CN110128422A - The synthetic method of 5- methoxyl group -7- azaindole - Google Patents

Abstract

The present invention relates to a kind of synthetic methods of 5- methoxyl group -7- azaindole.The present invention provides a kind of synthetic methods of 5- methoxyl group -7- azaindole, including following processes: process a): being that compound 2 is prepared in raw material with compound 1；Process b): 5- methoxyl group -7- azaindole is prepared by compound 2.Synthetic method of the invention substantially reduces synthetic route compared with prior art, and this method effectively prevents the by-product of the prior art, and total recovery improves.

Description

The synthetic method of 5- methoxyl group -7- azaindole

Technical field

The present invention relates to pharmaceutical intermediate fields, and in particular to a kind of synthetic method of 5- methoxyl group -7- azaindole.

Background technique

Azaindole can regard the bioisostere of indoles as, and Indole Molecular unit plays in life process Huge effect, many drug molecules all contain indole unit, so azaindoles are set in pharmaceutical activity molecule Meter and synthesis aspect play an important role.Azaindole and its derivative have the activity for inhibiting multiple protein enzyme.Such as The compound of the azaindole structure containing 7- is a kind of important alkaloid in natural products, has the physiology such as anticancer, anti-diabetic Activity.Due to the special physicochemical property of such compound and pharmacological activity, so chemist is usually with 7- azaindole structure Compound carries out structure of modification as lead compound.5- methoxyl group -7- azaindole is as the pass for preparing active pharmaceutical ingredient Key intermediate is presently mainly prepared by 5- bromo-7-azaindole.

It is prepared are as follows:

And bromo- 7 azaindole of 5- as raw material is not easy to obtain, preparation cost is higher.At present about the bromo- 7 azepine Yin of 5- The preparation method of diindyl mainly include the following types:

US20100204214、US20070049615、heterocycle,2003,60(4):865-877、JACS,2006, 128 (45): 14426-14437 and chemmedchem, 2007,2 (7): 1071-1075 is disclosed using following methods system Standby bromo- 7 azaindole of 5-, by bromination, elimination, reduction, is aoxidized, reactional equation using 7- azaindole as raw material Formula is as follows:

This method step is long, and a large amount of bromine is needed to participate in reaction, last to eliminate again, generates a large amount of waste liquids, cumbersome, always Yield is low.

WO2003064413, WO2004078757 and WO2007135398 are disclosed using 7- azaindole as raw material, warp Hydro-reduction, bromination and dehydrogenation obtain 5- bromo-7-azaindole, and reaction route is as follows:

The disadvantage is that bromine is excessively used for bromination step, a large amount of waste liquids are generated, it is seriously polluted；Dehydrogenation step is adopted With manganese dioxide, a large amount of slag containing Mns are generated, bring pollution.

synthesis 2008,(13):2049-2054、WO20060183758、WO20080124849、 It is raw material that WO2009016460 and US20110028511, which discloses the bromo- 2-aminopyridine of 5-, through iodate, Sonogashira Cross-coupling, then hydrolysis, cyclization obtain 5- bromo-7-azaindole in highly basic, and reaction route is as follows:

The route uses various metals catalyst, and the bad purifying of cross-coupling by-product, condition is more harsh, industrial cost It is high.

Chinese Patent Application No. CN201210025316 provides a kind of preparation method of 5- bromo-7-azaindole, with 7- Azaindole is raw material, mainly includes step: 7- azaindole is reacted with sodium hydrogensulfite generates dihydro -7- azaindole -2- Sulfonate sodium；Dihydro -7- azaindole -2- sulfonate sodium occurs bromo-reaction and generates dihydro -5- bromo-7-azaindole -2- sulphur Acid sodium-salt；Dihydro -5- bromo-7-azaindole -2- sulfonate sodium takes off sodium sulfonate under alkaline condition and generates the bromo- 7- azepine Yin of 5- Diindyl, reaction route are as follows:

The preparation method has that bromine consumption is big, in bromination process more than cross-coupling by-product, generates a large amount of waste liquids, It is cumbersome.

It is raw material that WO2011110479 and WO2011109932, which discloses the bromo- 3- methyl-2-amino pyridine of 5-, in tetrahydro Pyrroles and lower generate of n,N-Dimethylformamide dimethylacetal (DMF-DMA) effect obtain intermediate, utilize with rear center body LDA (N, N- lithium diisopropylamine) cyclization obtains 5- bromo-7-azaindole, reaction route are as follows:

Although this method shortens synthetic route, but total recovery is relatively low.

Chinese Patent Application No. CN201410596601.3 is disclosed using 2- amino -3- methyl -5- bromopyridine as raw material, Caro's acid oxidation under generate 2- nitro -3- methyl -5- bromopyridine, then in nafoxidine and n,N-Dimethylformamide Lower generate of dimethylacetal (DMF-DMA) effect obtains intermediate, finally in Raney's nickel/85% hydrazine hydrate system or other low price Lower reduction cyclization is acted under metal and forms 5- bromo-7-azaindole, and reaction route is as follows:

This method generates a large amount of spent acid, and three wastes pressure is big, and industrial cost is high.

Also, the technique for preparing 5- bromo-7-azaindole reported at present has the following disadvantages:

1. the raw material that is related to or reagent is expensive.

2. being unfavorable for realizing industrialization for producing relatively hazardous oxidative deamination process comprising some.

3. by-product is more, purification process loses yield, and it is low to result in total recovery.

Summary of the invention

For this purpose, the problem of technology solved by the invention, is: preparing 5- first using 5- bromo-7-azaindole in the prior art Oxygroup -7- azaindole, but 5- bromo-7-azaindole is not easy to obtain, production cost is higher, and yield is low.

The object of the present invention is to provide a kind of synthetic methods of 5- methoxyl group -7- azaindole, with existing preparation 5- The method of methoxyl group -7- azaindole is compared, simple process, low to working condition requirement, and purification of products is easy and high income, is shown Write the production efficiency and product quality for improving 5- methoxyl group -7- azaindole.

The present invention provides a kind of 5- methoxyl group -7- azaindoles, and it includes following processes:

Process a): being that compound 2 is prepared in raw material with compound 1；

Process b): 5- methoxyl group -7- azaindole is prepared by compound 2.

Specifically, the invention proposes following technical solutions.

The present invention provides a kind of synthetic methods of 5- methoxyl group -7- azaindole, and it includes following processes:

Process a): being that compound 2 is prepared in raw material with compound 1；

Process b): 5- methoxyl group -7- azaindole is prepared by compound 2.

Preferably, for synthetic method described above, wherein process b) is that compound 2 is dissolved in third is organic molten In agent, alkali is then added and is reacted, is subsequently added into n,N-Dimethylformamide and forms aldehyde radical intermediate, last aldehyde radical intermediate In acid condition after cyclization, crystallization obtains product；Wherein, alkali is preferably added to methyl deprotonation；More preferably, it is described Cyclization is to be quenched under the conditions of acid quencher and cyclization under acid condition.

Preferably, for synthetic method described above, wherein in process b), the alkali is selected from n-BuLi, two different One of propyl amido lithium, bis- (trimethyl silicon substrate) lithium amides or bis- (trimethyl silicon substrate) Sodamides, preferably n-BuLi.

Preferably, for synthetic method described above, wherein in process b), the third organic solvent is selected from four Hydrogen furans, acetonitrile, methylene chloride, chloroform, carbon tetrachloride, ether, methyl-propyl ether, n-butyl ether, glycol dimethyl ether, diethyl two In diethylene glycol dimethyl ether, methyl phenyl ethers anisole, methyl tertiary butyl ether(MTBE), 1,2- dichloroethanes, benzene, toluene, paraxylene, hexane, heptane or octane One kind, preferably tetrahydrofuran；Preferably, the mass ratio of the compound 2 and the third organic solvent is 1:2~100, Preferably 1:5~80 are more preferably 1:8~15.

Preferably, for synthetic method described above, wherein in process b), the acidity quencher is selected from dense salt One of acid, sulfuric acid, nitric acid, acetic acid or citric acid, preferably concentrated hydrochloric acid；Preferably, the compound 2 is quenched with the acidity The mass ratio of agent of going out is 1:2~10, and preferably 1:2~5 are more preferably 1:2.5~3.

Preferably, for synthetic method described above, wherein in process b), mole of the compound 2 and the alkali Than for 1:2.0~6.0, preferably 1:2.0~2.5；Preferably, the compound 2 and the n,N-Dimethylformamide are rubbed You, than being 1:1.0~10.0, preferably 1:1.0~5, are more preferably 1:1.0~1.5.

Preferably, for synthetic method described above, wherein in process b), the temperature that alkali is added is -40~30 DEG C, Preferably -20~0 DEG C；Preferably, the reaction time is 2-12 hours；Preferably, be added n,N dimethylformamide temperature be- 40~25 DEG C, preferably -20~20 DEG C；Preferably, the reaction time is 2-12 hours, preferably 4-6 hours.

Preferably, for synthetic method described above, wherein in process b), the reaction temperature being quenched be- 10~30 DEG C, preferably 0~5 DEG C；Preferably, the reaction temperature of the cyclization is 0~45 DEG C, preferably 40~45 DEG C；It is preferred that , the reaction time of the cyclization is 1-6 hours.

Preferably, for synthetic method described above, wherein process a) includes the following steps (1) and step (2):

(1) synthesis of 2- amino -3- methyl -5- methoxypyridine: compound 1 is dissolved in the first organic solvent, Under the action of first catalyst, compound 1 is reacted with methoxide, obtains compound 2- amino -3- methyl -5- methoxyl group pyrrole Pyridine；

(2) synthesis of compound 2: compound 2- amino -3- methyl -5- methoxypyridine is reacted with amino protecting agent To compound 2.

Preferably, for synthetic method described above, wherein in the step (2), by compound 2- amino -3- first Base -5- methoxypyridine dissolves in a second organic solvent, then in the presence of the second catalyst, with amino protecting agent and alkali It is reacted to obtain the compound 2 of amido protecting, wherein in compound 2, R is amino protecting group；It is preferred that with amino protecting agent After alkali reaction, quencher is further added and is quenched, the compound 2 of amido protecting is recrystallized to give.

