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A kind of preparation method of 4,6-dichloro-2-methyl-5-nitropyrimidine

A technology of nitropyrimidine and methylpyrimidine, which is applied in the field of pharmaceutical chemistry, can solve the problems of ecological environment pollution and the production of highly toxic substances, and achieve the effect of strong operability and short technical process

Active Publication Date: 2015-10-14
台州煜农生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is: in the prior art, in the process of producing 4,6-dichloro-2-methyl-5-nitropyrimidine, highly toxic substances are produced, which pollutes the ecological environment

Method used

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  • A kind of preparation method of 4,6-dichloro-2-methyl-5-nitropyrimidine
  • A kind of preparation method of 4,6-dichloro-2-methyl-5-nitropyrimidine

Examples

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example 1

[0025] Preparation of 4,6-Dihydroxy-2-methylpyrimidine

[0026] Add acetamidine hydrochloride (47.3 g, 0.50 mol), diethyl malonate (76.5 g, 0.52 mol) and methanol (200 ml) into a 1.0L reaction flask, and add 30% (mass fraction of solute) while stirring at room temperature Sodium methoxide-methanol solution (275.5 g, 1.53 mol), stirred and heated to reflux for 3 hours, followed by TLC. After the reaction is complete, cool, filter, wash with water and methanol, and then dissolve the filter cake in 350 ml of water. Adjust pH=2 with hydrochloric acid, white precipitate precipitates out, stand still, filter, wash with water, and dry to obtain 4,6-dihydroxy-2-methylpyrimidine (57.5g) as an off-white solid, with a yield of 91.2% (based on acetamidine hydrochloride meter),

[0027] M.p.338-345℃, 1 H NMR: (400Hz, DMSO-d 6 ), δ (ppm): 11.75 (s, 2H, -OH), 4.95 (s, 1H, CH-), 2.21 (s, 3H, CH 3 -).;

[0028] (1) Preparation of 4,6-dihydroxy-2-methyl-5-nitropyrimidine

[0029] Add the prepared 4,6...

example 2

[0035] Preparation of 4,6-Dihydroxy-2-methylpyrimidine

[0036] Add acetamidine hydrochloride (47.3 g, 0.50 mol), diethyl malonate (76.5 g, 0.52 mol) and ethanol (150 ml) into a 1.0L reaction flask, and add 20% (mass fraction of solute) while stirring at room temperature Sodium ethoxide-ethanol solution (476.0 g, 1.42 mol), stirred and heated under reflux for 4 hours, followed by TLC. After the reaction is complete, cool, filter, wash with water and methanol, then dissolve the filter cake in 450 ml of water, sulfuric acid Adjust pH=1, white precipitate precipitates out, stand still, filter, wash with water, and dry to obtain off-white solid 4,6-dihydroxy-2-methylpyrimidine (56.6g), the yield is 89.8% (calculated as acetamidine hydrochloride) ).

[0037] (1) Preparation of 4,6-dihydroxy-2-methyl-5-nitropyrimidine

[0038] Add the prepared 4,6-dihydroxy-2-methylpyrimidine (12.6g, 0.10mol), trichloroacetic acid (12.3g, 0.075mol), and acetic acid (102ml, 1.80mol) prepared above into a ...

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for preparing 4, 6-dichloro-2-methyl-5-nitro pyrimidine. The method mainly comprises the steps that hydrochloric acid ethanamidine and malonic acid diethyl ester serving as raw materials are reacted with alkoxy sodium and other base catalysts to prepare 4, 6-dihydroxy-2-methyl pyrimidine in a cyclization mode, nitratlon reaction is carried out on the 4, 6-dihydroxy-2-methyl pyrimidine in trichloroacetic acid and acetic acid serving as a solvent through nitric acid to obtain 4, 6-dihydroxy-2-methyl-5-nitro pyrimidine, and chlorination reaction is carried out on the 4, 6-dihydroxy-2-methyl-5-nitro pyrimidine through phosphorus oxychloride under the action of acid-binding agent triethylamine and other organic alkali to prepare the 4, 6-dichloro-2-methyl-5-nitro pyrimidine. According to the method, highly-toxic or high toxic raw materials are replaced by non-toxic or low-toxicity raw materials, the technique of clean production is achieved, the wastewater quantity is small, the catalyzers and the organic solvents can be recycled, the process is short, operability is high, and the 4, 6-dichloro-2-methyl-5-nitro pyrimidine is suitable for quantity production.

Description

Technical field [0001] The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of 4,6-dichloro-2-methyl-5-nitropyrimidine. Background technique [0002] Moxonidine1 is a second-generation central antihypertensive drug developed by Beiersdorf, Germany. It is a selective agonist with high affinity for imidazoline I1 receptors (1, SAPalkhiwala, A. Yu, WHFrishman, Imidazoline receptor agonist drugs for treatment of systemic hypertension and congestive heart failure. Heart Dis. 2000, 2(1): 83-92., 2, S. Deftereos, G. Giannopoulos, C. Kossyvakis, et.al., Effectiveness of Moxonidine to Reduce Atrial Fibrillation Burden in Hypertensive Patients, American Journal of Cardiology, 2013, 112(5):684-687.). [0003] 4,6-Dichloro-2-methyl-5-nitropyrimidine is a key intermediate for the preparation of moxonidine. At present, there are some reports on the preparation method of 4,6-dichloro-2-methyl-5-nitropyrimidine. Some preparation methods...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/30
CPCC07D239/30
Inventor 徐德锋
Owner 台州煜农生物科技有限公司
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