CN115073303A - Preparation method of terbinafine hydrochloride Z-type isomer - Google Patents
Preparation method of terbinafine hydrochloride Z-type isomer Download PDFInfo
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- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
- C07C209/88—Separation of optical isomers
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- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
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- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/42—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing triple carbon-to-carbon bonds, e.g. with metal-alkynes
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- C07B2200/09—Geometrical isomers
Abstract
The invention discloses a preparation method of terbinafine hydrochloride Z-type isomer, which comprises the steps of taking tert-butyl acetylene as a starting material, converting the tert-butyl acetylene into 3, 3-dimethyl-1-butynyl lithium through n-butyl lithium reaction, synthesizing an intermediate 13-hydroxy-6, 6-dimethyl-1-heptene-4-alkyne with acrolein, and synthesizing an intermediate 2E/Z-1-bromo-6, 6-dimethyl-2-heptene-4-alkyne through halogenation; condensing the intermediate 2 and N-methyl-1-naphthylmethylamine into terbinafine free alkali under the alkaline condition, salifying with hydrogen chloride, and refining with methyl tert-butyl ether to obtain high-purity terbinafine hydrochloride isomer (Z) -N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthylmethylamine. The method has the advantages of short process route, relatively simple synthesis steps, easily available experimental raw materials, relatively mild reaction conditions, stable product quality, simple and easily implemented whole-process operation and higher purity of the prepared sample, and can be used for preparing a terbinafine Z-type isomer reference substance.
Description
Technical Field
The invention relates to a preparation method of an allylamine medicine terbinafine hydrochloride isomer impurity- (Z) -N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthalene methylamine with broad-spectrum antifungal activity, belonging to the technical field of medicines.
Background
The specific name of terbinafine hydrochloride in terbinafine hydrochloride is terbinafine hydrochloride, and the chemical name is (E) -N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthylmethylamine hydrochloride. The structural formula is as follows:
the chemical name of the Z-type isomer impurity of the terbinafine hydrochloride is (Z) -N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthylmethylamine hydrochloride. The structural formula is as follows:
terbinafine hydrochloride belongs to an allylamine antifungal drug, and has the bactericidal effect by reducing the synthesis of ergosterol through inhibiting the activity of squalene epoxidase. Can be used for treating skin, hair and nail infection caused by Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton clinorum, Trichophyton violaceum, etc., Microsporum canis, Epidermophyton floccosum, etc.
Terbinafine hydrochloride is a fungicide which can be used for external application and oral administration, and the existing dosage forms of terbinafine hydrochloride include tablets, granules, suppositories, sprays, liniments, creams and the like, and the terbinafine hydrochloride has an inhibitory effect on most pathogenic fungi, wherein the most sensitive patient is dermatophyte. The dermatophyte has high incidence rate of infection and long disease duration, and the current treatment medicines have a plurality of types, but have good treatment effect, low disease recurrence rate and little drug toxic and side effect. Griseofulvin medicines released decades ago are not used due to poor curative effect; ketoconazole drugs have serious toxic and side effects due to long-term administration; the new triazole medicine has high curative effect and low side effect, but the price is high, so that the triazole medicine is difficult to be widely used by common people. The terbinafine hydrochloride has wide antibacterial spectrum and strong antibacterial effect, can kill and inhibit bacteria, can cure most of dermatomycosis by external use or short-course oral administration, has low recurrence rate, little side effect and high safety, has MIC almost equal to MFC, and can be widely applied to the treatment of various dermatomycosis, especially onychomycosis. Thus, terbinafine hydrochloride is spotlighted by the world.
Terbinafine hydrochloride has cis-trans isomer structure, which is (E) -N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthalene methylamine hydrochloride and (Z) -N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthalene methylamine hydrochloride respectively, wherein the terbinafine hydrochloride Z isomer has low biological activity, and the effective component which plays a role in eliminating fungi substances is terbinafine hydrochloride E isomer. However, free trans-and cis-terbinafine hydrochloride compounds exist simultaneously in the production process of the terbinafine hydrochloride bulk drug. In order to more accurately detect the target product trans-terbinafine hydrochloride, the position determination of cis-terbinafine hydrochloride is particularly important. The high purity of the Z isomer facilitates analysis and control of the quality of terbinafine hydrochloride.
Patent application with publication number CN 104725240B discloses a preparation method of terbinafine hydrochloride Z-type isomer. The patent application only describes a refining method for preparing Z-type isomer from terbinafine E/Z mixture, and does not provide a complete synthetic process route, and the refining solvent adopted by the method is 4-chlorophenyl tert-butyl ether, which is expensive and has lower yield of refined products. And the condition of raising the temperature to 100-150 ℃ in the conversion process is harsh and is not easy to control.
