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Preparation method of 4-[(4,6-dihydroxyl-2-pyrimidinyl)amino] cyanobenzene

A benzonitrile and dihydroxyl technology, applied in the field of compound preparation, can solve the problems of incomplete reaction of raw materials, reduced production efficiency, insufficient product purity, etc., and achieve the effects of complete and stable reaction, improved production efficiency, and shortened reaction route.

Active Publication Date: 2011-03-30
浙江瑞博制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] Then, in the production process, if p-cyanoaniline hydrochloride is to be prepared, the reaction steps will undoubtedly increase, the cost will increase, and the production efficiency will decrease.
And, also find following problem after repeating the described method of the first step: make solvent with ethylene glycol dimethyl ether, price height (20,000 / ton), there is toxicity and recovery rate is not high; Under this reaction condition, raw material cannot The reaction is complete, resulting in a yield of less than 50% after repetition; and the purity of the obtained product is not enough, and there are residual impurities of raw material p-cyanoaniline hydrochloride; the crude product is insoluble in acetone and cannot be recrystallized with acetone
The problem that this method exists is: reaction has impurity, and raw material has surplus; Claisen condensation reaction (Claisen condensation reaction) can take place in diethyl malonate self under alkalinity, promptly has side reaction to take place; Due to the poor quality of sodium ethylate , so that the reaction system becomes viscous and the color becomes darker; the post-treatment product is difficult to filter, and the product color is reddish
[0016] In a word, prepare 4-[(4,6-dihydroxy-2-pyrimidinyl) amino] benzonitrile with prior art method, can occur that above-mentioned reaction step is long, and production efficiency is low, and cost is high; Reaction yield is low, reaction Incomplete, there are side reactions, high impurity content, unsatisfactory post-processing procedures, etc.

Method used

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  • Preparation method of 4-[(4,6-dihydroxyl-2-pyrimidinyl)amino] cyanobenzene
  • Preparation method of 4-[(4,6-dihydroxyl-2-pyrimidinyl)amino] cyanobenzene
  • Preparation method of 4-[(4,6-dihydroxyl-2-pyrimidinyl)amino] cyanobenzene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Put 40.0 grams of p-cyanoaniline, 150 ml of n-butanol, 50.1 grams of 50% cyanamide / water solution into a 250ml four-necked bottle, add 142.5 grams of 36% hydrochloric acid dropwise at 90°C, adjust the pH to about 3-4, and heat to After reacting at 90°C for 10 hours, 30.1 g of cyanamide was added, and the reaction was continued for 10 hours. After the reaction is complete, the solution is clarified, and activated carbon is added for decolorization and filtration. The filtrate is distilled under reduced pressure to about 140ml of solvent until solids are precipitated. Add 60ml of acetone, stir and filter, wash with acetone, and dry to obtain 63 grams of white solids. The crude yield is 95%. The volumetric water was recrystallized once, the filter cake was washed with a small amount of acetone, and 49.7 g was dried, with a yield of 75%. The mother liquor was recovered and applied mechanically, with a total yield of 85%. Melting point 237-241°C, HPLC purity 99.5%. 1H NMR (...

Embodiment 2

[0049] Put 20.0 grams of p-cyanoaniline, 100 ml of water, 21.4 grams of 50% cyanamide / water solution into a 250ml four-necked bottle, add 34.5 grams of 36% hydrochloric acid dropwise at 90°C, adjust the pH to about 1~2, and heat to 100°C after completion After 10 hours of reaction, 14.3 grams of cyanamide was added, and the reaction was continued for 10 hours. After the reaction is complete, the solution is clarified, added activated carbon for decolorization and filtration, and the filtrate is distilled under reduced pressure to about 100ml of solvent until solids are precipitated. Add 60ml of acetone, stir and filter, wash with acetone, and dry to obtain 32.5 grams of white solids. The crude yield is 98%. The volumetric water was recrystallized once, the filter cake was washed with a small amount of acetone, and 20.5 g was dried, with a yield of 65%. The mother liquor was recovered and applied mechanically, with a total yield of 75%. The melting point is 237-240°C, the HPLC ...

Embodiment 3

[0051] Put 40.0 grams of p-cyanoaniline, 150 ml of ethanol, 50.1 grams of 50% cyanamide / water solution into a 250ml four-necked bottle, add 275.5 grams of 36% hydrochloric acid dropwise at 90°C, adjust the pH to about 4~5, and heat to 110°C after completion After 10 hours of reaction, 30.1 grams of cyanamide was added, and the reaction was continued for 10 hours. After the reaction is complete, the solution is clarified, and activated carbon is added for decolorization and filtration. The filtrate is distilled under reduced pressure to about 140ml of solvent until solids are precipitated. Add 60ml of acetone, stir and filter, wash with acetone, and dry to obtain 61 grams of white solids. The crude yield is 92%. Recrystallize once with volumetric water, wash the filter cake with a small amount of acetone, dry 36.5 grams, the yield is 55%, the mother liquor is recovered and used mechanically, the total yield is 65%. Melting point 236-241°C, HPLC purity 99.0%. The structural dat...

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Abstract

The invention relates to a preparation method of 4-[(4,6-dihydroxyl-2-pyrimidinyl)amino] cyanobenzene. The method comprises the following steps: a, using an aqueous solution of para-cyanoaniline and mono cyanamide as a raw material, water or alcohol solvent as the single solvent or a mixed solvent of water and alcohol solvents as the reaction solvent, and hydrochloric acid as a catalyst to react so as to obtain an N-(4-cyanophenyl)guanidine hydrochloride; and b, using the N-(4-cyanophenyl)guanidine hydrochloride as the raw material, methanol as the reaction solvent, and sodium methoxide and dimethyl malonate as the reaction reagents to react so as to obtain the 4-[(4,6-dihydroxyl-2-pyrimidinyl)amino] cyanobenzene. The method is an improvement of the prior art and has the advantages of short reaction process, high production efficiency, high reaction yield, low cost, low impurity content, complete and stable reaction and the like.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a preparation method of 4-[(4,6-dihydroxy-2-pyrimidinyl)amino]benzonitrile. Background technique [0002] 4-[(4,6-dihydroxy-2-pyrimidinyl)amino]benzonitrile (English name: 4-[(4,6-dihydroxy-2-pyrimidinyl)amino]-Benzonitrile), chemical structure as formula I Shown: [0003] [0004] CAS number: 374067-80-8, molecular formula is C 11 h 8 N 4 o 2 . It is an important intermediate used to prepare some pyrimidine compounds (as shown in the following scheme 1) and anti-HIV-1 drugs (as shown in the following scheme 2), and has very high practical value in the fields of chemical synthesis and pharmaceuticals. [0005] [0006] At present, regarding the preparation method of Compound I, the reported synthetic route is shown in the figure below (reference: International Patent Application WO2008 / 080964, applicant: Tibotec Pharmaceutical Company, publication date: July 10, 2...

Claims

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Application Information

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IPC IPC(8): C07D239/545C07C279/18C07C277/08
Inventor 车大庆张达
Owner 浙江瑞博制药有限公司
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