Preferably, for synthetic method described above, wherein in step (1), first organic solvent is selected from Methanol, ethyl alcohol, ethylene glycol, propyl alcohol, isopropanol, glycerine, Propylene Glycol, n-butyl alcohol, 2- butanol, 2- methyl-1-propyl alcohol, 2- One or more of methyl-2-propanol, methyl glycerine, 2- methyl glycerine and diformazan ethyl glycol, preferably first Alcohol；Preferably, the mass ratio of the compound 1 and first organic solvent is 1:0.5~50, preferably 1:3~10.

Preferably, for synthetic method described above, wherein in step (1), first catalyst is selected from gold Belong to one of copper, cuprous salt or mantoquita；Preferably, first catalyst selected from copper powder, cuprous bromide, cuprous oxide, One of copper oxide or copper sulphate.

Preferably, for synthetic method described above, wherein in step (1), the compound 1 and described first The molar ratio of catalyst is 1:0.05~2, preferably 1:0.1~1.5, is more preferably 1:0.1~0.5；Preferably, the methanol Salt is selected from one of sodium methoxide, potassium methoxide or lithium methoxide, preferably sodium methoxide；Preferably, the compound 1 and the first The molar ratio of alkoxide is 1:0.8~20, preferably 1:1~15, preferably 1:1.5~3.0.

Preferably, for synthetic method described above, wherein in step (1), the temperature of the reaction is 80~ 150 DEG C, preferably 100~130 DEG C are more preferably 120~130 DEG C；Preferably, the time of the reaction is 1~20 hour, excellent It is selected as 1~15 hour, is more preferably 3~8 hours.

Preferably, for synthetic method described above, wherein in step (2), second organic solvent is selected from Tetrahydrofuran, acetonitrile, methanol, ethyl alcohol, ethylene glycol, propyl alcohol, isopropanol, glycerine, Propylene Glycol, n-butyl alcohol, 2- butanol, 2- One in methyl-1-propyl alcohol, 2- methyl-2-propanol, methyl glycerine, 2- methyl glycerine, diformazan ethyl glycol and the tert-butyl alcohol Kind is two or more, preferably the tert-butyl alcohol；Preferably, the compound 2- amino -3- methyl -5- methoxypyridine and described the The mass ratio of two organic solvents is 1:0.5~30.0, preferably 1:1~20, is more preferably 1:1.0~5.0.

Preferably, for synthetic method described above, wherein in step (2), second catalyst is selected from pyrrole Pyridine, N, N- diisopropylethylamine, tetramethylethylenediamine, tripropylamine, 4-dimethylaminopyridine, triethylenediamine, the tetrabutyl One or more of ammonium hydroxide, gamma-chloropropylmethyldimethoxysilane, N-methylmorpholine and triethylamine, preferably For 4-dimethylaminopyridine；Preferably, the compound 2- amino -3- methyl -5- methoxypyridine and second catalyst Molar ratio be 1:0.01~1.0, preferably 1:0.02~0.2 is more preferably 1:0.02~0.05.

Preferably, for synthetic method described above, wherein in step (2), the amino protecting agent is two carbonic acid Di tert butyl carbonate；Preferably, when reaction, the amino protecting agent is to be melt into liquid form or be dissolved in shape in the 4th organic solvent It is added dropwise at the form of solution；Preferably, the compound 2- amino -3- methyl -5- methoxypyridine and amino protecting agent rub You, than being 1:1~10, preferably 1:1.1~5, are more preferably 1:2.1-2.5；Preferably, the 4th organic solvent is selected from Tetrahydrofuran, acetonitrile, methanol, ethyl alcohol, ethylene glycol, propyl alcohol, isopropanol, glycerine, Propylene Glycol, n-butyl alcohol, 2- butanol, 2- One in methyl-1-propyl alcohol, 2- methyl-2-propanol, methyl glycerine, 2- methyl glycerine, diformazan ethyl glycol and the tert-butyl alcohol Kind is two or more, preferably the tert-butyl alcohol；Preferably, the mass ratio of the amino protecting agent and the 4th organic solvent is 1: 0.5~30, preferably 1:1~20 are more preferably 1:0.5~4.

Preferably, for synthetic method described above, wherein in step (2), the alkali is selected from alkali metal or alkali The diisopropyl amination of the hydroxide of earth metal, the carbonate of alkali or alkaline earth metal, the alkyl salt of alkali metal, alkali metal One of salt or double trimethyl silicon substrate amides, preferably sodium hydroxide, potassium hydroxide, n-BuLi, s-butyl lithium, isobutyl One of base lithium, tert-butyl lithium or double trimethyl silicon substrate Sodamides；Preferably, the compound 2- amino -3- methyl -5- first The molar ratio of oxygroup pyridine and the alkali is 1:1.0~5.0, preferably 1:1.5~2.5.

Preferably, for synthetic method described above, wherein in step (2), the reaction temperature be -40 DEG C~ 85 DEG C, preferably 60~85 DEG C；Preferably, the reaction time after amino protecting agent is added is 1~40 hour, and preferably 6-8 is small When；Preferably, the reaction time after alkali is added is 1~40 hour, preferably 6~10 hours.

Preferably, for synthetic method described above, wherein the quencher selected from hydrochloric acid, sulfuric acid, nitric acid, water, One of formic acid, acetic acid or citric acid.

Beneficial effect obtained by the present invention is:

Preparation method of the present invention, substantially reduces synthetic route compared with the synthetic method reported at present；It is used Raw material is 2- amino -3- methyl -5- bromopyridine, and compared with the 5- bromo-7-azaindole of prior art, raw material is cheap and easy to get；It should Scheme effectively prevents the by-product of the prior art, and total recovery improves, and products obtained therefrom purity is higher, and the raw materials used in the present invention And reagent be it is cheap and easy to get, it is low for equipment requirements, be highly susceptible to realize industrialization.

Detailed description of the invention

Fig. 1 is the GC spectrogram of one step of embodiment (1) obtained compound.

Fig. 2 is the GC-MS spectrogram of one step of embodiment (1) obtained compound.

Fig. 3 is the HPLC spectrogram of the obtained compound 2 of embodiment one.

Fig. 4 is the LC-MS spectrogram of the obtained compound 2 of embodiment one

Fig. 5 is the obtained compound 2 of embodiment one¹H NMR spectra.

Fig. 6 is the HPLC spectrogram of the obtained product of embodiment one.

Fig. 7 is the LC-MS spectrogram of the obtained product of embodiment one

Fig. 8 is the obtained product of embodiment one¹H NMR spectra.

Specific embodiment

As described above, it includes following works the present invention provides a kind of synthetic method of 5- methoxyl group -7- azaindole Sequence:

Process a): being that compound 2 is prepared in raw material with compound 1；

Process b): 5- methoxyl group -7- azaindole is prepared by compound 2.

In a kind of currently preferred specific embodiment, wherein process b) is that compound 2 is dissolved in third is organic In solvent, alkali is then added and is reacted, is subsequently added into n,N-Dimethylformamide and forms aldehyde radical intermediate, among last aldehyde radical For body in acid condition after cyclization, crystallization obtains product；Wherein, alkali is preferably added to methyl deprotonation；More preferably, described Cyclization is to be quenched under the conditions of acid quencher and cyclization in acid condition.

In a kind of currently preferred specific embodiment, wherein in process b), the alkali is selected from n-BuLi, two One of isopropyl amido lithium, bis- (trimethyl silicon substrate) lithium amides or bis- (trimethyl silicon substrate) Sodamides；Preferably normal-butyl Lithium.

In a kind of currently preferred specific embodiment, wherein in process b), the third organic solvent is selected from Tetrahydrofuran, acetonitrile, methylene chloride, chloroform, carbon tetrachloride, ether, methyl-propyl ether, n-butyl ether, glycol dimethyl ether, diethyl Glycol dimethyl ether, methyl phenyl ethers anisole, methyl tertiary butyl ether(MTBE), 1,2- dichloroethanes, benzene, toluene, paraxylene, hexane, heptane or octane One of, preferably tetrahydrofuran；Preferably, the mass ratio of the compound 2 and the third organic solvent be 1:2~ 100, preferably 1:5~80 are more preferably 1:8~15.

In a kind of currently preferred specific embodiment, wherein the acidity quencher is selected from concentrated hydrochloric acid, sulphur One of acid, nitric acid, acetic acid or citric acid, preferably concentrated hydrochloric acid；Preferably, the compound 2 and the acid quencher Mass ratio be 1:2~10, preferably 1:2~5 are more preferably 1:2.5~3；Preferably, the concentrated hydrochloric acid refers to mass fraction For the hydrochloric acid of 25-35%.

In a kind of currently preferred specific embodiment, wherein in process b), the compound 2 and the alkali Molar ratio is 1:2.0~6.0, preferably 1:2.0~2.5；Preferably, the compound 2 and the n,N-Dimethylformamide Molar ratio be 1:1.0~10.0, preferably 1:1.0~5 are more preferably 1:1.0~1.5.

In a kind of currently preferred specific embodiment, wherein in process b), the temperature that alkali is added is -40~30 DEG C, preferably -20~0 DEG C；Preferably, the reaction time is 2-12 hours；Preferably, the temperature of n,N dimethylformamide is added It is -40~25 DEG C, preferably -20~20 DEG C；Preferably, the reaction time is 2-12 hours, preferably 4-6 hours.

In a kind of currently preferred specific embodiment, wherein in process b), the reaction temperature being quenched It is -10~30 DEG C, preferably 0~5 DEG C；Preferably, the reaction temperature of the cyclization is 0~45 DEG C, preferably 40~45 DEG C；It is excellent Choosing, the reaction time of the cyclization is 1-6 hours.

In a kind of currently preferred specific embodiment, wherein process a) includes the following steps (1) and step (2):

(1) synthesis of 2- amino -3- methyl -5- methoxypyridine: compound 1 is dissolved in the first organic solvent, Under the action of first catalyst, compound 1 is reacted with methoxide, obtains compound 2- amino -3- methyl -5- methoxyl group pyrrole Pyridine；

(2) synthesis of compound 2: compound 2- amino -3- methyl -5- methoxypyridine is reacted with amino protecting agent To compound 2.