The invention provides a preparation method of terbinafine hydrochloride Z-type isomer, and further provides an analysis and detection method of terbinafine hydrochloride Z-type isomer, raw materials used in the preparation method are all available in the market, the price is low, each yield is high, the condition is mild, the synthesis steps are simple, the product quality is stable, the experimental operation is simple, and the purity of a prepared sample is high and reaches more than 99.0%.
Disclosure of Invention
The invention aims to provide a preparation method of terbinafine hydrochloride Z-type isomer, and a high-purity isomer impurity compound for analyzing terbinafine hydrochloride impurities, which is an allylamine drug with broad-spectrum antifungal activity, is obtained by the method.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention relates to a preparation method of terbinafine hydrochloride Z-type isomer, wherein the structural formula of the terbinafine hydrochloride Z-type isomer is shown as a formula I:
the preparation method comprises the following steps:
1) tert-butyl acetylene is used as a starting material and is converted into 3, 3-dimethyl-1-butynyl lithium through n-butyl lithium reaction, and the 3, 3-dimethyl-1-heptylene-4-yne is synthesized with acrolein to form an intermediate 13-hydroxy-6, 6-dimethyl-1-heptylene-4-yne;
2) the intermediate 1 and a halogenated reagent are subjected to halogenation reaction to synthesize an intermediate 2E/Z-1-bromo-6, 6-dimethyl-2-heptene-4-alkyne;
3) condensing the intermediate 2 and N-methyl-1-naphthylmethylamine under an alkaline condition to obtain E/Z-N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthylmethylamine, namely a terbinafine free alkali E/Z mixture;
4) adding an organic solvent into a terbinafine free alkali E/Z mixture for dissolving, introducing hydrogen chloride for salification, and refining by methyl tert-butyl ether to obtain a high-purity terbinafine hydrochloride isomer (Z) -N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthylmethylamine;
the route is as follows:
preferably, in the step 1), the molar ratio of the tert-butyl acetylene to the n-butyl lithium is 1: 1-3, and the molar ratio of the tert-butyl acetylene to the acrolein is 1: 1-5.
Among them, preferably, the halogenating agent in step 2) is hydrobromic acid/phosphorus tribromide.
Among them, the basic condition in step 3) is preferably the presence of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium hydroxide, diethylamine, triethylamine, pyridine, or the like.
Among them, preferably, the organic solvent described in step 4) is ethyl acetate, isopropanol, n-butanol, acetone, dioxane, petroleum ether, n-hexane, n-heptane, cyclohexane or toluene.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention discloses a preparation method of terbinafine hydrochloride Z-type isomer, which comprises the steps of reacting tert-butyl acetylene with N-butyl lithium, synthesizing an intermediate 1 with acrolein, synthesizing an intermediate 2 through halogenation, introducing hydrogen chloride gas into the intermediate 2 and condensing the intermediate 2 with N-methyl-1-naphthylmethylamine under an alkaline condition to form salt, and refining the salt by methyl tert-butyl ether to obtain the high-purity terbinafine hydrochloride isomer (Z) -N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthylmethylamine. The method has the advantages of relatively simple synthesis steps, easily obtained experimental raw materials, mild reaction conditions, stable product quality, simple and easily implemented whole-process operation and high purity of prepared samples.
2. The invention can obtain terbinafine hydrochloride Z-type isomer with higher purity, can be used as a terbinafine hydrochloride Z-type isomer reference substance for quality analysis of terbinafine hydrochloride, inspects the separation degree between impurities and samples, and realizes more accurate analysis method.
Drawings
FIG. 1 is the NMR spectrum of terbinafine hydrochloride Z-type isomer.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are merely exemplary of the invention and that all other embodiments that can be made by one skilled in the art without inventive faculty based on the embodiments described herein are within the scope of the invention.
