2-substituent-7-fluorine-4-aromatic mixed base quinazoline derivant and preparation method and use thereof

A technology of fluoroquinazoline and its derivatives, which is applied in the field of medicine and can solve problems such as difficult resection, short survival period of tumors, and high risk

Inactive Publication Date: 2012-09-19
SICHUAN UNIV
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Problems solved by technology

Most of the patients are between 20-50 years old, and the peak is 30-40 years old. It has the characteristics of "three highs and one low" such as morbidity, recurrence rate, high mortality rate and low cure rate. At present, there is no radical cure
The prognosis of malignant glioma is extremely poor, mainly due to its highly invasive growth characteristics. Except for early tumors that are small and located in appropriate locations, it is difficult to completely remove them. In the late stage, the operation is not only difficult, but also dangerous, and often tolerated or Resistant to traditional radiotherapy and chemotherapy, even if the treatment is effective in a short period of time, recurrence will occur quickly, so the survival period of this type of tumor is very short, with a median survival time of less than 18 months and a 2-year survival rate of about 5%

Method used

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  • 2-substituent-7-fluorine-4-aromatic mixed base quinazoline derivant and preparation method and use thereof
  • 2-substituent-7-fluorine-4-aromatic mixed base quinazoline derivant and preparation method and use thereof
  • 2-substituent-7-fluorine-4-aromatic mixed base quinazoline derivant and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0019] The preparation of experimental example 1 key intermediate 4-chloro-7-fluoroquinazoline 3a

[0020]

[0021] a) 4-Fluoroanthranilic acid 1 (1.55g, 10mmol), triethyl orthoformate (2.16mL, 13mmol) and ammonium acetate (1g, 13mmol) were uniformly mixed together and reacted under microwave irradiation (210W) After 5 minutes, cool to room temperature, filter, wash the filter cake with water, and recrystallize with ethanol to obtain 0.75 g of white solid as 7-fluoro-4(3H)quinazolinone 2a. Yield 46%.

[0022] 1 H-NMR (400MHz, DMSO-d 6 ): δ12.52 (br s, 1H), 8.18 (dd, J=2.4, 8.0Hz, 2H), 7.48 (dd, J=2.0, 8.0Hz, 1H), 7.42 (dd, J=2.4, 8.0Hz , 1H).

[0023] ESI-MS: m / z 183.03 (M+H + ).

[0024] b) Suspend the 7-fluoro-4(3H)quinazolinone solid 2a (0.50g, 3mmol) obtained above and N,N-diisopropylethylamine (DIPEA, 1.57mL, 9mmol) in 15mL In anhydrous toluene, heat to reflux for one hour, cool to room temperature, add POCl to the reaction solution 3 (0.82mL, 9mmol), heated to...

experiment example 2

[0025] Experimental example 2 Preparation of key intermediate 2-chloromethyl-4-chloro-7-fluoroquinazoline 3b

[0026]

[0027] a) Sodium metal (0.025g) was added to anhydrous methanol (5mL), stirred under nitrogen protection until the reaction was complete, chloroacetonitrile (1.125g, 15mmol) was added dropwise to the above reaction solution, and after stirring at room temperature for 40 minutes, Then add 4-fluoroanthranilic acid 1 (0.776g, 5mmol) in methanol solution (25mL), the whole reaction system was stirred at room temperature under the protection of nitrogen for 2 hours, the pH was adjusted to 6-7 with dilute hydrochloric acid, and the solid was precipitated by suction filtration , washed the filter cake with cold methanol, and dried to obtain 0.778 g of white solid 2-chloromethyl-7-fluoro-4(3H)quinazolinone 2b, yield 72%.

[0028] 1 H-NMR (400MHz, DMSO-d 6 ): δ12.72 (br s, 1H), 8.18 (dd, J=2.4, 8.0Hz, 1H), 7.48 (dd, J=2.0, 8.0Hz, 1H), 7.42 (dd, J=2.4, 8.0Hz , 1H)...

experiment example 3

[0032] Experimental Example 3 Preparation of key intermediate 2-methyl-4-chloro-7-fluoroquinazoline 3c

[0033]

[0034] a) Dissolve 4-fluoro-2-aminobenzoic acid 1 (1.55g, 10mmol) in acetic anhydride (20ml, 200mmol), heat to reflux, react for 2 hours under nitrogen protection, cool to room temperature, and filter with suction A solid was precipitated, and the filter cake was washed with ether and dried to obtain 1 g of benzoxazinone intermediate with a yield of 56%.

[0035] b) Heat the benzoxazinone intermediate (1g, 5.58mmol) and ammonium acetate (1.5g, 19mmol) synthesized above to reflux, add 5mL of acetic acid, react until complete, cool to 50°C, add 8mL of methanol, and heat To reflux, react for 45 minutes, cool to room temperature, filter out the solid with suction, wash the filter cake with methanol to obtain 0.54 g of white solid 2-methyl-7-fluoro-4(3H)quinazolinone 2c, yield 54% .

[0036] c) Suspend the 2-methyl-7-fluoro-4(3H)quinazolinone solid (0.54g, 3mmol) a...

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Abstract

The invention discloses a 2-substituent-7-fluorine-4-aromatic mixed base quinazoline derivant with a novel structure and a preparation method and the use of the derivant in preparation of anti-glioma drug composite. The general combining route includes utilizing 4-fluorine-o-aminobenzoic acid 1 as a general raw material, conducting cyclization to obtain quinazolinone 2, conducting chloro to obtain a key intermediate 3, enabling the intermediate 3 and aniline (phenol or benzene sulfur) compounds to be concentrated, and conducting three steps of reaction (a, b and c) to obtain a compound of a target product 4. Considering that 4-aniline-quinazoline compound has wide biological activity, especially salient antitumor activity, the inventor observes and combines a series of novel 2-substituent-7-fluorine-4-substituent quinazoline derivants in screening of glioma cell lines (U251, U87 and U172). The derivants show good antitumor activity and have wide prospect in treatment of brain tumors.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a class of 2-substituted-7-fluoro-4-arylheteroquinazoline derivatives with novel structure, a preparation method and its application in the preparation of an anti-glioma pharmaceutical composition. Background technique [0002] Gliomas are derived from neurostromal cells and are tumors that arise in the neuroectoderm. The incidence of glioma accounts for about 44.69% of intracranial tumors. It is the most common intracranial tumor, and most of them are malignant tumors. The age of the patients is mostly between 20-50 years old, with the highest peak at 30-40 years old. It has the characteristics of "three highs and one low" such as morbidity, recurrence rate, high mortality rate and low cure rate. At present, there is no radical cure. The prognosis of malignant glioma is extremely poor, mainly due to its highly invasive growth characteristics. Except for early tumors that are...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D401/12C07D413/12C07D239/90C07D417/12C07D403/12A61K31/517A61P35/00C07D239/86C07D239/95
Inventor 杨黎吴扬魏于全
Owner SICHUAN UNIV
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