A preparation method of terbinafine hydrochloride Z-isomer

Abstract

The invention discloses a method for preparing a Z-type isomer of terbinafine hydrochloride. The method uses tert-butyl acetylene as a starting material, converts it into 3,3-dimethyl-1-butynyl lithium through a reaction with n-butyl lithium, synthesizes an intermediate 13-hydroxy-6,6-dimethyl-1-heptene-4-yne with acrolein, and then synthesizes an intermediate 2E / Z-1-bromo-6,6-dimethyl-2-heptene-4-yne through halogenation; the intermediate 2 is condensed with N-methyl-1-naphthylmethylamine under alkaline conditions to synthesize terbinafine free base, and then salifies it with hydrogen chloride and refines it with methyl tert-butyl ether to obtain a high-purity terbinafine hydrochloride isomer (Z)-N-(6,6-dimethylheptene-2-en-4-ynyl)-N-methyl-1-naphthylmethylamine. The process route of the invention is short, the synthesis steps are relatively simple, the raw materials used in the experiment are easily available, the reaction conditions are relatively mild, the product quality is stable, the whole operation is simple and easy to implement, the prepared sample has high purity, and can be used for the preparation of terbinafine Z-isomer reference substance.

Description

Technical Field

[0001] The invention relates to a method for preparing an isomeric impurity of terbinafine hydrochloride, an allylamine drug with broad-spectrum antifungal activity, namely (Z)-N-(6,6-dimethylhept-2-en-4-ynyl)-N-methyl-1-naphthylmethylamine, and belongs to the technical field of medicine. Background Art

[0002] Terbinafine hydrochloride is also known as terbinafine hydrochloride in Chinese, and its chemical name is (E)-N-(6,6-dimethylhept-2-en-4-ynyl)-N-methyl-1-naphthylamine hydrochloride. Its structural formula is:

[0003]

[0004] The chemical name of the impurity of terbinafine hydrochloride Z-isomer is (Z)-N-(6,6-dimethylhept-2-en-4-ynyl)-N-methyl-1-naphthylamine hydrochloride. Its structural formula is:

[0005]

[0006] Terbinafine hydrochloride belongs to the class of allylamine antifungal drugs. It inhibits the activity of squalene epoxidase to reduce the synthesis of ergosterol and thus has a bactericidal effect. It can be used to treat skin, hair and nail infections caused by Trichophyton (Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton verrucosum, Trichophyton tonsurans and Trichophyton violaceum, etc.), Microsporum canis and Epidermophyton floccosum.

[0007] Terbinafine hydrochloride is an antifungal drug that can be used externally or orally. Its current dosage forms include tablets, granules, suppositories, sprays, liniments, creams, etc. It has an inhibitory effect on most pathogenic fungi, among which dermatophytes are the most sensitive. The incidence of skin fungal infections is high and the duration of illness is long. Although there are many types of current treatment drugs, there are few with good treatment effects, low recurrence rates, and low drug toxicity and side effects. Griseofulvin drugs introduced decades ago were discontinued due to poor efficacy; ketoconazole drugs have serious toxicity and side effects when administered for a long time; although the new triazole drugs have high efficacy and low side effects, they are expensive and difficult to be widely used by the general public. Terbinafine hydrochloride has a wide antibacterial spectrum and strong antibacterial effect. It can kill bacteria and inhibit bacteria. External use or short-term oral treatment can cure most skin fungal diseases, and has a low recurrence rate, few side effects, and high safety. Its MIC and MFC are almost equal, and it can be widely used to treat various skin fungal diseases, especially onychomycosis. Therefore, terbinafine hydrochloride has attracted worldwide attention.

[0008] Terbinafine hydrochloride has cis and trans isomer structures, namely (E)-N-(6,6-dimethylhept-2-en-4-ynyl)-N-methyl-1-naphthylamine hydrochloride and (Z)-N-(6,6-dimethylhept-2-en-4-ynyl)-N-methyl-1-naphthylamine hydrochloride. The Z-isomer of terbinafine hydrochloride has low biological activity, and the active ingredient of the fungicide substance is the E-isomer of terbinafine hydrochloride. However, in the production process of terbinafine hydrochloride raw materials, free trans- and cis-terbinafine hydrochloride compounds exist at the same time. In order to more accurately detect the target product trans-terbinafine hydrochloride, it is particularly important to determine the position of cis-terbinafine hydrochloride. High-purity Z-isomers are helpful for the analysis and control of the quality of terbinafine hydrochloride.

[0009] The patent application with publication number CN 104725240 B discloses a method for preparing the Z-isomer of terbinafine hydrochloride. The patent application only describes a purification method for preparing the Z-isomer from the terbinafine E / Z mixture, but does not propose a complete synthetic process route. In addition, the purification solvent used in the method is 4-chlorophenyl tert-butyl ether, which is expensive and has a low yield of the refined product. Moreover, the temperature rise to 100-150° C. during the conversion process is relatively harsh and difficult to control.

