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Synthetic method of 3-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione derivative

A technology of methoxybenzyl and synthetic method, which is applied in the field of organic synthesis, can solve the problems of low yield of target product, impossibility of reaction, low yield, etc., and achieve the effect of product purification ease and yield advantage

Active Publication Date: 2012-08-08
常熟东南高新技术创业服务有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when the starting material is extended to non-benzene aliphatic ring system or aromatic heterocyclic ring system, such as ethyl 3-aminothiophene-2-carboxylate, ethyl 3-aminopyrrole-2-carboxylate, 2-amino-1-cyclo Ethyl pentenecarboxylate and ethyl 1-tert-butoxycarbonyl-4-amino-5,6-dihydro-2H-pyridine-3-carboxylate, etc., these two routes have shown their limitations
Route 1 can generate a considerable amount of by-products: 1,3-bis-(4-methoxybenzyl)urea, which is produced by 4-methoxybenzyl isocyanate in the reaction system and the 4-methoxybenzyl isocyanate in the reaction process. Formed by condensation of methoxybenzylamine, resulting in low yield of the target product and difficult purification
And when attempting to synthesize non-benzene aliphatic ring system or aromatic heterocyclic system target product by route 2, productive rate is low, even reaction cannot carry out

Method used

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  • Synthetic method of 3-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione derivative
  • Synthetic method of 3-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione derivative
  • Synthetic method of 3-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1 Synthesis of 3-(4-methoxybenzyl)-1H-thiophene[3,2-d]pyrimidine-2,4-dione (3) (method 1)

[0063]

[0064] 3-Amino-thiophene-2-carboxylic acid methyl ester (1) (4.7g, 30mmol) was added to dichloromethane (100ml) and saturated aqueous sodium bicarbonate (135ml) in a 500ml reaction flask at 0°C , forming a two-phase mixed system. Then slowly drop 20% phosgene toluene solution (16.9 ml, 34.5 mmol) into the mixed system with a syringe. After the dropwise addition was complete, the reaction mixture was stirred at 0° C. for an additional 15 minutes, then warmed to room temperature (20° C.) and stirred for an additional 1 hour. After the two phases were separated, the aqueous phase was extracted with 25 ml of dichloromethane, and the combined organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated by rotary evaporation to about 30 ml, and the preparation of the isocyanate (2) dichloromethane solution was completed.

[0065] Dilute the dic...

Embodiment 2

[0069] Example 2 Synthesis of 3-(4-methoxybenzyl)-1H-thiophene[3,2-d]pyrimidine-2,4-dione (method 2)

[0070] Except using the toluene solution of 3.4g (11.5mmol) trimeric phosgene to replace 20% phosgene toluene solution (16.9ml, 34.5mmol) in embodiment 1, be used for other reaction process and treatment method of synthetic target compound and Example 1 is the same. 7.4 g of the target compound (3) was obtained with a yield of 86%. LC-MS and 1 The H-NMR analysis spectrum is the same as in Example 1.

Embodiment 3

[0071] Example 3 Synthesis of 6-bromo-3-(4-methoxybenzyl)-1H-thiophene[3,2-d]pyrimidine-2,4-dione (6)

[0072]

[0073] The reaction raw material 3-amino-5-bromothiophene-2-carboxylic acid methyl ester (4) was prepared according to the method cited in patent WO2010 / 101302A1. At 0°C, in a 500ml reaction flask, 3-amino-5-bromothiophene-2-carboxylic acid methyl ester (4.7g, 20mmol) was added to dichloromethane (85ml) and saturated aqueous sodium bicarbonate (100ml) , forming a two-phase mixed system. Then slowly drop 20% phosgene toluene solution (12.0 ml, 23 mmol) into the mixed system with a syringe. After the dropwise addition was complete, the reaction mixture was stirred at 0° C. for an additional 15 minutes, then warmed to room temperature (20° C.) and stirred for an additional 1 hour. After the two phases were separated, the aqueous phase was extracted with 20 ml of dichloromethane, and the combined organic phase was dried over anhydrous magnesium sulfate, filtered, c...

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Abstract

A synthetic method of a 3-(4- methoxy-benzyl)-1H-pyrimidine-2, 4-dione derivative having a structure as shown in the general formula (III) comprises the following steps of: performing a reaction between carbamic acid as shown in formula (SM) or its ester and phosgene or triphosgene so as to generate isocyanate as shown in formula (I); performing a reaction between isocyanate (I) and 4-methoxybenzylamine to generate intermediate carbamide as shown in formula (II); and performing cyclisation on intermediate carbamide to prepare the target compound (III), wherein C ring represents substituted or non-substituted cycloaliphatic ring or aromatic heterocycles and R is H or C1-C5 alkyl. According to the method provided by the invention, synthesis of the 3-(4- methoxy-benzyl)-1H-pyrimidine-2, 4-dione derivative having cycloaliphatic ring or aromatic heterocycles can be realized.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and relates to a synthesis method of 3-(4-methoxy-benzyl)-1H-pyrimidine-2,4-dione derivatives. Background technique [0002] In the past ten years, 3-(4-methoxybenzyl)-1H-pyrimidine-2,4-dione and its derivatives, especially 3-(4-methoxybenzyl)-1H-quinazoline- 2,4-diketone compounds (structure shown in formula 1, wherein R = H, 6-OMe, 6-Cl or 6-CO 2 Me et al.), their application in pharmaceutical research and development has aroused widespread interest. [0003] [0004] Formula 1 [0005] After further simple synthesis or modification, these intermediate molecules can show certain biological activities and can be potentially used to treat diseases such as allergy, asthma, measles, arteriosclerosis, arthritis, or osteoporosis. For example: U.S. Patent 6,407,116 B1 reports 1-(4-bromobutyl)-3-(4-methoxybenzyl)-1H-quinazoline-2,4-dione (structure shown in formula 2 ) can be used as a...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D487/04C07D239/70C07D239/96C07D471/04
Inventor 赵立人金利君赵一栋吴旻丹赵德超
Owner 常熟东南高新技术创业服务有限公司
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