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Preparation method for key intermediate of letrozole

An intermediate, letrozole technology, applied in the field of preparation of pharmaceutical intermediates

Inactive Publication Date: 2021-07-06
HANGZHOU ZHONGMEI HUADONG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0030] It is not difficult to find out from above-mentioned synthetic route, all there is certain defect in present synthetic route

Method used

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  • Preparation method for key intermediate of letrozole
  • Preparation method for key intermediate of letrozole
  • Preparation method for key intermediate of letrozole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Add N,N-dimethylformamide (200mL) into a 500mL three-necked flask, and add 2-(4-cyanophenyl)formylformic acid (II) (35.1g, 0.2mol) and 4-bromoformylformic acid (II) successively under nitrogen Benzonitrile (III) (36.3g, 0.2mol), cesium carbonate (40.0g, 0.4mol), PdCl 2 (1.79g, 0.01mol), CuI (3.8g, 0.02mol) and 2,2'-bipyridine (3.2g, 0.02mol), stirred, heated to 100 ° C for 12 hours, HPLC detected that the reaction was complete (2-( 4-cyanophenyl)formylformic acid content is lower than 1%), cool down to room temperature, add water slowly, and solids will precipitate out. The solid was dissolved in ethyl acetate and extracted (50mL x 3), the obtained organic phase was washed successively with 5% aqueous hydrochloric acid (100mL) and saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure A crude product was obtained, which was recrystallized from methyl tert-butyl ether (150 mL) t...

Embodiment 2

[0058] Add 1,4-dioxane (200mL) into a 500mL three-necked flask, add 2-(4-cyanophenyl)formylformic acid (II) (35.1g, 0.2mol) under nitrogen, 4-bromobenzene Nitrile (III) (36.3g, 0.2mol), sodium ethoxide (27.3g, 0.4mol), Pd(PPh 3 ) 4 (11.8g, 0.01mol), CuBr (4.3g, 0.03mol), 1,10-phenanthroline (7.3g, 0.04mol), stirred, heated up to 80°C for reflux reaction for 24 hours, HPLC detected that the reaction was complete (2- (4-cyanophenyl)formylformic acid (III) content is less than 1%), cooled to room temperature, slowly added water to precipitate a solid, dissolved in ethyl acetate and extracted (50mL x 3). The obtained organic phase was washed with 5% aqueous hydrochloric acid (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated, and recrystallized with methyl tert-butyl ether (150 mL) to obtain a white solid product (41.9 g, yield: 90.3%).

Embodiment 3

[0060] Dimethylsulfoxide (200mL) was added to a 500mL three-necked flask, and 2-(4-cyanophenyl)formylformic acid (II) (35.1g, 0.2mol), 4-bromobenzonitrile (III ) (18.2g, 0.1mol), sodium hydroxide (40.1g, 1mol), PdBr 2 (0.53g, 0.002mol), CuOAc (0.49g, 0.004mol), 1,10-phenanthroline (1.46g, 0.008mol) and tricyclohexylphosphine (2.24g, 0.008mol), stirred and heated to 140°C , reacted for 5 hours, HPLC detected that the reaction was complete (4-bromobenzonitrile (III) content was less than 1%), cooled to room temperature, slowly added water to precipitate a solid, and the solid was dissolved in ethyl acetate and extracted (50mL x3). The obtained organic phase was washed successively with 5% aqueous hydrochloric acid solution (100 mL) and saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was reconstituted with methyl tert-butyl ether (150 mL). Crystallization gave a whit...

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Abstract

The invention provides a preparation method for a key intermediate (I) of letrozole. According to the method, 2-(4-cyanophenyl)formylformic acid (II) and 4-halogenated cyanophenyl (III) are used as raw materials and subjected to one-step reaction in the presence of alkali, a solvent and a catalyst so as to generate a target product. The preparation method is novel in route, simple and controllable in operation, high in reaction yield, economical and capable of ensuring that high-purity letrozole is obtained through subsequent preparation, and provides guarantees for industrial large-scale production of high-purity letrozole.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, in particular to a synthesis method of a third-generation aromatase inhibitor letrozole intermediate. Background technique [0002] Letrozole (Letrozole), chemical name 4,4'-(1H-1,2,4-triazole-1-methine)-dibenzonitrile, is the third generation of high selectivity developed by Novartis Aromatase inhibitors reduce estrogen levels by inhibiting aromatase, and their in vivo activity is 150-250 times stronger than the first-generation aromatase inhibitor aminoglutethimide, especially suitable for postmenopausal breast cancer patients. Because of its high selectivity, it does not affect the function of glucocorticoids, mineralocorticoids and thyroid gland, and large doses have no inhibitory effect on the secretion of adrenal corticosteroids, so it has a high therapeutic index. [0003] The second chapter of Jiangxi Normal University's master's thesis "Synthesis of t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30C07C255/56
CPCC07C253/30C07C255/56
Inventor 周玉宝曾海涛徐仲军郑六军边红玲
Owner HANGZHOU ZHONGMEI HUADONG PHARMA
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