selected from tetrahydrofuran, acetonitrile, methanol, ethanol, ethylene glycol, propanol, isopropanol, glycerol, methyl glycol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, methyl glycerol, 2-methyl glycerol, dimethyl glycol and tert-butanol, preferably tert-butanol; preferably, the mass ratio of the amino protective agent to the fourth organic solvent is 1: 0.5-30, preferably 1: 1-20, and more preferably 1: 0.5-4.

In a preferred embodiment of the present invention, wherein, in step (2), the base is selected from one of hydroxides of alkali metals or alkaline earth metals, carbonates of alkali metals or alkaline earth metals, alkyl salts of alkali metals, diisopropylaminates of alkali metals or bistrimethylsilyl amide salts, preferably one of sodium hydroxide, potassium hydroxide, n-butyllithium, sec-butyllithium, isobutyllithium, tert-butyllithium or bistrimethylsilyl amide sodium; preferably, the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the base is 1: 1.0-5.0, preferably 1: 1.5-2.5.

In a preferred embodiment of the present invention, in the step (2), the reaction temperature is-40 ℃ to 85 ℃, preferably 60 ℃ to 85 ℃; preferably, the reaction time after the amino protective agent is added is 1-40 hours; preferably, the reaction time after the alkali is added is 1-40 hours, preferably 6-10 hours; preferably, the reaction temperature after the amino protective agent is added is-40 ℃ to 85 ℃, preferably 60 ℃ to 85 ℃, and the reaction temperature after the alkali is added is-40 ℃ to 85 ℃, preferably 60 ℃ to 85 ℃.

In a preferred embodiment of the present invention, the quenching agent is selected from one of hydrochloric acid, sulfuric acid, nitric acid, water, formic acid, acetic acid or citric acid.

The following examples are provided to illustrate the synthesis of the invention in further detail, wherein the chemicals used in the examples are all of the chemically pure grade of conventional reagents.

EXAMPLE Synthesis of 5-methoxy-7-azaindole

The synthetic route is as follows:

(1) synthesis of Compound 2-amino-3-methyl-5-methoxypyridine:

adding 400.0g (2.14mol, 1.0eq) of compound 1 and 2kg of methanol into a 5L autoclave, stirring until the solid is completely dissolved, sequentially adding 346.6g (6.42mol, 3.0eq) of sodium methoxide and 68.0g (1.07mol, 0.5eq) of copper powder, heating to 130 ℃ for reacting for 8 hours, cooling to 25 ℃, filtering the materials in the autoclave, leaching a filter cake with a small amount of methanol, concentrating a mother solution until the mother solution is cut off, adding dichloromethane and water into the mixture to extract and separate layers, extracting a water phase once again with dichloromethane, combining an organic phase, concentrating and recovering the solvent, rectifying a crude product under reduced pressure by a 40cm packing column, collecting a fraction T85-90 ℃/P2-3 mmHg, obtaining 153.5g of compound in total, wherein the purity is 98.4%, and the yield is 52%;

the structure of the compound obtained above was confirmed by GC (Agilent 7820A), and the results are shown in fig. 1, and the retention time, peak area, and peak height of each peak are shown in the following table:

the structure of the compound obtained in step (1) was confirmed by GC-MS, and the results are shown in FIG. 2, in which Agilent GC 7890 and MS 5975 were used as the equipment

The chromatographic column has DB-5ms, 30m × 0.25mm, and film thickness of 0.25 μm

Carrier gas: flow rate of He column: 0.7ml/min was unchanged

Sample inlet temperature: 280 ℃, ion source temperature: 230 deg.C

MS temperature: 150 ℃, Aux-2 temperature: 200 deg.C

The split ratio is as follows: 100:1

Temperature of the column box: keeping at 70 deg.C for 0min, and keeping at 10 deg.C/min to 280 deg.C for 10min

Dissolving 100mg of sample in 1ml of acetonitrile, injecting 0.1 mu l of the sample, recording a spectrogram, and comparing fragments with a standard to obtain;

as can be seen from fig. 1 and 2, the resulting compound is 2-amino-3-methyl-5-methoxypyridine;

(2) synthesis of Compound 2:

adding 20.7g (0.15mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in step (1) and 82.9g of tert-butanol into a 500ml four-necked flask at 40 ℃, adding 1.1g (0.007mol, 0.05eq) of 4-dimethylaminopyridine after all the materials are dissolved, heating to 80-85 ℃, dissolving 81.8g (0.38mol, 2.5eq) of di-tert-butyl dicarbonate in 82.9g of tert-butanol, keeping the temperature in the four-necked flask at 80-85 ℃, dropwise adding, continuing to react for 6 hours at the temperature after dropwise adding to obtain an intermediate compound, adding 12.0g of sodium hydroxide (0.30mol, 2.0eq), continuing to react at the temperature, when the reaction time is 6 hours, quenching the reaction liquid to neutrality by using acetic acid after the reaction is finished, heating to 80-85 ℃, distilling off the solvent to stop flowing, Extracting with tetrahydrofuran for 2 times, then combining the organic phases, evaporating the solvent to dryness, and crystallizing to obtain 34.0g of compound 2 with a yield of 95%;

the structure of the obtained compound 2 was confirmed by HPLC, and its spectrum is shown in fig. 3, in which retention time, peak width, peak area, peak height, and peak area% are shown in the following table:

peak #	Retention time (min)	Peak width (min)	Peak area (mAU s)	Peak height (mAU)	Peak area (%)
						1	3.054	0.0596	5.94597	1.52166	0.2059
2	3.389	0.0482	8.74662e-1	2.81860e-1	0.0303
						3	4.582	0.0535	1.89292	5.32736e-1	0.0655
4	6.422	0.0510	2876.74316	861.54211	99.6075
						5	6.797	0.0558	2.05389	5.72743e-1	0.0711
6	7.880	0.0736	5.68572e-1	1.19322e-1	0.0197
						Total amount of			2888.07918	864.57043	100％

As can be seen from fig. 3, the purity of the obtained compound 2 was 99.6%.

Performing structure confirmation on the obtained compound 2 by adopting LC-MS, wherein the spectrogram is shown in figure 4, wherein a mobile phase A is 0.1% formic acid aqueous solution, and the preparation method comprises the steps of dissolving 1ml formic acid in 1000ml water and uniformly mixing; the mobile phase B is acetonitrile, and the gradient elution is carried out according to the following mode, the chromatographic column is Agilent poroshell 120EC-C18,4 mu m and 150 multiplied by 4.6mm (cargo number: 693970-902), the detection wavelength is 220nm, the column temperature is 30 ℃, the flow rate is 1.0ml/min, the voltage is 150V, the gas temperature is 325 ℃, the dry gas flow is 11l/min, and the sample injection amount is 0.5 microliter.

Time (min)	Mobile phase A (V/V%)	Mobile phase B (V/V%)
			0	95	5
10	10	90
			13	10	90
13.1	95	5
			16	95	5

As can be seen from FIG. 4, the resulting compound 2 is 2-tert-butoxyamino-3-methyl-5-methoxypyridine.

