Synthesis method of 6-bromophthalazine

Abstract

The invention relates to a synthetic method of 6-bromophthalazine. The synthetic method comprises the following steps: 1) taking 4-bromo-1,2-xylene as a raw material, and adopting a free radical reaction to synthesize a compound III; 2) generating a compound IV from the compound III obtained in the step 1) and tert-butyl carbazate under the action of a sodium hydroxide water solution (50%) and a phase transfer catalyst TEAB; 3) generating a compound V from the compound IV obtained in the step 2) under the action of EA / HCl; and 4) generating a compound I from the compound V obtained in the step3) under the action of triethylamine and DDQ. The problems that in the prior art, the intermediates are unstable, and process amplification is difficult are solved. The shortages that the reaction conditions are severe, and the requirements on equipment and operators are very high, and the overall reaction yield is low are overcome. The synthesis method has the advantages of mild reaction conditions, high yield in each step, simple post-treatment, easiness in operation and suitability for process amplification.

Description

technical field

[0001] The invention relates to the technical field of synthesis of organic chemical intermediates, in particular to a synthesis method of 6-bromophthalazine. Background technique

[0002] 6-Bromophthalazine is a heterocyclic compound of phthalazines, which is an extremely important class of pharmaceutical intermediates with broad application prospects. The intermediate and its derivatives are used to construct many pharmaceutical active molecules. Such as the preparation of protein kinase inhibitors for the treatment of proliferative diseases, Eph receptor regulators for the treatment of nervous disorders, PI3 kinase inhibitors for the treatment of cancer, etc.

[0003] At present, the synthetic route of synthetic 6-bromophthalazine mainly contains two kinds of methods:

[0004] 1. Preparation with 4-bromophthalic acid as raw material

[0005]

[0006] This method is based on 4-bromophthalic acid as raw material, through three steps: 1) sodium borohydr...

Examples

Embodiment 1

[0037]

[0038] 4-Bromo-1,2-xylene (200g, 1.08mol, 1.0eq), NBS (500g, 2.81mol, 2.6eq) and AIBN (19.7g, 0.12mol, 0.11eq) were added to 2L of tetrachloride In carbon, the temperature was raised to reflux, reacted under this condition for 3 hours, cooled to room temperature, filtered, and the filtrate was spin-dried and then slurried with 400 mL of petroleum ether, filtered, and the solvent was removed under reduced pressure to obtain compound III (297 g, yield 80.1%);

Embodiment 2

[0040]

[0041] Compound III (280g, 0.82mol, 1.0eq) and tert-butyl hydrazinodicarboxylate (189.7 g, 0.82mol, 1.0eq) were dissolved in 2.8L of toluene, and a phase transfer catalyst TEAB (5.8g, 0.04 mol, 0.05eq) and 1.4L of 50% sodium hydroxide aqueous solution, then heated up to 100°C, reacted for 10 hours, after the reaction was completed, lowered to room temperature, separated, washed the organic phase with water, washed with saturated saline and dried, and then spin-dried , adding 500mL of methyl tert-butyl ether to the crude product, beating for 0.5 hours, filtering and drying to obtain compound IV (310g, yield 91.8%).

Embodiment 3

[0043]

[0044] Compound IV (300g, 0.73mol, 0.0eq) was dissolved in 1.5L of ethyl acetate, the temperature was lowered to 0°C, the temperature was controlled at 0-5°C, and 1.5L of ethyl acetate / HCl solution (4M) was added dropwise thereto , after the dropwise addition was completed, it was slowly raised to room temperature, reacted for 2 hours, and was filtered to obtain compound V (198 g, yield 95.4%).

technical field

[0001] The invention relates to the technical field of synthesis of organic chemical intermediates, in particular to a synthesis method of 6-bromophthalazine. Background technique

[0002] 6-Bromophthalazine is a heterocyclic compound of phthalazines, which is an extremely important class of pharmaceutical intermediates with broad application prospects. The intermediate and its derivatives are used to construct many pharmaceutical active molecules. Such as the preparation of protein kinase inhibitors for the treatment of proliferative diseases, Eph receptor regulators for the treatment of nervous disorders, PI3 kinase inhibitors for the treatment of cancer, etc.

[0003] At present, the synthetic route of synthetic 6-bromophthalazine mainly contains two kinds of methods:

[0004] 1. Preparation with 4-bromophthalic acid as raw material

[0005]

[0006] This method is based on 4-bromophthalic acid as raw material, through three steps: 1) sodium borohydr...

Examples

Embodiment 1

[0037]

[0038] 4-Bromo-1,2-xylene (200g, 1.08mol, 1.0eq), NBS (500g, 2.81mol, 2.6eq) and AIBN (19.7g, 0.12mol, 0.11eq) were added to 2L of tetrachloride In carbon, the temperature was raised to reflux, reacted under this condition for 3 hours, cooled to room temperature, filtered, and the filtrate was spin-dried and then slurried with 400 mL of petroleum ether, filtered, and the solvent was removed under reduced pressure to obtain compound III (297 g, yield 80.1%);

Embodiment 2

[0040]

[0041] Compound III (280g, 0.82mol, 1.0eq) and tert-butyl hydrazinodicarboxylate (189.7 g, 0.82mol, 1.0eq) were dissolved in 2.8L of toluene, and a phase transfer catalyst TEAB (5.8g, 0.04 mol, 0.05eq) and 1.4L of 50% sodium hydroxide aqueous solution, then heated up to 100°C, reacted for 10 hours, after the reaction was completed, lowered to room temperature, separated, washed the organic phase with water, washed with saturated saline and dried, and then spin-dried , adding 500mL of methyl tert-butyl ether to the crude product, beating for 0.5 hours, filtering and drying to obtain compound IV (310g, yield 91.8%).

Embodiment 3

[0043]

[0044] Compound IV (300g, 0.73mol, 0.0eq) was dissolved in 1.5L of ethyl acetate, the temperature was lowered to 0°C, the temperature was controlled at 0-5°C, and 1.5L of ethyl acetate / HCl solution (4M) was added dropwise thereto , after the dropwise addition was completed, it was slowly raised to room temperature, reacted for 2 hours, and was filtered to obtain compound V (198 g, yield 95.4%).

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