Synthesis method of tert-butyl-[2-(biphenyl-4-yl)-1-(hydroxymethyl)ethyl] carbamate

A technology of carbamate and synthesis method, which is applied in the field of synthesis of pharmaceutical intermediate tert-butyl-[2--1-ethyl] carbamate, which can solve the problem of high production equipment requirements, potential safety hazards, Strong corrosion of equipment and other problems, to achieve the effect of reduced production cost, easy operation, and reduced corrosion

Inactive Publication Date: 2009-02-11
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

(European Journal of Medicinal Chemistry 40 (2005) 563-581) etc. (European Journal of Medicinal Chemistry 40 (2005) 563-581) have researched to some extent on the intermediate compound (III) synthesis of this material, by diethyl acetamidomalonate and 4-bromomethyl biphenyl in Reaction under the existence of sodium ethylate obtains compound (III), adopts the method for hydrolysis decarboxylation with hydrochloric acid in this document, stronger to equipment corrosion
In addition, the reduction method literature of compound V (European Journal of Medicinal Chemistry 40 (2005) 563-581) uses expensive lithium aluminum hydride reagent, which requires strict reaction conditions such as anhydrous and oxygen-free, and has high requirements for production equipment. It is difficult to operate during post-processing, and a large amount of hydrogen is produced, which poses a safety hazard
[0003] There is no bibliographical report yet by the method for compound (VIII) synthetic compound (VIII) by compound (III)

Method used

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  • Synthesis method of tert-butyl-[2-(biphenyl-4-yl)-1-(hydroxymethyl)ethyl] carbamate
  • Synthesis method of tert-butyl-[2-(biphenyl-4-yl)-1-(hydroxymethyl)ethyl] carbamate

Examples

Experimental program
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Effect test

Embodiment 1

[0052] Example 1 Synthesis of 2-acetamido-2-(biphenyl-4-ylmethyl) dimethyl malonate

[0053] According to the molar ratio of dimethyl acetamidomalonate: 4-chloromethyl biphenyl: sodium: ethanol = 1: 1: 1.1: 10 for the following reaction:

[0054] Add ethanol to a three-necked flask with a drying tube, cool to below 10°C, add 12.65g of metallic sodium in batches, add 94.58g of dimethyl acetamidomalonate after the metallic sodium is completely dissolved, and react at 20-30°C After 2 hours, 101.34 g of 4-chloromethylbiphenyl was added, and the temperature was raised to 50-60° C. to react for 20 hours, and the reaction was completed. Add water, cool down and crystallize, suction filter, and dry to obtain dimethyl 2-acetamido-2-(biphenyl-4-ylmethyl)malonate, the content of which is ≥98% by HPLC analysis, and the yield is 82% (calculated as dimethyl acetamidomalonate).

Embodiment 2

[0055] Example 2 Synthesis of 2-acetylamino-2-(biphenyl-4-ylmethyl)diethyl malonate

[0056] According to the molar ratio of diethyl acetamidomalonate: 4-chloromethyl biphenyl: sodium: ethanol = 1: 1: 1.1: 10 to carry out the following reaction:

[0057] Add ethanol to a three-neck flask with a drying tube, cool to below 10°C, add 12.65g of sodium metal in batches, and add 108.61g of diethyl acetamidomalonate after the sodium metal is completely dissolved, and react at 20-30°C After 2 hours, 101.34 g of 4-chloromethylbiphenyl was added, and the temperature was raised to 50-60° C. to react for 20 hours, and the reaction was completed. Add water, cool down and crystallize, suction filter, and dry to obtain diethyl 2-acetamido-2-(biphenyl-4-ylmethyl)malonate, the content of which is ≥98% by HPLC analysis, and the yield is 85% (calculated as diethyl acetamidomalonate).

Embodiment 3

[0058] Example 3 Synthesis of 2-acetylamino-2-(biphenyl-4-ylmethyl)diethyl malonate

[0059] According to the molar ratio of diethyl acetamidomalonate: biphenyl-4-yl methyl methanesulfonate: sodium: ethanol = 1: 1: 1.1: 10 to carry out the following reaction:

[0060] Add ethanol to a three-neck flask with a drying tube, cool to below 10°C, add 12.65g of sodium metal in batches, and add 108.61g of diethyl acetamidomalonate after the sodium metal is completely dissolved, and react at 20-30°C After 2 hours, 131.15 g of biphenyl-4-ylmethyl methanesulfonate was added, and the temperature was raised to 50-60° C. for 20 hours to complete the reaction. Add water, cool down and crystallize, suction filter, and dry to obtain diethyl 2-acetamido-2-(biphenyl-4-ylmethyl)malonate, the content of which is ≥98% by HPLC analysis, and the yield is 83% (calculated as diethyl acetamidomalonate).

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Abstract

The invention discloses a synthesis method of a pharmaceutical intermediate of tertiary butyl-(2-(biphenyl-4-yl)-1-(methylol) ethyl) carbamate, which comprises the steps that: diethyl acetamidornalonate and 4-substituent biphenyl are taken as initial raw materials and undergone six steps of reactions including condensation, decarboxylation, hydrolysis, reduction and acylation to obtain the tertiary butyl-(2-(biphenyl-4-yl)-1-(methylol) ethyl) carbamate. The method of the invention has the advantages of available raw materials, convenient operation, high reaction yield rate, recoverable solvents used in the synthesis course, thereby reducing environmental pollution and greatly reducing production cost; according to test results, the products obtained by the method has reliable quality and stable performance.

Description

(1) Technical field [0001] The invention relates to a method for synthesizing a pharmaceutical intermediate tert-butyl-[2-(biphenyl-4-yl)-1-(hydroxymethyl)ethyl]carbamate. (2) Background technology [0002] Tert-butyl-[2-(biphenyl-4-yl)-1-(hydroxymethyl)ethyl]carbamate is an important intermediate widely used in many fields such as medicine, pesticide and chemical industry . (European Journal of Medicinal Chemistry 40 (2005) 563-581) etc. (European Journal of Medicinal Chemistry 40 (2005) 563-581) have researched to some extent on the intermediate compound (III) synthesis of this material, by diethyl acetamidomalonate and 4-bromomethyl biphenyl in Compound (III) is obtained by reacting in the presence of sodium ethylate. In this document, hydrochloric acid hydrolysis and decarboxylation is used, which is relatively corrosive to equipment. In addition, the reduction method literature of compound V (European Journal of Medicinal Chemistry 40 (2005) 563-581) uses expensive li...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/16C07C269/04
Inventor 张兴贤童建成杨平何万平朱晓珍陈巧虹杨平锋徐宏烈
Owner ZHEJIANG UNIV OF TECH
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