Preparation method for nevirapine intermediate

A kind of methyl pyridine and amino technology, applied in the field of compound preparation, can solve the problems such as shortening synthesis steps, waste acid unfavorable environmental protection, etc., to achieve the effect of high yield

Inactive Publication Date: 2016-12-21
HUNAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0042] This preparation method improves Gupton's process route, replaces malononitrile with cyanoacetamide, shortens the synthesis steps, and reduces some costs, but the waste acid produced is not conducive to environmental protection

Method used

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  • Preparation method for nevirapine intermediate
  • Preparation method for nevirapine intermediate
  • Preparation method for nevirapine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Preparation of 3-bromo-4-methylpyridine

[0069] Add 0.054mol 4-methylpyridine to a 60mL constant pressure dropping funnel; under nitrogen protection and stirring at room temperature, slowly add dropwise to 0.07mol AlCl 3 and 0.01mol potassium bromide, after dropping, continue to stir for 1h; use a condensing device, raise the temperature to 120°C, add 0.07mol bromine dropwise, and dropwise add 0.07mol bromine for about 1h; keep stirring for 26h; the reaction liquid is cooled to At room temperature, the reaction solution was poured into crushed ice under stirring; sodium hydroxide was added, stirred and dissolved; the aqueous layer was extracted with dichloromethane, the organic layers were combined, and the solvent was recovered by rotary evaporation; the obtained oil was subjected to column chromatography (V 石油醚 :V 乙酸乙酯 =6:1) 5.3 g of 3-bromo-4-picoline was obtained as a brownish yellow oil with a purity of 99.9% and a yield of 57%. 1 H NMR (400MHz, CDCl 3 )δ: 2.31...

Embodiment 2

[0071] Preparation of 3-amino-4-picoline

[0072] Prepare 3-amino-4-picoline according to the method described in Example 2 of Chinese patent [CN100999491]: add 300mL methanol, 150g3-bromo-4-picoline, 5g copper sulfate, and feed ammonia into the autoclave When the pressure reaches 5atm, heat to 160°C, react for 8h, cool, filter with suction, and concentrate the filtrate under reduced pressure to obtain a solid that is recrystallized with ethyl acetate to obtain 89g of 3-amino-4-picoline with a yield of 95%.

Embodiment 3

[0074] Preparation of 3-amino-4-picoline

[0075] Prepare 3-amino-4-methylpyridine according to the method described in Example 3 of Chinese patent [CN100999491]: add 500mL concentrated ammonia water, 150g 3-bromo-4-methylpyridine, 5g copper sulfate in the autoclave, and Heated to 180°C, reacted for 8 hours, cooled, extracted three times with 500 mL of dichloromethane, and concentrated under reduced pressure to obtain 84 g of 3-amino-4-picoline with a yield of 90%.

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Abstract

The invention relates to a preparation method for an intermediate, i.e., 2-chloro-3-amino-4-methylpyridine, of an anti-AIDs drug nevirapine. The intermediate has a chemical structural formula I as described in the specification. The preparation method is characterized in that 4-methylpyridine is subjected to halogenation, ammonia substitution and chlorination so as to prepare 2-chloro-3-amino-4-methylpyridine. The preparation reactions are as shown in the specifications, wherein X is bromine or chlorine; a halogenation condition is Br2 / AlCl3 / 95-105 DEG C, Br2 / AlCl3 / MBr / 110 to 130 DEG C (wherein M is Li, Na or K), Br2 / Fe / 135-145 DEG C, Cl2 / AlCl3, Br2 / FeCl3 or Br2 / SnCl4; an ammonia substitution condition is NH3(g) / CuSO4 / CH3OH / 170-190 DEG C, NH3(aq) / CuSO4 / 170-190 DEG C, or NaNH2; and a chlorination reaction condition is Cl2 / AlCl3 or HCl / H2O2 / 30-50 DEG C.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of 3-bromo-4-picoline, an intermediate of anti-AIDS drug nevirapine. Background technique [0002] Nevirapine is mainly used to prevent mother-to-child viral transmission and is currently one of the most widely used anti-AIDS drugs. Nevirapine can effectively inhibit the activity of HIV reverse transcriptase, effectively reduce the amount of virus in the body, and restore the immune function of the human body. Compared with other anti-AIDS drugs, nevirapine has strong antiviral effect, less side effects, high bioavailability and low cost. The molecular formula of nevirapine is C 15 h 14 ON 4 , chemical name: 4-methyl-5,11-dihydro-11-cyclopropylhexahydrobispyrido[1,4]diazepine-6-one, is a white powdery solid. The structural formula is as follows: [0003] [0004] In 1991, Hargrave et al [J Med Chem, 1991,34 (7), 2231-2241] described the synthetic...

Claims

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Application Information

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IPC IPC(8): C07D213/73C07D213/61
CPCC07D213/73C07D213/61
Inventor 胡艾希陈爱羽顾宇鹏聂剑霞叶姣
Owner HUNAN UNIV
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