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CN-122010937-A - Synthesis method of 1H-pyrrolo [3,2-B ] pyridine-6-amine

CN122010937ACN 122010937 ACN122010937 ACN 122010937ACN-122010937-A

Abstract

The invention relates to a synthesis method of 1H-pyrrolo [3,2-B ] pyridine-6-amine. The method comprises the steps of reacting 5-bromo-2-methyl-3-nitropyridine with N, N-dimethylformamide dimethyl acetal to obtain (E) -2- (5-bromo-3-nitropyridine-2-yl) -N, N-dimethylethylene-1-amine, adding the (E) -2- (5-bromo-3-nitropyridine-2-yl) -N, N-dimethylethylene-1-amine into acetic acid, reducing and cyclizing the (E) -2- (5-bromo-3-nitropyridine-2-yl) -N-dimethylethylene-1-amine by using an iron-based catalyst to obtain 6-bromo-4-azaindole, adding the 6-bromo-4-azaindole into ammonia water, and reacting the 6-azaindole with a copper-based catalyst to obtain 1H-pyrrolo [3,2-B ] pyridine-6-amine. The 1H-pyrrolo [3,2-B ] pyridin-6-amine is efficiently obtained by a three-step synthesis. The Fe@PMMA-b-PDMAEMA and PE wax coated iron powder compound is used as an iron-based catalyst, the proportion of the Fe@PMMA-b-PDMAEMA and PE wax coated iron powder is reasonably adjusted, the catalytic effect of reduction and cyclization reaction is remarkably improved and further optimized, and the conversion rate is improved, so that the high yield of the product is realized.

Inventors

  • XU HONGYAN
  • TANG LIDONG

Assignees

  • 康化（上海）新药研发有限公司

Dates

Publication Date
20260512
Application Date
20260127

Claims (10)

  1. 1. A synthesis method of 1H-pyrrolo [3,2-B ] pyridine-6-amine is characterized by comprising the following steps: Step 1, reacting 5-bromo-2-methyl-3-nitropyridine with N, N-dimethylformamide dimethyl acetal in DMF to obtain (E) -2- (5-bromo-3-nitropyridin-2-yl) -N, N-dimethylethylene-1-amine; Step 2, (E) -2- (5-bromo-3-nitropyridin-2-yl) -N, N-dimethylethylene-1-amine is added into acetic acid, and is reduced and cyclized by an iron-based catalyst to obtain 6-bromo-4-azaindole; step 3, adding 6-bromo-4-azaindole into ammonia water, and reacting under a copper-based catalyst to obtain 1H-pyrrolo [3,2-B ] pyridin-6-amine; the synthetic method comprises the following steps: 。
  2. 2. The method for synthesizing 1H-pyrrolo [3,2-B ] pyridin-6-amine according to claim 1, wherein the molar ratio of the iron-based catalyst to (E) -2- (5-bromo-3-nitropyridin-2-yl) -N, N-dimethylethylene-1-amine is 3-5:1.
  3. 3. The method for synthesizing 1H-pyrrolo [3,2-B ] pyridin-6-amine according to claim 1, wherein the iron-based catalyst comprises iron powder.
  4. 4. The method for synthesizing 1H-pyrrolo [3,2-B ] pyridin-6-amine according to claim 1, wherein the iron-based catalyst comprises Fe@PMMA-B-PDMAEMA and PE wax coated iron powder.
  5. 5. The method for synthesizing 1H-pyrrolo [3,2-B ] pyridin-6-amine according to claim 4, wherein the mass ratio of Fe@PMMA-B-PDMAEMA to PE wax coated iron powder is 8-12:1.
  6. 6. The method for synthesizing 1H-pyrrolo [3,2-B ] pyridin-6-amine according to claim 4, wherein the preparation method of Fe@PMMA-B-PDMAEMA comprises the steps of grafting iron powder with aminosilane, brominating to obtain Fe-Br, and sequentially initiating atom transfer radical polymerization of PMMA and PDMAEMA by taking Fe-Br as a catalyst to obtain the product.
  7. 7. A process for the synthesis of 1H-pyrrolo [3,2-B ] pyridin-6-amine according to claim 1, wherein the copper-based catalyst comprises copper sulfate.
  8. 8. A process for the synthesis of 1H-pyrrolo [3,2-B ] pyridin-6-amine according to claim 1, wherein the molar percentage of copper-based catalyst is 20% to 30% mol, based on 6-bromo-4-azaindole.
  9. 9. The method for synthesizing 1H-pyrrolo [3,2-B ] pyridin-6-amine according to claim 1, wherein the molar ratio of 5-bromo-2-methyl-3-nitropyridine to N, N-dimethylformamide dimethyl acetal is 1:1.1-1.3.
  10. 10. The synthesis method of 1H-pyrrolo [3,2-B ] pyridin-6-amine according to claim 1, wherein the reaction temperature in step 1 is 85-95 ℃, the reaction temperature in step 2 is 95-105 ℃, and the reaction temperature in step 3 is 95-105 ℃.

