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A kind of preparation method of intermediate of heterocyclic urea indoleamine-2,3-dioxygenase inhibitor

A technology of dioxygenase and indoleamine, which is applied in the intermediate of heterocyclic urea indoleamine-2,3-dioxygenase inhibitor, 3--4--1,2,4-oxadi In the field of preparation of oxazol-5-one, it can solve the problems that impurities affect the product purity, the product cost is difficult to reduce, and the reaction selectivity is poor, so as to achieve the effect of low cost, easy operation and improved selectivity

Active Publication Date: 2021-03-19
宁夏蓝博思化学技术有限公司
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Problems solved by technology

[0007] The problem that this method exists: in the process that compound 2 prepares compound 3, because the amino group on the 3-position of compound 2 and the amino group on the 4-position oxime exist simultaneously, the reaction selectivity is poor, the yield is low when making diazotization, only 51- 53%, making it difficult to reduce product costs, and it is easy to introduce impurities to affect product purity

Method used

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  • A kind of preparation method of intermediate of heterocyclic urea indoleamine-2,3-dioxygenase inhibitor
  • A kind of preparation method of intermediate of heterocyclic urea indoleamine-2,3-dioxygenase inhibitor
  • A kind of preparation method of intermediate of heterocyclic urea indoleamine-2,3-dioxygenase inhibitor

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Embodiment 1

[0029] Preparation of 3-Amino-4-Aminoximidofurazan Intermediate 2

[0030] In a 1L three-neck flask, dissolve malononitrile (33.0g, 0.5mol) in 2mol / L hydrochloric acid (200mL), and add NaNO2 (69.0g, 1.0mol) in water (100mL) dropwise at a temperature of 0-15°C , dropwise, stirred at room temperature for 2 hours, cooled to 0°C, added dropwise a solution of hydroxylamine hydrochloride (104.2g, 1.5mol) dissolved in water (75mL), stirred at room temperature for 30 minutes after the addition, and slowly raised the temperature to reflux and stirred for 2 hours. Cool to below 20°C and adjust pH to 7-8 with 10mol / L sodium hydroxide solution, stir at 0-5°C for 1 hour, filter to obtain 62.2g of white powder, yield 87.2%, HPLC purity 98.3%, m.p.192-193 ℃, MS:144.0[M+H] + .

[0031] Preparation of 4-diphenylmethyleneamino-N-(3-bromo-4-fluorophenyl)-N’-hydroxy-1,2,5-oxadiazole-3-carboxamidine intermediate 4

[0032] Add benzophenone (79.3g, 0.435mol), trimethyl orthoformate (69.2g, 0.652...

Embodiment 2

[0036] Preparation of 3-Amino-4-Aminoximidofurazan Intermediate 2

[0037]In a 1L three-neck flask, dissolve malononitrile (33.0g, 0.5mol) in 4mol / L hydrochloric acid (100mL), and add NaNO2 (51.8g, 0.75mol) in water (150mL) dropwise at a temperature of 0-15°C , dropwise, stirred at room temperature for 2 hours, cooled to 0°C, added dropwise a solution of hydroxylamine hydrochloride (69.5g, 1.0mol) dissolved in water (50mL), stirred at room temperature for 30 minutes after the addition, slowly warmed to reflux and stirred for 2 hours, Cool to below 20°C and adjust pH to 7-8 with 10mol / L sodium hydroxide solution, stir at 0-5°C for 1 hour, filter to obtain 60.2g of white powder, yield 84.5%, HPLC purity 98.2%, m.p.192-193 ℃.

[0038] Preparation of 4-diphenylmethyleneamino-N-(3-bromo-4-fluorophenyl)-N’-hydroxy-1,2,5-oxadiazole-3-carboxamidine intermediate 4

[0039] Add benzophenone (92.2g, 0.506mol), triethyl orthoformate (81.3g, 0.549mol), p-toluenesulfonic acid (0.73g, 4.2m...

Embodiment 3

[0043] Preparation of 3-Amino-4-Aminoximidofurazan Intermediate 2

[0044] In a 1L three-neck flask, dissolve malononitrile (33.0g, 0.5mol) in 6mol / L hydrochloric acid (40mL), and add NaNO2 (69.0g, 1.0mol) in water (100mL) dropwise at a temperature of 0-15°C , dropwise, stirred at room temperature for 2 hours, cooled to 0°C, added dropwise a solution of hydroxylamine hydrochloride (104.2g, 1.5mol) dissolved in water (75mL), stirred at room temperature for 30 minutes after the addition, and slowly raised the temperature to reflux and stirred for 2 hours. Cool to below 20°C, adjust pH to 7-8 with 10mol / L sodium hydroxide solution, stir at 0-5°C for 1 hour, filter to obtain 62.4g of white powder, yield 87.5%, HPLC purity 98.0%, m.p.192-193 ℃.

[0045] Preparation of 4-diphenylmethyleneamino-N-(3-bromo-4-fluorophenyl)-N’-hydroxy-1,2,5-oxadiazole-3-carboxamidine intermediate 4

[0046] Add benzophenone (79.8g, 0.438mol), trimethyl orthoformate (69.6g, 0.656mol), p-toluenesulfonic...

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Abstract

The invention discloses a preparing method of a heterocyclic urea indoleamine-2-3-dioxygenase enzyme inhibitor intermediate. Malononitrile and hydroxylamine hydrochloride serve as raw materials, and 3-amino-4-aminoxime furza is obtained through a sodium nitrite reaction; afterwards, benzophenone is adopted for amino protection, and then 3-amino-4-aminoxime furza is reacted with 3-bromine-4-fluoroaniline after being diazotized with tert-butyl nitrite to obtain 4-diphenyl agag amino-N-(3-bromine-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadizole-3-formamidine; after protection of carbonic ester ring closure and benzophenone, the heterocyclic urea indole amines-2-3-dioxygenase enzyme inhibitor intermediate, namely 3-(4-amino-1,2,5-oxadiazole-3-radical)-4-(3-bromine-4-fluorophenyl)-1,2,4-oxidazole-5(4H)-ketone is generated. The preparing method is high in reaction yield, convenient to operate, low in cost and suitable for industrialized production.

Description

Technical field: [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, in particular to a heterocyclic urea indoleamine-2,3-dioxygenase inhibitor intermediate, namely 3-(4-amino-1,2,5-oxadi Preparation method of oxazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. Background technique: [0002] Epacadostat (INCB024360) is a potent and selective indoleamine 2,3-dioxygenase (IDO1) inhibitor indicated for the treatment of cancers and solid tumors associated with IDO1 dysregulation such as metastatic melanoma, ovarian cancer and Non-small cell lung cancer. 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H) - Ketone is an important intermediate for the synthesis of IDO1 inhibitors, and its structural formula is as follows: [0003] [0004] 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2 reported in Chinese patent CN106967004, US patent US20150133674, and WO2017106062 , The synth...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D271/08
CPCC07D271/08
Inventor 高峰曾赛兰潘瑞亮张六六蒋军强张行行
Owner 宁夏蓝博思化学技术有限公司
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