The structure of the obtained Compound 2 was confirmed to be H¹NMR (Bruker 400MHz) was confirmed, the results of which are shown in FIG. 5;

as can be seen from FIG. 5, the obtained compound 2 is 2-tert-butoxyamino-3-methyl-5-methoxypyridine, 93.26% in the figure is the content of the compound 2 measured by the nuclear magnetic internal standard method, and the internal standard substance is 1,3, 5-trimethoxybenzene;

(3) synthesis of the product

Introducing nitrogen into a 2L four-mouth bottle, adding 72.0g (0.3mol, 1.0eq) of the compound 2 obtained in the step (2) and 720ml of tetrahydrofuran, cooling to-10 +/-5 ℃, dropwise adding 204.0g (0.75mol, 2.5eq) of 2.5M N-butyllithium in hexane at the temperature, reacting for 2.5 hours at the temperature after dropwise adding, dropwise adding 26.3g (0.36mol, 1.2eq) of N, N-dimethyl formamide at the temperature, stirring for 6 hours at-10 +/-5 ℃ after dropwise adding until the reaction is complete, slowly pouring the mixture in the bottle at 0 +/-5 ℃ into 216g of 35% concentrated hydrochloric acid, quenching the reaction at 0 +/-5 ℃, heating the reaction solution to 40-45 ℃ for 2 hours, removing the organic layer in layers after the reaction is finished, neutralizing the aqueous phase with sodium hydroxide until the pH is 11-12, extracting with tetrahydrofuran twice, washing the combined organic phase with saturated salt solution once, combining the organic phases, recovering the solvent, and crystallizing to obtain 35.3g of product with the yield of 79%;

the structure of the obtained product was confirmed by HPLC, and the spectrum thereof is shown in fig. 6, in which retention time, peak width, peak area, peak height, and peak area% are shown in the following table:

peak #	Retention time (min)	Peak width (min)	Peak area (mAU s)	Peak height (mAU)	Peak area (%)
						1	3.106	0.0577	6.41556	1.71332	0.0998
2	3.793	0.0551	3.60813	1.02432	0.0561
						3	5.189	0.0652	14.62234	3.20728	0.2275
4	5.771	0.0524	6396.51953	1943.46350	99.5289
						5	6.727	0.0650	5.63282	1.24069	0.0876
Total amount of			6426.79838	1950.64911	100％

As can be seen from fig. 6, the purity of the obtained product was 99.5%.

Performing structure confirmation on the obtained product by LC-MS, wherein the spectrogram is shown in FIG. 7, mobile phase A is 0.1% formic acid water solution, and the preparation method comprises dissolving 1ml formic acid in 1000ml water, and mixing; the mobile phase B is acetonitrile, and the gradient elution is carried out according to the following mode, wherein a chromatographic column is Agilent poroshell 120EC-C18,4 mu m and 150 multiplied by 4.6mm (cargo number: 693970-902), the detection wavelength is 220nm, the column temperature is 30 ℃, the flow rate is 1.0ml/min, the voltage is 150V, the gas temperature is 325 ℃, the dry gas flow is 11l/min, and the sample injection amount is 0.5 microliter.

As can be seen in FIG. 7, the resulting product is 5-methoxy-7-azaindole.

The structure of the obtained product was confirmed by H¹Confirmation by NMR, the results of which are shown in FIG. 8;

as can be seen from FIG. 8, the obtained product is 5-methoxy-7-azaindole, 94.88% in the figure is the content of the product determined by a nuclear magnetic internal standard method, and the internal standard substance is 1,3, 5-trimethoxybenzene.

EXAMPLE Synthesis of bis 5-methoxy-7-azaindole

(1) Synthesis of Compound 2-amino-3-methyl-5-methoxypyridine:

adding 200.0g (1.07mol, 1.0eq) of compound 1 and 1kg of methanol into a 2L autoclave, stirring until all solids are dissolved, sequentially adding 173.4g (3.21mol, 3.0eq) of sodium methoxide and 76.8g (0.53mol, 0.5eq) of cuprous bromide, heating to 130 ℃ for reaction for 20 hours, cooling to 25 ℃, filtering the materials in the autoclave, leaching a filter cake with a small amount of methanol, concentrating a mother liquor until cut off, adding dichloromethane and water for extraction and demixing, extracting a water phase once again with dichloromethane, combining organic phases, concentrating until cut off, performing reduced pressure rectification on a crude product through a 40cm packing column, collecting fractions with the T being 85-90 ℃/P being 2-3mmHg, obtaining 43.0g of compound in total, wherein the purity is 98.2%, and the yield is 29%;

the obtained compound was analyzed in the same manner as in example one, and it was confirmed that the obtained compound was 2-amino-3-methyl-5-methoxypyridine;

(2) synthesis of Compound 2:

adding 20.7g (0.15mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in step (1) and 621g of tetrahydrofuran into a 2L four-neck flask at 0 ℃, adding 0.12g (0.0015mol, 0.01eq) of pyridine after all the materials are dissolved, cooling to-10 ℃, dissolving 81.8g (0.38mol, 2.5eq) of di-tert-butyl dicarbonate in 82.9g of tetrahydrofuran, maintaining the temperature in the four-neck flask at-10-0 ℃, dropwise adding, continuing to react at the temperature for 8 hours to obtain an intermediate compound after the dropwise adding is finished, then adding 12.0g of sodium hydroxide (0.30mol, 2.0eq), continuing to react at the temperature for 6 hours, after the reaction is finished, quenching the reaction liquid to be neutral by 25% hydrochloric acid, separating an organic layer, then combining the organic layer, evaporating the solvent to dryness and then crystallizing, 18.2g of compound 2 was obtained, purity 94.3%, yield 51%;

the obtained compound 2 was confirmed by the same method as in example one, and the obtained compound 2 was analyzed to be 2-tert-butoxyamino-3-methyl-5-methoxypyridine;

(3) synthesis of the product

Introducing nitrogen into a 1L four-mouth bottle, adding 22.7g (0.096mol, 1.0eq) of the compound 2 obtained in the step (2) and 340.5ml of tetrahydrofuran, cooling to-40 +/-5 ℃, dropwise adding 52.0g (0.192mol, 2.0eq) of 2.5M N-butyllithium in hexane at the temperature, keeping the temperature at-40 +/-5 ℃ for further reaction for 2 hours after the dropwise addition is finished, dropwise adding 10.5g (0.144mol, 1.5eq) of N, N-dimethylformamide at the temperature, keeping the temperature at-40 +/-5 ℃ for stirring for 20 hours after the dropwise addition is finished, keeping the mixture in the bottle at 0 +/-5 ℃ and slowly pouring into 45.4g of 35% concentrated hydrochloric acid for quenching reaction, keeping the temperature at 0 +/-5 ℃ for quenching reaction, heating the reaction solution to 40-45 ℃ for 2 hours, demixing and removing an organic layer after the reaction is finished, neutralizing an aqueous phase with sodium hydroxide until the pH is 12-11, extracting with tetrahydrofuran twice, washing the combined organic phase with saturated salt solution once, combining the organic phases, recovering the solvent, and crystallizing to obtain 10.0g of product with purity of 95.6% and yield of 71%;

the structure of the obtained product was confirmed in the same manner as in example one, and it was confirmed that the obtained product was 5-methoxy-7-azaindole.

EXAMPLE Synthesis of tris 5-methoxy-7-azaindole

(1) Synthesis of Compound 2-amino-3-methyl-5-methoxypyridine:

adding 200.0g (1.07mol, 1.0eq) of compound 1 and 1kg of methanol into a 2L autoclave, stirring until all solids are dissolved, sequentially adding 225.1g (3.21mol, 3.0eq) of potassium methoxide and 42.6g (0.54mol, 0.5eq) of copper sulfate, heating to 130 ℃ for reaction for 20 hours, cooling to 25 ℃, filtering the materials in the autoclave, leaching a filter cake with a small amount of methanol, concentrating a mother liquor until the mother liquor is cut off, adding dichloromethane and water for extraction and demixing, extracting an aqueous phase once again by dichloromethane, concentrating an organic phase until the organic phase is cut off, performing reduced pressure rectification on a crude product through a 40cm packing column, collecting a fraction T mmHg of 85-90 ℃/P of 2-3, obtaining 67.6g of compound in total, wherein the purity is 98.1%, and the yield is 46%;

the structure of the obtained compound was confirmed in the same manner as in example one, and it was confirmed that the obtained compound was 2-amino-3-methyl-5-methoxypyridine.

