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Method for synthesizing optically active intermediate N-tert-butoxycarbonyl-2-amino-8-nonenoic dicyclohexylamine salt

A technology of nonenoic acid dicyclohexylamine salt and tert-butoxycarbonyl, which is applied in the field of medicine, can solve the problems of expensive raw materials, cumbersome purification, and high cost, and achieve the effects of mild reaction conditions, short synthetic routes, and good product quality

Active Publication Date: 2016-06-29
南通药享科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] 4. Azidation: The reaction uses strong bases such as butyl lithium and KHDMS, which have relatively high requirements on the operating environment (strictly anhydrous, ultra-low temperature, etc.), and are not suitable for scale-up production
[0020] (1) The route for synthesizing N-tert-butoxycarbonyl-2-amino-8-nonenoic acid dicyclohexylamine salt is long, the purification is cumbersome, and the conditions of the synthesis process are harsh;
[0021] (2) The required raw materials for the synthesis of N-tert-butoxycarbonyl-2-amino-8-nonenoic acid dicyclohexylamine salt are expensive and the cost is high;
[0022] (3) the yield of gained product is low, is unfavorable for industrialized large-scale production

Method used

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  • Method for synthesizing optically active intermediate N-tert-butoxycarbonyl-2-amino-8-nonenoic dicyclohexylamine salt
  • Method for synthesizing optically active intermediate N-tert-butoxycarbonyl-2-amino-8-nonenoic dicyclohexylamine salt
  • Method for synthesizing optically active intermediate N-tert-butoxycarbonyl-2-amino-8-nonenoic dicyclohexylamine salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1: a kind of synthetic method of optically active intermediate N-tert-butoxycarbonyl-2-amino-8-nonenoic acid dicyclohexylamine salt, specifically comprises the following steps:

[0051] S1. generate intermediate IV, which comprises the following substeps:

[0052] S11. Alkylation: Add methyl acetamidomalonate and 7-bromo-1-heptene to tetrahydrofuran, then add sodium iodide and sodium hydroxide to react at 0°C to obtain an alkylated product The molar mass ratio of methyl acetamidomalonate, 7-bromo-1-heptene and sodium iodide is 1:0.8:0.1; the molar mass ratio of methyl acetamidomalonate and sodium hydroxide is 1: 1;

[0053] S12. Hydrolyzing the alkylation product: performing a hydrolysis reaction on the alkylation product obtained in step S11 in a sodium hydroxide solution with a pH value of 12 at 0°C;

[0054] S13. Decarboxylation: add a hydrochloric acid solution with a pH value of 3 to the hydrolyzed solution, and perform a decarboxylation reaction at a ...

Embodiment 2

[0058] Embodiment 2: a kind of synthetic method of optically active intermediate N-tert-butoxycarbonyl-2-amino-8-nonenoic acid dicyclohexylamine salt, specifically comprises the following steps:

[0059] S1. generate intermediate IV, which comprises the following substeps:

[0060] S11. Alkylation: Add ethyl acetamidomalonate and 7-chloro-1-heptene to N,N-dimethylformamide and N,N-dimethylacetamide solvent, then add potassium iodide in Under the alkaline condition of 150 ℃, react to obtain the alkylation product; the alkali is potassium hydroxide and potassium carbonate; the molar mass ratio of ethyl acetamidomalonate, 7-chloro-1-heptene and potassium iodide is 1:2:0.5; the molar mass ratio of ethyl acetamidomalonate to base is 1:4;

[0061] S12. Hydrolyzing the alkylation product: performing a hydrolysis reaction on the alkylation product obtained in step S11 in a sodium hydroxide solution with a pH value of 10 at 100°C;

[0062] S13. Decarboxylation: add a sulfuric acid so...

Embodiment 3

[0066] Embodiment 3: a kind of synthetic method of optically active intermediate N-tert-butoxycarbonyl-2-amino-8-nonenoic acid dicyclohexylamine salt, specifically comprises the following steps:

[0067] S1. generate intermediate IV, which comprises the following substeps:

[0068] S11. Alkylation: Add tert-butyl acetamidomalonate and 7-iodo-1-heptene to toluene and water, then add tetrabutylammonium bromide to react under alkaline conditions at 75°C to obtain alkanes Alkylation product; Described alkali is cesium carbonate, sodium hydride and sodium methylate; The molar mass ratio of tert-butyl acetamidomalonate, 7-iodo-1-heptene and tetrabutylammonium bromide is 1:1: 0.4; The molar mass ratio of tert-butyl acetamidomalonate to base is 1:3;

[0069] S12. Hydrolyzing the alkylation product: performing a hydrolysis reaction on the alkylation product obtained in step S11 in an acetic acid solution at 50° C.;

[0070] S13. Decarboxylation: add a phosphoric acid solution with a ...

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Abstract

The invention discloses a method for synthesizing an optically active intermediate N-tert-butoxycarbonyl-2-amino-8-nonenoic dicyclohexylamine salt. The method includes: taking acetamino malonate as an original raw material, performing alkylation reaction, hydrolysis and decarboxylation to generate an intermediate IV, subjecting the intermediate IV to tert-butoxycarbonyl protection to obtain an intermediate III, hydrolyzing the intermediate III under the action of enzymes to obtain an intermediate II, and allowing salt forming reaction between the intermediate II and dicyclohexylamine to obtain the target product. The method has the advantages of short synthetic route, easiness in purification of the synthesized product, mild reaction conditions and environment friendliness; the required raw material is cheap and low in cost; the obtained product is high in yield and quality and suitable for mass industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing an optically active intermediate N-tert-butoxycarbonyl-2-amino-8-nonenoic acid dicyclohexylamine salt. Background technique [0002] Viral hepatitis C, referred to as hepatitis C, hepatitis C, is a viral hepatitis caused by hepatitis C virus (HCV) infection, mainly through blood transfusion, acupuncture, drug abuse, etc., according to the statistics of the World Health Organization, the global The infection rate of HCV is about 3%, it is estimated that about 180 million people are infected with HCV, and there are about 35,000 new cases of hepatitis C every year. Hepatitis C is a global epidemic, which can lead to chronic inflammation, necrosis and fibrosis of the liver, and some patients can develop liver cirrhosis or even hepatocellular carcinoma. The mortality rate associated with HCV infection will continue to increase in the next 20 yea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/22C07C209/00C07C211/35
CPCC07B2200/07C07C209/00C07C231/12C07C269/00C07C269/06C07C233/47C07C271/64C07C271/22C07C211/35
Inventor 张坤张文泰徐华
Owner 南通药享科技有限公司
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