Description

Synthesis method of 1H-pyrrolo [3,2-B ] pyridine-6-amine Technical Field The invention relates to a method for synthesizing heterocyclic compounds, in particular to a method for synthesizing 1H-pyrrolo [3,2-B ] pyridine-6-amine. Background Fused azaheterocyclic compounds are favored for their versatility and structural diversity in pharmaceuticals. These compounds not only enhance the potency and selectivity of the drug, but also enhance the bioavailability and stability of the drug. In the new approved drugs, the occurrence frequency and the diversity of the fused nitrogen heterocycle are improved remarkably, and the fused nitrogen heterocycle is especially in the anticancer field. 1H-pyrrolo [3,2-B ] pyridine-6-amine is used as an emerging fusion nitrogen heterocyclic compound, and has very important application prospect in medicine screening. However, no industrial synthesis of 1H-pyrrolo [3,2-B ] pyridin-6-amine has been reported in the prior art. This has led to the dilemma that researchers and related industries are not able to obtain an efficient synthetic route when the compound is needed to be used, limiting its application and development in the related fields. In addition, the synthetic route needs to meet the requirement of higher synthetic conversion rate to meet the industrial requirement, so that it is necessary to provide a high-yield synthetic method of 1H-pyrrolo [3,2-B ] pyridin-6-amine. Disclosure of Invention Thus, in order to synthesize 1H-pyrrolo [3,2-B ] pyridin-6-amine in high yield, the present application provides a method for synthesizing 1H-pyrrolo [3,2-B ] pyridin-6-amine. In a first aspect, the application provides a method for synthesizing 1H-pyrrolo [3,2-B ] pyridin-6-amine, comprising the steps of: Step 1, reacting 5-bromo-2-methyl-3-nitropyridine with N, N-dimethylformamide dimethyl acetal in DMF to obtain (E) -2- (5-bromo-3-nitropyridin-2-yl) -N, N-dimethylethylene-1-amine; Step 2, (E) -2- (5-bromo-3-nitropyridin-2-yl) -N, N-dimethylethylene-1-amine is added into acetic acid, and is reduced and cyclized by an iron-based catalyst to obtain 6-bromo-4-azaindole; step 3, adding 6-bromo-4-azaindole into ammonia water, and reacting under a copper-based catalyst to obtain 1H-pyrrolo [3,2-B ] pyridin-6-amine; the synthetic method comprises the following steps: 。 the invention effectively obtains the 1H-pyrrolo [3,2-B ] pyridine-6-amine through three-step synthesis. Has the characteristics of easily available raw materials, short synthetic route, simple operation and high yield. Step 1, taking 5-bromo-2-methyl-3-nitropyridine as a raw material, reacting with N, N-dimethylformamide dimethyl acetal DMF-DMA to access alkenyl ammonia on pyridine ring, providing an active site for subsequent ring closing reaction, the process uses DMF as solvent, has good solubility to reactants, reduces the generation of byproducts, and obtains (E) -2- (5-bromo-3-nitropyridin-2-yl) -N, N-dimethylethylene-1-amine with high yield. Preferably, the step 1 further comprises the post-treatment steps of cooling, vacuum concentration, pulping by adding water at a low temperature, filtering and collecting precipitated reddish brown solid. Step 2, taking (E) -2- (5-bromo-3-nitropyridin-2-yl) -N, N-dimethylethylene-1-amine as a raw material, and carrying out selective reduction through nitro in a molecule to obtain 6-bromo-4-azaindole by intramolecular ring closure. The auxiliary reaction system of the step is simple and efficient, acetic acid provides weak acid environment to promote nitroreduction, the ring closing speed is accelerated, the electron transfer efficiency of the iron-based catalyst is high, the nitroreduction is accelerated, and the ring closing induction period is shortened. The iron loses electrons in the acetic acid to generate ferrous ions to promote the generation of nitro radical anions, and further takes protons of the acetic acid to realize multi-step reaction to finally finish ring closure. In the step 3, 6-bromo-4-azaindole reacts under a copper-based catalyst to obtain 1H-pyrrolo [3,2-B ] pyridin-6-amine. Preferably, the reaction is followed by post-treatment of cooling, extraction with ethyl acetate, washing with brine, drying over sodium sulfate, filtration, concentration, and recrystallization to obtain the product. Obtaining the 1H-pyrrolo [3,2-B ] pyridine-6-amine with higher yield. In some embodiments, the molar ratio of the iron-based catalyst to (E) -2- (5-bromo-3-nitropyridin-2-yl) -N, N-dimethylethylene-1-amine is 3-5:1. In some embodiments, the iron-based catalyst comprises iron powder. Iron is an electron donor for the reaction, iron powder has a larger surface area than iron nuggets and iron flakes, and an excessive amount of iron powder can reduce part of the generated ferric iron to ferrous iron in the reaction, thereby maintaining redox cycle and promoting continuous progress of nitro reduction. In some embodiments, the iron-based catalyst comprises Fe@PMMA-b-PDMAEMA an