A method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine

A technology of aminopyrimidine and propylthio group, which is applied in the field of synthesizing 4,6-dichloro-2--5-aminopyrimidine, can solve the problems of complicated operation, increased one-step reaction, high price and the like, and achieves simple and simple operation. , the effect of low cost

Active Publication Date: 2018-07-10
XIAMEN MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] This route has the following defects: first, nitric acid is used for nitration reaction, which will produce a large amount of waste acid waste water, which not only causes great harm to the environment, but also is highly corrosive to equipment; secondly, the chlorination reaction adopts column chromatography purification , is unfavorable for scale-up production; the whole route contains four-step reactions, and the total yield is only 25%
But also there are following defects in this route: at first utilize diazonium salt to prepare 4,6-dihydroxy-2-(propylthio)-5-(p-tolyl azo) pyrimidine in the route, not only operation is loaded down with trivial details, reaction Harsh conditions require strict control of the reaction temperature, and the preparation of diazonium salts also requires a large amount of acid; secondly, expensive 50% platinum carbon is used as a catalyst in the route, and the amount of use is large (substrate 1.1kg, 50% platinum carbon 0.81 kg), so the route cost is high
Although the use of expensive platinum carbon is avoided, this method not only adds a one-step reaction, but also because Raney-Ni is flammable and has low safety during preparation and use, so this method is also not suitable for industrial production

Method used

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  • A method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine
  • A method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine
  • A method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine

Examples

Experimental program
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Effect test

Embodiment 1

[0042] Example 1 Synthesis of 2,4,6-trihydroxy-5-acetamidopyrimidine (Ⅳa)

[0043] At room temperature, 50.0 g of diethyl acetamidomalonate (III), 28.8 g of urea, 77.0 g of sodium ethoxide and 750 mL of ethanol were mixed with each other, and refluxed for 15 hours. After the reaction was finished, filter and wash the filter cake with 50 mL of ethanol to collect the filter cake. The obtained solid was dissolved in 1 L of water, and the pH was adjusted to neutral with hydrochloric acid. A solid precipitated out. After the solid was separated and fully dried, 39.3 g of 2,4,6-trihydroxy-5-acetamidopyrimidine (Ⅳa) was obtained, which was directly carried out Next reaction. ESI-MS m / z:186[M+H] + ; 1 HNMR (400MHz, D 2 O) δ2.13(s,3H).

Embodiment 2

[0044] Example 2 Synthesis of 2,4,6-trihydroxy-5-benzamidopyrimidine (Ⅳb)

[0045] At room temperature, 6.43 g of diethyl benzamidomalonate (Ⅲ), 2.9 g of urea, 7.7 g of sodium ethoxide and 75 mL of ethanol were mixed with each other, and refluxed for 13 hours. After the reaction, the solvent was removed under reduced pressure, and 100 mL of water was added. The pH was adjusted to neutral with hydrochloric acid, and the aqueous solution was extracted with 200 mL of chloroform, repeated three times, and the chloroform layers were combined. After drying, the solvent was removed to obtain 5 g of oil containing 2,4,6-trihydroxy-5-benzamidopyrimidine (IVb), which was directly carried out to the next reaction. ESI-MS m / z:248[M+H] + .

Embodiment 3

[0046] Example 3 Synthesis of 2,4,6-trichloro-5-aminopyrimidine (Ⅴ)

[0047] Mix 33.0 g of the crude compound (IVa) obtained in Example 1, 21.2 g of pyridine and 500 mL of toluene, then add 62.2 g of phosphorus oxychloride, and heat to reflux for 24 hours. After the reaction was finished, the solvent and most of the remaining phosphorus oxychloride were removed by concentration. The residue was poured into ice water and extracted twice with 500 mL ethyl acetate. After the organic phases were combined, they were washed once with 300 mL of saturated sodium bicarbonate solution. The organic phase was dried and concentrated to obtain 35.1 g of an oily substance containing 2,4,6-trichloro-5-aminopyrimidine (V). ESI-MS m / z:199[M+H] + .

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Abstract

The invention discloses a novel method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine (I), namely an important intermediate of ticagrelor. The method comprises the following steps: carrying out a condensation reaction between substituted aminomalonic acid diethyl ester (III) and urea to generate 2,4,6-trihydroxy-5-substituted aminopyrimidine (IV); conducting chlorination on the obtained compound 2,4,6-trihydroxy-5-substituted aminopyrimidine (IV), to obtain 2,4,6-trichloro-5-aminopyrimidine (V); carrying out a reaction between the obtained compound 2,4,6-trichloro-5-aminopyrimidine (V), and propanethiol to generate 4,6-dichloro-2-(propylthio)-5-aminopyrimidine (I). The synthetic route adopted in the method is low in cost, simple to operate, and suitable for industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing 4,6-dichloro-2-(propylthio)-5-aminopyrimidine. Background technique [0002] Ticagrelor (Ⅱ), the chemical name is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino] -5-(Propylthio)-3H-[1,2,3]triazolo[4,5-D]-3-pyrimidinyl]-5-(2-hydroxyethoxy)cyclopentane- 1,2-Ethanol, developed by AstraZeneca, is a new type of selective small molecule anticoagulant. The drug can reversibly act on the purinoceptor 2 receptor (purinoceptor 2, P2) subtype P2Y12 on vascular smooth muscle cells (VSMC), and has obvious inhibitory effect on platelet aggregation caused by ADP, and the effect is rapid after oral administration, so Can effectively improve the symptoms of patients with acute coronary heart disease. [0003] [0004] 4,6-dichloro-2-(propylthio)-5-aminopyrimidine (I) is an important fragment intermediate in the synthesis of ticagrelor. The methods for synthesizing this intermediate are all r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 陈欢生陈宇
Owner XIAMEN MEDICAL COLLEGE
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