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Method for preparing 5- chlorine -4 hydroxy -2ú¿1óÄú®- pyridone and intermediate

An intermediate and preparation process technology, applied in the field of pharmaceutical synthesis, can solve the problems of dark color, reduced reaction speed, increased amount of sulfuryl chloride and the like

Active Publication Date: 2007-02-21
南京亚东启天药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After groping, it is found that the reaction needs to be carried out at a lower temperature, but the reaction time needs to be greatly extended (greater than 24 hours) to obtain the compound V of higher yield
In addition, we also found that avoiding light is conducive to the reaction. Even if the reaction is performed under ordinary fluorescent lamps, the reaction speed is greatly reduced, and the amount of sulfuryl chloride is significantly increased. The reason for the analysis may be caused by the decomposition of sulfuryl chloride under light.
Compound V was hydrolyzed with 40% sulfuric acid according to the literature (Hetercycl.1993, 36:145) to obtain the desired product I, but the by-product 5-chloro-3-cyano-4-hydroxyl-2(1H)- Pyridone (VI) can be hydrolyzed with 47% hydrobromic acid to obtain the product, but the color is darker, and the melting point is still low after recrystallization

Method used

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  • Method for preparing 5- chlorine -4 hydroxy -2ú¿1óÄú®- pyridone and intermediate
  • Method for preparing 5- chlorine -4 hydroxy -2ú¿1óÄú®- pyridone and intermediate
  • Method for preparing 5- chlorine -4 hydroxy -2ú¿1óÄú®- pyridone and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 2,5-dichloro-3-cyano-4-methoxypyridine (III)

[0034] Mix 13.0ml (0.16mol) of sulfonyl chloride and 280ml of glacial acetic acid, avoid light, and add dropwise 20g (0.133mol) of 3-cyano-4-methoxy-2(1H)-pyridone and 100ml of ice Suspension composed of acetic acid, dropwise, stirred and reacted at 50°C for 15 minutes, added 2.0ml (0.025mol) of sulfuryl chloride, reacted for 15 minutes, recovered the solvent under reduced pressure, added 12ml each of methanol and isopropyl ether to the residue, After cooling, it was filtered with suction to obtain 24.2 g of off-white crystal III, with a yield of 89.4%, m.p.166-168°C. 1 H-NMR (DMSO-d 6 , 500MHz) δ: 4.29 (s, 3H, OCH 3 ), 7.89 (s, 1H, ArH); MS (ESI (+) 70V, m / z): 203.1 (M+H) + .

Embodiment 2

[0036] 2,5-dichloro-3-cyano-4-methoxypyridine (III)

[0037] Mix 9.6ml (0.12mol) of sulfonyl chloride and 150ml of glacial acetic acid, and add dropwise a mixture of 10g (0.067mol) of 3-cyano-4-methoxy-2(1H)-pyridone and 50ml of glacial acetic acid under stirring at room temperature. Suspension, after dripping, stirred and reacted at 50°C for 30 minutes, recovered the solvent under reduced pressure, added 7.5ml each of methanol and isopropyl ether to the residue, and filtered with suction after cooling to obtain 11.3g of off-white crystal III, with a yield of 83.5%. m.p.166-168°C.

Embodiment 3

[0039] 2,5-dichloro-3-cyano-4-methoxypyridine (III)

[0040] Mix 7.0ml (0.087mol) of sulfonyl chloride and 100ml of glacial acetic acid, avoid light, and add dropwise 10g (0.067mol) of 3-cyano-4-methoxy-2(1H)-pyridone and 100ml of DMF under stirring at room temperature After dripping, stir and react at 55°C for 20 minutes, add 1.0ml (0.012mol) of sulfuryl chloride, react for 30 minutes, recover the solvent under reduced pressure, add 7.5ml each of methanol and isopropyl ether to the residue, and cool After suction filtration, 10.8 g of off-white crystal III was obtained, with a yield of 79.8%, m.p.165-167°C.

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Abstract

This invention relates to a method for preparing 5-chloro-4-hydroxy-2(1H)-pyridone. This invention also discloses a new intermediate for the compound and its preparation method.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a preparation method of 5-chloro-4-hydroxyl-2(1H)-pyridone, and the invention also discloses a new intermediate synthesized in the preparation. Background technique [0002] 5-Chloro-4-hydroxy-2(1H)-pyridone (CDHP, Gimeracil, I) is a bioregulator of 5-fluorouracil (5-FU), which can effectively inhibit the activity of dihydropyrimidine dehydrogenase. It is widely used in clinical anti-tumor all over the world, and has achieved good curative effect, and has the characteristics of safety, potency and long-term effect. [0003] [0004] There are currently five synthetic methods for 5-chloro-4-hydroxyl-2(1H)-pyridone: [0005] Method 1 (Rec Trav Chim.1954, 73:704; ibid.1953, 72:853; J Heterocycl Chem.1975, 12:389): [0006] Using 4-nitropyridine-N-oxide as raw material, it is obtained through 5 steps of reaction, with a total yield of 12%, in which a tube lock reaction is requi...

Claims

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Application Information

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IPC IPC(8): C07D213/69C07D213/85
Inventor 徐云根毛丹张飞皇
Owner 南京亚东启天药业有限公司
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