(2) Synthesis of Compound 2:

adding 20.7g (0.15mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in step (1) and 20.7g of acetonitrile into a 500ml four-necked flask, adding 1.8g (0.015mol, 0.1eq) of 4-dimethylaminopyridine after the materials are completely dissolved, heating to 20-25 ℃, dissolving 35.5g (0.165mol, 1.1eq) of di-tert-butyl dicarbonate in 142g of tetrahydrofuran, maintaining the temperature in the four-necked flask at 20-25 ℃, dropwise adding, continuing to react at the temperature for 8 hours to obtain an intermediate compound, adding 21g of potassium hydroxide (0.375mol, 2.5eq) and continuing to react at the temperature for 8 hours, after the reaction is finished, quenching the reaction solution to neutrality with 25% hydrochloric acid, separating an organic layer, combining the organic layer, evaporating the solvent to dryness and then crystallizing, 8.6g of compound 2 was obtained with a purity of 95.0% and a yield of 24%;

the structure of the obtained compound 2 was confirmed in the same manner as in example one, and it was confirmed that the obtained compound 2 was 2-tert-butoxyamino-3-methyl-5-methoxypyridine.

(3) Synthesis of the product

Introducing nitrogen into a 1L four-mouth bottle, adding 22.7g (0.096mol, 1.0eq) of compound 2 and 181.6ml of tetrahydrofuran, cooling to-10 +/-5 ℃, controlling the temperature, dropwise adding 155.9g (0.576mol, 6.0eq) of 2.5M lithium diisopropylamide solution in hexane at the temperature, continuing to react at the temperature for 3 hours after the dropwise addition is finished, dropwise adding 7.0g (0.096mol, 1eq) of N, N-dimethylformamide at the temperature, keeping at-10 +/-5 ℃ and stirring for 7 hours after the dropwise addition is finished, keeping the mixture in the bottle at 0 +/-5 ℃ and slowly pouring into 56.8g of 25% hydrochloric acid, keeping at 0 +/-5 ℃ for quenching reaction, raising the temperature to 40-45 ℃ after the quenching is finished, reacting for 2.5 hours, demixing and removing an organic layer after the reaction is finished, neutralizing the aqueous phase to pH by sodium hydroxide, extracting twice by tetrahydrofuran, the combined organic phases were washed once with saturated brine and the combined organic phases were crystallized after recovery of the solvent to give 7.9g of product with a purity of 96.1% and a yield of 56%.

EXAMPLE Synthesis of tetra-5-methoxy-7-azaindole

(1) Synthesis of Compound 2-amino-3-methyl-5-methoxypyridine:

adding 40.0g (0.21mol, 1.0eq) of compound 1 and 2000g of ethanol into a 5L high-pressure autoclave, stirring until the solid is completely dissolved, sequentially adding 12.0g (0.315mol, 1.5eq) of lithium methoxide and 3.0g (0.021mol, 0.1eq) of cuprous bromide, heating to 140 ℃ and 150 ℃ for reaction for 8 hours, cooling to 25 ℃, filtering the materials in the autoclave, leaching filter cakes with a small amount of methanol, concentrating mother liquor until cut-off, adding dichloromethane and water for extraction and demixing, extracting the water phase once again with dichloromethane, combining organic phases and concentrating until cut-off, performing reduced pressure rectification on the crude product through a 40cm filler column, collecting fractions with the T being 85-90 ℃/P being 2-3mmHg, obtaining 8.3g of compound in total, the purity being 98.2%, and the yield being 28%;

the structure of the obtained compound was confirmed by the same method as in example one, and it was confirmed that the obtained compound was 2-amino-3-methyl-5-methoxypyridine;

(2) synthesis of Compound 2

Adding 37.3g (0.27mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in step (1) and 187.0g of tetrahydrofuran into a 500ml four-necked flask, dropwise adding 110.2g (0.41mol, 1.5eq) of a 2.5M n-butyllithium hexane solution into the reaction solution at-5 ℃ after the materials are completely dissolved, reacting at-5 ℃ for 1-2 hours, dropwise adding 123.1g (0.57mol, 2.1eq) of di-tert-butyl dicarbonate into the reaction solution at-5 ℃ and maintaining the temperature at-5 ℃ for reaction for 3 hours, quenching the reaction mixture with water, filtering to collect precipitates, washing the filter cake with water, and then vacuum drying to obtain 33.5g of the compound 2 with purity of 92.8%, yield of 52%;

the structure of the obtained compound 2 was confirmed in the same manner as in example one, and it was confirmed that the obtained compound 2 was 2-tert-butoxyamino-3-methyl-5-methoxypyridine;

(3) synthesis of the product

Introducing nitrogen into a 500ml four-neck flask for protection, adding 22.7g (0.096mol, 1.0eq) of the compound 2 obtained in the step (2) and 113.5ml of tetrahydrofuran, cooling to-10 +/-5 ℃, dropwise adding 65g (0.24mol, 2.5eq) of 2.5M N-butyllithium in hexane at the temperature, continuing the reaction at the temperature for 3 hours after the dropwise addition, dropwise adding 33.2g (0.48mol, 5eq) of N, N-dimethylformamide at the temperature, stirring at-10 +/-5 ℃ for 6 hours after the dropwise addition, slowly pouring the mixture in the flask at 0 +/-5 ℃ into 136.2g of 25% hydrochloric acid, quenching the reaction at the temperature of 0 +/-5 ℃, then heating the quenched reaction solution to 40-45 ℃ for reaction for 3.5 hours, removing the organic layer by layer after the reaction is finished, neutralizing the aqueous phase with sodium hydroxide until the pH is 7-8, filtration gave 7.8g of product, 98.5% purity and 55% yield.

EXAMPLE Synthesis of penta-5-methoxy-7-azaindole

(1) Synthesis of Compound 2-amino-3-methyl-5-methoxypyridine:

40.0g (0.21mol, 1.0eq) of the compound 1 and 200g of methanol are added into a 500ml autoclave, the mixture is stirred until all solids are dissolved, 34.7g (0.64mol, 3.0eq) of sodium methoxide and 7.2g (0.11mol, 0.5eq) of cuprous bromide are sequentially added, the mixture is heated to 100 ℃ and reacted for 20 hours, the temperature is reduced to 25 ℃, the materials in the autoclave are filtered, a small amount of methanol is used for leaching filter cakes, mother liquor is concentrated until the flow is cut off, dichloromethane and water are added into the mixture for extraction and demixing, the water phase is extracted once again by dichloromethane, the organic phase is combined and concentrated until the flow is cut off, the crude product is rectified under reduced pressure by a 40cm filler column, fractions with the T being 85-90 ℃/P being 2-3mmHg are collected, 8.9g of the compound is obtained in total, the purity is 97.6%, and the yield is 30%.