In a kind of currently preferred specific embodiment, wherein in the step (2), by compound 2- amino -3- Methyl -5- methoxypyridine dissolve in a second organic solvent, then in the presence of the second catalyst, with amino protecting agent and Alkali is reacted, and the compound 2 of amido protecting is obtained, and wherein in compound 2, R is amino protecting group；It is preferred that with amido protecting After agent and alkali reaction, quencher is further added and is quenched, the compound 2 of amido protecting is recrystallized to give；Preferably, change Closing object 2- amino -3- methyl -5- methoxypyridine can first be reacted with amino protecting agent, then react with alkali again To compound 2, be also possible to compound 2- amino -3- methyl -5- methoxypyridine and first reacted with alkali, then again with amino Protective agent is reacted to obtain compound 2.

In a kind of currently preferred specific embodiment, wherein in step (1), the first organic solvent choosing From in methanol, ethyl alcohol, ethylene glycol, propyl alcohol, isopropanol, glycerine, Propylene Glycol, n-butyl alcohol, 2- butanol, 2- methyl-1-the third One or more of alcohol, 2- methyl-2-propanol, methyl glycerine, 2- methyl glycerine and diformazan ethyl glycol, preferably For methanol；Preferably, the mass ratio of the compound 1 and first organic solvent is 1:0.5~50, preferably 1:3~10.

In a kind of currently preferred specific embodiment, wherein in step (1), first catalyst is selected from In one of metallic copper, cuprous salt or mantoquita；Preferably, first catalyst is sub- selected from copper powder, cuprous bromide, oxidation One of copper, copper oxide or copper sulphate；Preferably, the molar ratio of the compound 1 and first catalyst is 1:0.05 ~2.0, preferably 1:0.1~1.5 are more preferably 1:0.1~0.5；Preferably, the methoxide is selected from sodium methoxide, methanol One of potassium or lithium methoxide, preferably sodium methoxide；Preferably, the molar ratio of the compound 1 and the methoxide is 1:0.8 ~20, preferably 1:1~15 are more preferably 1:1.5~3.0.

In a kind of currently preferred specific embodiment, wherein in step (1), the temperature of the reaction is 80 ~150 DEG C, preferably 100~130 DEG C are more preferably 120~130 DEG C；Preferably, the time of the reaction is 1~20 hour, Preferably 1~15 hour, be more preferably 3~8 hours.

In a kind of currently preferred specific embodiment, wherein in step (2), the second organic solvent choosing From in tetrahydrofuran, acetonitrile, methanol, ethyl alcohol, ethylene glycol, propyl alcohol, isopropanol, glycerine, Propylene Glycol, n-butyl alcohol, 2- fourth In alcohol, 2- methyl-1-propyl alcohol, 2- methyl-2-propanol, methyl glycerine, 2- methyl glycerine, diformazan ethyl glycol and the tert-butyl alcohol One or more, the preferably tert-butyl alcohol；Preferably, the compound 2- amino -3- methyl -5- methoxypyridine and institute The mass ratio for stating the second organic solvent is 1:0.5~30.0, preferably 1:1~20, is more preferably 1:1.0~5.0.

In a kind of currently preferred specific embodiment, wherein in step (2), second catalyst is selected from In pyridine, N, N- diisopropylethylamine, tetramethylethylenediamine, tripropylamine, 4-dimethylaminopyridine, triethylenediamine, four One or more of butyl ammonium hydroxide, gamma-chloropropylmethyldimethoxysilane, N-methylmorpholine and triethylamine, Preferably 4-dimethylaminopyridine；Preferably, the compound 2- amino -3- methyl -5- methoxypyridine and described second is urged The molar ratio of agent is 1:0.01~1:1.0, preferably 1:0.02~0.2, is more preferably 1:0.02~0.05.

In a kind of currently preferred specific embodiment, wherein in step (2), the amino protecting agent is two Dimethyl dicarbonate butyl ester；Preferably, when reaction, the amino protecting agent is to be melt into liquid form or be dissolved in the 4th organic solvent In form be added dropwise；Preferably, the molar ratio of compound 2- amino-the 3- methyl -5- methoxypyridine and amino protecting agent It is more preferably 1:2.1-2.5 for 1:1~10, preferably 1:1.1~5；Preferably, the 4th organic solvent is selected from tetrahydro Furans, acetonitrile, methanol, ethyl alcohol, ethylene glycol, propyl alcohol, isopropanol, glycerine, Propylene Glycol, n-butyl alcohol, 2- butanol, 2- first One of base -1- propyl alcohol, 2- methyl-2-propanol, methyl glycerine, 2- methyl glycerine, diformazan ethyl glycol and tert-butyl alcohol Or two or more, the preferably tert-butyl alcohol；Preferably, the mass ratio of the amino protecting agent and the 4th organic solvent is 1: 0.5~30, preferably 1:1~20 are more preferably 1:0.5~4.

In a kind of currently preferred specific embodiment, wherein in step (2), the alkali is selected from alkali metal Or the diisopropyl of the alkyl salt of the hydroxide of alkaline-earth metal, the carbonate of alkali or alkaline earth metal, alkali metal, alkali metal One of amination salt or double trimethyl silicon substrate amides, preferably sodium hydroxide, potassium hydroxide, n-BuLi, s-butyl lithium, One of isobutyl group lithium, tert-butyl lithium or double trimethyl silicon substrate Sodamides；Preferably, the compound 2- amino -3- methyl - The molar ratio of 5- methoxypyridine and the alkali is 1:1.0~5.0, preferably 1:1.5~2.5.

In a kind of currently preferred specific embodiment, wherein in step (2), the reaction temperature is -40 DEG C ~85 DEG C, preferably 60~85 DEG C；Preferably, the reaction time after amino protecting agent is added is 1~40 hour；Preferably, add Reaction time after entering alkali is 1~40 hour, preferably 6~10 hours；Preferably, the reaction being added after amino protecting agent Temperature be -40 DEG C~85 DEG C, preferably 60~85 DEG C, it is described be added alkali after reaction temperature be -40 DEG C~85 DEG C, preferably 60 ~85 DEG C.

In a kind of currently preferred specific embodiment, wherein the quencher selected from hydrochloric acid, sulfuric acid, nitric acid, One of water, formic acid, acetic acid or citric acid.

The following examples are described in further detail to the synthetic method of invention, wherein used in embodiment Chemical substance is the pure rank of chemistry of conventional reagent.

The synthesis of one 5- methoxyl group -7- azaindole of embodiment

Its synthetic route are as follows:

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

The methanol of the compound 1 of 400.0g (2.14mol, 1.0eq) and 2kg is added in 5L autoclave, stirring is to admittedly Body all after dissolution, sequentially adds the sodium methoxide of 346.6g (6.42mol, 3.0eq) and the copper of 68.0g (1.07mol, 0.5eq) Powder is heated to 130 DEG C and reacts 8 hours, is cooled to 25 DEG C, by material filtering in kettle, filter cake is eluted with a small amount of methanol, mother liquor concentrations To cutout, methylene chloride is added thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, merges organic phase concentration Recycling design, crude product carry out rectification under vacuum by 40cm filled column, collect T=85-90 DEG C/P=2-3mmHg fraction, total to obtain Obtain the compound of 153.5g, purity 98.4%, yield 52%；

The structural confirmation of above-mentioned obtained compound is confirmed that result is such as using GC (Agilent 7820A) Shown in Fig. 1, the retention time at each peak, peak area and peak height are as shown in the table:

Step (1) obtained compound is subjected to structural confirmation using GC-MS, result is as shown in Figure 2, wherein makes Equipment is Agilent GC 7890, MS 5975

Chromatographic column is DB-5ms, 30m × 0.25mm, 0.25 μm of film thickness

Carrier gas: He column flow: 0.7ml/min is constant

Injector temperature: 280 DEG C, ion source temperature: 230 DEG C

MS temperature: 150 DEG C, Aux-2 temperature: 200 DEG C

Split ratio: 100:1

Post case temperature: 70 DEG C of holding 0min keep the temperature 10min with 10 DEG C/min to 280 DEG C

100mg sample is dissolved in 1ml acetonitrile, injects 0.1 μ l, records spectrogram, fragment and standard comparing are obtained；

Can be seen that obtained compound from Fig. 1 and Fig. 2 is 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of compound 2:

At 40 DEG C, 20.7g (0.15mol, 1.0eq) step (1) obtained compound 2- ammonia is added to 500ml four-hole bottle 1.1g (0.007mol, 0.05eq) is added after material all dissolution in base -3- methyl -5- methoxypyridine and the 82.9g tert-butyl alcohol 4-dimethylaminopyridine is warming up to 80-85 DEG C, and 81.8g (0.38mol, 2.5eq) di-tert-butyl dicarbonate is dissolved in 82.9g The tert-butyl alcohol in, and keep in four-hole bottle 80-85 DEG C of temperature dropwise addition, the reaction was continued at such a temperature after being added dropwise 6 hours To midbody compound, 12.0g sodium hydroxide (0.30mol, 2.0eq) then is added, and the reaction was continued in the temperature, reaction Time is 6 hours, after reaction, using acetic acid quenching reaction liquid to neutrality, be warming up to 80-85 DEG C be evaporated off solvent to cutout, With tetrahydrofuran extraction 2 times, is crystallized after being then combined with organic phase and solvent evaporated, obtain 34.0g compound 2, yield 95%；

The structure of obtained compound 2 is confirmed that spectrogram is as shown in Figure 3 using HPLC, wherein when reservation Between, peak width, peak area, peak height and peak area % it is as shown in the 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			2888.07918	864.57043	100%

From figure 3, it can be seen that the purity of obtained compound 2 is 99.6%.

