Synthesis method for 4-methoxy-2-methyl benzyl cyanide

A technology of methylbenzene acetonitrile and synthesis method, applied in chemical instruments and methods, preparation of carboxylic acid nitrile, preparation of organic compounds, etc., can solve the problems of low yield, difficult operation, difficult purification and the like

Active Publication Date: 2014-07-16
渭南瑞联制药有限责任公司
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Problems solved by technology

[0004] Currently, the synthetic methods of 4-methoxy-2-methylbenzylnitrile all use the highly toxic substance NaCN or KCN (Journal of Medicinal Chemistry; vol.44; nb.24; (2001); p.4230-4251, etc.) , has the characteristics of difficult operation, difficult purification and low yield

Method used

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  • Synthesis method for 4-methoxy-2-methyl benzyl cyanide
  • Synthesis method for 4-methoxy-2-methyl benzyl cyanide

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Add 100g of 3,4-dimethylphenol into a 500mL three-neck flask containing 123.9g of dimethyl sulfate and stir, start to add 131.5g of 32.3% NaOH solution dropwise, and control the temperature to 30°C during the dropwise addition. After the dropwise addition was completed, the temperature was controlled to 0-50°C and the reaction was stirred for 2 hours. Then, 500 mL of water was added, 500 mL×3 times of petroleum ether extraction, and the petroleum ether was concentrated to obtain 107 g of yellow liquid 3,4-dimethylanisole ( Yield 96%, GC=99%).

Embodiment 2

[0035] Add 50g of 3,4-dimethylanisole, 91.7g of copper sulfate pentahydrate and 297.7g of potassium persulfate into 1275mL of acetonitrile and 1275mL of water, heat up and control the temperature to 90°C, stir and react for half an hour, then cool down to 20°C to 30°C, extracted 500mL×3 times with dichloromethane, dried over anhydrous magnesium sulfate, concentrated dichloromethane to obtain 55.1g of 4-methoxy-2methylbenzaldehyde (100% yield, GC = 95%).

Embodiment 3

[0037] Add 110.89g of potassium tert-butoxide to a 2L three-neck flask containing 339g of chloromethyl ether triphenylphosphine salt and 660mL of THF (tetrahydrofuran). -2 methyl benzaldehyde dubbed solution. After the dropwise addition is completed, control the temperature to 10°C and react for 1 hour, extract 550mL with toluene×1 time, add 225mL ethanol and 225mL water to wash, dry over anhydrous magnesium sulfate, and concentrate to obtain high-purity 1-methoxy-2- 115.4 g of methyl-4-(2-methoxyvinyl)benzene (88.4% yield, GC=98%).

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Abstract

The invention relates to a synthesis method for 4-methoxy-2-methyl benzyl cyanide. The synthesis method takes 3, 4-dimethylphenol which is cheap and simple and easy to purchase as the raw material, and comprises six steps: methylation, oxidation, Witting reaction, alkene ether hydrolysis, oximation and dehydration. The synthesis method uses the simple and cheap raw material, is simple to operate, is easy for industrial production, has short production cycle, only needs purification in the last step of the six so as to obtain high-quality 4-methoxy-2-methyl benzyl cyanide, and avoids using extremely toxic substances like NaCN and KCN, thus filling the blank home and abroad.

Description

technical field [0001] The invention relates to a method for synthesizing high-purity pharmaceutical intermediate 4-methoxy-2-methylbenzylnitrile. Background technique [0002] 4-methoxy-2-methylbenzylnitrile is an important pharmaceutical intermediate, which is mainly used in the preparation of corticotropin-releasing factor (CRF) receptor antagonists, and corticotropin-releasing factor (CRF) is Regulates all body stress responses. It is reported in many patent applications (EP1354884A1, WO2006 / 044958, CN101273043A, etc.), which are cited as reference. [0003] As CRF receptor agonists (e.g., CRF1 and CRF2), CRF is known to be the major physiological secretagogue controlling the activity of the hypothalamic-pituitary-adrenal (HPA) axis, which Regulates hormonal stress response. CRF also plays an important role in autonomic and behavioral responses to stress. Physiological changes in CRF have been associated with various diseases, including depression and anxiety. CRF r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/37C07C253/00
Inventor 冯光军沈宁赵佳宁刘骞峰杨燕
Owner 渭南瑞联制药有限责任公司
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