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A method for the continuous preparation of olaparib intermediates using a microchannel modular reaction device

A technology of micro-channel reaction and micro-channel module is applied in the field of preparing intermediates of antineoplastic drug olaparib, which can solve the problems of low yield, many by-products, difficult to purify, etc., and achieves high profit, low toxicity and pollution, The effect of increasing productivity

Active Publication Date: 2020-09-04
NANJING TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Purpose of the invention: In view of the shortcomings of the existing antineoplastic drug olaparib in the synthesis and preparation process, such as low yield, many by-products, and difficulty in purification, the present invention provides a continuous preparation method using a microchannel modular reaction device. The method of the intermediate of olaparib, the method is simple and quick to operate, the yield is high, the production cost is low, the application prospect is good, and it has the value of industrialized scale-up production

Method used

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  • A method for the continuous preparation of olaparib intermediates using a microchannel modular reaction device
  • A method for the continuous preparation of olaparib intermediates using a microchannel modular reaction device
  • A method for the continuous preparation of olaparib intermediates using a microchannel modular reaction device

Examples

Experimental program
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Effect test

Embodiment 1

[0037] (1) In a microchannel reaction device, a dichloromethane solution (50 mL) of 3-hydroxyisobenzofuran-1 (3H)-one (0.033 mol) and a dichloromethane solution of dimethyl phosphite (0.091 mol) were mixed Methane solution (50 mL) was pumped into the first mixing valve 3 from pump A1 and pump B2 respectively, the flow rate of pump A1 was 0.18 mL / min, and the flow rate of pump B2 was 0.026 mL / min. Enter the first microreactor 4 after fully mixing, the volume of the first microreactor 4 is 40mL, and the reaction residence time is 25min. The reaction temperature is 100°C, and the reaction liquid is collected in the first separation device 5, which is a container for holding water and dichloromethane, and the obtained (3-oxo-1,3- Dihydroisobenzofuran-1-yl) dimethyl dihydroisobenzofuran-1-yl) phosphate (compound 1) effluent, yield 85%.

[0038] (2) As the reaction solution obtained in step (1) flows into the second mixing valve, the flow rate is 1.24mL / min, and a dichloromethane s...

Embodiment 2

[0049] The operation is the same as in Example 1, the only difference is:

[0050] In step (1), the reaction temperature in the first microreactor is 90°C, and finally (3-oxo-1,3-dihydroisobenzofuran-1-yl) dimethyl phosphate (compound 1) is obtained The effluent, the yield was 76%.

Embodiment 3

[0052] The operation is the same as in Example 1, the only difference is:

[0053] In step (1), the reaction temperature in the first microreactor is 120°C, and finally (3-oxo-1,3-dihydroisobenzofuran-1-yl) dimethyl phosphate (compound 1) is obtained The effluent, the yield was 72%.

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Abstract

The invention discloses a method for continuously preparing an olaparib intermediate by a microchannel modular reaction device. The method comprises the following steps: performing reaction on a dichloromethane solution of 3-hydroxyisobenzofuran-1(3H)-ketone and a dichloromethane solution of dimethyl phosphate in a first microreactor, and performing liquid separation to obtain effluent of (3-oxo-1,3-dihydroisobenzyfuran-1-yl)dimethyl phosphate; performing reaction on the effluent, a dichloromethane solution of 2-fluorine-5-formyl benzene nitrile and a dichloromethane solution of triethylaminein a second microreactor to generate reaction liquid of 2-fluorine-5-(3-oxo-3H-isobenzofuran-1-yl methylene)benzyl cyanide; and performing reaction on the reaction liquid and a homogenous mixed solution which is obtained by stirring an ethanol solution of sodium hydroxide and hydrazine hydrate in a third microreactor and treating the effluent to obtain the olaparib intermediate 2-fluorine-5-[(4-oxo-3,4-dihydrodiazene-1-yl-)methyl]benzoic acid.

Description

technical field [0001] The invention relates to a method for preparing an antineoplastic drug olaparib intermediate, in particular to a method for preparing an important intermediate 2-fluoro-5-[(4-oxo -3,4-Dihydronaphthalene-1-yl)methyl]benzoic acid method. Background technique [0002] Olaparib (Olaparib), chemical name 1-(cyclopropylformyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2- Fluorobenzoyl]piperazine is a powerful oral PARP inhibitor, which can promote the apoptosis of tumor cells by inhibiting the DNA damage repair of tumor cells, and at the same time can enhance the curative effect of radiotherapy, alkylating agent and platinum drug chemotherapy. Olaparib is currently in clinical phase II, and it is mainly used for the treatment of breast cancer gene 1 or 2 (BRCA-1 or BRCA-2) gene mutation cancer (mainly present in breast cancer, ovarian cancer, etc.). [0003] According to the report of domestic and international literature to the synthetic route of ol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D237/32
CPCC07D237/32
Inventor 郭凯秦红方正乔凯欧阳平凯
Owner NANJING TECH UNIV
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