A kind of preparation method of icotinib key intermediate

A technology of icotinib and intermediates, which is applied in the field of drug synthesis, can solve the problems of a large number of acidic waste liquids, operation hazards, environmental hazards, etc., and achieves the effects of high reaction yield, avoiding operation hazards and simple operation.

Active Publication Date: 2022-02-18
诺为泰医药科技(上海)有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Wherein 4-chloro-quinazolino[6.7-6]-12-crown-4 is the key intermediate for preparing icotinib, and its production cost and quality directly affect icotinib. The preparation methods of 4-chloro-quinazolino[6.7-6]-12-crown-4 are very limited, mainly using ethyl 3,4-dihydroxybenzoate as the starting material, after cyclization, digestion, reduct

Method used

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  • A kind of preparation method of icotinib key intermediate
  • A kind of preparation method of icotinib key intermediate
  • A kind of preparation method of icotinib key intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019]

[0020] In the supercritical reactor, place triethylenedi(p-toluenesulfonate) 50g and 20g of ethyl 3,4-dihydroxybenzoate in the reactor, then start stirring after the whole system is vacuumized, to Ammonia gas is passed into the reactor to make the pressure in the reactor reach normal pressure, and then carbon dioxide is fed into the reactor, and the pressure in the reactor increases to 12MPa, and the carbon dioxide gradually becomes liquid, and triethylenedi(p-toluenesulfonate ) and ethyl 3,4-dihydroxybenzoate were fully dissolved, the temperature in the reactor was raised to 50°C, the reaction was stopped after a certain period of time, carbon dioxide was released slowly, and a turbid solid appeared in the reactor, and then 70 mL of methanol was added to it Mixed solution with 30mL of acetone, stirred at 0°C for 10min, filtered with suction and dried to obtain 27.2g of ethyl 3,4-(benzo-12-crown-4)benzoate, which can effectively avoid by-products of ester hydrolysis...

Embodiment 2

[0022]

[0023] Dissolve 30g of ethyl 3,4-(benzo-12-crown-4)benzoate in 300mL of dichloroethane, stir at 40°C for 20min, then add N-chlorosuccinimide in three batches 15g, each batch of 5g at an interval of 1h, after adding the last batch of NCS, slowly raise the temperature to 55°C, after a period of reaction, TLC monitors the complete reaction of the raw materials, cool down to room temperature, filter the reaction solution, pour the filtrate into 1000mL of ice water, add Saturated sodium hydroxide solution 200mL, separate the organic phase, adjust the pH of the organic phase to be neutral with dilute hydrochloric acid solution, separate the organic phase again, dry with anhydrous magnesium sulfate and concentrate to obtain 6-chloro-3,4-( Benzo-12-crown-4) ethyl benzoate 30g, 1 H NMR (400Hz, DMSO-d 6 ):7.34(s,1H),6.95(s,1H),4.26(dd,J 1 =8.0Hz,J 2 =4.0Hz,2H),4.01(t,J 1 =4.0Hz,J 2 =4.0Hz, 2H), 3.98-3.96(m, 2H), 3.81(t, J 1 =4.0Hz,J 2 =4.0Hz, 2H), 3.69-3.66(m, 2H), 3....

Embodiment 3

[0025]

[0026] Dissolve 30g of ethyl 3,4-(benzo-12-crown-4)benzoate in 300mL of dichloroethane, stir at 40°C for 20min, then add 15g of N-chlorosuccinimide at one time , slowly raised the temperature to 60°C, after a period of reaction, TLC monitored the complete reaction of the raw materials, cooled to room temperature, filtered the reaction solution, poured the filtrate into 1000mL of ice water, added 200mL of saturated sodium hydroxide solution, separated the organic phase, the organic phase The pH was then adjusted to be neutral with dilute hydrochloric acid solution, and the organic phase was separated again, dried over anhydrous magnesium sulfate, and then concentrated to obtain 22 g of ethyl 6-chloro-3,4-(benzo-12-crown-4)benzoate, 1 H NMR (400Hz, DMSO-d 6 ):7.34(s,1H),6.95(s,1H),4.26(dd,J 1 =8.0Hz,J 2 =4.0Hz,2H),4.01(t,J 1 =4.0Hz,J 2 =4.0Hz, 2H), 3.98-3.96(m, 2H), 3.81(t, J 1 =4.0Hz,J 2 =4.0Hz, 2H), 3.69-3.66(m, 2H), 3.61(s, 4H), 1.28(t, J 1 =4.0Hz,J 2 =4.0...

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Abstract

The invention discloses a preparation method of a key intermediate of icotinib, belonging to the technical field of drug synthesis. The main points of the technical scheme of the present invention are: the present invention uses triethylene diethylene glycol (p-toluenesulfonate) and N-Boc-3,4-dihydroxyaniline as raw materials respectively, and undergoes crown ether cyclization reaction and halogenation reaction respectively. , amination reaction (amidation reaction), through the quinoline ring closure reaction, and finally through the chlorination reaction to obtain the key intermediate 4-chloro-quinazolino[6.7-6]-12-crown-of Icotinib 4. The newly designed synthetic route avoids the need to use strong acid solution in the original route, avoids the danger of operation and produces a large amount of acidic waste liquid, and the new route is not only simple to operate but also has a high reaction yield.

Description

technical field [0001] The invention belongs to the technical field of synthesis of drugs, and in particular relates to a preparation method of a key intermediate of icotinib. Background technique [0002] Icotinib (Conmana, Icotinib Hydrochloride) is an anti-tumor Class 1.1 new drug independently developed by Chinese scientists and clinical tumor experts based on Erlotinib by Betta Pharmaceuticals Co., Ltd. In June 2009, it was approved by the State Food and Drug Administration for the treatment of NSCLC patients with EGFR mutations. The great significance of icotinib is not only that it has better safety than erlotinib and gefitinib, but also has obvious advantages in toxicity and side effects, and the incidence of rash and diarrhea is lower, so that more patients can benefit and more The most important thing is to break the monopoly of foreign pharmaceutical companies on the market of small molecule targeted drugs, so that my country has EGFR inhibitors with high quality,...

Claims

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Application Information

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IPC IPC(8): C07D491/056
CPCC07D491/056Y02P20/54
Inventor 侯延生毛龙飞汪贞贞
Owner 诺为泰医药科技(上海)有限公司
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