The structure of the obtained compound was confirmed in the same manner as in example one, and the obtained compound was confirmed to be 2-amino-3-methyl-5-methoxypyridine;

(2) synthesis of Compound 2:

adding 37.3g (0.27mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in step (1) and 187.0g of tetrahydrofuran into a 500ml four-necked flask, dropwise adding 161.6g (0.59mol, 2.2eq) of a 2.5M hexane solution of n-butyllithium into the reaction solution at-5 ℃ after the materials are completely dissolved, reacting at-5 ℃ for 1-2 hours, adding 73.7g (0.34mol, 1.25eq) of di-tert-butyl dicarbonate into the reaction solution at-5 ℃ and reacting at-5 ℃ for 3 hours, quenching the reaction mixture with citric acid, filtering and collecting precipitates, washing the filter cake with water, and crystallizing in an organic solvent to obtain 28.3g of compound 2 with purity of 97.8% and yield of 44%;

the structure of the obtained compound 2 was confirmed in the same manner as in example one, and it was confirmed that the obtained compound 2 was 2-tert-butoxyamino-3-methyl-5-methoxypyrimidine;

(3) synthesis of the product

Introducing nitrogen into a 250ml four-mouth bottle, adding 22.7g (0.096mol, 1.0eq) of the compound 2 obtained in the step (2) and 68ml of tetrahydrofuran, cooling to-10 +/-5 ℃, dropwise adding 65g (0.24mol, 2.5eq) of 2.5M N-butyllithium hexane solution at the temperature, continuing to react at the temperature for 3 hours after dropwise adding, dropwise adding 8.3g (0.12mol, 1.2eq) of N, N-dimethyl formamide at the temperature, keeping at-10 +/-5 ℃ for 4 hours after dropwise adding, keeping the mixture in the bottle at 0 +/-5 ℃, slowly pouring into 68.3g of 35% hydrochloric acid for quenching reaction, keeping at 0 +/-5 ℃ all times for quenching, then heating the quenched reaction solution to 40-45 ℃ for reacting for 1.5 hours, removing the organic layer by layer after the reaction is finished, neutralizing the aqueous phase with sodium hydroxide until the pH is 11-12, extracting with tetrahydrofuran twice, washing the combined organic phase with saturated salt solution once, combining the organic phases, recovering the solvent, and crystallizing to obtain 1.7g of product with purity of 89.1% and yield of 12%;

EXAMPLE synthesis of hexa5-methoxy-7-azaindole

(1) Synthesis of Compound 2-amino-3-methyl-5-methoxypyridine:

adding 40.0g (0.21mol, 1.0eq) of compound 1 and 200g of methanol into a 500ml autoclave, stirring until all solids are dissolved, sequentially adding 170g (3.15mol, 15eq) of sodium methoxide and 5.1g (0.06mol, 0.3eq) of copper oxide, heating to 140 ℃ and 150 ℃ for reaction for 8 hours, cooling to 25 ℃, filtering materials in the autoclave, leaching filter cakes with a small amount of methanol, concentrating mother liquor until cut off, adding dichloromethane and water for extraction and layering, extracting a water phase once again by dichloromethane, concentrating an organic phase until cut off, rectifying a crude product under reduced pressure by a 40cm packing column, collecting a fraction T.mmHg-85-90 ℃/P-2-3, obtaining 12.1g of compound in total, wherein the purity is 96.9%, and the yield is 41%;

the structure of the obtained compound was confirmed in the same manner as in example one, and it was confirmed that the obtained compound was 2-amino-3-methyl-5-methoxypyridine;

(2) synthesis of Compound 2

Adding 9.4g (0.05mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxy pyridine obtained in the step (1) into 47.0g of tetrahydrofuran to prepare a solution A for later use; introducing nitrogen into a 250ml four-neck flask for protection, adding 22.1g (0.12mol, 2.4eq) of 2.0M sodium bistrimethylsilyl amide (NaHMDS) tetrahydrofuran solution, dropwise adding the solution A into the reaction solution at-5 ℃, keeping the temperature of-5 ℃ for reaction for 1-2 hours, adding 4.4g (0.06mol, 1.1eq) of di-tert-butyl dicarbonate into the reaction solution at-5 ℃, keeping the temperature of-5 ℃ for reaction for 3 hours, quenching the reaction mixture with water, filtering to collect precipitates, washing filter cakes with water, and then carrying out vacuum drying to obtain 9.7g of compound 2 with the purity of 98.2% and the yield of 68%;

(3) synthesis of the product

Introducing nitrogen into a 500ml four-neck flask for protection, adding 22.7g (0.096mol, 1.0eq) of the compound 2 obtained in the step (2) and 136ml of tetrahydrofuran, cooling to-20 +/-5 ℃, dropwise adding 65g (0.24mol, 2.5eq) of 2.5M N-butyllithium hexane solution at the temperature, continuing to react at the temperature for 4 hours after dropwise adding, dropwise adding 8.3g (0.12mol, 1.2eq) of N, N-dimethyl formamide at the temperature, keeping at-20 +/-5 ℃ for 10 hours after dropwise adding, slowly pouring the mixture in the flask at 0 +/-5 ℃ into 68.3g of 35% hydrochloric acid for quenching reaction, keeping at 0 +/-5 ℃ all times for quenching, then heating the quenched reaction solution to 40-45 ℃ for reaction for 1 hour, demixing and removing an organic layer after the reaction is finished, neutralizing an aqueous phase by sodium hydroxide until the pH is 11-12, then extracting twice with tetrahydrofuran, washing the combined organic phase once with saturated salt solution, combining the organic phases, recovering the solvent, and crystallizing to obtain 5.6g of product with the purity of 93.5% and the yield of 40%.

EXAMPLE Synthesis of hepta-5-methoxy-7-azaindole

(1) Synthesis of compound 2-amino-3-methyl-5-methoxypyridine

Adding 40.0g (0.21mol, 1.0eq) of compound 1 and 200g of methanol into a 500ml high-pressure kettle, stirring until the solid is completely dissolved, sequentially adding 34.7g (0.64mol, 3.0eq) of sodium methoxide and 8.7g (0.11mol, 0.5eq) of copper oxide, heating to 140 ℃ and 150 ℃ for reaction for 8 hours, cooling to 25 ℃, filtering the materials in the kettle, leaching filter cakes with a small amount of methanol, concentrating mother liquor until cut-off, adding dichlorosilane and water into the mixture for extraction and demixing, extracting the water phase once again with dichloromethane, combining organic phases for concentrating until cut-off, performing reduced pressure rectification on the crude product through a 40cm filler column, collecting fractions with the T being 85-90 ℃/P being 2-3mmHg, obtaining 12.1g of compound in total, the purity being 98.1%, and the yield being 44%;

(2) synthesis of Compound 2

Adding 20.7g (0.15mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in step (1) and 82.9g of acetonitrile into a 250ml four-necked flask, adding 1.1g (0.007mol, 0.05eq) of 4-dimethylaminopyridine after the materials are completely dissolved, heating to 60 ℃, dissolving 32.3g (0.15mol, 1eq) of di-tert-butyl dicarbonate in 82.9g of acetonitrile, dropwise adding while maintaining the temperature of 60-65 ℃ in the four-necked flask, continuing the reaction at the temperature for 8 hours after the dropwise addition to obtain an intermediate compound, adding 12.0g of sodium hydroxide (0.30mol, 2.0eq) and continuing the reaction at the temperature for 6 hours, after the reaction is finished, quenching the reaction solution to neutrality with hydrochloric acid, cutting off the temperature to 80-85 ℃, distilling off the solvent, extracting with tetrahydrofuran for 2 times, then combining the organic phases, evaporating the solvent to dryness, crystallizing to separate out the organic layer, then combining the organic phases, evaporating the solvent to dryness, crystallizing to obtain 25.7g of compound 2 with the purity of 95.9 percent and the yield of 72 percent;

(3) and (3) synthesis of a product:

introducing nitrogen into a 500ml four-neck flask for protection, adding 22.6g (0.095mol, 1.0eq) of the compound 2 obtained in the step (2) and 121.2g of tetrahydrofuran, cooling to-10 +/-5 ℃, dropping 64.6g (0.24mol, 2.5eq) of 2.5M N-butyllithium in hexane at the temperature, stirring at-10 +/-5 ℃ for 4 hours, dropping 8.3g (0.11mol, 1.2eq) of N, N-dimethylformamide at the temperature, stirring at-10 +/-5 ℃ for 2 hours, keeping the mixture in the flask at-10 +/-5 ℃ and slowly pouring into 68.1g of 35% concentrated hydrochloric acid for quenching, keeping the temperature at 0 +/-5 ℃ for quenching, heating the quenched reaction solution to 40-45 ℃ for reaction for 2 hours, removing the organic layer, neutralizing the aqueous phase with sodium hydroxide until the pH is 11-12, then, the mixture was extracted twice with methyl t-butyl ether, and the combined organic phases were washed once with saturated brine, and then the solvent was distilled off under normal pressure to obtain 4.9g of a product having a purity of 93.3% and a yield of 35%.

