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Preparation method of erlotinib intermediate

A technology of intermediates and compounds, which is applied in the field of drug synthesis, can solve the problems of low reaction yield and achieve the effects of high conversion rate, mild reaction conditions and short reaction time

Active Publication Date: 2017-08-15
YANGZHOU POLYTECHNIC INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the above synthetic route, the synthesis of erlo-4 needs to be heated to about 160°C, and the reaction yield is not high, so developing a new method for synthesizing erlo-4 for the synthesis of erlotinib has become the focus of research

Method used

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  • Preparation method of erlotinib intermediate
  • Preparation method of erlotinib intermediate
  • Preparation method of erlotinib intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0033]

[0034] Weigh compound 1 (285 mg, 1.0 mmol) and dissolve it in DMF (10 mL), add paraformaldehyde (300 mg, 10 mmol) and a catalytic amount of boron trifluoride diethyl ether at room temperature, heat to 50 ° C, stir the reaction, and detect the reaction by TLC The raw material (compound 1) completely disappeared (about 5h of reaction), stop heating and cool down to room temperature, pour the reaction solution into ice water (about 100mL), stir for 5-10min, filter cake with suction, add 20mL of acetonitrile to the filter cake, heat for 50 ℃ until the solid was completely dissolved, and naturally cooled to room temperature to crystallize, suction filtered, the filter cake was washed twice with acetonitrile, and dried in vacuo to obtain 292 mg of a white solid (the yield was about 98.9%), which was compound 2 (ESI-MS (m / z ): 296.11[M+H] + , 318.09[M+Na] + , 1 H NMR (400MHz, CDCl 3 ):δ8.23(s,1H,H-2),7.50(s,1H,H-5),7.18(s,1H,H-8),4.28-4.20(m,8H,CH 2 ×4),3.43(s,3H,CH ...

Embodiment 2

[0036] Weigh compound 1 (285 mg, 1.0 mmol) and dissolve it in THF (10 mL), add paraformaldehyde (600 mg, 20 mmol) and a catalytic amount of boron trifluoride diethyl ether at room temperature, heat to 60 ° C, stir the reaction, and detect the reaction by TLC The raw material (compound 1) completely disappeared (about 3h of reaction), stop heating and cool down to room temperature, pour the reaction solution into ice water (about 100mL), stir for 5-10min, filter cake with suction, add 20mL of acetonitrile to the filter cake, heat for 50 ℃ until the solid was completely dissolved, and naturally cooled to room temperature to crystallize, suction filtered, the filter cake was washed twice with acetonitrile, and dried in vacuo to obtain 293 mg of a white solid (the yield was about 99.2%), which was compound 2 (structure confirmation data and Example 1 consistent).

Embodiment 3

[0038] Weigh compound 1 (285mg, 1.0mmol) and dissolve it in DMF (10mL), add paraformaldehyde (300mg, 10mmol) at room temperature, heat to 50°C, stir and react (about 5h), TLC detection shows that the compound in the reaction solution 1 is still the main point, that is, it almost reacts without adding boron trifluoride ether.

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Abstract

The invention relates to a preparation method of an erlotinib intermediate. The preparation method concretely comprises the following steps: implanting a synthesis route described in the description; adding a compound 2 into ammonia water, adding a catalytic amount of tetrabutyl ammonium bromide at the room temperature, and carrying out ultrasonic treatment for 5-30min to generate a compound 3, wherein the ultrasonic frequency is 30-50kHz.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of an erlotinib intermediate. Background technique [0002] Erlotinib Hydrochloride (Erlotinib Hydrochloride) is a tyrosinase inhibitor developed by OSI Pharmaceuticals in the United States. It is currently clinically used for the treatment of non-small cell lung cancer. Its chemical name is: N-(3-ethynylphenyl)-[6,7-bis(2-methoxyethoxy)]quinazolin-4-amine hydrochloride. The chemical structure is shown below: [0003] [0004] The synthetic route of Erlotinib is mainly the U.S. Patent US5747498A reported by Pfizer, and its synthetic route is as follows: [0005] [0006] [0007] In the above synthesis route, the synthesis of erlo-4 needs to be heated to about 160°C, and the reaction yield is not high, so developing a new method for the synthesis of erlo-4 for the synthesis of erlotinib has become the focus of research. Contents of the i...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D263/56C07D239/88
CPCC07D239/88C07D239/94C07D263/56
Inventor 王雪陈雨晴
Owner YANGZHOU POLYTECHNIC INST
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