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O-p-methoxyphenyl-N,N-ethyl dibenzyl-tyrosine and synthesizing method

A dibenzyl tyrosine ethyl ester and methoxyphenyl technology, which is applied in the field of synthesis of L-levothyroxine sodium, can solve the problems of many reaction by-products, harsh conditions, and low yield of the main product, etc. Effects of short time, short synthesis cycle, and reduced reaction cost

Inactive Publication Date: 2010-04-21
ZHEJIANG SCI-TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0022] The Ullmann reaction is one of the important methods for preparing diaryl ethers, but the classic Ullmann reaction is the coupling of aromatic halides and phenoxides under the action of copper powder at a high temperature of 250-300°C. Or excessive copper powder, so that large-scale production faces huge environmental pressure, and many functional groups can not withstand such high temperature conditions, resulting in more reaction by-products and low yield of main products

Method used

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  • O-p-methoxyphenyl-N,N-ethyl dibenzyl-tyrosine and synthesizing method
  • O-p-methoxyphenyl-N,N-ethyl dibenzyl-tyrosine and synthesizing method
  • O-p-methoxyphenyl-N,N-ethyl dibenzyl-tyrosine and synthesizing method

Examples

Experimental program
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Effect test

Embodiment 1

[0051] At room temperature, p-bromoanisole (13mmol, 2.43g), N,N-dibenzyltyrosine ethyl ester (10mmol, 4.21g), potassium phosphate (13mmol, 2.75g), N,N-dimethyl Glycine hydrochloride (3.5mmol, 0.49g) and copper sulfate pentahydrate (2mmol, 0.49g) were placed in a 100mL three-necked flask filled with N,N-dimethylformamide (50mL). The suspension of the above mixture was heated and stirred at 100°C for 8 hours. After the reaction was completed and the reaction liquid was cooled to room temperature, it was filtered, an appropriate amount of water was added to the filtrate and extracted with ether, the filter cake was washed with an appropriate amount of ether, and the combined organic liquid was washed with water for 2 to 3 times and then dried overnight with anhydrous sodium sulfate. The desiccant was filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator to obtain a crude product. Chromatographic separation was carried out on silica gel column ...

Embodiment 2

[0053] At room temperature, p-bromoanisole (13mmol, 2.43g), N,N-dibenzyltyrosine ethyl ester (10mmol, 4.21g), potassium phosphate (13mmol, 2.75g), N,N-dimethyl Glycine hydrochloride (3.5mmol, 0.49g) and copper acetate monohydrate (2mmol, 0.40g) were placed in a 100mL three-necked flask filled with N,N-dimethylformamide (50mL). The suspension of the above mixture was heated and stirred at 100°C for 8 hours. The post-processing operation was the same as in Example 1 to obtain a light yellow transparent viscous liquid product. The yield was 48.5%, e.e% was 92.7%.

Embodiment 3

[0055] At room temperature, p-bromoanisole (13mmol, 2.43g), N,N-dibenzyltyrosine ethyl ester (10mmol, 4.21g), potassium phosphate (13mmol, 2.75g), N,N-dimethyl Glycine hydrochloride (3.5mmol, 0.49g) and copper sulfate pentahydrate (2mmol, 0.49g) were placed in a 100mL three-necked flask filled with N-methylpyrrolidone (50mL). The suspension of the above mixture was heated and stirred at 100°C for 8 hours. The post-processing operation was the same as in Example 1 to obtain a light yellow transparent viscous liquid product. The yield was 56.1%, e.e% was 90.2%.

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Abstract

The invention discloses an O-p-methoxyphenyl-N,N-ethyl dibenzyl-tyrosine and a synthesizing method. N,N-ethyl dibenzyl-tyrosine and para-bromoanisole are taken as raw materials; under the catalysis of blue vitriod or monohydrate cupric acetate, potassium phosphate is used as alkali, N,N-dimethylglycine hydrochloride is used as a ligand, and coupled reaction is carried out in N,N-dimethylformamide or N-methylpyrrolidone solution at 100 DEG C to obtain the O-p-methoxyphenyl-N,N-ethyl dibenzyl-tyrosine with middling yield and excellent optical purity. In the method, a cuprous salt with poor stability to air and high price is not used as a catalyst, but the potassium phosphate with low price is used as an acid-binding agent, the cheap para-bromoanisole is used as a coupling component, and inert gases for protection and a solvent for purification are not needed during reaction. The preparation method has simple and convenient operation, less equipment requirements, low reaction cost, short process flow and favorable industrialized application prospect and can be developed and used for producing dextrothyroxine sodium.

Description

technical field [0001] The present invention relates to organic synthesis and pharmaceutical intermediate preparation method, especially relate to organic synthesis and pharmaceutical intermediate preparation O-p-methoxyphenyl-N, N-dibenzyl tyrosine ethyl ester and synthetic method, the obtained compound can be further Developed for the synthesis of L-levothyroxine sodium. Background technique [0002] L-Levothyroxine sodium (L-Thyroxine, L-T 4 , the structural formula is shown in the figure below) is a specific drug for the treatment of various thyroid diseases, which was jointly developed by Sando and MOVA Pharmaceuticals, a subsidiary of Novartis, and was approved by the US FDA in June 2004. Thyroid disease, thyroid dysfunction syndrome, hyperthyroidism, hypothyroidism, thyroiditis and thyroid cancer. L-T 4 It can be metabolized into the homologous synthetic hormone L-T of thyroid in the body 3 , so long-term use will not produce serious side effects, is the first cho...

Claims

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Application Information

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IPC IPC(8): C07C229/36C07C227/16B01J31/04B01J27/055
Inventor 夏敏华允宇韩益丰
Owner ZHEJIANG SCI-TECH UNIV
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