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Synthesis method of 6-ethyl-4-hydroxyl-5-fluorine-2-cloro pyridine ammonium salt

A technology of chloropyrimidine ammonium salt and synthesis method, which is applied in the field of synthesis of 6-ethyl-4-hydroxy-5-fluoro-2-chloropyrimidine ammonium salt, and can solve the problem of poor oxidation effect compared to iodine, low yield waste liquid, etc. problems, to avoid the use of format reagents and iodine, good product quality, and low production costs

Active Publication Date: 2011-07-20
上海永阔生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are domestic research groups ("Chemical Reagents", 2004, 265-266) use potassium iodide / potassium permanganate to oxidize, but its oxidation effect is far less than that of iodine, the yield is very low and a large amount of waste liquid is produced

Method used

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  • Synthesis method of 6-ethyl-4-hydroxyl-5-fluorine-2-cloro pyridine ammonium salt
  • Synthesis method of 6-ethyl-4-hydroxyl-5-fluorine-2-cloro pyridine ammonium salt
  • Synthesis method of 6-ethyl-4-hydroxyl-5-fluorine-2-cloro pyridine ammonium salt

Examples

Experimental program
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Effect test

Embodiment 12

[0038] Example 1.2 Condensation reaction

[0039] Add 160ml methanol to a 250ml reaction flask, add 9.3g (0.405mol) sodium metal in batches with stirring. After the sodium reaction is completed, the reaction solution is cooled to about 5℃ with an ice water bath, and then 42g (0.203mol) O are added separately -Methylisourea sulfuric acid monomethyl salt and 20g (0.135mol) 2-fluoro-3-oxopentanoic acid methyl ester, after the addition, keep it under 25℃ for half an hour, then heat to reflux (65℃)3 hour. The reaction was stopped and the methanol was evaporated under reduced pressure. The residue was dissolved in 200ml of water. The pH value was adjusted to about 3 with 6M HCl. A solid was precipitated. After cooling in an ice water bath for 2 hours, it was filtered. The resulting mother liquor was concentrated again to obtain a total of 9.7g The intermediate (II) is a white powder with a weight yield of 48.5%.

Embodiment 13

[0040] Example 1.3 Condensation reaction

[0041] Add 160ml methanol into a 250ml reaction flask, add 6.2g (0.270mol) sodium metal in batches with stirring. After the sodium reaction is completed, the reaction solution is cooled to about 5℃ in an ice water bath, and then 84g (0.406mol) O are added separately -Methylisourea sulfuric acid monomethyl salt and 20g (0.135mol) 2-fluoro-3-oxopentanoic acid methyl ester, after the addition, keep the temperature below 25°C for half an hour, and then heat and reflux for 3 hours. The reaction was stopped and the methanol was evaporated under reduced pressure. The residue was dissolved in 200ml of water. The pH was adjusted to about 3 with 6M HCl. A solid was precipitated. After cooling in an ice-water bath for 2 hours, it was filtered. The mother liquor was concentrated again to obtain 10.3g. The intermediate (II) has a weight yield of 51.5%.

Embodiment 14

[0042] Example 1.4 Condensation reaction

[0043] Add 160ml methanol into a 250ml reaction flask, add 6.2g (0.270mol) sodium metal in batches with stirring, after the sodium reaction is completed, the reaction solution is cooled to about 5℃ with an ice water bath, and then 28g (0.135mol) O are added separately -Methylisourea sulfate monomethyl salt and 20g (0.135mol) 2-fluoro-3-oxopentanoic acid methyl ester, after the addition, the reaction is maintained at 35°C for 6 hours. The reaction was stopped and the methanol was evaporated under reduced pressure. The residue was dissolved in 200ml of water. The pH was adjusted to about 3 with 6M HCl. A solid was precipitated. After cooling in an ice-water bath for 2 hours, it was filtered. The resulting mother liquor was concentrated again to obtain a total of 8.5g The intermediate (II) has a weight yield of 42.5%.

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Abstract

The invention discloses a synthesis method of 6-ethyl-4-hydroxyl-5-fluorine-2-cloro pyridine ammonium salt with a structure showed as a formula (I), comprising the following steps: taking 2-fluorine-3-oxo valerate as a starting material, and condensing with O-methylisourea in alcoholic solution of sodium alcoholate to prepare an intermediate (II); carrying out acid-catalyzed hydrolysis on the intermediate (II) to prepare an intermediate (III); carrying out chlorinated reaction on the intermediate (III) by adopting chlorinated reagent to prepare a compound (IV); and preparing an intermediate (V) by the compound (IV) in alkaline water solution through hydroxyl substitution, and ammoniating the intermediat (V) by ammonia water to form salt, namely, obtaining the 6-ethyl-4-hydroxyl-5-fluorine-2-cloro pyridine ammonium salt. The synthesis method adopts cheap and easily-obtained starting raw material, avoids the use of format reagent and iodine, simplifies operations, reduces environmentalpollution, is beneficial to industrial production and has lower production cost and good product quality.

Description

Technical field [0001] The invention specifically relates to a method for synthesizing the intermediate 6-ethyl-4-hydroxy-5-fluoro-2-chloropyrimidine ammonium salt (hereinafter referred to as EFCP) of the antifungal drug voriconazole. Background technique [0002] Antifungal drugs are a class of essential drugs that have been vigorously developed in countries around the world in recent years. In recent years, due to the widespread application of cytotoxic drugs, immunosuppressants, broad-spectrum antibiotics, the development of treatment methods such as organ transplantation, catheter technology, intravenous hypernutrition, and clinical serious diseases such as tumors, blood diseases, AIDS, diabetes, and senile diseases The morbidity of AIDS continues to rise, making deep fungal infections on the rise, especially cancer and AIDS patients are extremely susceptible to fungal infections. In recent years, triazole antifungal drugs have stronger antibacterial activity and lower toxic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/36
Inventor 周卫朱广友胡惟孝王敏杨忠愚
Owner 上海永阔生物医药科技有限公司
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