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A kind of synthetic method of (r)-4-aminophenethyl-(2-hydroxyl-2-phenethyl)-tert-butyl carbamate

A technology of aminophenethyl and carbamic acid, which is applied in the synthesis of -4-aminophenethyl-tert-butyl carbamate and the synthesis of pharmaceutical intermediates, which can solve skin irritation and sensitization, post-treatment The steps are cumbersome, the operator is unfavorable, etc., to achieve the effect of less environmental pollution, simple and easy handling, and high operational safety

Active Publication Date: 2015-08-19
SUZHOU UUGENE BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] 1) The toxic S-styrene oxide reagent is used in the synthesis method, which has an inhibitory effect on the central nervous system, stimulates and sensitizes the skin, and has positive results in various mutagenic tests, which is unfavorable to operators
[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 large amount of three wastes, and the product yield is low.

Method used

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  • A kind of synthetic method of (r)-4-aminophenethyl-(2-hydroxyl-2-phenethyl)-tert-butyl carbamate
  • A kind of synthetic method of (r)-4-aminophenethyl-(2-hydroxyl-2-phenethyl)-tert-butyl carbamate
  • A kind of synthetic method of (r)-4-aminophenethyl-(2-hydroxyl-2-phenethyl)-tert-butyl carbamate

Examples

Experimental program
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Effect test

Embodiment 1

[0048] 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.

[0049] 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 solut...

Embodiment 2

[0053] 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.

[0054] 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

[0058] 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.

[0059] 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 (R)-4-amino phenethyl-(2-hydroxy-2-phenylethyl)-tert-butyl carbamate synthesis method, and belongs to the technical field of drug synthesis. With the present invention, problems of low product yield, complex treatment steps, heavy environment pollution and the like of the synthesis method in the prior art are solved. The synthesis method comprises the following steps that: hydroxyl on p-nitrophenylethanol is oxidized into aldehyde to obtain p-nitrophenylacetaldehyde; amino on (R)-2-amino-1-phenylethanol and the aldehyde on the p-nitrophenylacetaldehyde are subjected to dehydration condensation reduction to obtain (R)-2-p-nitrophenylethylamine-1-phenylethanol; (Boc)2O is adopted to replace amino on the (R)-2-p-nitrophenylethylamine-1-phenylethanol; and nitro on (R)-4-nitro phenethyl-(2-hydroxy-2-phenylethyl)-tert-butyl carbamate is reduced into amino so as to obtain the final product. The synthesis method has characteristics of low production cost, high product yield, and low environmental pollution.

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-aminophenethyl-(2-hydroxyl-2-phenethyl)-tert-butyl carbamate, belonging to pharmaceutical The field of synthetic technology. 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 during the bladder filling-voiding cycle, thereby promoting the increase of bladder capacity, so mirabegron is used to treat patients with urge incontinence, urgency, and frequent urination Symptoms 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 Patents(China)
IPC IPC(8): C07C271/20C07C269/06
Inventor 胡凡王伸勇贾新赞王晓俊胡长春
Owner SUZHOU UUGENE BIOPHARMA
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