Synthesizing method of (R)-4-nitrophenethyl-(2-hydroxy-2-phenylethyl)-tert-butyl carbamate

A technology of nitrophenethyl and nitrophenethylamine is applied in the field of pharmaceutical synthesis, can solve the problems of complicated post-processing steps, high production cost, low product yield and the like, and achieves simple and easy processing, low cost, high purity effect

Active Publication Date: 2013-08-07
SUZHOU UUGENE BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] 2) The expensive S-styrene oxide reagent is used in this synthesis method, and column chromatography is required for separation after the reaction, resulting in high production cost
[0010] 3) After the reaction is completed, the reaction solution needs to be separated by column chromatography twice to obtain the pure product. The post-processing steps are cumbersome and will produce a lot of waste, and the product yield is low, only 22%.

Method used

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  • Synthesizing method of (R)-4-nitrophenethyl-(2-hydroxy-2-phenylethyl)-tert-butyl carbamate
  • Synthesizing method of (R)-4-nitrophenethyl-(2-hydroxy-2-phenylethyl)-tert-butyl carbamate
  • Synthesizing method of (R)-4-nitrophenethyl-(2-hydroxy-2-phenylethyl)-tert-butyl carbamate

Examples

Experimental program
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Effect test

Embodiment 1

[0042] Under the protection of nitrogen, 1.67g of p-nitrophenylethanol and 7g of o-iodobenzoic acid were successively dissolved in 50mL of ethyl acetate to form a reaction solution, and the reaction solution was refluxed and stirred for 1 hour until the reaction was detected by TLC. The complete reaction solution was lowered to room temperature, and the filtrate and filter cake were obtained by suction filtration. The filter cake was washed twice with 20 mL of ethyl acetate to obtain p-nitrophenylacetaldehyde, and the filtrates were combined and concentrated for further use.

[0043]At 0°C, under the protection of nitrogen, add 1.37g (R)-2-amino-1-phenylethanol into a 100mL three-necked flask, and then drop 50mL of dichloromethane dissolved in the crude p-nitrophenylacetaldehyde Add it to a three-necked flask to form a reaction solution. Under the protection of nitrogen, the stirring was continued for 1 hour, and 0.76 g of sodium borohydride was added into the reaction soluti...

Embodiment 2

[0046] Under the protection of nitrogen, 3.34g of p-nitrophenylethanol and 10.1g of potassium permanganate were sequentially dissolved in 100mL of 1,4-dioxane to form a reaction solution, and the reaction solution was refluxed and stirred for 3 hours until the reaction was detected by TLC. The complete reaction solution was lowered to room temperature, and the filtrate and filter cake were obtained by suction filtration. The filter cake was washed twice with 40 mL of 1,4-dioxane to obtain p-nitrophenylacetaldehyde, and the filtrates were combined, concentrated and used mechanically.

[0047] At 0°C, under the protection of nitrogen, 2.7g (R)-2-amino-1-phenylethanol was added to a 250mL three-necked flask, and then 100mL tetrahydrofuran dissolved in the crude p-nitrophenylacetaldehyde was added dropwise to A reaction solution was formed in a three-necked flask. Under the protection of nitrogen, the stirring was continued for 2 hours, and 2.3 g of metallic nickel was added into...

Embodiment 3

[0050] Under the protection of nitrogen, 2.5g of p-nitrophenylethanol and 3.1g of manganese dioxide were successively dissolved in 80mL of 1,2 dichloroethane to form a reaction solution, and the reaction solution was refluxed and stirred for 2 hours until the reaction was detected by TLC. The complete reaction solution was lowered to room temperature, and the filtrate and filter cake were obtained by suction filtration. The filter cake was washed twice with 30 mL of 1,2 dichloroethane to obtain p-nitrophenylacetaldehyde, and the filtrates were combined and concentrated for further use.

[0051] At 0°C, under the protection of nitrogen, 2.05g (R)-2-amino-1-phenylethanol was added to a 250mL three-necked flask, and then 80mL of tetrahydrofuran dissolved in the crude p-nitrophenylacetaldehyde was added dropwise to A reaction solution was formed in a three-necked flask. Under the protection of nitrogen, the stirring was continued for 2 hours, and 1.03 g of sodium borohydride was ...

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Abstract

The invention provides a synthesizing method of (R)-4-nitrophenethyl-(2-hydroxy-2-phenylethyl)-tert-butyl carbamate, and belongs to the technical field of medicine synthesis. The method assists in solving problems of low product yield, requirement on column chromatographic separation, and unsuitability for large-scale industrial productions of (R)-4-nitrophenethyl-(2-hydroxy-2-phenylethyl)-tert-butyl carbamate synthesizing methods in prior art. The method comprises the steps that: (1) hydroxyl group on p-aminophenylethanol is oxidized into aldehyde group, such that nitrobenzene acetaldehyde is obtained; (2) (R)-2-amino-1-phenylethanol is subjected to reductive amination, such that (R)-2-p-nitrobenzene ethylamine-1-phenylethanol is obtained; and (3) (Boc)2O is used for substituting the amino group on (R)-2-p-nitrobenzene ethylamine-1-phenylethanol, such that the final product is obtained. With the method, production cost is low, and finished product yield is high. The method is suitable for large-scale industrial productions.

Description

technical field [0001] The present invention relates to a synthetic method of a pharmaceutical intermediate, in particular to a synthetic method of (R)-4-nitrophenethyl-(2-hydroxyl-2-phenethyl)-tert-butyl carbamate, belonging to Pharmaceutical synthesis technology field. Background technique [0002] Statistics show that there are a large number of people suffering from overactive bladder, for example, there are about 33 million people in the United States. The use of mirabegron can relax the detrusor smooth muscle in the storage of bladder filling-voiding cycle, thereby promoting the increase of bladder capacity, so mirabegron is used to treat symptoms of urgency urinary incontinence, urgency, and frequent urination of overactive bladder. In addition, with the improvement of people's social and economic life, diabetes has gradually become a common endocrine and metabolic disease that plagues people. Studies have found that amide derivatives have a better effect of promot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/14C07C269/04
Inventor 胡凡王伸勇贾新赞王晓俊胡隽恺
Owner SUZHOU UUGENE BIOPHARMA
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