Pyrazolopyrimidine derivative, its preparation method, and its use in preparation of medicines

Abstract

Provided are a 4-position substituted pyrazolopyrimidine derivative having a structure represented by formula I, and a use thereof in drug preparation. The pyrazolopyrimidine derivative is used for preparing a kinase inhibitor, a drug for treating an autoimmune disease, an angiogenesis inhibitor, and an antitumor drug.

Description

technical field

[0001] The invention belongs to the technical field of organic synthetic medicines, in particular to pyrazolopyrimidine derivatives, their preparation methods and their application in medicine preparation. Background technique

[0002] Kinases widely exist in organisms, and they play a vital role in regulating cell proliferation, growth, differentiation, apoptosis, aging and other processes. Abnormal kinase activity can lead to the occurrence of many major diseases including cancer, various autoimmune diseases (such as lupus erythematosus, rheumatoid arthritis, psoriasis, etc.), diabetes, inflammation, etc. In view of this, kinases, as one of the most important targets for disease treatment, have become the hotspots of current research.

[0003] According to the human gene map, 518 kinases have been identified in humans. The relationship between various kinases and tumors and various autoimmune diseases has been elucidated. For example: VEGFR2 (Vascular en...

Examples

Embodiment 1、4

[0538] Preparation of Example 1, 4-chloro-1H-pyrazolopyrimidine (2)

[0539]

[0540] 10mL POCl 3 (Phosphorus oxychloride) was added to 5g allopurinol (compound 1), DMF (N,N-dimethylformamide, 5mL) was slowly added dropwise at 0°C, and then DMA (N,N- Dimethylaniline, 1 mL) was stirred at room temperature for several minutes, and then the reaction system was heated to 120°C for 5 h. After the reaction was completely cooled, a large amount of ice water was added to quench the excess phosphorus oxychloride, and then extracted twice with ethyl acetate, and the ethyl acetate layer was spin-dried to obtain 3.2 g of solid, with a yield of 56.4%.

[0541] 1 H NMR (400MHz, DMSO-d 6 ): δ14.12 (s, 1H), 9.32 (s, 1H), 7.55 (s, 1H) ppm.

Embodiment 2

[0542] Preparation of Example 2, 4-(1H-pyrazolo-4-phenoxy)aniline (3a-1)

[0543]

[0544] Add p-aminophenol (0.55g, 5.5mmol) and sodium hydroxide (0.20g, 5.5mmol) into 10mL of water, stir at room temperature for 30 minutes, then add potassium carbonate (0.76g, 5.5mmol), while raising the temperature to 60°C, And slowly add the tetrahydrofuran solution of 4-chloro-1H-pyrazolopyrimidine (Intermediate 2) (0.94g, 6.6mmol) into the above reaction solution, stop the reaction after 1 hour, evaporate the tetrahydrofuran in the reaction system to dryness, The remaining system was extracted twice with ethyl acetate and water, the ethyl acetate layer was dried with anhydrous magnesium sulfate and spin-dried, and purified by column to obtain 4-(1H-pyrazolo-4-phenoxy)aniline (3a-1) , 0.77g, yield 62.1%.

[0545] 1 H NMR (400MHz, DMSO-d 6 ): δ14.07(s,1H),8.50(s,1H),7.67(s,1H),6.96(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),5.20 (s,2H) ppm. LCMS m / z: 228.1 [M+H].

Embodiment 3

[0546] Example 3, Preparation of 4-(1H-pyrazolo-4-phenoxy)-2-methylaniline (3a-2)

[0547]

[0548] Using intermediate (2) and 4-amino-3-methylphenol according to the synthesis method of intermediate (3a-1), intermediate (3a-2) was obtained with a yield of 64.2%.

[0549] 1 H NMR (400MHz, DMSO-d 6 ): δ14.04(s,1H),8.49(s,1H),7.65(s,1H),6.89(d,J=2.4Hz,1H),6.85(d,J=8.0Hz,1H),6.68 (d, J=8.4Hz, 1H), 4.94(s, 2H), 2.08(s, 3H) ppm.

technical field

[0001] The invention belongs to the technical field of organic synthetic medicines, in particular to pyrazolopyrimidine derivatives, their preparation methods and their application in medicine preparation. Background technique

[0002] Kinases widely exist in organisms, and they play a vital role in regulating cell proliferation, growth, differentiation, apoptosis, aging and other processes. Abnormal kinase activity can lead to the occurrence of many major diseases including cancer, various autoimmune diseases (such as lupus erythematosus, rheumatoid arthritis, psoriasis, etc.), diabetes, inflammation, etc. In view of this, kinases, as one of the most important targets for disease treatment, have become the hotspots of current research.

[0003] According to the human gene map, 518 kinases have been identified in humans. The relationship between various kinases and tumors and various autoimmune diseases has been elucidated. For example: VEGFR2 (Vascular en...

Examples

Embodiment 1、4

[0538] Preparation of Example 1, 4-chloro-1H-pyrazolopyrimidine (2)

[0539]

[0540] 10mL POCl 3 (Phosphorus oxychloride) was added to 5g allopurinol (compound 1), DMF (N,N-dimethylformamide, 5mL) was slowly added dropwise at 0°C, and then DMA (N,N- Dimethylaniline, 1 mL) was stirred at room temperature for several minutes, and then the reaction system was heated to 120°C for 5 h. After the reaction was completely cooled, a large amount of ice water was added to quench the excess phosphorus oxychloride, and then extracted twice with ethyl acetate, and the ethyl acetate layer was spin-dried to obtain 3.2 g of solid, with a yield of 56.4%.

[0541] 1 H NMR (400MHz, DMSO-d 6 ): δ14.12 (s, 1H), 9.32 (s, 1H), 7.55 (s, 1H) ppm.

Embodiment 2

[0542] Preparation of Example 2, 4-(1H-pyrazolo-4-phenoxy)aniline (3a-1)

[0543]

[0544] Add p-aminophenol (0.55g, 5.5mmol) and sodium hydroxide (0.20g, 5.5mmol) into 10mL of water, stir at room temperature for 30 minutes, then add potassium carbonate (0.76g, 5.5mmol), while raising the temperature to 60°C, And slowly add the tetrahydrofuran solution of 4-chloro-1H-pyrazolopyrimidine (Intermediate 2) (0.94g, 6.6mmol) into the above reaction solution, stop the reaction after 1 hour, evaporate the tetrahydrofuran in the reaction system to dryness, The remaining system was extracted twice with ethyl acetate and water, the ethyl acetate layer was dried with anhydrous magnesium sulfate and spin-dried, and purified by column to obtain 4-(1H-pyrazolo-4-phenoxy)aniline (3a-1) , 0.77g, yield 62.1%.

[0545] 1 H NMR (400MHz, DMSO-d 6 ): δ14.07(s,1H),8.50(s,1H),7.67(s,1H),6.96(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),5.20 (s,2H) ppm. LCMS m / z: 228.1 [M+H].

Embodiment 3

[0546] Example 3, Preparation of 4-(1H-pyrazolo-4-phenoxy)-2-methylaniline (3a-2)

[0547]

[0548] Using intermediate (2) and 4-amino-3-methylphenol according to the synthesis method of intermediate (3a-1), intermediate (3a-2) was obtained with a yield of 64.2%.

[0549] 1 H NMR (400MHz, DMSO-d 6 ): δ14.04(s,1H),8.49(s,1H),7.65(s,1H),6.89(d,J=2.4Hz,1H),6.85(d,J=8.0Hz,1H),6.68 (d, J=8.4Hz, 1H), 4.94(s, 2H), 2.08(s, 3H) ppm.

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