CN104725240B - Method for preparing terbinafine hydrochloride Z-shaped isomer - Google Patents
Method for preparing terbinafine hydrochloride Z-shaped isomer Download PDFInfo
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Abstract
The invention discloses a method for preparing a terbinafine hydrochloride Z-shaped isomer serving as a high-purity isomer impurity compound for allylamine medicament terbinafine hydrochloride impurity analysis. The preparation method comprises the following steps: 1, adding a terbinafine EZ mixture to isopropanol, heating to 40-86 DEG C for dissolving, preserving the heat for 0.5-4 hours, slowly cooling to 10-20 DEG C, preserving the heat for 1-3 hours, cooling to -10-0 DEG C, preserving the heat for 1-5 hours, filtering, and concentrating the filtrate under reduced pressure to obtain an oily matter; and 2, adding 4-chlorphenyl-tert-butyl ether into the oily matter obtained in step 1, heating to 100-150 DEG C, preserving the heat for 1-5 hours, cooling to 0-40 DEG C, preserving the heat for 1-10 hours, and filtering to obtain an off-white compound. The method has the positive effect of obtaining the terbinafine hydrochloride isomer with relatively high purity. The isomer serving as a known impurity is used in quality analysis of terbinafine hydrochloride to determine the position of an impurity in a sample and survey the resolution between the impurity and the sample, so that the analysis method is more accurate. The preparation conditions are mild, the synthesis steps are simple, and the quality of the product is stable.
Description
Technical field：
The invention belongs to field of medicaments, and in particular to the Allylamines medicine terbinafine HCl of broad-spectrum antifungal activity is different
Structure body impurity, the preparation method of (Z)-N- (6,6- dimethyl hept-2-ene" -4- alkynyls)-N- methyl isophthalic acids-naphthalene methylamine.
Background technology：
Terbinafine HCl is a kind of Allylamines medicine with broad-spectrum antifungal activity.This product can be disturbed specifically very
The early stage biosynthesis of bacterium ergosterol, suppresses the squalene epoxidase of fungi with high selectivity, forms fungal cell membrane
During squalene epoxidation reaction be obstructed, so as to reach kill or suppress fungi effect.
Main method of administration is still oral formulations at present, therefore medicine Pureness control is highlighted most important.The special ratio of hydrochloric acid
Naphthalene sweet smell its structure is E, and its Z configurational isomer bioactivity is low, but two kinds of configuration materials are always simultaneously in process of production
In the presence of.The Z-type isomers of high-purity contributes to the analysis and control to finished product quality
Terbinafine HCl Z-type isomer impurities, (Z)-N- (6,6- dimethyl hept-2-ene" -4- alkynyls)-N- methyl isophthalic acids -
Naphthalene methylamine its structural formula is：
The patent document prepared on terbinafine HCl is relatively more, all describe in detail the preparation of terbinafine HCl
Technique, but without the analysis on impurity, detection is recorded, to realize the control to drug quality.
The content of the invention
It is an object of the invention to provide one kind (Z)-N- (6,6- dimethyl hept-2-ene" -4- alkynyls)-N- methyl isophthalic acids-naphthalene
The synthetic method of methylamine, is obtained as the Allylamines medicine terbinafine HCl impurity of broad-spectrum antifungal activity by the method
The isomer impurities compound of the high-purity of analysis.
Synthetic method of the invention is comprised the following steps：
Ith, terbinafine HCl EZ mixtures addition isopropanol is heated to 40-86 DEG C of dissolving, and is incubated 0.5~4 hour,
Slow cooling to 10~20 DEG C be incubated 1~3 hour, then be cooled to -10~0 DEG C be incubated 1~5 hour, filtering, filtrate decompression concentration
Obtain grease.
Wherein, the addition of isopropanol is respectively the 2~15 of terbinafine HCl EZ mixture quality volume ratios
2nd, 4- chlorphenyl tertbutyl ethers are added in the grease for obtaining to step 1,100~150 DEG C, insulation 1~5 are warming up to
Hour, then it is cooled to 0~40 degree Celsius, and 1~10 hour is incubated, filter to obtain off-white color compound
Wherein, the addition of 4- chlorphenyls tertbutyl ether is respectively the 1 of terbinafine HCl EZ mixture quality volume ratios
~9.
High-purity hydrochloric acid is confirmed as after being analyzed to structure using nuclear magnetic resonance to step 2 gained off-white color compound special
Than naphthalene sweet smell isomers (Z)-N- (6,6- dimethyl hept-2-ene" -4- alkynyls)-N- methyl isophthalic acids-naphthalene methylamine.Using high performance liquid chromatography
After instrument carries out purity testing, its purity is more than 99.0%.1H-NMH(CHCl3)
The positive effect of the present invention is to have obtained purity terbinafine HCl isomers higher.As known impurities
In for the quality analysis of terbinafine HCl, impurity position in sample is specified, investigate impurity and sample room separating degree, make analysis
Method is more accurate.