Obtained compound 2 is subjected to structural confirmation using LC-MS, spectrogram is as shown in Figure 4, wherein mobile phase A is 0.1% aqueous formic acid, preparation method are that 1ml formic acid is dissolved in 1000ml water, are mixed；Mobile phase B is acetonitrile, under The mode of stating carries out gradient elution, and chromatographic column is Agilent poroshell 120EC-C18, and 4 μm, 150 × 4.6mm (article No.: 693970-902), Detection wavelength 220nm, column temperature are 30 DEG C, flow velocity 1.0ml/min, voltage 150V, and gas temperature is 325 DEG C, dry gas stream 11l/min, sample volume is 0.5 microlitre.

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

From fig. 4, it can be seen that obtained compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxypyridine.

The structural confirmation of obtained compound 2 is used into H¹- NMR (Bruker 400MHz) is confirmed that result is such as Shown in Fig. 5；

From fig. 5, it can be seen that obtained compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxypyridine, figure In 93.26% be using nuclear-magnetism internal mark method determination compound 2 content, internal standard compound 1,3,5- trimethoxy-benzene；

(3) synthesis of product

It is passed through nitrogen protection to 2L four-hole bottle, 72.0g (0.3mol, 1.0eq) step (2) obtained compound 2 is added With the tetrahydrofuran of 720ml, -10 ± 5 DEG C are cooled to, and controls and 204.0g (0.75mol, 2.5eq) is added dropwise at such a temperature The hexane solution of 2.5M n-BuLi, in the temperature, the reaction was continued 2.5 hours after being added dropwise, and is then added dropwise at such a temperature The n,N-Dimethylformamide of 26.3g (0.36mol, 1.2eq) after being added dropwise, keeps -10 ± 5 DEG C of stirrings extremely to react for 6 hours Completely, mixture in bottle is kept for 0 ± 5 DEG C slowly to pour into 35% concentrated hydrochloric acid of 216g, and keeps 0 ± 5 DEG C of quenching reaction, Reaction solution is warming up to 40-45 DEG C to react 2 hours, to be layered removing organic layer after reaction, by water phase in sodium hydroxide With to pH=11~12, then it is extracted twice with tetrahydrofuran, after combined organic phase washed once with saturated salt solution, is merged It is crystallized to obtain 35.3g product, yield 79% after organic phase recycling design；

The structure of obtained product is confirmed that spectrogram is as shown in Figure 6 using HPLC, wherein retention time, peak Width, peak area, peak height and peak area % are as shown in the 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			6426.79838	1950.64911	100%

From fig. 6, it can be seen that the purity of obtained product is 99.5%.

Obtained product is subjected to structural confirmation using LC-MS, spectrogram is as shown in table 7, wherein mobile phase A is 0.1% aqueous formic acid, preparation method are that 1ml formic acid is dissolved in 1000ml water, are mixed；Mobile phase B is acetonitrile, under The mode of stating carries out gradient elution, and chromatographic column is Agilent poroshell 120EC-C18, and 4 μm, 150 × 4.6mm (article No.: 693970-902), Detection wavelength 220nm, column temperature are 30 DEG C, flow velocity 1.0ml/min, voltage 150V, and gas temperature is 325 DEG C, dry gas stream 11l/min, sample volume is 0.5 microlitre.

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

From figure 7 it can be seen that obtained product is 5- methoxyl group -7- azaindole.

The structural confirmation of obtained product is used into H¹- NMR is confirmed that result is as shown in Figure 8；

From figure 8, it is seen that obtained product is 5- methoxyl group -7- azaindole, 94.88% in figure is using core The content of the product of magnetic internal mark method determination, internal standard compound 1,3,5- trimethoxy-benzene.

The synthesis of two 5- methoxyl group -7- azaindole of embodiment

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

The methanol of the compound 1 of 200.0g (1.07mol, 1.0eq) and 1kg is added in 2L autoclave, stirring is to admittedly Body all after dissolution, sequentially adds the sodium methoxide of 173.4g (3.21mol, 3.0eq) and the bromine of 76.8g (0.53mol, 0.5eq) Change it is cuprous, be heated to 130 DEG C react 20 hours, be cooled to 25 DEG C, by material filtering in kettle, filter cake elute with a small amount of methanol, mother Liquid is concentrated into cutout, and methylene chloride is added thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, merges organic It is mutually concentrated into cutout, crude product carries out rectification under vacuum by 40cm filled column, collects T=85-90 DEG C/P=2-3mmHg fraction, altogether Meter obtains the compound of 43.0g, purity 98.2%, yield 29%；

Obtained compound is analyzed using the identical method of embodiment one, confirmed, obtained compound For 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of compound 2:

At 0 DEG C, 20.7g (0.15mol, 1.0eq) step (1) obtained compound 2- amino-is added to 2L four-hole bottle 0.12g (0.0015mol, 0.01eq) is added after material all dissolution in 3- methyl -5- methoxypyridine and 621g tetrahydrofuran Pyridine is cooled to -10 DEG C, and 81.8g (0.38mol, 2.5eq) di-tert-butyl dicarbonate is dissolved in the tetrahydrofuran of 82.9g, And -10-0 DEG C of temperature dropwise additions in four-hole bottle are kept, the reaction was continued at such a temperature after being added dropwise 8 hours obtains intermediate compound Then 12.0g sodium hydroxide (0.30mol, 2.0eq) is added in object, and the reaction was continued in the temperature, and the reaction time is 6 hours, After reaction, with 25% hydrochloric acid reaction solution to neutrality, organic layer is separated, organic phase is then combined with and solvent evaporated is laggard Row crystallization, obtains 18.2g compound 2, purity 94.3%, yield 51%；

Obtained compound 2 is confirmed using the identical method of embodiment one, through analyzing obtained compound 2 For 2- tert-butoxy amino -3- methyl -5- methoxypyridine；

(3) synthesis of product

It is passed through nitrogen protection to 1L four-hole bottle, 22.7g (0.096mol, 1.0eq) step (2) obtained compound is added The tetrahydrofuran of 2 and 340.5ml is cooled to -40 ± 5 DEG C, and controls and 52.0g (0.192mol, 2.0eq) is added dropwise at such a temperature The hexane solution of 2.5M n-BuLi, after being added dropwise, being kept for -40 ± 5 DEG C, the reaction was continued 2 hours, then drips at such a temperature The n,N-Dimethylformamide for adding 10.5g (0.144mol, 1.5eq) after being added dropwise, is kept for -40 ± 5 DEG C stir 20 hours, Mixture in bottle is kept into quenching reaction in 0 ± 5 DEG C of 35% concentrated hydrochloric acid for slowly pouring into 45.4g, and is kept for 0 ± 5 DEG C and is quenched Reaction solution is warming up to 40-45 DEG C and reacted 2 hours, to be layered removing organic layer after reaction, by water phase with hydroxide by reaction Sodium is neutralized to pH=11~12, is then extracted twice with tetrahydrofuran, after combined organic phase washed once with saturated salt solution, It is crystallized to obtain 10.0g product, purity 95.6%, yield 71% after merging organic phase recycling design；

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

The synthesis of three 5- methoxyl group -7- azaindole of embodiment

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

The methanol of the compound 1 of 200.0g (1.07mol, 1.0eq) and 1kg is added in 2L autoclave, stirring is to admittedly Body all after dissolution, sequentially adds the potassium methoxide of 225.1g (3.21mol, 3.0eq) and the sulphur of 42.6g (0.54mol, 0.5eq) Sour copper is heated to 130 DEG C and reacts 20 hours, is cooled to 25 DEG C, by material filtering in kettle, filter cake is eluted with a small amount of methanol, mother liquor It is concentrated into cutout, methylene chloride is added thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, merges organic phase It is concentrated into cutout, crude product carries out rectification under vacuum by 40cm filled column, collects T=85-90 DEG C/P=2-3mmHg fraction, amounts to Obtain the compound of 67.6g, purity 98.1%, yield 46%；

Structural confirmation, confirmed obtainedization are carried out to obtained compound using the method being the same as example 1 Conjunction object is 2- amino -3- methyl -5- methoxypyridine.

(2) synthesis of compound 2:

At 0 DEG C, 20.7g (0.15mol, 1.0eq) step (1) obtained compound 2- ammonia is added to 500ml four-hole bottle 1.8g (0.015mol, 0.1eq) 4- is added after material all dissolution in base -3- methyl -5- methoxypyridine and 20.7g acetonitrile Dimethylamino naphthyridine is warming up to 20-25 DEG C, and 35.5g (0.165mol, 1.1eq) di-tert-butyl dicarbonate is dissolved in 142g's In tetrahydrofuran, and 20-25 DEG C of temperature dropwise addition in four-hole bottle is kept, the reaction was continued at such a temperature after being added dropwise 8 hours To midbody compound, 21g potassium hydroxide (0.375mol, 2.5eq) then is added, and the reaction was continued in the temperature, reaction Time is 8 hours, after reaction, with 25% hydrochloric acid reaction solution to neutrality, separates organic layer, is then combined with organic phase simultaneously It is crystallized after solvent evaporated, obtains 8.6g compound 2, purity 95.0%, yield 24%；

Structural confirmation is carried out to obtained compound 2 using the method being the same as example 1, it is confirmed obtained Compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxypyridine.

(3) synthesis of product

It is passed through nitrogen protection to 1L four-hole bottle, the four of 22.7g (0.096mol, 1.0eq) compound 2 and 181.6ml are added Hydrogen furans is cooled to -10 ± 5 DEG C, and controls and 155.9g (0.576mol, 6.0eq) 2.5M diisopropyl is added dropwise at such a temperature The hexane solution of amido lithium continues to react at such a temperature 3 hours after being added dropwise, 7.0g is then added dropwise at such a temperature The n,N-Dimethylformamide of (0.096mol, 1eq) after being added dropwise, is kept for -10 ± 5 DEG C stir 7 hours, will mixed in bottle Object keeps whole in 0 ± 5 DEG C of 25% hydrochloric acid for slowly pouring into 56.8g and keeps 0 ± 5 DEG C of quenching reaction, heats up after being quenched To 40-45 DEG C react 2.5 hours, after reaction layering remove organic layer, by water phase with sodium hydroxide be neutralized to pH=11~ 12, it is then extracted twice with tetrahydrofuran, after combined organic phase washed once with saturated salt solution, it is molten to merge organic phase recycling It is crystallized to obtain 7.9g product, purity 96.1%, yield 56% after agent.