EXAMPLE Synthesis of octa5-methoxy-7-azaindole

(1) Synthesis of compound 2-amino-3-methyl-5-methoxypyridine

Adding 40.0g (0.21mol, 1.0eq) of compound 1 and 120g of methanol into a 200ml high-pressure kettle, stirring until the solid is completely dissolved, sequentially adding 12.7g (0.23mol, 1.1eq) of sodium methoxide and 20.0g (0.32mol, 1.5eq) of copper powder, heating to 100 ℃ and 105 ℃ for reaction for 15 hours, cooling to 25 ℃, filtering the materials in the kettle, leaching a filter cake with a small amount of methanol, concentrating a mother solution until cut off, adding dichlorosilane and water into the mixture for extraction and demixing, extracting the water phase once again with dichloromethane, combining organic phases for concentrating until cut off, rectifying the crude product under reduced pressure through a 40cm filler column, collecting fractions with the T being 85-90 ℃/P being 2-3mmHg, obtaining 5.6g of compound in total, the purity being 92.5%, and the yield being 19%;

(2) synthesis of Compound 2:

adding 20.7g (0.15mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in the step (1) and 414g of methanol into a 2L four-neck flask at 0 ℃, adding 0.37g (0.003mol, 0.02eq) of 4-dimethylaminopyridine after all the materials are dissolved, heating to 60 ℃, dissolving 81.8g (0.38mol, 2.5eq) of di-tert-butyl dicarbonate in 122.8g of tert-butyl alcohol, keeping the temperature in the four-neck flask at 60-65 ℃, dropwise adding, keeping the temperature at 80-85 ℃ after dropwise adding, continuously reacting for 1 hour to obtain an intermediate compound, adding 30.0g of sodium hydroxide (0.75mol, 5.0eq), continuously reacting at the temperature for 40 hours, quenching the reaction liquid with dilute acetic acid to be neutral, heating to 80-85 ℃, distilling to remove the solvent to 80-85 ℃, and distilling to remove the solvent, Extracting with tetrahydrofuran for 2 times, combining organic phases, evaporating the solvent to dryness, crystallizing to separate out the organic layer, combining the organic phases, evaporating the solvent to dryness, crystallizing to obtain 7.5g of compound 2 with the purity of 88.2% and the yield of 21%;

(3) and (3) synthesis of a product:

introducing nitrogen into a 3L four-neck flask, adding 22.6g (0.096mol, 1.0eq) of the compound 2 obtained in step (2) and 1816g of acetonitrile, cooling to-5 deg.C, dropwise adding 64.8g (0.24mol, 2.5eq) of 2.5M N-butyllithium in hexane at the temperature, after the dropwise addition, keeping at-5 deg.C and stirring for 6 hours, dropwise adding 69.6g (0.96mol, 10eq) of N, N-dimethylformamide at the temperature, keeping at 20-25 deg.C and stirring for 24 hours after the dropwise addition, keeping the mixture in the flask at-10 + -5 deg.C and slowly pouring into 45.4g of acetic acid to quench the reaction, keeping at the temperature and reacting for 6 hours, removing the organic layer, neutralizing the aqueous phase with sodium hydroxide to pH 11-12, extracting with methyl tert-butyl ether twice, washing the combined organic phase with saturated saline once, distilling under normal pressure to remove the solvent to obtain 1.6g of product with the purity of 85.6 percent and the yield of 11 percent;

EXAMPLE Synthesis of nona-5-methoxy 7-azaindole

(1) Synthesis of compound 2-amino-3-methyl-5-methoxypyridine

Adding 40.0g (0.21mol, 1.0eq) of compound 1 and 20g of methanol into a 200ml high-pressure kettle, stirring until the solid is completely dissolved, sequentially adding 17.0g (0.32mol, 1.5eq) of sodium methoxide and 0.14g (0.01mol, 0.05eq) of copper powder, heating to 80-85 ℃ for reaction for 3 hours, cooling to 25 ℃, filtering the materials in the kettle, leaching a filter cake with a small amount of methanol, concentrating a mother solution until cut off, adding dichloromethane and water into the mixture for extraction and demixing, extracting the water phase once again with dichloromethane, combining organic phases for concentrating until cut off, performing reduced pressure rectification on the crude product through a 40cm filler column, collecting fractions with the T being 85-90 ℃/P being 2-3mmHg, obtaining 1.5g of compound in total, wherein the purity is 89.8%, and the yield is 5%;

(2) synthesis of Compound 2

Adding 20.7g (0.15mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in step (1) and 103.6g of tetrahydrofuran into a 1L four-necked flask at 0 ℃, then adding 3.7g (0.03mol, 0.2eq) of 4-dimethylaminopyridine, cooling to-40 ℃, keeping-40 +/-5 ℃, adding 40.8g (0.15mol, 1.0eq) of 2.5M n-butyllithium in hexane, continuing to react for 15 hours at the temperature, dissolving 327.4g (1.5mol, 10eq) of di-tert-butyl dicarbonate in 40.9g of tetrahydrofuran, keeping the temperature in the four-necked flask at-40 +/-5 ℃, dropwise adding, continuing to react for 40 hours at the temperature after dropwise adding, quenching the reaction solution to neutrality with 25% hydrochloric acid after the reaction is finished, heating to 80-85 ℃, removing the solvent by evaporation, and stopping the flow, extracting with tetrahydrofuran for 2 times, combining the organic phases, evaporating the solvent to dryness, crystallizing to separate out the organic layer, combining the organic phases, evaporating the solvent to dryness, crystallizing to obtain 13.2g of compound 2 with the purity of 89.5 percent and the yield of 37 percent;

(3) and (3) synthesis of a product:

introducing nitrogen into a 3L four-port bottle, adding 22.6g (0.095mol, 1.0eq) of the compound 2 obtained in the step (2) and 2270g of dichloromethane, cooling to-5 ℃, dropwise adding 51.8g (0.19mol, 2.0eq) of 2.5M N-butyllithium in hexane at the temperature, keeping the temperature at 30 +/-5 ℃ after dropwise adding, continuing stirring for 2 hours, then cooling to-10 +/-5 ℃, dropwise adding 55.7g (0.77mol, 8.0eq) of N, N-dimethylformamide, keeping the temperature at-10 +/-5 ℃ after dropwise adding, stirring for 6 hours, slowly raising the mixture in the bottle to 10 +/-5 ℃, slowly pouring into 136.2g of 30% citric acid while keeping the temperature, continuing the reaction for 6 hours at the temperature, removing an organic layer, neutralizing an aqueous phase with sodium hydroxide until the pH is 11-12, extracting twice with methyl tert-butyl ether, washing the combined organic phase with saturated salt solution, and distilling under normal pressure to remove solvent to obtain 2.0g of product with purity of 88.7% and yield of 14%;

