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Synthetic method of renal fibrosis resistant medicine 1-(substituted benzyl)-5- trifluoromethyl-2(1H)-pyridone hydrochloride

A technology of trifluoromethylpyridine and trifluoromethyl, applied in the field of ZHC-116 hydrochloride), can solve the problems of ring-forming side reactions, affecting product yield, low reported yield, etc. The effect of complete reaction and improved yield

Active Publication Date: 2018-02-02
GUANGZHOU NANXIN PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The synthesis process of ZHC-116 hydrochloride involves the synthesis of an intermediate, that is, compound 7 (see the following formula), the synthesis method of patent CN102149683B, involving 1-chloropropyl-4-methylpiperazine and raw material 1- (4-aminobenzyl)-5-trifluoromethylpyridin-2(1H)-one (compound 3), because 1-chloropropyl-4-methylpiperazine is prone to self-cycling side reaction in the reaction, Seriously affect the product yield, and its reported yield is very low, only 21%. At the same time, the post-reaction treatment needs to purify the product through column chromatography, which is difficult to scale up and synthesize, so the method is not suitable for industrial production

Method used

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  • Synthetic method of renal fibrosis resistant medicine 1-(substituted benzyl)-5- trifluoromethyl-2(1H)-pyridone hydrochloride
  • Synthetic method of renal fibrosis resistant medicine 1-(substituted benzyl)-5- trifluoromethyl-2(1H)-pyridone hydrochloride
  • Synthetic method of renal fibrosis resistant medicine 1-(substituted benzyl)-5- trifluoromethyl-2(1H)-pyridone hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation of 5-trifluoromethylpyridin-2(1H)-one (compound 1)

[0041] In the reaction bottle, add 2-chloro-5-trifluoromethylpyridine 50g (275mmol), dioxane 60mL, 8M hydrochloric acid 60mL (480mmol), stir and heat to 90-94 0 C, react for 17-19 hours, until the TLC plate shows that the reaction is complete, and the temperature is controlled at 70 0 C. Evaporate the solvent under reduced pressure until no obvious liquid distills out, add 60mL of water, stir for 20min, filter with suction, wash the filter cake with 200mL of water until neutral, and 0 C was dried in vacuo to obtain 40.0 g of a yellow solid (compound 1), with a yield of 88%. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 6.68 (dd, 1H, J = 9.6Hz), 7.63(dd, 1H, J 1 = 9.6Hz, J 2 = 2.6Hz), 7.78(s, 1H), 13.15(s, 1H). 13 C NMR (125 MHz, DMSO-d6) δ (ppm): 111.19, 121.13, 123.18, 134.29, 137.57. MS(ESI) m / z: 164.0 [M+H] + . The product test data is consistent with the structure.

Embodiment 2

[0042] Example 2 1-(4-nitrobenzyl)-5-trifluoromethylpyridin-2(1H)-one (compound 2)

[0043] In the reaction flask, add compound 1 40g (245mmol), p-nitrobenzyl bromide 79.3g (368mmol), dioxane 300mL, K 2 CO 3 64.0g (463mmol), stirred and heated to 105 0 C was refluxed, and after 2 hours of reaction, it was heated and filtered, and the filter residue was washed with dioxane, and the combined filtrate was heated at 60 0 C reduced pressure to evaporate the solvent, temperature control 78-80 0 C. Add 95% ethanol dropwise to the concentrate until the solution is dissolved, stir for 30min, and cool to 0 0 C, suction filtration, wet product at 60 0 C was dried in vacuo to obtain 58.0 g of light yellow solid (compound 2), with a yield of 90%. 1 H NMR (500 MHz, DMSO-d6) δ (ppm): 5.25 (s, 2H), 6.71 (d, J = 9.6Hz, 1H), 7.47(d, J 1 = 9.4Hz, J 2 = 2.6 Hz 1H), 7.48(d, J = 8.7 Hz, 2H), 7.55(s,1H), 8.23(d, J = 8.8 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ (ppm): 52.38, 110.39, ...

Embodiment 3

[0044] Example 3 1-(4-aminobenzyl)-5-trifluoromethylpyridin-2(1H)-one (compound 3)

[0045] In the reaction bottle, add compound 2 50.0g (168mmol), 95% ethanol 300mL, stir and heat to 74 0 C, slowly drop in 33.6g (672mmol) of 80% hydrazine hydrate, after adding, heat to 75-80 0 C stirred overnight, concentrated the reaction solution to 1 / 4 under reduced pressure, added ethyl acetate (200mL)-water (100mL) mixture, stirred and separated, the aqueous phase was washed with 50mL of ethyl acetate, combined organic phase, washed with 50mL of brine Once, the organic phase was concentrated to dryness under reduced pressure, 50 mL of n-heptane was added, stirred for 30 min, and filtered to obtain 43.9 g of white solid (compound 3), with a yield of 96%. 1 H NMR (500 MHz,DMSO-d6) δ(ppm): 3.75 (s, 2H), 5.03(s, 2H), 6.66 (d, J = 6.7 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.3Hz, 2H), 7.42 (dd, J 1 = 9.6, J 2 = 2.6 Hz, 1H), 7.64 (s, 1H). 13 C NMR (125 MHz, DMSO-d6) δ (p...

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Abstract

The invention relates to a synthetic method of a renal fibrosis resistant medicine 1-((4-(4-methyl piperazine-1-yl)amino)benzyl-5-trifluoromethyl-2(1H)-ketone hydrochloride(ZHC-116 hydrochloride). According to the invention, 2-chloro-5-trifluoromethylpyridine(commercially available) which is used as a raw material undergoes nine synthesis steps to prepare 1-((4-(4-methyl piperazine-1-yl)amino)benzyl-5-trifluoromethyl-2(1H)-ketone. In comparison with existing methods reported in literature, the method of the invention is effective and practical, is adopted to raise total synthetic yield and issuitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to the field of drug synthesis, in particular to an anti-renal fibrosis drug 1-(substituted benzyl)-5-trifluoromethyl-2(1H)-pyridone hydrochloride, that is, 1-(4-(3 -(4-Methyl-1-piperazinyl)propyl)amino)benzyl-5-trifluoromethyl-2(1H)-pyridone hydrochloride (ZHC-116 hydrochloride), the synthetic method . Background technique [0002] Fibrosis can occur in various organs of the human body. The main pathological changes are the increase of fibrous connective tissue and the reduction of parenchymal cells in organ tissues. Continuous progress can lead to organ structural damage, functional decline, and even failure, seriously threatening human health and life. Tissue fibrosis plays an important role in the occurrence and development of diseases in major organs of the human body. Extensive research has been conducted on the mechanism, diagnosis and prevention measures of organ or tissue fibrosis. US Patent US5310562 first...

Claims

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Application Information

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IPC IPC(8): C07D213/64A61P13/12
CPCC07D213/64
Inventor 林寨伟罗军奇朱建平胡高云张士喜
Owner GUANGZHOU NANXIN PHARMA
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