Mild condition of the present invention, synthesis step is simple, and product quality stabilization, experimental implementation is simple, prepare sample purity compared with
It is high.
Brief description of the drawings：
Fig. 1 measures terbinafine HCl localizing sample figure for liquid chromatograph.
Fig. 2 measures terbinafine HCl and terbinafine HCl isomers localizing sample figure for liquid chromatograph.
Fig. 3 measures terbinafine HCl isomer sample figure for liquid chromatograph
Specific embodiment：
Weigh during terbinafine HCl EZ mixtures 50.0g puts 500ml three-necked bottles, be added thereto to isopropanol 200ml, rise
Temperature is incubated 2 hours to 70 DEG C.Slow cooling is incubated 2 hours to 20 degrees Celsius, then is cooled to 0 DEG C, is incubated 2 hours.Filtering, filter
Liquid is concentrated under reduced pressure to obtain grease.
10g grease is placed in 100ml three-necked bottles, 4- chlorphenyl tertbutyl ether 50ml are added, 120 DEG C are warming up to, protected
Temperature 1 hour.10 DEG C are cooled to again, 3 hours are incubated, and filter to obtain off-white color compound, terbinafine HCl Z-type isomers.1H-
NMR (400MHz, CDCl3) δ 1.25 (s, 9H), 2.27 (d, 2H), 3.03 (d, 2H), 4.06 (d, 2H), 5.62 (t, 1H), 6.21
(t, 1H), 7.10 (m, 1H), 7.19 (m, 1H), 7.29 (m, 1H), 7.31 (m, 1H), 7.51 (m, 1H), 7.64 (m, 1H), 7.77
(m, 1H)
It is filler (150mm × 3.0mm, 5 μm, or the suitable chromatographic column of efficiency) with octadecylsilane chemically bonded silica；
With triethylamine buffer solution, (0.2% triethylamine solution adjusts pH value to 7.5)-methanol-acetonitrile (30 with glacial acetic acid:42:28) it is stream
Dynamic phase A, with triethylamine buffer solution-methanol-acetonitrile (5:57:38) it is Mobile phase B, according to the form below carries out linear gradient elution；Flow velocity
It is 0.8ml per minute；Detection wavelength is 280nm
Its purity is measured more than 99.0%
Claims (1)
1. a kind of preparation method of terbinafine HCl Z-type isomers, comprises the following steps：
(1) terbinafine HCl EZ mixtures addition isopropanol is heated to 40-86 DEG C of dissolving, and is incubated 0.5~4 hour, delayed
Slowly 10~20 DEG C are cooled to and are incubated 1~3 hour, then be cooled to -10~0 DEG C and be incubated 1~5 hour, filtering, filtrate decompression is concentrated to give
Grease, wherein, the addition of isopropanol is respectively 2~15g/ml of terbinafine HCl EZ mixture quality volume ratios；
(2) 4- chlorphenyl tertbutyl ethers are added in the grease for obtaining to step 1,100~150 DEG C are warming up to, insulation 1~5 is small
When, then be cooled to 0~40 degree Celsius, be incubated 1~10 hour, filter off-white color compound form terbinafine HCl Z-type
Isomers, wherein, the addition of 4- chlorphenyl tertbutyl ethers be respectively terbinafine HCl EZ mixture quality volume ratios 1~
9g/ml。
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| CN201510076153.9A CN104725240B (en) | 2015-02-12 | 2015-02-12 | Method for preparing terbinafine hydrochloride Z-shaped isomer |
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| CN104725240B true CN104725240B (en) | 2017-05-24 |
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Families Citing this family (1)
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| CN115073303A (en) * | 2022-06-28 | 2022-09-20 | 乐泰药业(兰西)有限公司 | Preparation method of terbinafine hydrochloride Z-type isomer |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE10272T1 (en) * | 1979-08-22 | 1984-11-15 | Sandoz Ag | PROPENYLAMINES, PROCESSES FOR THEIR MANUFACTURE, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE AS MEDICINAL PRODUCTS. |
| JP3116364B2 (en) * | 1989-10-02 | 2000-12-11 | 萬有製薬株式会社 | Method for producing enyne derivatives |
| SK5202000A3 (en) * | 2000-04-07 | 2001-12-03 | Slovakofarma As | Method for the preparation of (e)-n-(6,6-dimethyl-2-hepten-4- inyl)-n-methyl-1-naphthalenemethylamine (terbinaphin) |
| CN1155557C (en) * | 2001-12-25 | 2004-06-30 | 中国科学院上海有机化学研究所 | Synthesis of terbinafine hydrochloride |
| GB0503942D0 (en) * | 2005-02-25 | 2005-04-06 | Novartis Ag | Purification process |
| CN101870655A (en) * | 2009-04-21 | 2010-10-27 | 扬子江药业集团北京海燕药业有限公司 | Preparation method of Terbinafine hydrochloride |
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