Example Synthesis of deca5-methoxy-7-azaindole

(1) Synthesis of compound 2-amino-3-methyl-5-methoxypyridine

Adding 40.0g (0.21mol, 1.0eq) of compound 1 and 2000g of methanol into a 5L autoclave, stirring until all solids are dissolved, sequentially adding 9.3g (0.17mol, 0.8eq) of sodium methoxide and 27.2g (0.43mol, 2.0eq) of copper powder, heating to 120 ℃ and 125 ℃ for reaction for 8 hours, cooling to 25 ℃, filtering the materials in the autoclave, leaching filter cakes with a small amount of methanol, concentrating mother liquor until cut off, adding dichloromethane and water into the mixture for extraction and demixing, extracting the water phase once again by dichloromethane, combining organic phases for concentration until cut off, carrying out reduced pressure rectification on the crude product by a 40cm packing column, collecting fractions with the T being 85-90 ℃/P being 2-3mmHg, obtaining 5.3g of compound in total, the purity being 90.3%, and the yield being 18%;

(2) Synthesis of Compound 2

Adding 20.7g (0.15mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in the step (1) and 621g of tetrahydrofuran into a 2L four-neck flask at 0 ℃, adding 18.3g (0.15mol, 1.0eq) of 4-dimethylaminopyridine after the materials are completely dissolved, and cooling to 0 ℃; maintaining the temperature, dropwise adding 82.5g (0.45mol,3.0eq) of sodium bistrimethylsilyl amide, and reacting at the temperature for 6 hours; dissolving 81.8g (0.38mol, 3.0eq) of di-tert-butyl dicarbonate in 40.9g of tetrahydrofuran, keeping the temperature in a four-mouth bottle at 0-5 ℃, dropwise adding, continuing to react for 30 hours at 20-25 ℃ after dropwise adding, quenching the reaction solution to be neutral by 25% hydrochloric acid after the reaction is finished, heating to 80-85 ℃, distilling off the solvent until the solution is cut off, extracting for 2 times by the tetrahydrofuran, combining organic phases, crystallizing after the solvent is evaporated to dryness, separating an organic layer, combining the organic phases, crystallizing after the solvent is evaporated to dryness, obtaining 18.6g of compound 2 with the purity of 95.5%, and the yield of 52%;

(3) and (3) synthesis of a product:

introducing nitrogen into a 2L four-neck flask for protection, adding 22.7g (0.096mol, 1.0eq) of the compound 2 obtained in the step (2) and 908g of tetrahydrofuran, cooling to-10 +/-5 ℃, dropwise adding 246.9g (0.57mol, 6.0eq) of 2.0M lithium diisopropylamide in hexane at the temperature, keeping the temperature at 20 +/-5 ℃ after dropwise adding, continuing to stir for 4 hours, cooling to-20 +/-5 ℃, dropwise adding 34.8g (0.48mol, 5.0eq) of N, N-dimethylformamide at the temperature, keeping the temperature at-20 +/-5 ℃ after dropwise adding, stirring for 4 hours, keeping the temperature in the flask at 0 +/-5 ℃, pouring the mixture in the flask into 113.5g of 35% concentrated hydrochloric acid, keeping the temperature at 0 +/-5 ℃ all to quench the reaction, continuing to react for 6 hours at the temperature, removing an organic layer, and slowly pouring an aqueous phase with sodium hydroxide until the pH is 12-12, extracting twice with methyl tert-butyl ether, washing the combined organic phase once with saturated salt solution, and distilling under normal pressure to remove the solvent to obtain 6.4g of product with purity of 95.6% and yield of 45%;

EXAMPLE Synthesis of undec 5-methoxy-7-azaindole

(1) Synthesis of compound 2-amino-3-methyl-5-methoxypyridine

Adding 40.0g (0.21mol, 1.0eq) of compound 1 and 1200g of ethanol into a 2L autoclave, stirring until all solids are dissolved, sequentially adding 231.2g (4.3mol, 20.0eq) of sodium methoxide and 24.5g (0.39mol, 1.8eq) of copper powder, heating to 150 ℃ and 155 ℃ for reaction for 15 hours, cooling to 25 ℃, filtering the materials in the autoclave, leaching a filter cake with a small amount of methanol, concentrating a mother solution until cut off, adding dichlorosilane and water into the mixture for extraction and demixing, extracting the water phase once again with dichloromethane, combining organic phases for concentration until cut off, rectifying the crude product under reduced pressure through a 40cm filler column, collecting fractions with the T being 85-90 ℃/P being 2-3mmHg, obtaining 9.2g of compound in total, wherein the purity is 96.6%, and the yield is 31%;

(2) synthesis of Compound 2

Adding 20.7g (0.15mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in step (1) and 310.5g of tetrahydrofuran into a 2L four-necked flask at 0 ℃, adding 9.2g (0.075mol, 0.5eq) of 4-dimethylaminopyridine after all the materials are dissolved, heating to 60 ℃, dissolving 36.0g (0.17mol, 1.1eq) of di-tert-butyl dicarbonate in 1080.3g of tetrahydrofuran, keeping the temperature of the four-necked flask at 60-65 ℃, dropwise adding, continuing to react for 15 hours at the temperature after dropwise adding to obtain an intermediate compound, adding 21.0g of potassium hydroxide (0.38mol, 2.5eq), continuing to react at 20-25 ℃, keeping the reaction time at 8 hours, quenching the reaction liquid with water to neutrality after the dropwise adding, heating to 80-85 ℃, evaporating the solvent to cut off, extracting with tetrahydrofuran for 2 times, combining the organic phases, evaporating the solvent to dryness, crystallizing to separate out the organic layer, combining the organic phases, evaporating the solvent to dryness, and crystallizing to obtain 10.4g of compound 2 with the purity of 92.0% and the yield of 29%;

the structure of the obtained compound 2 was confirmed by the method described in example one, and it was confirmed that the obtained compound 2 was 2-tert-butoxyamino-3-methyl-5-methoxypyridine;

(3) and (3) synthesis of a product:

introducing nitrogen into a 2L four-neck flask, adding 22.7g (0.096mol, 1.0eq) of the compound 2 obtained in the step (2) and 454g of tetrahydrofuran, cooling to-20 +/-5 ℃, dropwise adding 64.8g (0.24mol, 2.5eq) of 2.5M N-butyllithium in hexane at the temperature, keeping the temperature at-20 +/-5 ℃ after dropwise adding, continuing to stir for 12 hours, dropwise adding 10.4g (0.14mol, 1.5eq) of N, N-dimethylformamide at the temperature, keeping the temperature at 20 +/-5 ℃ after dropwise adding, stirring for 10 hours after dropwise adding, keeping the mixture in the flask at-10 +/-5 ℃, slowly pouring into 227.0g of 35% concentrated hydrochloric acid to quench the reaction, keeping the temperature at 0 +/-5 ℃ all over, continuing to react for 1 hour at the temperature after quenching, removing an organic layer, neutralizing an aqueous phase with sodium hydroxide until the pH is 11-12, extracting twice with methyl tert-butyl ether, washing the combined organic phase with saturated salt solution, and distilling under normal pressure to remove the solvent to obtain 8.9g of product with purity of 97.0% and yield of 63%;

EXAMPLE Synthesis of dodeca5-methoxy-7-azaindole

(1) Synthesis of compound 2-amino-3-methyl-5-methoxypyridine

Adding 400.0g (2.14mol, 1.0eq) of compound 1 and 2kg of methanol into a 5L autoclave, stirring until the solid is completely dissolved, sequentially adding 346.6g (6.42mol, 3.0eq) of sodium methoxide and 68.0g (1.07mol, 0.5eq) of copper powder, heating to 130 ℃ for reacting for 8 hours, cooling to 25 ℃, filtering the materials in the autoclave, leaching a filter cake with a small amount of methanol, concentrating a mother solution until the mother solution is cut off, adding dichloromethane and water into the mixture for extraction and demixing, extracting a water phase once again by dichloromethane, combining an organic phase for concentration and recovery of the solvent, rectifying the crude product under reduced pressure by a 40cm packing column, collecting fractions with the T of 85-90 ℃/P of 2-3mmHg, obtaining 153.5g of compound in total, wherein the purity is 98.4%, and the yield is 52%;

