CN107840843A - A kind of synthetic method of AZD2171 intermediate - Google Patents

Abstract

The present invention relates to the field of pharmaceutical synthesis, in particular to a synthetic method of a cediranib intermediate. The synthetic method comprises: adding a certain amount of reaction solvent to a flask, introducing an inert protective gas, and adding a certain amount of cediranib under the condition of avoiding light 4-Chloro-6-Methoxy 7-Benzyloxy-Quinazoline, 4-Fluoro-5 Hydroxy-2-Methylindole and base, start to stir, after reacting at a certain temperature for a period of time, the reaction is mixed solution, the reaction mixture was cooled to room temperature, filtered, and the filtrate was collected. The filtrate was transferred to a 2L high-pressure reactor, the catalyst was added, hydrogen gas was introduced, and stirring was started. After a period of reaction at a certain temperature, the reaction liquid was removed and the reaction liquid was carried out. Filtrate, after desolvation of the filtrate under reduced pressure, rinse with water, filter, and vacuum-dry the filter cake to obtain the cediranib intermediate, whose structural formula is as follows: The invention avoids the complicated separation process of the synthesized intermediate, has simple operation, further improves the yield, and is convenient for industrial scale-up production.

Description

A kind of synthetic method of cediranib intermediate

technical field

The invention relates to the field of drug synthesis, in particular to a method for synthesizing a cediranib intermediate.

Background technique

Cediranib is an oral small-molecule multi-target receptor tyrosine kinase inhibitor for the treatment of cancer. It has a certain anti-tumor effect on recurrent ovarian cancer. Multiple clinical studies in solid tumors such as prostate cancer and prostate cancer are still ongoing.

The chemical name of cediranib (II) is 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-[3-(pyrrolidin-1-yl ) propoxy] quinazoline, its structural formula is as follows:

The key intermediate (I) chemical name of cediranib is 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-hydroxyl-quinazoline, which The structural formula is as follows:

Patent CN101528688A discloses a cediranib intermediate 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-hydroxyl-quinazoline (I) The preparation method, 4-chloro-6-methoxy 7-benzyloxy-quinazoline (II) and 4-fluoro-5 hydroxyl-2-methylindole (III) react under the catalysis of base to generate 4 -(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-benzyloxy-quinazoline (IV), and then undergo a series of extraction, precipitation, decolorization, etc. The purification procedure obtained pure 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-benzyloxy-quinazoline (IV), followed by hydroxyl The deprotection reaction obtains 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-hydroxyl-quinazoline (I), and its technological process is as follows:

This method involves laborious and time-consuming separation or purification procedures, which is not convenient for industrial operation.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies of the prior art and provide a preparation method of an intermediate of cediranib. The preparation method has simple process, convenient post-treatment operation and is suitable for industrial production.

The technical solution adopted by the present invention to solve its technical problems is:

A kind of synthetic method of cediranib intermediate (I), this synthetic method comprises the following steps:

(1) Add a certain amount of reaction solvent into the flask, pass into an inert protective gas, and add a certain amount of 4-chloro-6-methoxyl 7-benzyloxy-quinazoline, 4-fluoro- 5 hydroxy-2-methylindole and alkali, start stirring, after reacting for a period of time at a certain temperature, a reaction mixture is obtained;

(2) cooling the reaction mixture obtained in step (1) to room temperature, filtering, and collecting the filtrate;

(3) The filtrate obtained in step (2) is transferred to a 2L autoclave, a catalyst is added, after hydrogen is fed to a certain pressure, stirring is started, and after a period of reaction at a certain temperature, the reaction solution is removed;

(4) filter the reaction solution obtained in step (3), after the filtrate decompression precipitation, add water to rinse, filter, and filter cake is vacuum-dried to obtain the cediranib intermediate (I), and its structural formula is as follows:

Wherein said step (1), the inert protective gas is at normal pressure, and the normal pressure can be maintained in the mode of exhausting bubbles while ventilating.

Wherein said step (1), the mol ratio of 4-chloro-6-methoxy 7-benzyloxy-quinazoline to 4-fluoro-5 hydroxyl-2-methylindole is 1: (0.5～ 5), preferably 1:(0.9-1.2).

As preferably, in the step (1), the base is at least one of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium hydride, sodium methoxide or sodium ethoxide .

Wherein said step (1), the molar ratio of base to 4-chloro-6-methoxy 7-benzyloxy-quinazoline is (1～50): 1, preferably (3～5): 1 .

