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Preparation method of dexmedetomidine hydrochloride and its intermediate

A technology for dexmedetomidine and intermediates, applied in the field of preparation of dexmedetomidine hydrochloride and its intermediates, can solve the problems of long steps, low molar yield, unsuitable for industrial production, etc.

Active Publication Date: 2018-06-12
SHANGHAI BOCIMED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to overcome the preparation method step of dexmedetomidine hydrochloride in the prior art is long, needs to use chiral resolution, overall molar yield is lower (only 6.9%), material loss is big, The prepared product has low purity and does not meet the standards of raw materials, and is not suitable for defects such as industrial production. A preparation method for dexmedetomidine hydrochloride and its intermediates is provided

Method used

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  • Preparation method of dexmedetomidine hydrochloride and its intermediate
  • Preparation method of dexmedetomidine hydrochloride and its intermediate
  • Preparation method of dexmedetomidine hydrochloride and its intermediate

Examples

Experimental program
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Embodiment 1

[0106] Example 1: Preparation of trimethylsilyl-2,3-dimethylphenylacetylene

[0107]

[0108]Under the protection of argon, 55.0 g of 2,3-dimethylbromobenzene was added to 440 mL of tetrahydrofuran, followed by 1.05 g of bistriphenylphosphine palladium dichloride, 62.0 g of cuprous iodide, and 60.0 g of triethylamine. After vacuum degassing and argon replacement, heat to 45°C, slowly add a solution of 35.0 g of trimethylsilylacetylene in 140 mL of tetrahydrofuran dropwise, and react for 8 to 10 hours. After cooling, filter, add mass concentration and be 10% ammonium chloride aqueous solution (the described mass concentration refers to the quality of ammonium chloride accounts for the percentage of ammonium chloride aqueous solution total mass) 100mL and water 100mL, extract with n-heptane 200mL Twice, merging organic phase with mass concentration is that 10% sodium bicarbonate aqueous solution (described mass concentration refers to the percentage that the quality of sodium...

Embodiment 2

[0109] Example 2: Preparation of trimethylsilyl-2,3-dimethylphenylacetylene

[0110]

[0111] Under the protection of argon, 55.0 g of 2,3-dimethylbromobenzene was added to 825 mL of 2-methyltetrahydrofuran, and then 2.19 g of dichlorobis(tricyclohexylsulfone)palladium, 84.5 g of cuprous iodide, and Isopropylethylamine 115g. After vacuum degassing and argon replacement, heat to 30°C, slowly add dropwise a solution of 43.8 g of trimethylsilylacetylene in 140 mL of 2-methyltetrahydrofuran, and react for 13 to 15 hours. After cooling, filter, add mass concentration and be 10% ammonium chloride aqueous solution (the described mass concentration refers to the quality of ammonium chloride accounts for the percentage of ammonium chloride aqueous solution total mass) 100mL and water 100mL, extract with n-heptane 200mL Twice, merging organic phase with mass concentration is that 10% sodium bicarbonate aqueous solution (described mass concentration refers to the percentage that the ...

Embodiment 3

[0112] Example 3: Preparation of trimethylsilyl-2,3-dimethylphenylacetylene

[0113]

[0114] Under argon protection, add 55.0 g of 2,3-dimethylbromobenzene to 303 mL of 1,4-dioxane, and then add [1,1'-bis(diphenylphosphino)ferrocene] 0.59 g of palladium dichloride, 45.0 g of cuprous iodide, and 71.0 g of tri-n-butylamine. After vacuum degassing and argon replacement, heat to 60°C, slowly add dropwise a solution of 30.6 g of trimethylsilylacetylene in 140 mL of 1,4-dioxane, and react for 5 to 7 hours. After cooling, filter, add mass concentration and be 10% ammonium chloride aqueous solution (the described mass concentration refers to the quality of ammonium chloride accounts for the percentage of ammonium chloride aqueous solution total mass) 1000mL and water 1000mL, extract with n-heptane 600mL Twice, merging organic phase with mass concentration is that 10% sodium bicarbonate aqueous solution (described mass concentration refers to the percentage that the quality of sod...

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Abstract

The invention discloses a preparation method of dexmedetomidine hydrochloride and its intermediate. A preparation method of dexmedetomidine L-tartrate comprises the steps of subjecting dexmedetomidineintermediate III and hydrogen to reduction reaction in an organic solvent in the presence of a chiral catalyst, and subjecting the reduced product and tartaric acid to neutralization reaction to obtain dexmedetomidine L-tartrate II, wherein the chiral catalyst is (+)-1,2-bis(2S-5S)-diethylphospholano-benzene(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate. The preparation method herein has ashort step path, has no need for chiral splitting, and has high total molar yield; the product prepared herein has high purity, reaches the standard for bulk pharmaceutical chemicals and is suitablefor industrial production.

Description

technical field [0001] The invention relates to a preparation method of dexmedetomidine hydrochloride and an intermediate thereof. Background technique [0002] Dexmedetomidine hydrochloride I was jointly developed by Orion and Hospira, and was approved for marketing by the US Food and Drug Administration on December 17, 1999, and then approved by Japan on January 29, 2004. It was approved for marketing by the Comprehensive Agency for Pharmaceuticals and Medical Devices, and was approved for marketing by the European Medicines Agency on September 16, 2011. It is marketed by Hospira in the United States and Japan under the product name Precedex; it is marketed in Europe by Orion under the product name Dexdor. [0003] [0004] Dexmedetomidine hydrochloride is a relatively selective α2-adrenoceptor agonist with sedative effect. Continuous infusion of dexmedetomidine hydrochloride for no more than 24 hours can be used to sedate patients at the beginning of intubation and m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58C07F7/08C07C1/32C07C15/48C07C17/08C07C22/04
Inventor 陈健乔岩河应述欢
Owner SHANGHAI BOCIMED PHARMA CO LTD
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