EXAMPLE 13 Synthesis of hydroxy-6, 6-dimethyl-1-hepten-4-yne
Adding 50.0g of tert-butyl acetylene and 150ml of tetrahydrofuran into a 1000ml glass three-mouth reaction bottle under the protection of nitrogen, cooling to-40-90 ℃, slowly dropwise adding 255ml of n-butyl lithium n-hexane solution (2.5M), keeping the temperature for 1-3 hours after dropwise adding, converting into 3, 3-dimethyl-1-butynyl lithium, controlling the temperature to-40-90 ℃, dropwise adding a mixed solution of 37.5g of acrolein and 100ml of tetrahydrofuran, heating to room temperature, and stirring overnight; cooling the reaction solution, adjusting the pH to 3-5 with 20% hydrochloric acid, stirring for 0.5 h, standing for liquid separation, collecting organic phase, concentrating under reduced pressure, diluting the concentrated residual solution with n-hexane, washing with water, drying with anhydrous sodium sulfate, and concentrating to obtain intermediate 1, namely 77.0g of 3-hydroxy-6, 6-dimethyl-1-heptene-4-alkyne, with the yield of 97.5%
EXAMPLE 21 Synthesis of bromo-6, 6-dimethyl-2-hepten-4-yne
Adding 436.6g of 40% hydrobromic acid into a 1000ml glass three-mouth reaction bottle, controlling the temperature below 50 ℃, slowly adding 113.2g of phosphorus tribromide, cooling to below 10 ℃, slowly adding 77.0g of intermediate 13-hydroxy-6, 6-dimethyl-1-heptene-4-alkyne and 90ml of ethanol mixed solution, and reacting for 1-3 hours at room temperature.
After the reaction is completed, standing and separating, collecting an organic phase, diluting the organic phase by using 150ml of normal hexane, washing the organic phase by using 300ml of water 2 times, drying the organic phase by using anhydrous sodium sulfate, and concentrating the mixture to obtain a light yellow liquid intermediate 2, namely 108.8g of a mixture of E/Z-1-bromo-6, 6-dimethyl-2-hepten-4-yne, wherein the yield is 97.12%.
EXAMPLE 3 Synthesis of N- (6, 6-dimethylhept-2-en-4-ynyl) -N-methyl-1-naphthalenemethylamine
Adding 286.0g of 10% sodium hydroxide solution and 72.5g of N-methyl-1-naphthylmethylamine into a 1000ml glass three-neck flask, controlling the temperature to be 20-30 ℃ under the protection of nitrogen, dropwise adding 100.0g of mixture of intermediate 2E/Z-1-bromo-6, 6-dimethyl-2-heptene-4-alkyne, and reacting at room temperature for 3 hours after dropwise adding.
TLC detection till the N-methyl-1-naphthylmethylamine disappears and the reaction is finished. And adding ethyl acetate into the reaction liquid for extraction, standing, separating liquid, collecting an organic phase, adding a proper amount of water for washing, separating a water phase, washing the organic phase by using saturated saline solution, drying by using anhydrous sodium sulfate, and concentrating to obtain yellow oily matter (E/Z) -N- (6, 6-dimethylhept-2-ene-4-alkynyl) -N-methyl-1-naphthylmethylamine, namely 134.3g of a terbinafine free alkali E/Z mixture, wherein the yield is 92.7%.
EXAMPLE 4 purification of terbinafine hydrochloride Z-isomer
Adding 100.0g of terbinafine free alkali E/Z mixture and 400ml of ethyl acetate into a 1000ml glass three-necked bottle, stirring, dissolving and clarifying, controlling the temperature to be 20-30 ℃, introducing 12.5g of hydrogen chloride gas, stirring for 3 hours, slowly cooling to-10-0 ℃, preserving heat for 3 hours, filtering, and concentrating the filtrate under reduced pressure to obtain 47.2g of oily matter.
Putting 45.3g of oily matter into a 500ml three-necked bottle, adding 225ml of methyl tert-butyl ether, heating to 50 ℃ to dissolve, cooling to 10-15 ℃, preserving heat for 3 hours, filtering and drying to obtain 42.7g of white-like compound with the yield of 37.96%. And detecting the final product by a nuclear magnetic resonance spectrometer, and confirming that the substance is terbinafine hydrochloride Z-type isomer by a detection result. The detection NMR spectrum is shown in FIG. 1. The nuclear magnetic resonance data is as follows:
1 H-HNR(400MHZ,CDCl 3 )δ1.24(s，9H)，2.65(d，3H)，3.96(d，2H)，4.70(d，2H)，5.97(t，1H)，6.31(t，1H)，7.55(m，1H)，7.58(m，1H)，7.65(m，1H)，7.92(m，1H)，7.95(m，1H)，8.00(m，1H)，8.10(m，1H)，12.60(m，1H)
EXAMPLE 5 terbinafine hydrochloride Z-isomer purity assay
Weighing a proper amount of terbinafine hydrochloride Z-type isomer obtained by synthesis in example 4, adding a solvent for dissolution, and carrying out gradient elution according to the following detection method: octadecylsilane bonded silica gel as a packing material (ZORBAX Eclipse plus C183.0mm x 150mm, 5um or equivalent chromatography column is recommended); taking triethylamine buffer solution (0.2% triethylamine solution is taken, adjusting pH to 7.5 with glacial acetic acid) -methanol-acetonitrile (30:42:28) as a mobile phase A, and taking triethylamine buffer solution-methanol-acetonitrile (5:57:38) as a mobile phase B; the flow rate was 0.8ml per minute, the detection wavelength was 280nm, and gradient elution was performed as in Table 1 below.
