Synthetic method of 7-azaindole-5-chloro-6-carboxylic acid

Abstract

The invention relates to a synthetic method of 7-azaindole-5-chloro-6-carboxylic acid, which mainly solves the technical problem that no effective synthetic method suitable for the industrialization is provided. The synthetic method comprises the following steps: dissolving 3,6-dichloropyridine-2-carboxylic acid in a solvent of tertiary butanol and pyridine, adding paratoluensulfonyl chloride, obtaining a compound 1, wherein the product is unnecessary to purify; coupling the compound 1 and diphenyl amine under the catalysis of Pd2(dba)3 and xant-Phos, adding hydroxylamine hydrochloride, and purifying a crude product by virtue of column chromatography, thus obtaining a compound 2; dissolving the compound 2 in acetic acid, adding NIS, heating to facilitate the reaction, and purifying a crudeproduct by virtue of column chromatography to obtain a compound 3; dissolving the compound 3 in tetrahydrofuran, adding trimethylsilylacetylene, cuprous iodide, Pd(PPh3)2Cl2 and triethylamine, and reacting under the protection of nitrogen, thus obtaining a product 4 which does not require to be purified; and dissolving the compound 4 in dry N-methyl pyrrolidone, adding potassium tert-butoxide, heating, reacting, standing overnight, washing a crude product by using acetate, and filtering to obtain a target product.

Description

technical field

[0001] The present invention relates to azaindole heterocyclic compounds, in particular to a synthesis method of 7-azaindole-5-chloro-6-carboxylic acid (CAS No. 1246088-49-2). Background technique

[0002] Azaindole heterocyclic compounds are a class of important organic compounds widely distributed in nature, with diverse biological activities and high research value in medicinal chemistry. For example, variolin B (Chem. Rev., 2009, 109, 3080–3098) is a compound containing a 7-azaindole ring isolated from Antarctic sponge. cancer agent. There is also diazarebeccamycin (Eur. J. Med. Chem., 2003, 38, 123–140), a synthetic 7-azaindole derivative, which has also been shown to have good anticancer activity.

[0003] 7-azaindole-5-chloro-6-carboxylic acid, as a pharmaceutical intermediate, can be used to synthesize various 7-azaindole derivatives. But so far there is no public report about its industrial synthesis method. Contents of the invention

[0004] T...

Examples

Embodiment 1

[0016] Example 1: Preparation of 7-azaindole-5-chloro-6-carboxylic acid.

[0017] step 1:

[0018] 3,6-Dichloropyridine-2-carboxylic acid (78.3 g, 0.408 mol) was dissolved in tert-butanol (780 mL) and pyridine (215 mL), and cooled to 0°C in an ice-water bath. P-toluenesulfonyl chloride (185 g, 0.97 mol) was added in portions, and after the addition was completed, the mixture was raised to room temperature and stirred overnight. The reaction solution was concentrated to dryness, and the residue was added to 5% aqueous citric acid solution (2 L) and extracted with ethyl acetate (2 L). The organic phase was washed with 5% sodium bicarbonate aqueous solution (500 mL) and saturated brine (500 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound 1 (100 g, 98% yield). 1 H NMR (400 MHz, CDCl 3 )1.63 (s, 9H), 7.35 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H).

[0019] Step 2:

[0020] Compound 1 (50 g, 0...

Embodiment 2

[0027] Example 2, the coupling reaction temperature in step 2 is 85°C, and the reaction time is 2 hours; the reaction temperature in step 3 is 50°C; the reaction temperature in step 4 is 20°C, and the reaction time is 2 hours; the reaction temperature in step 5 is 60°C. All the other are with embodiment 1.

Embodiment 3

[0028] Example 3, the coupling reaction temperature in step 2 is 95°C, and the reaction time is 1 hour; the reaction temperature in step 3 is 60°C; the reaction temperature in step 4 is 35°C, and the reaction time is 0.5 hour; the reaction temperature in step 5 is 70°C. All the other are with embodiment 1.

technical field

[0001] The present invention relates to azaindole heterocyclic compounds, in particular to a synthesis method of 7-azaindole-5-chloro-6-carboxylic acid (CAS No. 1246088-49-2). Background technique

[0002] Azaindole heterocyclic compounds are a class of important organic compounds widely distributed in nature, with diverse biological activities and high research value in medicinal chemistry. For example, variolin B (Chem. Rev., 2009, 109, 3080–3098) is a compound containing a 7-azaindole ring isolated from Antarctic sponge. cancer agent. There is also diazarebeccamycin (Eur. J. Med. Chem., 2003, 38, 123–140), a synthetic 7-azaindole derivative, which has also been shown to have good anticancer activity.

[0003] 7-azaindole-5-chloro-6-carboxylic acid, as a pharmaceutical intermediate, can be used to synthesize various 7-azaindole derivatives. But so far there is no public report about its industrial synthesis method. Contents of the invention

[0004] T...

Examples

Embodiment 1

[0016] Example 1: Preparation of 7-azaindole-5-chloro-6-carboxylic acid.

[0017] step 1:

[0018] 3,6-Dichloropyridine-2-carboxylic acid (78.3 g, 0.408 mol) was dissolved in tert-butanol (780 mL) and pyridine (215 mL), and cooled to 0°C in an ice-water bath. P-toluenesulfonyl chloride (185 g, 0.97 mol) was added in portions, and after the addition was completed, the mixture was raised to room temperature and stirred overnight. The reaction solution was concentrated to dryness, and the residue was added to 5% aqueous citric acid solution (2 L) and extracted with ethyl acetate (2 L). The organic phase was washed with 5% sodium bicarbonate aqueous solution (500 mL) and saturated brine (500 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain compound 1 (100 g, 98% yield). 1 H NMR (400 MHz, CDCl 3 )1.63 (s, 9H), 7.35 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H).

[0019] Step 2:

[0020] Compound 1 (50 g, 0...

Embodiment 2

[0027] Example 2, the coupling reaction temperature in step 2 is 85°C, and the reaction time is 2 hours; the reaction temperature in step 3 is 50°C; the reaction temperature in step 4 is 20°C, and the reaction time is 2 hours; the reaction temperature in step 5 is 60°C. All the other are with embodiment 1.

Embodiment 3

[0028] Example 3, the coupling reaction temperature in step 2 is 95°C, and the reaction time is 1 hour; the reaction temperature in step 3 is 60°C; the reaction temperature in step 4 is 35°C, and the reaction time is 0.5 hour; the reaction temperature in step 5 is 70°C. All the other are with embodiment 1.

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