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Method for preparing 2-pyridinemethanol-alpha-methyl-alpha-phenyl serving as intermediate of doxylamine succinate

A technology of pyridyl phenyl methyl carbinol and doxylamine succinate, applied in the field of medicine, can solve the problem that 2-pyridyl phenyl methyl carbinol cannot be industrialized, and achieves rapid reaction, high conversion rate, high purity effect

Inactive Publication Date: 2015-10-28
NANJING GRITPHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to solve the problem that the synthesis of 2-pyridylphenylmethylcarbinol from 2-benzoylpyridine and methylmagnesium bromide cannot be industrialized, the invention provides a doxylamine succinate intermediate 2-pyridylbenzene The preparation method of phenylmethyl carbinol, the method process is simple, safe and reliable, can obtain the intermediate 2-pyridyl phenylmethyl carbinol efficiently and at low cost, and solve the above-mentioned industrialization problems

Method used

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  • Method for preparing 2-pyridinemethanol-alpha-methyl-alpha-phenyl serving as intermediate of doxylamine succinate
  • Method for preparing 2-pyridinemethanol-alpha-methyl-alpha-phenyl serving as intermediate of doxylamine succinate
  • Method for preparing 2-pyridinemethanol-alpha-methyl-alpha-phenyl serving as intermediate of doxylamine succinate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The reaction equation is as follows:

[0032]

[0033] S1: Synthesis of 2-pyridylphenylmethylcarbinol

[0034] Add 10.5g of 2-benzoylpyridine into a 250ml three-necked round-bottomed flask under nitrogen protection, dissolve in 30ml of anhydrous tetrahydrofuran, place in a -25°C cold bath, cool down to -20°C, and slowly add dropwise to 1mol / L methylmagnesium bromide anhydrous tetrahydrofuran solution 85mL, control the internal temperature not greater than -15°C during the dropwise addition, keep warm and stir for 1.5~2h after the dropwise addition.

[0035] TLC determines the end point of the reaction, and the developing agent is: V 石油醚 :V 乙酸乙酯 =5:1.

[0036] After the reaction was completed, 200 ml of 10% ammonium chloride ice water solution was slowly added dropwise to the flask under the protection of nitrogen, and the addition was completed in 0.5 hours, and the stirring was continued for 0.5 hours. Add ethyl acetate, stand still to separate the liquids, kee...

Embodiment 2

[0041] The reaction equation is as follows:

[0042]

[0043] S1: Synthesis of 2-pyridylphenylmethylcarbinol

[0044] Under nitrogen protection, add 10.5g of 2-benzoylpyridine into a 250ml three-neck round-bottomed flask, dissolve in 30ml of anhydrous tetrahydrofuran, put it in a -20°C cold bath, cool down to -20~-15°C, and slowly drop Add to 85 mL of 1 mol / L methylmagnesium chloride anhydrous tetrahydrofuran solution, control the internal temperature not to exceed -10°C during the dropwise addition, and keep stirring for 1.5 to 2 hours after the dropwise addition.

[0045] TLC determines the end point of the reaction, and the developing agent is: V 石油醚 :V 乙酸乙酯 =5:1.

[0046] After the reaction was completed, 200 ml of ammonium chloride ice-water solution was slowly added dropwise to the flask under the protection of nitrogen, and the addition was completed in 0.5 hours, and the stirring was continued for 0.5 hours. Add ethyl acetate, let stand to separate the liquids, ...

Embodiment 3

[0051] The reaction equation is as follows:

[0052]

[0053] S1: Synthesis of 2-pyridylphenylmethylcarbinol

[0054] Add 10.5g of 2-benzoylpyridine into a 250ml three-neck round-bottomed flask under nitrogen protection, dissolve in 30ml of anhydrous methyl tetrahydrofuran, place in a -25°C cold bath, cool down until the internal temperature reaches -20°C, and slowly add Add to 85mL of 3mol / L methylmagnesium bromide 2-methyltetrahydrofuran solution, control the internal temperature not to exceed -15°C during the dropwise addition, and keep stirring for 1.5-2h after the dropwise addition.

[0055] The end point of the reaction was determined by TLC, and the developer was: V petroleum ether: V ethyl acetate = 5:1.

[0056] After the reaction was completed, 200 ml of ammonium chloride ice-water solution was slowly added dropwise to the flask under the protection of nitrogen, and the addition was completed in 0.5 hours, and the stirring was continued for 0.5 hours. Add ethyl ...

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Abstract

The invention discloses a method for preparing 2-pyridinemethanol-alpha-methyl-alpha-phenyl serving as an intermediate of doxylamine succinate. The method includes the following steps: S1, benzoylpyridine is dissolved into organic solvents and reacted with methyl Grignard reagents at the low temperature, and after the reaction is completed, the target product 2-pyridinemethanol-alpha-methyl-alpha-phenyl is obtained through quenching separation; S2, the crude 2-pyridinemethanol-alpha-methyl-alpha-phenyl prepared in the step S1 is extracted and purified to obtain the fine 2-pyridinemethanol-alpha-methyl-alpha-phenyl. An acid-base inversion method in the step S2 includes the following specific steps: the crude 2-pyridinemethanol-alpha-methyl-alpha-phenyl is dissolved into purified water, the pH value is adjusted to enable the mixture to be faintly acid, impurity removal by extraction is carried out through ethyl acetate, the pH of a water layer is adjusted to enable the water layer to be faintly basic, the water layer is extracted through ethyl acetate, and an organic layer is desolvated to obtain the fine 2-pyridinemethanol-alpha-methyl-alpha-phenyl. The method is simple in technology, safe and reliable; the yield and the purity of the prepared 2-pyridinemethanol-alpha-methyl-alpha-phenyl serving as the intermediate of the doxylamine succinate are high, and the method is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the synthesis of an intermediate 2-pyridylphenylmethylcarbinol of an ethanol antihistamine drug doxylamine succinate. Background technique [0002] Doxylamine succinate belongs to ethanol antihistamine drug, which has antihistamine effect, anticholinergic effect and significant sedative and hypnotic effect. It is suitable for various allergic skin diseases, hay fever, allergic rhinitis, asthmatic Bronchitis, etc.; because it can produce drowsiness by inhibiting the central nervous system, it is also used as a sleeping pill for short-term treatment of insomnia. [0003] In October 1978, the FDA approved the marketing of doxylamine succinate 25mg tablets of CHATTEM Company, which is used to help alleviate the difficulty of falling asleep. Became OTC (over the counter) in 1979. It was approved in September 1996, and in August 2004, LNK was officially listed as a generic drug. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/30
CPCC07D213/30
Inventor 卢翔张元元霍立茹杨建楠陆滢炎赵卿李战
Owner NANJING GRITPHARMA CO LTD
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