TABLE 1
Gradient elution is carried out according to the detection method, and the purity is more than 99.0 percent. Is suitable for distinguishing terbinafine hydrochloride (E/Z) isomers.
Claims (5)
1. A preparation method of terbinafine hydrochloride Z-type isomer is disclosed, wherein the structural formula of the terbinafine hydrochloride Z-type isomer is shown as formula I:
the preparation method is characterized by comprising the following steps:
1) tert-butyl acetylene is used as a starting material and is converted into 3, 3-dimethyl-1-butynyl lithium through n-butyl lithium reaction, and the 3, 3-dimethyl-1-heptylene-4-yne is synthesized with acrolein to form an intermediate 13-hydroxy-6, 6-dimethyl-1-heptylene-4-yne;
2) the intermediate 1 and a halogenated reagent are subjected to halogenation reaction to synthesize an intermediate 2E/Z-1-bromo-6, 6-dimethyl-2-heptene-4-alkyne;
3) condensing the intermediate 2 and N-methyl-1-naphthylmethylamine under an alkaline condition to obtain E/Z-N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthylmethylamine, namely a terbinafine free alkali E/Z mixture;
4) adding an organic solvent into a terbinafine free alkali E/Z mixture for dissolving, introducing hydrogen chloride for salification, and refining by methyl tert-butyl ether to obtain a high-purity terbinafine hydrochloride isomer (Z) -N- (6, 6-dimethyl hept-2-ene-4-alkynyl) -N-methyl-1-naphthylmethylamine;
the route is as follows:
2. the method according to claim 1, wherein the molar ratio of tert-butyl acetylene to n-butyl lithium in step 1) is 1:1 to 3, and the molar ratio of tert-butyl acetylene to acrolein is 1:1 to 5.
3. The process of claim 1, wherein the halogenating agent in step 2) is hydrobromic acid/phosphorus tribromide.
4. The method of claim 1, wherein the basic conditions in step 3) are the presence of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium hydroxide, diethylamine, triethylamine or pyridine.
5. The method of claim 1, wherein the organic solvent in step 4) is ethyl acetate, isopropanol, n-butanol, acetone, dioxane, petroleum ether, n-hexane, n-heptane, cyclohexane or toluene.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1362400A (en) * | 2001-12-25 | 2002-08-07 | 中国科学院上海有机化学研究所 | Synthesis of terbinafine hydrochloride |
| CN1634858A (en) * | 2004-11-03 | 2005-07-06 | 浙江海正药业股份有限公司 | Process for preparing terbinafine hydrochliride |
| 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 |
| CN104725240A (en) * | 2015-02-12 | 2015-06-24 | 吉林修正药业新药开发有限公司 | Method for preparing terbinafine hydrochloride Z-shaped isomer |
| CN110423200A (en) * | 2019-08-29 | 2019-11-08 | 成都奥邦药业有限公司 | A kind of preparation method improving terbinafine HCl purity |
| CN114380696A (en) * | 2021-12-23 | 2022-04-22 | 山东诚汇双达药业有限公司 | Preparation method of terbinafine hydrochloride |
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- 2022-06-28 CN CN202210751755.XA patent/CN115073303A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1362400A (en) * | 2001-12-25 | 2002-08-07 | 中国科学院上海有机化学研究所 | Synthesis of terbinafine hydrochloride |
| CN1634858A (en) * | 2004-11-03 | 2005-07-06 | 浙江海正药业股份有限公司 | Process for preparing terbinafine hydrochliride |
| 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 |
| CN104725240A (en) * | 2015-02-12 | 2015-06-24 | 吉林修正药业新药开发有限公司 | Method for preparing terbinafine hydrochloride Z-shaped isomer |
| CN110423200A (en) * | 2019-08-29 | 2019-11-08 | 成都奥邦药业有限公司 | A kind of preparation method improving terbinafine HCl purity |
| CN114380696A (en) * | 2021-12-23 | 2022-04-22 | 山东诚汇双达药业有限公司 | Preparation method of terbinafine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| P. V. KAZAKOV等: ""A SIMPLE METHOD FOR OBTAINING TERBINAFINE HYDROCHLORIDE"", 《PHARMACEUTICAL CHEMISTRY JOURNAL》, vol. 38, no. 4, pages 206 - 208 * |
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