Wherein said step (1), the reaction solvent is tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene , dimethylbenzene, N-methylpyrrolidone, methyl alcohol, ethanol or one or more in water, the mol ratio of reaction solvent and 4-chloro-6-methoxy 7-benzyloxy-quinazoline is (1～ 1000):1, preferably (10-50):1.

Wherein said step (1), the reaction temperature is 20-100°C, preferably 70-90°C, and the reaction temperature is controlled by a low-temperature thermostat.

Preferably, the catalyst in the step (3) is Pd/C, and the loading of Pd is 1-10% by mass percentage.

Wherein the mass ratio of Pd/C to 4-chloro-6-methoxy 7-benzyloxy-quinazoline is (1-20):100, preferably (5-10):100.

Wherein said step (3), the reaction temperature is 0-60°C, preferably 10-30°C, and the reaction temperature is controlled by a low-temperature thermostat.

Wherein said step (3), the hydrogen pressure is 0-10 MPa, preferably 0 MPa.

The beneficial effects of the present invention are: the present invention changes and optimizes the synthesis process of the key intermediate of cediranib, avoids complicated separation and purification steps of the intermediate, is simple to operate, further improves the yield, and is convenient for scale-up and industrialization Production.

Detailed ways

The technical solution of the present invention will be further specifically described below through specific examples.

Example 1:

A kind of synthetic method of cediranib intermediate (I), this synthetic method comprises the following steps:

(1) Add 240mL THF (tetrahydrofuran) into a 500mL three-necked flask, feed nitrogen at normal pressure, and add 23.2g of 4-chloro-6-methoxy 7-benzyloxy-quinazoline (0.077mol ), 12.7g of 4-fluoro-5-hydroxy-2-methylindole (0.077mol) and 32g of potassium carbonate, started stirring, raised the temperature to 70°C, and reacted for 12h to obtain a reaction mixture;

(2) The reaction mixture obtained in step (1) is cooled to room temperature, filtered, and the potassium carbonate filter cake is rinsed with 120ml THF, and the filtrate is collected to obtain 360mL of filtrate;

(3) Transfer the filtrate obtained in step (2) to a 2L autoclave, add 2.32g of Pd/C catalyst (by mass percentage, the load of Pd is 10%), feed hydrogen to normal pressure, and start stirring , reacted at 20°C for 11 hours, and removed the reaction liquid;

(4) The reaction solution obtained in step (3) is filtered Pd/C, the Pd/C catalyst is rinsed with 50ml THF, and the rinse solution is added to the filtrate. After the filtrate is decompressed and precipitated, add 400mL water to rinse, filter, and filter cake After vacuum drying, the cediranib intermediate (I) was obtained, and 20 g of the cediranib intermediate (I) was collected with a total yield of 76.3%.

Example 2:

A kind of synthetic method of cediranib intermediate (I), this synthetic method comprises the following steps:

(1) Add 240mL THF (tetrahydrofuran) in the 500mL three-necked flask, pass into normal pressure argon, add 23.2g of 4-chloro-6-methoxy 7-benzyloxy-quinazoline (0.077 mol), 14g of 4-fluoro-5-hydroxy-2-methylindole (0.085mol) and 42.5g of sodium carbonate, start stirring, raise the temperature to 90°C, and react for 12h to obtain a reaction mixture;

(2) The reaction mixture obtained in step (1) is cooled to room temperature, filtered, and the sodium carbonate filter cake is rinsed with 120ml THF, and the filtrate is collected to obtain 360mL of filtrate;

(3) Transfer the filtrate obtained in step (2) to a 2L autoclave, add 4.64g of Pd/C catalyst (by mass percentage, the load of Pd is 5%), feed hydrogen to normal pressure, and start stirring , react at a temperature of 30°C for 10h, and remove the reaction liquid;

(4) The reaction solution obtained in step (3) is filtered Pd/C, rinsed with 50ml THF, after the filtrate is decompressed and precipitated, rinsed with 400mL water, filtered, and the filter cake is vacuum-dried to obtain the cediranib intermediate (I), 21.1 g of cediranib intermediate (I) was collected, with a total yield of 80.5%.