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

The synthesis of example IV 5- methoxyl group -7- azaindole

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

The ethyl alcohol of the compound 1 of 40.0g (0.21mol, 1.0eq) and 2000g is added in 5L autoclave, stirring is to admittedly Body all after dissolution, sequentially adds the lithium methoxide of 12.0g (0.315mol, 1.5eq) and the bromine of 3.0g (0.021mol, 0.1eq) Change it is cuprous, be heated to 140-150 DEG C react 8 hours, be cooled to 25 DEG C, by material filtering in kettle, filter cake is eluted with a small amount of methanol, Mother liquor concentrations are added methylene chloride thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, be associated with to stopping Machine is mutually concentrated into cutout, and crude product carries out rectification under vacuum by 40cm filled column, collects T=85-90 DEG C/P=2-3mmHg fraction, Total compound for obtaining 8.3g, purity 98.2%, yield 28%；

Structural confirmation, confirmed obtained chemical combination are carried out to obtained compound using the identical method of embodiment one Object is 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of compound 2

37.3g (0.27mol, 1.0eq) step (1) obtained compound 2- amino -3- first is added to 500ml four-hole bottle 110.2g is added dropwise into reaction solution in -5 DEG C after material all dissolution for base -5- methoxypyridine and 187.0g tetrahydrofuran The hexane solution of the n-BuLi of (0.41mol, 1.5eq) 2.5M, -5 DEG C after reaction 1-2 hours, by 123.1g (0.57mol, 2.1eq) di-tert-butyl dicarbonate is added drop-wise in reaction solution in -5 DEG C, and is kept for -5 DEG C react 3 hours, by reaction mixture water It is quenched, sediment is collected by filtration, filter cake is washed with water, is then dried in vacuo, obtain the compound 2 of 33.5g, purity 92.8%, Yield 52%；

Structural confirmation is carried out to obtained compound 2 using the method being the same as example 1, it is confirmed obtained Compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxypyridine；

(3) synthesis of product

It is passed through nitrogen protection to 500ml four-hole bottle, 22.7g (0.096mol, 1.0eq) step (2) obtainedization is added The tetrahydrofuran for closing object 2 and 113.5ml, is cooled to -10 ± 5 DEG C, and control be added dropwise at such a temperature 65g (0.24mol, 2.5eq) the hexane solution of 2.5M n-BuLi, in the temperature, the reaction was continued 3 hours after being added dropwise, and then drips at such a temperature The n,N-Dimethylformamide for adding 33.2g (0.48mol, 5eq) after being added dropwise, is kept for -10 ± 5 DEG C stir 6 hours, by bottle Middle mixture is kept for 0 ± 5 DEG C and slowly poured into 25% hydrochloric acid of 136.2g, and whole process keeps 0 ± 5 DEG C of quenching reaction, then will Reaction solution after being quenched is warming up to 40-45 DEG C and reacts 3.5 hours, and layering removes organic layer after reaction, by water phase with hydrogen-oxygen Change sodium and be neutralized to pH=7-8,7.8g product, purity 98.5%, yield 55% is obtained by filtration.

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

The synthesis of five 5- methoxyl group -7- azaindole of embodiment

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

The methanol of the compound 1 of 40.0g (0.21mol, 1.0eq) and 200g is added in 500ml autoclave, stirring is extremely Solid all after dissolution, sequentially adds the sodium methoxide of 34.7g (0.64mol, 3.0eq) and the bromine of 7.2g (0.11mol, 0.5eq) Change it is cuprous, be heated to 100-110 DEG C react 20 hours, be cooled to 25 DEG C, by material filtering in kettle, filter cake is drenched with a small amount of methanol It washes, mother liquor concentrations are added methylene chloride thereto and water extracting and demixing, water phase are extracted once again with methylene chloride to stopping, and close And organic phase is concentrated into cutout, crude product carries out rectification under vacuum by 40cm filled column, collects T=85-90 DEG C/P=2-3mmHg and evaporates Point, amount to the compound for obtaining 8.9g, purity 97.6%, yield 30%.

Structural confirmation is carried out to obtained compound using the method being the same as example 1, it is confirmed, it is obtained Compound is 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of compound 2:

37.3g (0.27mol, 1.0eq) step (1) obtained compound 2- amino -3- first is added to 500ml four-hole bottle 161.6g is added dropwise into reaction solution in -5 DEG C after material all dissolution for base -5- methoxypyridine and 187.0g tetrahydrofuran The hexane solution of the n-BuLi of (0.59mol, 2.2eq) 2.5M, -5 DEG C after reaction 1-2 hours, by 73.7g (0.34mol, 1.25eq) di-tert-butyl dicarbonate is added in reaction solution in -5 DEG C, and is kept for -5 DEG C react 3 hours, and reaction mixture is used Citric acid is quenched, and sediment is collected by filtration, and filter cake is washed with water, crystallizes in organic solvent, obtains the compound 2 of 28.3g, pure Degree 97.8%, yield 44%；

Structural confirmation is carried out to obtained compound 2 using the method being the same as example 1, it is confirmed obtained Compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxy pyrimidine；

(3) synthesis of product

It is passed through nitrogen protection to 250ml four-hole bottle, 22.7g (0.096mol, 1.0eq) step (2) obtainedization is added The tetrahydrofuran for closing object 2 and 68ml is cooled to -10 ± 5 DEG C, and controls and 65g (0.24mol, 2.5eq) is added dropwise at such a temperature The hexane solution of 2.5M n-BuLi, the reaction was continued at such a temperature after being added dropwise 3 hours, is then added dropwise at such a temperature The n,N-Dimethylformamide of 8.3g (0.12mol, 1.2eq) after being added dropwise, is kept for -10 ± 5 DEG C react 4 hours, will be in bottle Mixture keeps quenching reaction in 0 ± 5 DEG C of 35% hydrochloric acid for slowly pouring into 68.3g, and whole process keeps 0 ± 5 DEG C of quenching reaction, so Afterwards by the reaction solution after being quenched be warming up to 40-45 DEG C react 1.5 hours, after reaction layering remove organic layer, by water phase with Sodium hydroxide is neutralized to pH=11~12, is then extracted twice with tetrahydrofuran, and combined organic phase is with saturated common salt water washing After primary, crystallized to obtain 1.7g product, purity 89.1%, yield 12% after merging organic phase recycling design；

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

The synthesis of six 5- methoxyl group -7- azaindole of embodiment

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

The methanol of the compound 1 of 40.0g (0.21mol, 1.0eq) and 200g is added in 500ml autoclave, stirring is extremely Solid all after dissolution, sequentially adds the oxidation of the sodium methoxide and 5.1g (0.06mol, 0.3eq) of 170g (3.15mol, 15eq) Copper is heated to 140-150 DEG C and reacts 8 hours, is cooled to 25 DEG C, by material filtering in kettle, filter cake is eluted with a small amount of methanol, mother liquor It is concentrated into cutout, methylene chloride is added thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, merges organic phase It is concentrated into cutout, crude product carries out rectification under vacuum by 40cm filled column, collects T=85-90 DEG C/P=2-3mmHg fraction, amounts to Obtain the compound of 12.1g, purity 96.9%, yield 41%；

Structural confirmation, confirmed obtainedization are carried out to obtained compound using the method being the same as example 1 Conjunction object is 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of compound 2

By the obtained compound 2- amino -3- methyl -5- methoxypyridine of 9.4g (0.05mol, 1.0eq) step (1) It is added in 47.0g tetrahydrofuran, it is spare to be configured to solution A；It is passed through nitrogen protection into 250ml four-hole bottle, 22.1g is added Bis- trimethyl silicon substrate Sodamide (NaHMDS) tetrahydrofuran solutions of (0.12mol, 2.4eq) 2.0M, drip in -5 DEG C into reaction solution Add solution A, and keep -5 DEG C of reactions 1-2 hours, 4.4g (0.06mol, 1.1eq) di-tert-butyl dicarbonate is added in -5 DEG C It in reaction solution, and is kept for -5 DEG C react 3 hours, reaction mixture is quenched with water, sediment is collected by filtration, filter is washed with water Then cake is dried in vacuo, obtain the compound 2 of 9.7g, purity 98.2%, yield 68%；

Structural confirmation is carried out to obtained compound 2 using the method being the same as example 1, it is confirmed obtained Compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxypyridine；

(3) synthesis of product

It is passed through nitrogen protection to 500ml four-hole bottle, 22.7g (0.096mol, 1.0eq) step (2) obtainedization is added The tetrahydrofuran for closing object 2 and 136ml is cooled to -20 ± 5 DEG C, and controls and 65g (0.24mol, 2.5eq) is added dropwise at such a temperature The hexane solution of 2.5M n-BuLi, the reaction was continued at such a temperature after being added dropwise 4 hours, is then added dropwise at such a temperature The n,N-Dimethylformamide of 8.3g (0.12mol, 1.2eq) after being added dropwise, is kept for -20 ± 5 DEG C react 10 hours, by bottle Middle mixture keeps quenching reaction in 0 ± 5 DEG C of 35% hydrochloric acid for slowly pouring into 68.3g, and whole process keeps 0 ± 5 DEG C of quenching reaction, Then by the reaction solution after being quenched be warming up to 40-45 DEG C react 1 hour, after reaction layering remove organic layer, by water phase with Sodium hydroxide is neutralized to pH=11~12, is then extracted twice with tetrahydrofuran, and combined organic phase is with saturated common salt water washing After primary, crystallized to obtain 5.6g product, purity 93.5%, yield 40% after merging organic phase recycling design.