(2) synthesis of the product

Adding 48.0g (0.35mol, 1.0eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in step (1) and 240g of tetrahydrofuran to a 2L four-necked flask, after the materials were completely dissolved, dropwise adding 207.9g (0.76mol, 2.2eq) of a 2.5M N-butyllithium hexane solution to the reaction solution at-5 ℃ to react at-5 ℃ for 1 to 2 hours, then adding 83.4g (0.38mol, 1.1eq) of di-tert-butyl dicarbonate to the reaction solution at-5 ℃ to react at-5 ℃ for 3 hours, then dropwise adding 207.9g (0.76mol, 2.2eq) of a 2.5M N-butyllithium hexane solution to the reaction solution at-5 ℃ to react at-5 ℃ for 1 to 2 hours, maintaining the reaction solution at-5 ℃ to react at-5 ℃ for 1 to 2 hours, and dropwise adding 30.5g (0.42mol, 1.2eq) of N, N-dimethylformamide to the reaction solution at-5 ℃ to react, and continuing to react for 6-8 hours at the temperature, quenching the reaction mixture by hydrochloric acid, layering, neutralizing the water layer by alkali until the pH value is 11-12, extracting the water layer by an organic solvent, washing the organic layer by water, and crystallizing after recovering the solvent from the organic layer to obtain 7.0g of a product with the purity of 96.6 percent and the yield of 14 percent;

In conclusion, compared with the currently reported synthetic method, the preparation method greatly shortens the synthetic route, and compared with the 5-bromo-7-azaindole in the prior art, the raw material of the 2-amino-3-methyl-5-bromopyrimidine is cheap and easy to obtain, so that the product in the prior art is effectively avoided, and the purity of the obtained product is relatively high; in addition, the raw materials and the reagents used in the invention are cheap and easy to obtain, and industrialization is very easy to realize.

The foregoing is considered as illustrative and not restrictive in character, and that various modifications, equivalents, and improvements made within the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims

1. A method for synthesizing 5-methoxy-7-azaindole, which comprises the following steps:

step a): preparing a compound 2 by taking the compound 1 as a raw material;

step b): dissolving the compound 2 in a third organic solvent, adding alkali for reaction, adding N, N-dimethylformamide to form an aldehyde intermediate, and finally, cyclizing the aldehyde intermediate under an acidic condition, and crystallizing to obtain 5-methoxy-7-azaindole;

wherein, the step a) comprises the following steps (1) and (2):

the first organic solvent is selected from one or more of methanol, ethanol, ethylene glycol, propanol, isopropanol, glycerol, methyl glycol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, methyl glycerol, 2-methyl glycerol and dimethyl glycol;

the first catalyst is selected from one of metallic copper, cuprous salt or copper salt;

the reaction temperature is 80-150 ℃, the reaction time is 1-20 hours,

(2) synthesis of Compound 2: dissolving a compound 2-amino-3-methyl-5-methoxypyridine in a second organic solvent, and then reacting with an amino protective agent and a base in the presence of a second catalyst to obtain an amino-protected compound 2, wherein in the compound 2, R is an amino protecting group;

the second organic solvent is one or more selected from tetrahydrofuran, acetonitrile, methanol, ethanol, ethylene glycol, propanol, isopropanol, glycerol, methyl glycol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, methyl glycerol, 2-methyl glycerol, dimethyl glycol and tert-butanol;

the second catalyst is selected from one or more of pyridine, N-diisopropylethylamine, tetramethylethylenediamine, tripropylamine, 4-dimethylaminopyridine, triethylenediamine, tetrabutylammonium hydroxide, gamma-chloropropylmethyldimethoxysilane, N-methylmorpholine and triethylamine;

the alkali is selected from one of hydroxides of alkali metals or alkaline earth metals, carbonates of alkali metals or alkaline earth metals, alkyl salts of alkali metals, diisopropylaminating salts of alkali metals or bistrimethylsilyl amino salts;

in the step b), the base is selected from one of n-butyl lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide;

in the step b), the third organic solvent is one selected from tetrahydrofuran, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, methyl propyl ether, n-butyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, anisole, methyl tert-butyl ether, 1, 2-dichloroethane, benzene, toluene, p-xylene, hexane, heptane and octane;

in the step b), adding alkali at-40-30 ℃;

in the step b), alkali is added for reaction for 2 to 12 hours.

2. The synthetic method of claim 1, wherein a base is added to deprotonate the methyl group.

3. The synthesis of claim 1, wherein the cyclization under acidic conditions is quenching and cyclization under acidic quencher conditions.

4. The synthesis method according to claim 1, wherein in the step b), the base is n-butyllithium.

5. The method according to claim 1, wherein in step b), the third organic solvent is tetrahydrofuran.

6. The synthesis method according to claim 1, wherein in the step b), the mass ratio of the compound 2 to the third organic solvent is 1:2 to 100.

7. The synthesis method according to claim 3, wherein in the step b), the mass ratio of the compound 2 to the third organic solvent is 1:2 to 100.

8. The synthesis method according to claim 1, wherein in the step b), the mass ratio of the compound 2 to the third organic solvent is 1:5 to 80.

9. The synthesis method according to claim 1, wherein in the step b), the mass ratio of the compound 2 to the third organic solvent is 1: 8-15.

10. The method according to claim 3, wherein in the step b), the acidic quenching agent is selected from one of concentrated hydrochloric acid, sulfuric acid, nitric acid, acetic acid and citric acid.

11. The method according to claim 7, wherein in the step b), the acidic quenching agent is selected from one of concentrated hydrochloric acid, sulfuric acid, nitric acid, acetic acid and citric acid.

12. The process according to claim 3, wherein in step b), the acidic quencher is concentrated hydrochloric acid.

13. The method according to claim 3, wherein the mass ratio of the compound 2 to the acidic quencher in the step b) is 1:2 to 10.

14. The method according to claim 7, wherein the mass ratio of the compound 2 to the acidic quencher in the step b) is 1:2 to 10.

15. The method according to claim 10, wherein the mass ratio of the compound 2 to the acidic quencher in the step b) is 1:2 to 10.

16. The method according to claim 3, wherein the mass ratio of the compound 2 to the acidic quencher in the step b) is 1:2 to 5.

17. The method according to claim 3, wherein in the step b), the mass ratio of the compound 2 to the acidic quencher is 1: 2.5 to 3.

18. The synthesis method according to claim 1, wherein the molar ratio of the compound 2 to the base in the step b) is 1:2.0 to 6.0.

19. The synthesis method according to claim 6, wherein the molar ratio of the compound 2 to the base in the step b) is 1:2.0 to 6.0.

20. The method according to claim 10, wherein the molar ratio of the compound 2 to the base in the step b) is 1:2.0 to 6.0.

21. The method according to claim 13, wherein the molar ratio of the compound 2 to the base in the step b) is 1:2.0 to 6.0.

22. The synthesis method according to claim 1, wherein the molar ratio of the compound 2 to the base in the step b) is 1:2.0 to 2.5.

23. The method according to claim 1, wherein the molar ratio of the compound 2 to the N, N-dimethylformamide in the step b) is 1:1.0 to 10.0.

24. The method according to claim 6, wherein the molar ratio of the compound 2 to the N, N-dimethylformamide in the step b) is 1:1.0 to 10.0.

25. The method according to claim 10, wherein the molar ratio of the compound 2 to the N, N-dimethylformamide in the step b) is 1:1.0 to 10.0.

26. The method according to claim 13, wherein the molar ratio of the compound 2 to the N, N-dimethylformamide in the step b) is 1:1.0 to 10.0.

