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Preparation method of nevirapine intermediate

A picoline and amino technology is applied in the preparation of nevirapine intermediate 2-chloro-3-amino-4-picoline, and in the field of nevirapine intermediate preparation, and can solve the problems of long reaction route, low yield and the like, Achieve the effect of low Pd loading, high raw material conversion rate and lower production cost

Pending Publication Date: 2022-08-02
NANJING REDSUN BIOCHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In addition, the preparation methods of 2-chloro-3-amino-4-picoline mentioned in patents WO0043364A1, WO0043365A1, and US2002052507A1 also have problems such as long reaction routes and low yields

Method used

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  • Preparation method of nevirapine intermediate
  • Preparation method of nevirapine intermediate
  • Preparation method of nevirapine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] 0.5%Pd-1.5%Ru-25%Ni / SiO 2 Catalyst, the preparation method is as follows:

[0038] Step (1), SiO 2 Pretreatment: SiO 2 Roasted at 500℃ for 6h, cooled to room temperature, ground, and sieved to obtain SiO with a size of 100-150 mesh 2 ,spare;

[0039] Step (2), add 100g deionized water and 10g pretreated SiO to the reactor 2 , stirred, heated to 80 °C, took 50 mL of Pd 2+ PdCl at a concentration of 1g / L 2 Aqueous solution, 100mL Ru 3+ RuCl with a concentration of 1.5g / L 3 Aqueous solution, 100mL Ni 2+ Ni(NO) with a concentration of 25g / L 3 ) 2 ·6H 2O aqueous solution, add the three solutions dropwise at the same time and control the drop rate respectively, complete the dropwise addition within 2 hours at the same time, keep the temperature at 60 °C, continue stirring for 4 hours, then add dropwise NaOH solution to adjust the pH to 8-9, continue stirring for 4 hours, filter, The filter cake was washed with deionized water until the filtrate was neutral, dried ...

Embodiment 2

[0041] Under ice bath condition (0~5 ℃), add 2,6-dichloro-4-methylpyridine 16.5g (purity 98.0%, 0.1mol) and concentrated sulfuric acid (mass fraction 98%) 66g into the four-necked flask, Stir for 30min, then slowly add concentrated nitric acid 11.8g (mass fraction 80%, 0.15mol) dropwise, control the drop rate, maintain the temperature not more than 10 ℃, after the dropwise addition, continue to maintain the temperature not more than 10 ℃, stir for 30min, heat up to 60 ℃, the reaction is kept warm and the reaction is controlled in the middle until the reaction of the raw materials is completed. The reaction solution was lowered to normal temperature, slowly added to 150 g of ice water, fully stirred, filtered, the filter cake was washed with water, and dried in vacuum at 40 °C to obtain 2,6-dichloro-3-nitro-4-methylpyridine 20.2 g (purity 95.1%), yield 93.0%.

[0042] 20.2 g of 2,6-dichloro-3-nitro-4-methylpyridine (purity 95.1%, 0.093 mol), 100 g of absolute ethanol and 10.2 ...

Embodiment 3

[0044] 20.2 g of 2,6-dichloro-3-nitro-4-methylpyridine (purity 95.1%, 0.093 mol), 100 g of tetrahydrofuran, and 8.0 g of pyridine (purity 99%, 0.1 mol) were mixed to prepare 2,6- Dichloro-3-nitro-4-methylpyridine was dissolved in tetrahydrofuran, placed in a 250mL autoclave, and 2g of the catalyst (0.5%Pd-1.5%Ru-25%Ni / SiO) prepared in Example 1 was added 2 ), filled with nitrogen and replaced three times, charged to 3MPa, heated to 80°C for the reaction, continuously added hydrogen during the reaction, maintained the hydrogen pressure at 2.5-3.2MPa, kept the reaction at 80°C for 10h, and the reaction was completed; cooled down, released the pressure, filtered out Catalyst, filtrate sampling, HPLC quantitative analysis, the conversion rate of 2,6-dichloro-3-nitro-4-methylpyridine was calculated to be 94.4%, the selection of 2-chloro-3-amino-4-methylpyridine Sex is 90.8%.

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Abstract

The invention discloses a preparation method of nevirapine, which comprises the following steps: by taking 2, 6-dichloro-4-methylpyridine as a raw material, carrying out nitration reaction in a mixed acid consisting of concentrated sulfuric acid and nitric acid to obtain 2, 6-dichloro-3-nitro-4-methylpyridine; according to the method, 2, 6-dichloro-3-nitro-4-methylpyridine is used as a raw material, an organic solvent is used as a reaction solvent, and 2, 6-dichloro-3-nitro-4-methylpyridine is subjected to one-pot selective hydrodechlorination and nitro reduction in the presence of an acid-binding agent under the action of a Pd-Ru-Ni / SiO2 catalyst to obtain 2-chloro-3-amino-4-methylpyridine. According to the invention, the SiO2-loaded Pd-Ru-Ni multi-metal catalyst is adopted, so that the inactivation of the catalyst under a chlorine condition can be well avoided, and meanwhile, the method has the characteristics of selective dechlorination and nitro reduction; the catalyst is used for catalyzing 2, 6-dichloro-3-nitro-4-methylpyridine to prepare 2-chloro-3-amino-4-methylpyridine, the raw material conversion rate is high, and the product selectivity is good.

Description

technical field [0001] The invention belongs to the field of organic synthesis and relates to a preparation method of a nevirapine intermediate, in particular to a preparation method of a nevirapine intermediate 2-chloro-3-amino-4-methylpyridine. Background technique [0002] Nevirapine was developed by Berlinger Ingelheim, Germany, and was listed in the United States in 1996. It is a non-nucleoside reverse transcriptase inhibitor and is an anti-AIDS drug that can effectively inhibit human immunodeficiency virus (HIV-1). Compared with other anti-AIDS drugs, nevirapine has strong antiviral effect, long half-life, high bioavailability, good tolerance, few adverse reactions and low cost. [0003] 2-Chloro-3-amino-4-methylpyridine is the key intermediate of nevirapine, and its preparation method mainly includes the following: [0004] Method 1. Patents US5200522A, US5668287A, and US5686618A disclose: a method for synthesizing 2-chloro-3-amino-4-picoline using ethyl acetoacetate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/73B01J23/89
CPCC07D213/73B01J23/892
Inventor 岳瑞宽陈洪龙丁永山罗超然王文魁
Owner NANJING REDSUN BIOCHEM CO LTD
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