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

The synthesis of seven 5- methoxyl group -7- azaindole of embodiment

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

The methanol of the compound 1 of 40.0g (0.21mol, 1.0eq) and 200g is added in 500ml autoclave, stirring is extremely Solid all after dissolution, sequentially adds the sodium methoxide of 34.7g (0.64mol, 3.0eq) and the oxygen of 8.7g (0.11mol, 0.5eq) Change copper, be heated to 140-150 DEG C and react 8 hours, be cooled to 25 DEG C, by material filtering in kettle, filter cake is eluted with a small amount of methanol, female Liquid is concentrated into cutout, and methylene chloride is added thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, merges organic It is mutually concentrated into cutout, crude product carries out rectification under vacuum by 40cm filled column, collects T=85-90 DEG C/P=2-3mmHg fraction, altogether Meter obtains the compound of 12.1g, purity 98.1%, yield 44%；

Structural confirmation, confirmed obtainedization are carried out to obtained compound using the method being the same as example 1 Conjunction object is 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of compound 2

At 0 DEG C, 20.7g (0.15mol, 1.0eq) step (1) obtained compound 2- ammonia is added to 250ml four-hole bottle 1.1g (0.007mol, 0.05eq) 4- is added after material all dissolution in base -3- methyl -5- methoxypyridine and 82.9g acetonitrile Dimethylamino naphthyridine is warming up to 60 DEG C, and 32.3g (0.15mol, 1eq) di-tert-butyl dicarbonate is dissolved in the acetonitrile of 82.9g In, and 60-65 DEG C of temperature dropwise addition in four-hole bottle is kept, the reaction was continued at such a temperature after being added dropwise 8 hours obtains intermediate Then 12.0g sodium hydroxide (0.30mol, 2.0eq) is added in compound, and in the temperature, the reaction was continued, the reaction time 6 Hour, after reaction, with dilute hydrochloric acid quenching reaction liquid to neutrality, be warming up to 80-85 DEG C be evaporated off solvent to cutout, with tetrahydro furan It mutters extraction 2 times, is then combined with after organic phase and solvent evaporated and carries out crystallization and separate organic layer, be then combined with organic phase and be evaporated molten It is crystallized after agent, obtains 25.7g compound 2, purity 95.9%, yield 72%；

Structural confirmation is carried out to obtained compound 2 using the method being the same as example 1, it is confirmed obtained Compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxypyridine；

(3) synthesis of product:

It is passed through nitrogen protection to 500ml four-hole bottle, 22.6g (0.095mol, 1.0eq) step (2) obtainedization is added The tetrahydrofuran for closing object 2 and 121.2g, is cooled to -10 ± 5 DEG C, and control be added dropwise at such a temperature 64.6g (0.24mol, 2.5eq) the hexane solution of 2.5M n-BuLi, is added dropwise, and after keeping -10 ± 5 DEG C of stirrings 4 hours, is added dropwise at such a temperature The n,N-Dimethylformamide of 8.3g (0.11mol, 1.2eq) after being added dropwise, is kept for -10 ± 5 DEG C stir 2 hours, will be in bottle Mixture keeps quenching reaction in -10 ± 5 DEG C of concentrated hydrochloric acids for slowly pouring into 68.1g35%, and whole process is kept for 0 ± 5 DEG C be quenched instead It answers, the reaction solution after being quenched then is warming up to 40-45 DEG C and is reacted 2 hours, organic layer is removed, water phase is neutralized with sodium hydroxide It to pH=11-12, is then extracted twice with methyl tertiary butyl ether(MTBE), after combined organic phase washed once with saturated salt solution, often Pressure is distilled off solvent and obtains 4.9g product, purity 93.3%, yield 35%.

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

The synthesis of eight 5- methoxyl group -7- azaindole of embodiment

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

The methanol of the compound 1 of 40.0g (0.21mol, 1.0eq) and 120g is added in 200ml autoclave, stirring is extremely Solid all after dissolution, sequentially adds the sodium methoxide of 12.7g (0.23mol, 1.1eq) and the copper of 20.0g (0.32mol, 1.5eq) Powder is heated to 100-105 DEG C and reacts 15 hours, is cooled to 25 DEG C, and by material filtering in kettle, filter cake is eluted with a small amount of methanol, female Liquid is concentrated into cutout, and methylene chloride is added thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, merges organic It is mutually concentrated into cutout, crude product carries out rectification under vacuum by 40cm filled column, collects T=85-90 DEG C/P=2-3mmHg fraction, altogether Meter obtains the compound of 5.6g, purity 92.5%, yield 19%；

Structural confirmation, confirmed obtainedization are carried out to obtained compound using the method being the same as example 1 Conjunction object is 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of compound 2:

At 0 DEG C, 20.7g (0.15mol, 1.0eq) step (1) obtained compound 2- amino-is added to 2L four-hole bottle 0.37g (0.003mol, 0.02eq) 4- bis- is added after material all dissolution in 3- methyl -5- methoxypyridine and 414g methanol Methylamino pyridine is warming up to 60 DEG C, and 81.8g (0.38mol, 2.5eq) di-tert-butyl dicarbonate is dissolved in the tertiary fourth of 122.8g In alcohol, and 60-65 DEG C of temperature dropwise addition is kept in four-hole bottle, keeps 80-85 DEG C after being added dropwise the reaction was continued 1 hour to obtain centre Then 30.0g sodium hydroxide (0.75mol, 5.0eq) is added in body compound, and the reaction was continued in the temperature, and the reaction time is 40 hours, after reaction, with spirit of vinegar quenching reaction liquid to neutrality, be warming up to 80-85 DEG C be evaporated off solvent to cutout, with tetrahydro Furans extracts 2 times, is then combined with after organic phase and solvent evaporated and carries out crystallization and separate organic layer, is then combined with organic phase and is evaporated It is crystallized after solvent, obtains 7.5g compound 2, purity 88.2%, yield 21%；

Structural confirmation is carried out to obtained compound 2 using the method being the same as example 1, it is confirmed obtained Compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxypyridine；

(3) synthesis of product:

It is passed through nitrogen protection to 3L four-hole bottle, 22.6g (0.096mol, 1.0eq) step (2) obtained compound is added The acetonitrile of 2 and 1816g is cooled to -5 DEG C, and controls and 64.8g (0.24mol, 2.5eq) 2.5M normal-butyl is added dropwise at such a temperature The hexane solution of lithium after being added dropwise, is kept for -5 DEG C continue stirring 6 hours, 69.6g is then added dropwise at such a temperature The n,N-Dimethylformamide of (0.96mol, 10eq) after being added dropwise, is kept for 20-25 DEG C stir 24 hours, will mixed in bottle Object keeps quenching reaction in -10 ± 5 DEG C of acetic acid for slowly pouring into 45.4g, and after keeping the temperature the reaction was continued 6 hours, removes Organic layer is removed, water phase is neutralized to pH=11-12 with sodium hydroxide, is then extracted twice with methyl tertiary butyl ether(MTBE), merging has After machine mutually washed once with saturated salt solution, air-distillation removes solvent and obtains 1.6g product, purity 85.6%, yield 11%；

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

The synthesis of nine 5- methoxyl group 7- azaindole of embodiment

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

The methanol of the compound 1 of 40.0g (0.21mol, 1.0eq) and 20g is added in 200ml autoclave, stirring is extremely Solid all after dissolution, sequentially adds the sodium methoxide and 0.14g (0.01mol, 0.05eq) of 17.0g (0.32mol, 1.5eq) Copper powder is heated to 80-85 DEG C and reacts 3 hours, is cooled to 25 DEG C, by material filtering in kettle, filter cake is eluted with a small amount of methanol, mother liquor It is concentrated into cutout, methylene chloride is added thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, merges organic phase It is concentrated into cutout, crude product carries out rectification under vacuum by 40cm filled column, collects T=85-90 DEG C/P=2-3mmHg fraction, amounts to Obtain the compound of 1.5g, purity 89.8%, yield 5%；

Structural confirmation, confirmed obtainedization are carried out to obtained compound using the method being the same as example 1 Conjunction object is 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of compound 2

At 0 DEG C, 20.7g (0.15mol, 1.0eq) step (1) obtained compound 2- amino-is added to 1L four-hole bottle Then 3.7g (0.03mol, 0.2eq) 4- dimethylamino pyrrole is added in 3- methyl -5- methoxypyridine and 103.6g tetrahydrofuran Pyridine is cooled to -40 DEG C, keeps the hexane solution of -40 ± 5 DEG C of addition 40.8g (0.15mol, 1.0eq) 2.5M n-BuLis, and And after the reaction was continued 15 hours in the temperature, 327.4g (1.5mol, 10eq) di-tert-butyl dicarbonate is dissolved in the four of 40.9g In hydrogen furans, and temperature -40 ± 5 DEG C is kept in four-hole bottle to be added dropwise, the reaction was continued at such a temperature after being added dropwise 40 hours, instead After answering, with 25% hydrochloric acid reaction solution to neutrality, it is warming up to 80-85 DEG C and solvent is evaporated off to stopping, extracted with tetrahydrofuran It takes 2 times, is then combined with after organic phase and solvent evaporated and carries out crystallization and separate organic layer, after being then combined with organic phase and solvent evaporated It is crystallized, obtains 13.2g compound 2, purity 89.5%, yield 37%；

Structural confirmation is carried out to obtained compound 2 using the method being the same as example 1, it is confirmed obtained Compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxypyridine；

(3) synthesis of product:

It is passed through nitrogen protection to 3L four-hole bottle, 22.6g (0.095mol, 1.0eq) step (2) obtained compound is added The methylene chloride of 2 and 2270g is cooled to -5 DEG C, and controls and 51.8g (0.19mol, 2.0eq) 2.5M is being added dropwise just at such a temperature The hexane solution of butyl lithium keeps 30 ± 5 DEG C and continues stirring 2 hours, is then cooled to -10 ± 5 DEG C of dropwise additions after being added dropwise The n,N-Dimethylformamide of 55.7g (0.77mol, 8.0eq) after being added dropwise, is kept for -10 ± 5 DEG C stir 6 hours, by bottle Middle mixture is slowly increased to 10 ± 5 DEG C and the temperature is kept slowly to pour into quenching reaction in the citric acid of 136.2g30%, entirely Journey keeps 10 ± 5 DEG C of quenching reactions, continues to react 6 hours at such a temperature, removes organic layer, water phase is neutralized with sodium hydroxide It to pH=11-12, is then extracted twice with methyl tertiary butyl ether(MTBE), after combined organic phase washed once with saturated salt solution, often Pressure is distilled off solvent and obtains 2.0g product, purity 88.7%, yield 14%；

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

The synthesis of ten 5- methoxyl group -7- azaindole of embodiment

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

The methanol of the compound 1 of 40.0g (0.21mol, 1.0eq) and 2000g is added in 5L autoclave, stirring is to admittedly Body all after dissolution, sequentially adds the sodium methoxide of 9.3g (0.17mol, 0.8eq) and the copper powder of 27.2g (0.43mol, 2.0eq), It is heated to 120-125 DEG C to react 8 hours, is cooled to 25 DEG C, by material filtering in kettle, filter cake is eluted with a small amount of methanol, and mother liquor is dense It is reduced to cutout, methylene chloride is added thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, it is dense to merge organic phase It is reduced to cutout, crude product carries out rectification under vacuum by 40cm filled column, collects T=85-90 DEG C/P=2-3mmHg fraction, total to obtain Obtain the compound of 5.3g, purity 90.3%, yield 18%；

Structural confirmation, confirmed obtainedization are carried out to obtained compound using the method being the same as example 1 Conjunction object is 2- amino -3- methyl -5- methoxypyridine.

