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Synthetic method for 5-azaspiro[2.4]heptane-6-formic acid derivative

A synthesis method and azaspiro technology are applied in the field of medicine and chemical industry, which can solve the problems of harsh reaction conditions, long route and high cost, and achieve the effects of low reaction cost, simple operation and safe reagents.

Active Publication Date: 2015-07-22
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The reaction raw materials of this method are not easy to obtain, and the reaction conditions are harsh, the route is long, the cost is high, it is not easy to scale up, and it is not suitable for industrial production

Method used

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  • Synthetic method for 5-azaspiro[2.4]heptane-6-formic acid derivative
  • Synthetic method for 5-azaspiro[2.4]heptane-6-formic acid derivative
  • Synthetic method for 5-azaspiro[2.4]heptane-6-formic acid derivative

Examples

Experimental program
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Effect test

example 1

[0040] Example 1: Preparation of 1,1-cyclopropane dimethanol sulfinate

[0041]

[0042] 1,1-Cyclopropanedimethanol (102g, 1.0mol) was dissolved in dichloromethane, triethylamine (303g, 3.0mol) was added, cooled to 0°C, thionyl chloride (238g, 2.0mol) was added dropwise, React at 0°C to room temperature for 6-8 hours. The reaction was quenched by adding saturated ammonium chloride solution, the liquid was separated, the organic phase was concentrated and the solvent was removed, and a small amount of petroleum ether was beaten to obtain 137.4 g of a yellow solid product, 1,1-cyclopropanedimethanol sulfinate, with a molar yield of 93%.

[0043] 1 HNMR (400MHz, CDCl3) δ (ppm): 5.25 (d, J = 11.2Hz, 2H). 3.04 (d, J = 11.7Hz, 2H), 0.86 (dd, J = 8.0, 6.8Hz, 2H), 0.48 (dd,J=4.8,6.6Hz,2H).

[0044] EI(m / z):148.

example 2

[0045] Example 2: Preparation of 1,1-cyclopropane dimethanol sulfonate

[0046]

[0047] 1,1-cyclopropanedimethanol sulfinate (133g, 0.9mol) was dissolved in acetonitrile and water, added 2,2,6,6-tetramethylpiperidine oxide TEMPO (2.81g, 18mmol), cooled to At 0°C, add sodium hypochlorite solution dropwise, and react from 0°C to room temperature for 3-4 hours. Sodium thiosulfate solution was added to quench the reaction, most of the acetonitrile was spun off, ethyl acetate was added for separation, the organic phase was concentrated and most of the solvent was spun off, and petroleum ether was added for beating to obtain 136 g of white solid product with a molar yield of 92%.

[0048] 1 HNMR (400MHz, CDCl3) δ (ppm): 4.44 (s, 4H), 0.87 (s, 4H). EI (m / z): 164.

Embodiment 3

[0049] Example 3: Preparation of 1,1-cyclopropane dimethanol sulfonate

[0050] According to the operation steps of Example 2, the organic solvent acetonitrile is replaced by dichloromethane, ethyl acetate or isopropyl acetate, and the catalyst 2,2,6,6-tetramethylpiperidine oxide is replaced by iron trichloride or three Ruthenium chloride is replaced, and the oxidant sodium hypochlorite is replaced by sodium chlorite, sodium periodate or potassium iodate, and 1,1-cyclopropane dimethanol sulfonate can also be prepared.

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Abstract

The invention provides a synthetic method for a 5-azaspiro[2.4]heptane-6-formic acid derivative. The synthetic method comprises the following steps: taking 1,1-cyclopropane dimethanol as a starting material, reacting with dichlorosulfoxide, performing oxidization to obtain a sulfonate compound, condensing the sulfonate compound and imine prepared from glycine methyl ester in the presence of potassium tert-butoxide, finishing hydrolysis, cyclization and amino protection with a one-pot procedure by adjusting the acidity and alkalinity of a system to obtain a racemization product, and finally performing resolution to obtain a finished product; the total yield reaches more than 30%; a reaction route has short steps; a used reagent is safe; the method is simple to operate, low in reaction cost, relatively high in yield and suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthesis method of 5-azaspiro[2.4]heptane-6-carboxylic acid derivative, an intermediate of hepatitis C virus NS5A inhibitor. Background technique [0002] Hepatitis C virus infection seriously endangers human health and is one of the main causes of post-transfusion hepatitis. At present, the infection rate of hepatitis C in the world is 3%. From this, it is estimated that about 170 million to 200 million people are infected with hepatitis C virus (HCV), and about 3.5 million people are newly infected every year. Nonstructural 5A protein (NS5A) is a new target for the treatment of hepatitis C virus infection. Although NS5A protein does not have enzymatic activity, it plays an important role in viral RNA replication. Small molecule inhibitors of NS5A protein have shown strong The activity of inhibiting virus growth in vitro, and clinical evaluation also...

Claims

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Application Information

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IPC IPC(8): C07D209/54
CPCC07D209/54
Inventor 郑旭春张一平付晨晨
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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