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Synthetic method for 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl] benzonitrile

A technology of furan subunit and oxo substitution, applied in the direction of organic chemistry, can solve the problems of low total yield, long synthetic route, inconvenient operation, etc., and achieve simple process operation, increase yield, and simple and easy process operation Effect

Inactive Publication Date: 2015-12-23
ANHUI WANBANG MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This route uses strong base sodium methoxide and strong acid methanesulfonic acid. The reaction steps are 3 steps. The synthesis route is long, the total yield is low, the operation is extremely inconvenient, the impact on the environment is large, and the labor protection cost is high.

Method used

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  • Synthetic method for 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl] benzonitrile
  • Synthetic method for 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl] benzonitrile
  • Synthetic method for 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl] benzonitrile

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Add 50 mL of N,N-dimethylformamide to a 100 mL three-necked flask, and add 14.6 g (100 mmol) of 3-methyleneisobenzofuran-1(3H)-one and 6.3 g of potassium hydroxide ( 113mmol), 20.0g (100mmol) of 2-fluoro-5-bromoxynil, and 0.9g (5mmol) of palladium chloride, the temperature was raised to 110°C and the reaction was stirred for 2 hours. Remove N,N-dimethylformamide by distillation under reduced pressure, add 50mL of absolute ethanol to dissolve, add 100mL of water dropwise to the filtrate after suction filtration, stir at 0~10℃ for 1 hour to obtain 19.9g of light yellow solid, m.p.181~185 °C, yield 75.0%.

Embodiment 2

[0020] Add 50 mL of N,N-dimethylformamide to a 100 mL three-necked flask, and add 14.6 g (100 mmol) of 3-methyleneisobenzofuran-1(3H)-one and 6.3 g of potassium hydroxide ( 113mmol), 20.0g (100mmol) of 2-fluoro-5-bromoxynilil, 1.16g (1mmol) of tetrakis(triphenylphosphine)palladium, heated to 80°C and stirred for 3 hours. Remove N,N-dimethylformamide by distillation under reduced pressure, add 50 mL of absolute ethanol to dissolve, add 100 mL of water dropwise to the filtrate after suction filtration, and stir for 1 hour at 0~10°C to obtain 21.0 g of light yellow solid, m.p.182~186 °C, yield 79.2%.

Embodiment 3

[0022] Add 50 mL of N,N-dimethylformamide to a 100 mL three-necked flask, and add 14.6 g (100 mmol) of 3-methyleneisobenzofuran-1(3H)-one and 6.3 g of potassium hydroxide ( 113mmol), 20.0g (100mmol) of 2-fluoro-5-bromoxynil, and 0.9g (4mmol) of palladium acetate, heated to 100°C and stirred for 3 hours. Distill under reduced pressure to remove N,N-dimethylformamide, add 50mL of absolute ethanol to dissolve, add 100mL of water dropwise to the filtrate after suction filtration, stir at 0~10℃ for 1 hour to obtain 19.2g of light yellow solid, m.p.183~186 °C, yield 72.5%.

[0023] As can be seen from the above three examples, the yield of 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl]benzonitrile prepared by the method of the present invention is The yield is more than 70%, the reaction steps are short, the operation is convenient, the impact on the environment is small, the safety is high, and the quality and yield of the obtained product are greatly improved.

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Abstract

The invention discloses a new synthetic method for an Olaparib midbody 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene) methyl] benzonitrile. The method comprises: taking 3-methylene isobenzofuran-1(3H)-ketone and 2-fluoro-5 bromoxynil as reaction raw materials, and carrying out a coupling reaction under the catalysis of metal palladium compounds in an alkaline condition, thereby obtaining the 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl] benzonitrile, wherein a reaction yield is over 70%. Compared with an original process route, use of strong acid and strong base such as sodium methylate, methanesulfonic acid, and the like with strong corrosion to equipment is avoided, reaction steps are shortened, operation is more convenient, impact force on environment is reduced, and cost is reduced.

Description

technical field [0001] The present invention relates to a kind of synthetic method of known compound, more specifically relate to a kind of olaparib intermediate 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene) Synthetic method of methyl] benzonitrile. Background technique [0002] 2-Fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl]benzonitrile is an intermediate in the synthesis of the antineoplastic drug Olaparib. Olaparib is an inhibitor of polyadenosine diphosphate-ribose polymerase [poly(ADP-ribose) polymerase] (PARP), developed by AstraZeneca and launched in the United States in December 2014, the drug is suitable for in the treatment of advanced ovarian cancer. The synthesis route of the anticancer drug olaparib from 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl]benzonitrile is as follows: [0003] [0004] The synthesis of the intermediate 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl]benzonitrile has many reports in the literature, and the patent 2008801...

Claims

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Application Information

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IPC IPC(8): C07D307/88
CPCC07D307/88
Inventor 陈国祥陶春蕾邵凤杨欣怡王慧徐怀友
Owner ANHUI WANBANG MEDICAL TECH
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