(2) synthesis of compound 2

At 0 DEG C, 20.7g (0.15mol, 1.0eq) step (1) obtained compound 2- amino-is added to 2L four-hole bottle 18.3g (0.15mol, 1.0eq) 4- is added after material all dissolution in 3- methyl -5- methoxypyridine and 621g tetrahydrofuran Dimethylamino naphthyridine is cooled to 0 DEG C；Keep the temperature that 82.5g (0.45mol, 3.0eq) double trimethyl silicon substrate Sodamides are added dropwise Afterwards, it reacts 6 hours at such a temperature；81.8g (0.38mol, 3.0eq) di-tert-butyl dicarbonate is dissolved in the tetrahydro of 40.9g In furans, and 0-5 DEG C of temperature dropwise addition in four-hole bottle is kept, the reaction was continued at 20-25 DEG C 30 hours after being added dropwise, and reaction terminates Afterwards, it with 25% hydrochloric acid reaction solution to neutrality, is warming up to 80-85 DEG C and solvent is evaporated off to stopping, extracted 2 times with tetrahydrofuran, It is then combined with after organic phase and solvent evaporated and carries out crystallization and separate organic layer, tied after being then combined with organic phase and solvent evaporated Crystalline substance obtains 18.6g compound 2, purity 95.5%, yield 52%；

Structural confirmation is carried out to obtained compound 2 using the method being the same as example 1, it is confirmed obtained Compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxypyridine；

(3) synthesis of product:

It is passed through nitrogen protection to 2L four-hole bottle, 22.7g (0.096mol, 1.0eq) step (2) obtained compound is added The tetrahydrofuran of 2 and 908g is cooled to -10 ± 5 DEG C, and controls and 246.9g (0.57mol, 6.0eq) is added dropwise at such a temperature The hexane solution of 2.0M lithium diisopropylamine keeps 20 ± 5 DEG C and continues stirring 4 hours, is then cooled to -20 after being added dropwise ± 5 DEG C and at such a temperature be added dropwise 34.8g (0.48mol, 5.0eq) n,N-Dimethylformamide, after being added dropwise, keep- 20 ± 5 DEG C are stirred 4 hours, mixture in bottle are kept being quenched in 0 ± 5 DEG C of concentrated hydrochloric acid for slowly pouring into 113.5g35% anti- It answers, whole process keeps 0 ± 5 DEG C of quenching reaction, and then by the reaction solution after being quenched, the reaction was continued at such a temperature 6 hours, and removing has Water phase is neutralized to pH=11-12 with sodium hydroxide, is then extracted twice with methyl tertiary butyl ether(MTBE), combined organic phase by machine layer After washed once with saturated salt solution, air-distillation removes solvent and obtains 6.4g product, purity 95.6%, yield 45%；

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

The synthesis of 11 5- methoxyl group -7- azaindole of embodiment

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

The ethyl alcohol of the compound 1 of 40.0g (0.21mol, 1.0eq) and 1200g is added in 2L autoclave, stirring is to admittedly Body all after dissolution, sequentially adds the sodium methoxide of 231.2g (4.3mol, 20.0eq) and the copper of 24.5g (0.39mol, 1.8eq) Powder is heated to 150-155 DEG C and reacts 15 hours, is cooled to 25 DEG C, and by material filtering in kettle, filter cake is eluted with a small amount of methanol, female Liquid is concentrated into cutout, and methylene chloride is added thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, merges organic It is mutually concentrated into cutout, crude product carries out rectification under vacuum by 40cm filled column, collects T=85-90 DEG C/P=2-3mmHg fraction, altogether Meter obtains the compound of 9.2g, purity 96.6%, yield 31%；

Structural confirmation, confirmed obtainedization are carried out to obtained compound using the method being the same as example 1 Conjunction object is 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of compound 2

At 0 DEG C, 20.7g (0.15mol, 1.0eq) step (1) obtained compound 2- amino-is added to 2L four-hole bottle 9.2g (0.075mol, 0.5eq) is added after material all dissolution in 3- methyl -5- methoxypyridine and 310.5g tetrahydrofuran 4-dimethylaminopyridine is warming up to 60 DEG C, and 36.0g (0.17mol, 1.1eq) di-tert-butyl dicarbonate is dissolved in 1080.3g's In tetrahydrofuran, and 60-65 DEG C of temperature dropwise addition in four-hole bottle is kept, the reaction was continued at such a temperature after being added dropwise 15 hours To midbody compound, 21.0g potassium hydroxide (0.38mol, 2.5eq) then is added, and the reaction was continued at 20-25 DEG C, reaction Time is 8 hours, after reaction, goes out reaction solution to neutrality with water quenching, is warming up to 80-85 DEG C and solvent is evaporated off to stopping, with four Hydrogen furans extracts 2 times, is then combined with after organic phase and solvent evaporated and carries out crystallization and separate organic layer, is then combined with organic phase and steams It is crystallized after dry solvent, obtains 10.4g compound 2, purity 92.0%, yield 29%；

Structural confirmation is carried out to obtained compound 2 using with method described in embodiment one, it is confirmed obtained Compound 2 is 2- tert-butoxy amino -3- methyl -5- methoxypyridine；

(3) synthesis of product:

It is passed through nitrogen protection to 2L four-hole bottle, 22.7g (0.096mol, 1.0eq) step (2) obtained compound is added The tetrahydrofuran of 2 and 454g is cooled to -20 ± 5 DEG C, and controls and 64.8g (0.24mol, 2.5eq) 2.5M is added dropwise at such a temperature The hexane solution of n-BuLi keeps -20 ± 5 DEG C and continues stirring 12 hours, is then added dropwise at such a temperature after being added dropwise The n,N-Dimethylformamide of 10.4g (0.14mol, 1.5eq) after being added dropwise, is kept for 20 ± 5 DEG C stir 10 hours, by bottle Middle mixture keeps quenching reaction in -10 ± 5 DEG C of concentrated hydrochloric acids for slowly pouring into 227.0g35%, and whole process is kept for 0 ± 5 DEG C and is quenched Reaction, then by the reaction solution after being quenched, the reaction was continued at such a temperature 1 hour, organic layer is removed, by water phase with sodium hydroxide It is neutralized to pH=11-12, is then extracted twice with methyl tertiary butyl ether(MTBE), combined organic phase washed once with saturated salt solution Afterwards, air-distillation removes solvent and obtains 8.9g product, purity 97.0%, yield 63%；

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

The synthesis of 12 5- methoxyl group -7- azaindole of embodiment

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

The methanol of the compound 1 of 400.0g (2.14mol, 1.0eq) and 2kg is added in 5L autoclave, stirring is to admittedly Body all after dissolution, sequentially adds the sodium methoxide of 346.6g (6.42mol, 3.0eq) and the copper of 68.0g (1.07mol, 0.5eq) Powder is heated to 130 DEG C and reacts 8 hours, is cooled to 25 DEG C, by material filtering in kettle, filter cake is eluted with a small amount of methanol, mother liquor concentrations To cutout, methylene chloride is added thereto and water extracting and demixing, water phase are extracted once again with methylene chloride, merges organic phase concentration Recycling design, crude product carry out rectification under vacuum by 40cm filled column, collect T=85-90 DEG C/P=2-3mmHg fraction, total to obtain Obtain the compound of 153.5g, purity 98.4%, yield 52%；

Structural confirmation, confirmed obtainedization are carried out to obtained compound using the method being the same as example 1 Conjunction object is 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of product

48.0g (0.35mol, 1.0eq) step (1) obtained compound 2- amino -3- methyl-is added to 2L four-hole bottle 207.9g is added dropwise into reaction solution in -5 DEG C after material all dissolution for 5- methoxypyridine and 240g tetrahydrofuran The hexane solution of the n-BuLi of (0.76mol, 2.2eq) 2.5M, -5 DEG C after reaction 1-2 hours, then by 83.4g (0.38mol, 1.1eq) di-tert-butyl dicarbonate is added in reaction solution in -5 DEG C, and keep -5 DEG C react 3 hours, then in - The hexane solution of the n-BuLi of 5 DEG C of from dropwise addition 207.9g (0.76mol, 2.2eq) 2.5M to reaction solution, and keep -5 DEG C of reactions It 1-2 hours, is kept for -5 DEG C and 30.5g (0.42mol, 1.2eq) n,N-Dimethylformamide is added drop-wise in above-mentioned reaction solution, and after It is continuous to react 6-8 hour at this temperature again, reaction mixture hydrochloric acid is layered, water layer with alkali neutralization to pH=11-12, With organic solvent aqueous layer extracted, washed organic layer, after the recovered solvent of organic layer, crystallization obtains the product of 7.0g, purity 96.6%, yield 14%；

Structural confirmation, confirmed obtained product are carried out to obtained product using the method being the same as example 1 For 5- methoxyl group -7- azaindole.