27. The method according to claim 1, wherein the molar ratio of the compound 2 to the N, N-dimethylformamide in the step b) is 1:1.0 to 5.

28. The method according to claim 1, wherein the molar ratio of the compound 2 to the N, N-dimethylformamide in the step b) is 1:1.0 to 1.5.

29. The method according to claim 1, wherein the temperature of the alkali added in the step b) is-20 to 0 ℃.

30. The method according to claim 1, wherein the temperature of N, N-dimethylformamide added in step b) is-40 to 25 ℃.

31. The method according to claim 1, wherein the temperature of N, N-dimethylformamide added in step b) is-20 to 20 ℃.

32. The method according to claim 1, wherein the reaction time of the step b) is 2 to 12 hours by adding N, N-dimethylformamide.

33. The method according to claim 1, wherein the N, N-dimethylformamide is added for 4 to 6 hours in the step b).

34. The synthesis method according to any one of claims 1 to 33, wherein in the step b), the reaction temperature for quenching is-10 to 30 ℃.

35. The synthesis method according to any one of claims 1 to 33, wherein in step b), the reaction temperature for quenching is 0 to 5 ℃.

36. The synthesis method according to any one of claims 1 to 33, wherein in step b), the reaction temperature for the cyclization is 0 to 45 ℃.

37. The synthesis method according to any one of claims 1 to 33, wherein in step b), the reaction temperature for the cyclization is 40 to 45 ℃.

38. The synthesis process according to any one of claims 1 to 33, wherein in step b), the reaction time for the cyclization is from 1 to 6 hours.

39. The synthesis method according to any one of claims 1 to 33, wherein in the step (2), after the reaction with the amino protecting agent and the base, a quenching agent is further added for quenching, and recrystallization is performed to obtain the amino protected compound 2.

40. The synthesis of any one of claims 1-33, wherein in step (1), the first organic solvent is methanol.

41. The synthesis method according to any one of claims 1 to 33, wherein in step (1), the mass ratio of the compound 1 to the first organic solvent is 1:0.5 to 50.

42. The synthesis method according to any one of claims 1 to 33, wherein in step (1), the mass ratio of the compound 1 to the first organic solvent is 1:3 to 10.

43. The synthesis of any one of claims 1 to 33, wherein in step (1) the first catalyst is selected from one of copper powder, cuprous bromide, cuprous oxide, cupric oxide or cupric sulfate.

44. The synthesis process of any one of claims 1 to 33, wherein in step (1), the molar ratio of compound 1 to the first catalyst is 1:0.05 to 2.

45. The synthesis process of any one of claims 1 to 33, wherein in step (1), the molar ratio of compound 1 to the first catalyst is 1:0.1 to 1.5.

46. The synthesis process of any one of claims 1 to 33, wherein in step (1), the molar ratio of compound 1 to the first catalyst is 1:0.1 to 0.5.

47. The method of any one of claims 1 to 33, wherein in step (1) the methoxide is selected from one of sodium methoxide, potassium methoxide or lithium methoxide.

48. The synthetic method of any one of claims 1-33, wherein in step (1), the methoxide is sodium methoxide.

49. The synthetic method according to any one of claims 1-33, wherein in step (1), the molar ratio of compound 1 to methoxide is 1: 0.8-20.

50. The synthetic method of any one of claims 1-33, wherein in step (1), the molar ratio of said compound 1 to said methoxide is 1: 1-15.

51. The synthetic method of any one of claims 1-33, wherein in step (1), the molar ratio of compound 1 to methoxide is 1: 1.5-3.0.

52. The synthesis method according to any one of claims 1 to 33, wherein in step (1), the reaction temperature is 100 to 130 ℃.

53. The synthesis method according to any one of claims 1 to 33, wherein in step (1), the reaction temperature is 120 to 130 ℃.

54. The synthesis process according to any one of claims 1 to 33, wherein in step (1), the reaction time is 1 to 15 hours.

55. The synthetic method according to any one of claims 1-33, wherein in step (1), the reaction time is 3-8 hours.

56. The synthesis method according to claim 1, wherein in step (2), the second organic solvent is tert-butanol.

57. The synthesis method according to claim 1, wherein in the step (2), the mass ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the second organic solvent is 1:0.5 to 30.0.

58. The synthesis method according to claim 1, wherein in the step (2), the mass ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the second organic solvent is 1:1 to 20.

59. The synthesis method according to claim 1, wherein in the step (2), the mass ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the second organic solvent is 1:1.0 to 5.0.

60. The synthesis method according to claim 1, wherein in step (2), the second catalyst is 4-dimethylaminopyridine.

61. The synthesis method according to claim 1, wherein in the step (2), the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the second catalyst is 1:0.01 to 1.0.

62. The synthesis method according to claim 1, wherein in the step (2), the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the second catalyst is 1:0.02 to 0.2.

63. The synthesis method according to claim 1, wherein in the step (2), the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the second catalyst is 1:0.02 to 0.05.

64. The method of any one of claims 1-33, wherein in step (2), the amino protecting agent is di-tert-butyl dicarbonate.

65. The synthesis method according to any one of claims 1 to 33, wherein, in the step (2), the amino group protecting agent is added dropwise in the form of melting into a liquid form or dissolving in a fourth organic solvent to form a solution.

66. The synthesis method according to any one of claims 1 to 33, wherein in step (2), the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the amino protecting agent is 1:1 to 10.

67. The synthesis method according to any one of claims 1 to 33, wherein in step (2), the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the amino protecting agent is 1:1.1 to 5.

68. The synthesis of any one of claims 1-33, wherein in step (2), the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the amino protecting agent is 1: 2.1-2.5.

69. The method of claim 65, wherein the fourth organic solvent is one or more selected from the group consisting of tetrahydrofuran, acetonitrile, methanol, ethanol, ethylene glycol, propanol, isopropanol, glycerol, methyl glycol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, methyl glycerol, 2-methyl glycerol, dimethyl glycol, and tert-butanol.

70. The synthetic method of claim 65, wherein the fourth organic solvent is tert-butanol.

71. The synthesis method according to claim 65, wherein the mass ratio of the amino protecting agent to the fourth organic solvent is 1: 0.5-30.

72. The synthetic method of claim 65, wherein is 1:1 to 20.

73. The synthetic method of claim 65, wherein is 1: 0.5-4.

74. The method of claim 1, wherein in step (2), the base is one of sodium hydroxide, potassium hydroxide, n-butyllithium, sec-butyllithium, iso-butyllithium, tert-butyllithium, or sodium bistrimethylsilyl amide.

75. The synthesis method according to claim 1, wherein in the step (2), the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the base is 1:1.0 to 5.0.

76. The synthesis method according to claim 1, wherein in the step (2), the molar ratio of the compound 2-amino-3-methyl-5-methoxypyridine to the base is 1:1.5 to 2.5.

77. The synthesis process of any one of claims 1 to 33, wherein in step (2), the reaction temperature is from-40 ℃ to 85 ℃.

78. The synthetic method according to any one of claims 1-33, wherein in step (2), the reaction temperature is 60-85 ℃.

79. The synthesis method according to any one of claims 1 to 33, wherein in step (2), the reaction time after the addition of the amino protecting agent is 1 to 40 hours.

80. The method of any one of claims 1-33, wherein in step (2), the reaction time after addition of the amino protecting agent is 6-8 hours.

81. The synthesis method according to claim 1, wherein in the step (2), the reaction time after the addition of the base is 1 to 40 hours.

82. The synthesis method according to claim 1, wherein in the step (2), the reaction time after the addition of the base is 6 to 10 hours.

83. The synthesis method according to claim 39, wherein in step (2), the quenching agent is selected from one of hydrochloric acid, sulfuric acid, nitric acid, water, formic acid, acetic acid or citric acid.