Example 3:

A kind of synthetic method of cediranib intermediate (I), this synthetic method comprises the following steps:

(1) Add 240mL DMF (N,N-dimethylformamide) to a 500mL three-necked flask, pass through nitrogen at normal pressure, and add 23.2g of 4-chloro-6-methoxy 7-benzyloxy Base-quinazoline (0.077mol), 15.3g of 4-fluoro-5-hydroxy-2-methylindole (0.092mol) and 33.4g of anhydrous potassium phosphate, start stirring, heat up to 90°C, and react for 2h, to obtain a reaction mixture;

(2) The reaction mixture obtained in step (1) was cooled to room temperature, filtered, and the potassium phosphate filter cake was rinsed with 120ml DMF, and the filtrate was collected to obtain 360mL of filtrate;

(3) The filtrate that step (2) obtains is transferred in the autoclave of 2L, adds 4.64g Pd/C catalyst (by mass percentage, the loading capacity of Pd is 10%), feeds hydrogen to normal pressure, starts to stir , react at a temperature of 10°C for 9h, and remove the reaction solution;

(4) Filter the reaction solution obtained in step (3) over Pd/C, rinse with 50ml DMF, add 400mL water to rinse the filtrate after decompression precipitation, filter, and vacuum-dry the filter cake to obtain the cediranib intermediate (I), 21.6g of cediranib intermediate (I) was collected, with a total yield of 82.4%.

Example 4:

A kind of synthetic method of cediranib intermediate (I), this synthetic method comprises the following steps:

(1) Add 240mL DMAc (N,N-dimethylacetamide) to a 500mL three-necked flask, pass through nitrogen at normal pressure, and add 23.2g of 4-chloro-6-methoxy 7-benzyloxy Base-quinazoline (0.077mol), 16.5g of 4-fluoro-5-hydroxy-2-methylindole (0.10mol) and 32g of potassium carbonate, start stirring, heat up to 90°C, and react for 2h to obtain a reaction mixture liquid;

(2) The reaction mixture obtained in step (1) is cooled to room temperature, filtered, and the potassium phosphate filter cake is rinsed with 120ml DMAc, and the filtrate is collected to obtain 360mL of filtrate;

(3) the filtrate that step (2) is obtained is transferred in the autoclave of 2L, adds the mixed solution of 120ml DMAc and 50ml water, then adds 2.32g Pd/C catalyst (by mass percentage, the loading capacity of Pd is 10 %), feed hydrogen to normal pressure, start stirring, react at a temperature of 25°C for 9h, and remove the reaction solution;

(4) The reaction solution obtained in step (3) is filtered Pd/C, rinsed with 50ml DMAc, after the filtrate is decompressed and precipitated, rinsed with 400mL water, filtered, and the filter cake is vacuum-dried to obtain the cediranib intermediate (I), 23.4g of cediranib intermediate (I) was collected, with a total yield of 89.3%.

Example 5:

A kind of synthetic method of cediranib intermediate (I), this synthetic method comprises the following steps:

(1) Add 240mL DMF (N,N-dimethylformamide) to a 500mL three-necked flask, pass through nitrogen at normal pressure, and add 23.2g of 4-chloro-6-methoxy 7-benzyloxy Base-quinazoline (0.077mol), 14g of 4-fluoro-5-hydroxy-2-methylindole (0.085mol) and 32g of potassium carbonate, start stirring, heat up to 80°C, and react for 5h to obtain a reaction mixture ;

(2) The reaction mixture obtained in step (1) is cooled to room temperature, filtered, and the potassium phosphate filter cake is rinsed with 120ml DMAc, and the filtrate is collected to obtain 360mL of filtrate;

(3) The filtrate that step (2) is obtained is transferred in the autoclave of 2L, adds the mixed solution of 120mlDMF and 50ml methyl alcohol, then adds 2.32g Pd/C catalyst (by mass percentage, the load capacity of Pd is 10% ), feed hydrogen to normal pressure, start stirring, react at a temperature of 20°C for 9h, and remove the reaction solution;

(4) Filter the reaction solution obtained in step (3) over Pd/C, rinse with 50ml DMF, add 400mL water to rinse the filtrate after decompression precipitation, filter, and vacuum-dry the filter cake to obtain the cediranib intermediate (I), 22.3g of cediranib intermediate (I) was collected, with a total yield of 85.1%.

