Synthesis method for N-Methyl-o-Phenylenediamine (salt) and isomeride thereof

A technology of methyl-o-phenylenediamine and isomers, which is applied in the field of telmisartan intermediates of sartans for treating hypertension, can solve the problem of increasing the production cost of the intermediates and the expensive price of o-nitrochlorobenzene , product quality is difficult to guarantee and other problems, to achieve the effect of simple reaction, strong selectivity and high yield

Inactive Publication Date: 2012-07-11
YICHANG HEC CHANGJIANG PHARMA CO LTD
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  • Summary
  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0006] ①Using o-phenylenediamine as raw material and methyl iodide as methylating reagent for methylation reaction, N, N'-dimethyl-o-phenylenediamine is easily produced in this process, and the product quality is difficult to guarantee;
[0007] ② The raw material o-phenylenediamine is a highly carcinogenic compo

Method used

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  • Synthesis method for N-Methyl-o-Phenylenediamine (salt) and isomeride thereof
  • Synthesis method for N-Methyl-o-Phenylenediamine (salt) and isomeride thereof
  • Synthesis method for N-Methyl-o-Phenylenediamine (salt) and isomeride thereof

Examples

Experimental program
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Embodiment I

[0038] 1. Synthesis of N-methyl o-nitroaniline

[0039] Mix 40.0g, 0.29mol of o-nitroaniline with 200ml of acetone, then add 32g, 0.57mol of KOH, dropwise add 46g, 0.37mol of methylating reagent dimethyl sulfate, after monitoring the point of no raw material by TLC, add 20.0ml of ammonia water, and Press the acetone back to dryness, then add 200.0ml of water, stir and crystallize, separate by filtration, and dry to obtain 42.0g of N-methyl-o-nitroaniline, with a yield of 95.3%. Purity >99%.

[0040] 2. Synthesis of N-methyl o-phenylenediamine

[0041] Mix 20.0g, 0.13mol of N-methyl o-nitroaniline with 100ml of methanol, then add 0.05g of 10% Pd / C into the hydrogenation reactor, and feed hydrogen at 30-35°C under 0.2-0.5MPa about 3 hours. After filtration, 17.8 g of thionyl chloride, 0.15 mol, was added dropwise to the filtrate, and the temperature was lowered for filtration to obtain 25 g of N-methyl o-phenylenediamine dihydrochloride, with a yield of 98.4%.

Embodiment II

[0043] 1. Synthesis of N-methyl o-nitroaniline

[0044] Mix 40.0g, 0.29mol of o-nitroaniline and 200ml of N,N-dimethylformamide, then add 22.8g, 0.57mol of NaOH, dropwise add 52.5g, 0.37mol of methyl iodide reagent, and monitor by TLC After there is no raw material point, add 200.0 ml of water, stir and crystallize, filter and separate, and dry to obtain 42.0 g of N-methyl-o-nitroaniline, with a yield of 95.3%. Purity >99%.

[0045] 2. Synthesis of N-methyl o-phenylenediamine

[0046] Add 100ml of ethanol, 5ml of glacial acetic acid, 21.8g of reduced iron powder, 0.39mol into a 500ml reaction bottle, stir and activate at 50-55°C for 30 minutes, then add 20.0g of N-methyl o-nitroaniline, 0.13mol and heat up to reflux reaction about 2 hours. Filtrate while hot, add thionyl chloride 17.8g, 0.15mol dropwise to the filtrate, cool down and filter to obtain 22.8g of N-methyl o-phenylenediamine dihydrochloride, yield 90.0%.

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Abstract

The invention discloses a synthesis method for a telmisartan intermediate, N-Methyl-o-phenylenediamine (salt), and isomeride thereof. According to the synthesis method, o (m or p)-nitroaniline is subjected to methylation under the action of a methylation reagent and a catalyst so as to obtain N-Methyl-o (m or p)-nitroaniline; and then under the action of a reducing agent, the N-Methyl-o (m or p)-nitroaniline is used to prepare the N-Methyl-o (m or p)-phenylenediamine. According to the synthesis method, the o (m or p)-nitroaniline is adopted as an initial material and is cheap and easy to get, the selectivity of actions of the methylation reagent is strong, and by-product of N, N-dimethyl is avoided. The reaction in the two steps are all subjected to conventional unit operation, the reaction is simple and convenient, and the yield and quality are high, so that the synthesis method is applicable to mass industrial production.

Description

technical field [0001] The invention relates to a new preparation route of an intermediate of sartan medicine telmisartan for treating hypertension, in particular to a synthesis method of N-methyl o-phenylenediamine and a salt thereof. Background technique [0002] N-methyl o-phenylenediamine and its salts are key intermediates for the synthesis of Telmisartan. The existing production processes mainly include: [0003] 1. Using o-phenylenediamine as the starting material, methyl iodide as the methylating reagent, heating and refluxing in methanol to prepare the target product, [0004] [0005] There are following defects in this process: [0006] ①Using o-phenylenediamine as raw material and methyl iodide as methylating reagent for methylation reaction, N, N'-dimethyl-o-phenylenediamine is easily produced in this process, and the product quality is difficult to guarantee; [0007] ② The raw material o-phenylenediamine is a highly carcinogenic compound, and there is a ...

Claims

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Application Information

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IPC IPC(8): C07C211/51C07C209/36
Inventor 查高峰唐金龙何安张俊山
Owner YICHANG HEC CHANGJIANG PHARMA CO LTD
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