In conclusion preparation method of the present invention, substantially reduces synthesis compared with the synthetic method reported at present Route, raw material 2- amino -3- methyl -5- Bromopyrimidine of the present invention, compared with the 5- bromo-7-azaindole of prior art, Raw material is cheap and easy to get, efficiently avoids the product of the prior art, and the purity of products obtained therefrom is relatively high；And used in the present invention Raw material and reagent be it is cheap and easy to get, be highly susceptible to realize industrialization.

The above is only the preferred embodiment that the present invention is implemented, and not does limitation in any form to the present invention, all The modifications, equivalent substitutions and improvements etc. done within the spirit and principles in the present invention are required to be included in protection of the invention Within the scope of.

Claims (20)

1. a kind of synthetic method of 5- methoxyl group -7- azaindole, it includes following processes:

Process a): being that compound 2 is prepared in raw material with compound 1；

Process b): 5- methoxyl group -7- azaindole is prepared by compound 2.

2. synthetic method according to claim 1, wherein process b) is that compound 2 is dissolved in third organic solvent, Then alkali is added to be reacted, is subsequently added into n,N-Dimethylformamide and forms aldehyde radical intermediate, last aldehyde radical intermediate is in acid Property under the conditions of after cyclization, crystallization obtains product；Wherein, alkali is preferably added to methyl deprotonation；More preferably, described in acidity Under the conditions of cyclization be to be quenched under the conditions of acid quencher and cyclization.

3. synthetic method according to claim 2, wherein in process b), the alkali is selected from n-BuLi, diisopropyl One of amido lithium, bis- (trimethyl silicon substrate) lithium amides or bis- (trimethyl silicon substrate) Sodamides, preferably n-BuLi.

4. synthetic method according to claim 2 or 3, wherein in process b), the third organic solvent is selected from tetrahydro Furans, acetonitrile, methylene chloride, chloroform, carbon tetrachloride, ether, methyl-propyl ether, n-butyl ether, glycol dimethyl ether, diethylene glycol In dimethyl ether, methyl phenyl ethers anisole, methyl tertiary butyl ether(MTBE), 1,2- dichloroethanes, benzene, toluene, paraxylene, hexane, heptane or octane One kind, preferably tetrahydrofuran；Preferably, the mass ratio of the compound 2 and the third organic solvent is 1:2~100, excellent 1:5~80 are selected as, are more preferably 1:8~15.

5. according to the described in any item methods of claim 2-4, wherein in process b), the acidity quencher is selected from dense salt One of acid, sulfuric acid, nitric acid, acetic acid or citric acid, preferably concentrated hydrochloric acid；Preferably, the compound 2 is quenched with the acidity The mass ratio of agent of going out is 1:2~10, and preferably 1:2~5 are more preferably 1:2.5~3.

6. according to the described in any item synthetic methods of claim 2-5, wherein in process b), the compound 2 and the alkali Molar ratio is 1:2.0~6.0, preferably 1:2.0~2.5；Preferably, the compound 2 and the n,N-Dimethylformamide Molar ratio be 1:1.0~10.0, preferably 1:1.0~5 are more preferably 1:1.0~1.5.

7. according to the described in any item synthetic methods of claim 2-6, wherein in process b), the temperature that alkali is added is -40~30 DEG C, preferably -20~0 DEG C；Preferably, the reaction time is 2-12 hours；Preferably, the temperature of n,N dimethylformamide is added It is -40~25 DEG C, preferably -20~20 DEG C；Preferably, the reaction time is 2-12 hours, preferably 4-6 hours.

8. according to the described in any item synthetic methods of claim 2-7, wherein in process b), the reaction temperature being quenched Degree is -10~30 DEG C, preferably 0~5 DEG C；Preferably, the reaction temperature of the cyclization is 0~45 DEG C, preferably 40~45 DEG C； Preferably, the reaction time of the cyclization is 1-6 hours.

9. synthetic method according to claim 1-8, wherein process a) includes the following steps (1) and step (2):

(1) synthesis of 2- amino -3- methyl -5- methoxypyridine: compound 1 is dissolved in the first organic solvent, first Under the action of catalyst, compound 1 is reacted with methoxide, obtains compound 2- amino -3- methyl -5- methoxypyridine；

(2) synthesis of compound 2: by compound 2- amino -3- methyl -5- methoxypyridine and amino protecting agent reaction Close object 2.

10. synthetic method according to claim 9, wherein in the step (2), by compound 2- amino -3- methyl - 5- methoxypyridine dissolves in a second organic solvent, then in the presence of the second catalyst, with amino protecting agent and alkali into Row reaction obtains the compound 2 of amido protecting, and wherein in compound 2, R is amino protecting group；It is preferred that with amino protecting agent and After alkali reaction, quencher is further added and is quenched, the compound 2 of amido protecting is recrystallized to give.

11. synthetic method according to claim 9 or 10, wherein in step (1), first organic solvent is selected from In methanol, ethyl alcohol, ethylene glycol, propyl alcohol, isopropanol, glycerine, Propylene Glycol, n-butyl alcohol, 2- butanol, 2- methyl-1-propyl alcohol, One or more of 2- methyl-2-propanol, methyl glycerine, 2- methyl glycerine and diformazan ethyl glycol, preferably Methanol；Preferably, the mass ratio of the compound 1 and first organic solvent is 1:0.5~50, preferably 1:3~10.

12. according to the described in any item synthetic methods of claim 9-11, wherein in step (1), the first catalyst choosing From in one of metallic copper, cuprous salt or mantoquita；Preferably, first catalyst is selected from copper powder, cuprous bromide, oxidation One of cuprous, copper oxide or copper sulphate.

13. according to the described in any item synthetic methods of claim 9-12, wherein in step (1), the compound 1 and institute The molar ratio for stating the first catalyst is 1:0.05~2, preferably 1:0.1~1.5, is more preferably 1:0.1~0.5；Preferably, institute Methoxide is stated selected from one of sodium methoxide, potassium methoxide or lithium methoxide, preferably sodium methoxide；Preferably, the compound 1 with The molar ratio of the methoxide is 1:0.8~20, preferably 1:1~15, preferably 1:1.5~3.0.

14. according to the described in any item synthetic methods of claim 9-13, wherein in step (1), the temperature of the reaction is 80~150 DEG C, preferably 100~130 DEG C are more preferably 120~130 DEG C；Preferably, the time of the reaction is 1~20 small When, preferably 1~15 hour, be more preferably 3~8 hours.

15. the described in any item synthetic methods of 0-14 according to claim 1, wherein in step (2), described second is organic molten Agent be selected from tetrahydrofuran, acetonitrile, methanol, ethyl alcohol, ethylene glycol, propyl alcohol, isopropanol, glycerine, Propylene Glycol, n-butyl alcohol, 2- butanol, 2- methyl-1-propyl alcohol, 2- methyl-2-propanol, methyl glycerine, 2- methyl glycerine, diformazan ethyl glycol and tertiary fourth One or more of alcohol, the preferably tert-butyl alcohol；Preferably, the compound 2- amino -3- methyl -5- methoxypyridine Mass ratio with second organic solvent is 1:0.5~30.0, preferably 1:1~20, is more preferably 1:1.0~5.0.

16. according to the described in any item synthetic methods of claim 9-15, wherein in step (2), the second catalyst choosing From in pyridine, N, N- diisopropylethylamine, tetramethylethylenediamine, tripropylamine, 4-dimethylaminopyridine, triethylenediamine, One or both of tetrabutylammonium hydroxide, gamma-chloropropylmethyldimethoxysilane, N-methylmorpholine and triethylamine with On, preferably 4-dimethylaminopyridine；Preferably, the compound 2- amino -3- methyl -5- methoxypyridine and described second The molar ratio of catalyst is 1:0.01~1.0, preferably 1:0.02~0.2, is more preferably 1:0.02~0.05.

17. according to the described in any item synthetic methods of claim 9-16, wherein in step (2), the amino protecting agent is Di-tert-butyl dicarbonate；Preferably, when reaction, the amino protecting agent is to be melt into liquid form or to be dissolved in the 4th organic molten The form that solution is formed in agent is added dropwise；Preferably, the compound 2- amino -3- methyl -5- methoxypyridine and the amino Protectant molar ratio is 1:1~10, preferably 1:1.1~5, is more preferably 1:2.1-2.5；Preferably, the described 4th is organic Solvent is selected from tetrahydrofuran, acetonitrile, methanol, ethyl alcohol, ethylene glycol, propyl alcohol, isopropanol, glycerine, Propylene Glycol, 1- fourth Alcohol, 2- butanol, 2- methyl-1-propyl alcohol, 2- methyl-2-propanol, methyl glycerine, 2- methyl glycerine, diformazan ethyl glycol and One or more of tert-butyl alcohol, the preferably tert-butyl alcohol；Preferably, the amino protecting agent and the 4th organic solvent Mass ratio be 1:0.5~30, preferably 1:1~20 are more preferably 1:0.5~4.

18. the described in any item synthetic methods of 0-17 according to claim 1, wherein in step (2), the alkali is selected from alkali The hydroxide of metal or alkaline-earth metal, the carbonate of alkali or alkaline earth metal, the alkyl salt of alkali metal, alkali metal it is two different One of propyl amination salt or double trimethyl silicon substrate amides, preferably sodium hydroxide, potassium hydroxide, n-BuLi, Zhong Ding One of base lithium, isobutyl group lithium, tert-butyl lithium or double trimethyl silicon substrate Sodamides；Preferably, the compound 2- amino -3- The molar ratio of methyl -5- methoxypyridine and the alkali is 1:1.0~5.0, preferably 1:1.5~2.5.

19. the described in any item synthetic methods of 0-18 according to claim 1, wherein in step (2), the reaction temperature be- 40 DEG C~85 DEG C, preferably 60~85 DEG C；Preferably, the reaction time after amino protecting agent is added is 1~40 hour, preferably 6-8 hours；Preferably, the reaction time after alkali is added is 1~40 hour, preferably 6~10 hours.

20. the described in any item synthetic methods of 0-19 according to claim 1, wherein the quencher selected from hydrochloric acid, sulfuric acid, One of nitric acid, water, formic acid, acetic acid or citric acid.