Embodiment 6:

A kind of synthetic method of cediranib intermediate (I), this synthetic method comprises the following steps:

(1) Add 240mL DMF (N,N-dimethylformamide) to a 500mL three-necked flask, pass through nitrogen at normal pressure, and add 23.2g of 4-chloro-6-methoxy 7-benzyloxy Base-quinazoline (0.077m0l), 14g of 4-fluoro-5-hydroxy-2-methylindole (0.085mol) and 32g of potassium carbonate, start stirring, heat up to 90°C, and react for 2h to obtain a reaction mixture ;

(2) The reaction mixture obtained in step (1) was cooled to room temperature, filtered, and the potassium phosphate filter cake was rinsed with 120ml DMF, and the filtrate was collected to obtain 360mL of filtrate;

(3) the filtrate that step (2) is obtained is transferred in the autoclave of 2L, adds the mixed solution of 120ml DMF and 50ml ethanol, then adds 2.32g Pd/C catalyst (by mass percent, the loading capacity of Pd is 10 %), feed hydrogen to normal pressure, start stirring, react at a temperature of 20°C for 9h, and remove the reaction solution;

(4) Filter the reaction solution obtained in step (3) over Pd/C, rinse with 50ml DMF, add 400mL water to rinse the filtrate after decompression precipitation, filter, and vacuum-dry the filter cake to obtain the cediranib intermediate (I), 19.7g of cediranib intermediate (I) was collected, with a total yield of 75.2%.

The above-described embodiment is only a preferred solution of the present invention, and is not intended to limit the present invention in any form. For those skilled in the art, other modifications can be easily realized without violating the claims and equivalents. The invention is not limited to the specific details, while the general concepts are defined in scope.

Claims (10)

1. a synthetic method of cediranib intermediate (I), is characterized in that, the synthetic method may further comprise the steps: (1) Add a certain amount of reaction solvent into the flask, pass into an inert protective gas, and add a certain amount of 4-chloro-6-methoxyl 7-benzyloxy-quinazoline, 4-fluoro- 5 hydroxy-2-methylindole and alkali, start stirring, after reacting for a period of time at a certain temperature, a reaction mixture is obtained; (2) cooling the reaction mixture obtained in step (1) to room temperature, filtering, and collecting the filtrate; (3) The filtrate obtained in step (2) is transferred to a 2L autoclave, a catalyst is added, after hydrogen is fed to a certain pressure, stirring is started, and after a period of reaction at a certain temperature, the reaction solution is removed; (4) filter the reaction solution obtained in step (3), after the filtrate decompression precipitation, add water to rinse, filter, and filter cake is vacuum-dried to obtain the cediranib intermediate (I), and its structural formula is as follows: . 2. the synthetic method of cediranib intermediate (I) according to claim 1, is characterized in that, in described step (1), 4-chloro-6-methoxy 7-benzyloxy-quinone The molar ratio of oxazoline to 4-fluoro-5-hydroxy-2-methylindole is 1: (0.5-5). 3. the synthetic method of cediranib intermediate (I) according to claim 1, is characterized in that, in described step (1), alkali is sodium bicarbonate, sodium carbonate, salt of wormwood, potassium phosphate, hydrogen At least one of sodium oxide, potassium hydroxide, cesium carbonate, sodium hydride, sodium methoxide or sodium ethoxide. 4. the synthetic method of cediranib intermediate (I) according to claim 1, is characterized in that, in described step (1), alkali and 4-chloro-6-methoxy 7-benzyloxy -The molar ratio of quinazoline is (1～50):1. 5. the synthetic method of cediranib intermediate (I) according to claim 1, is characterized in that, in described step (1), reaction solvent is THF, 1,4-dioxane, N, One or more of N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, toluene, xylene, N-methylpyrrolidone, methanol, ethanol or water, the reaction solvent and The molar ratio of 4-chloro-6-methoxy 7-benzyloxy-quinazoline is (1～1000):1. 6. The synthetic method of cediranib intermediate (I) according to claim 1, characterized in that, in the step (1), the reaction temperature is 20-100°C. 7. the synthetic method of cediranib intermediate (I) according to claim 1, is characterized in that, in described step (3), catalyzer is Pd/C, and by mass percentage, the load capacity of Pd is 1- 10%. 8. the synthetic method of cediranib intermediate (I) according to claim 7, is characterized in that, the quality of Pd/C and 4-chloro-6-methoxy 7-benzyloxy-quinazoline The ratio is (1-20):100. 9. The synthetic method of cediranib intermediate (I) according to claim 1, characterized in that, in the step (3), the reaction temperature is 0-60°C. 10. the synthetic method of cediranib intermediate (I) according to claim 1, is characterized in that, in described step (3), hydrogen pressure is 0～10MPa.