[0010] The invention provides a preparation method of terbinafine hydrochloride Z-isomer, and further proposes an analysis and detection method of terbinafine hydrochloride Z-isomer. The raw materials used in the preparation method are all easily available in the market, low in price, and each step has a high yield, mild conditions, simple synthesis steps, stable product quality, simple experimental operation, and a high purity of the prepared sample, reaching more than 99.0%. Summary of the invention

[0011] The object of the present invention is to provide a method for preparing a Z-isomer of terbinafine hydrochloride, by which a high-purity isomer impurity compound for impurity analysis of terbinafine hydrochloride, an allylamine drug with broad-spectrum antifungal activity, is obtained.

[0012] In order to achieve the above object, the present invention adopts the following technical solutions:

[0013] The present invention discloses a method for preparing a terbinafine hydrochloride Z-isomer, wherein the structural formula of the terbinafine hydrochloride Z-isomer is as shown in Formula I:

[0014]

[0015] The preparation method comprises the steps of:

[0016] 1) Using tert-butylacetylene as the starting material, it is converted into 3,3-dimethyl-1-butynyl lithium through n-butyl lithium reaction, and then reacted with acrolein to synthesize the intermediate 13-hydroxy-6,6-dimethyl-1-heptene-4-yne;

[0017] 2) intermediate 1 is subjected to a halogenation reaction with a halogenating agent to synthesize intermediate 2E / Z-1-bromo-6,6-dimethyl-2-heptene-4-yne;

[0018] 3) Intermediate 2 is condensed with N-methyl-1-naphthylmethylamine under alkaline conditions to obtain E / ZN-(6,6-dimethylhept-2-en-4-ynyl)-N-methyl-1-naphthylmethylamine, i.e., terbinafine free base E / Z mixture;

[0019] 4) adding terbinafine free base E / Z mixture into an organic solvent to dissolve, passing hydrogen chloride to form a salt, and refining with methyl tert-butyl ether to obtain high-purity terbinafine hydrochloride isomer (Z)-N-(6,6-dimethylhept-2-en-4-ynyl)-N-methyl-1-naphthylmethylamine;

[0020] The route is as follows:

[0021]

[0022] Preferably, in step 1), the molar ratio of tert-butylacetylene to n-butyllithium is 1:1-3, and the molar ratio of tert-butylacetylene to acrolein is 1:1-5.

[0023] Wherein, preferably, the halogenating agent in step 2) is hydrobromic acid / phosphorus tribromide.

[0024] Among them, preferably, the alkaline conditions described in step 3) refer to the presence of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, diethylamine, triethylamine or pyridine.

[0025] Wherein, 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.

[0026] Compared with the prior art, the beneficial effects of the present invention are:

[0027] 1. The invention discloses a method for preparing a Z-type isomer of terbinafine hydrochloride, wherein the starting raw material tert-butyl acetylene is reacted with n-butyl lithium to synthesize intermediate 1 with acrolein, and then intermediate 2 is synthesized by halogenation reaction, and intermediate 2 is condensed with N-methyl-1-naphthylamine under alkaline conditions, and then hydrogen chloride gas is passed to form a salt and refined with methyl tert-butyl ether to obtain high-purity terbinafine hydrochloride isomer (Z)-N-(6,6-dimethylhept-2-ene-4-ynyl)-N-methyl-1-naphthylamine. The synthesis step of the present invention is relatively simple, the raw materials used in the experiment are easy to obtain, the reaction conditions are relatively mild, the product quality is stable, the whole process operation is simple and easy to implement, and the purity of the prepared sample is high.

[0028] 2. The invention can obtain a terbinafine hydrochloride Z-isomer with high purity, which can be used as a terbinafine Z-isomer reference substance for quality analysis of terbinafine hydrochloride, investigate the separation between impurities and samples, and realize a more accurate analysis method. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the nuclear magnetic resonance hydrogen spectrum of terbinafine hydrochloride Z isomer. DETAILED DESCRIPTION

[0030] The technical solutions in the embodiments of the present invention will be described clearly and completely below in combination with the embodiments of the present invention. Obviously, the described embodiments are only a part of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] Example 1 Synthesis of 3-hydroxy-6,6-dimethyl-1-heptene-4-yne

[0032] In a 1000ml glass three-necked reaction bottle, under nitrogen protection, 50.0g of tert-butylacetylene and 150ml of tetrahydrofuran were added, cooled to -40 to -90°C, 255ml of n-butyllithium n-hexane solution (2.5M) was slowly added dropwise, and the mixture was kept warm for 1 to 3 hours to convert into 3,3-dimethyl-1-butynyl lithium. The temperature was then controlled at -40 to -90°C, and a mixture of 37.5g of acrolein and 100ml of tetrahydrofuran was added dropwise, and the mixture was heated to room temperature and stirred overnight; the reaction solution was cooled, and the pH was adjusted to 3 to 5 with 20% hydrochloric acid, stirred for 0.5 hour, and allowed to stand for separation, and the organic phase was collected and concentrated under reduced pressure, and the concentrated residual liquid was diluted with n-hexane, washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain intermediate 1, i.e., 77.0g of 3-hydroxy-6,6-dimethyl-1-heptene-4-yne, with a yield of 97.5%.

[0033] Example 2 Synthesis of 1-bromo-6,6-dimethyl-2-heptene-4-yne

[0034] In a 1000ml glass three-necked reaction bottle, add 436.6g of 40% hydrobromic acid, control the temperature below 50°C, slowly add 113.2g of phosphorus tribromide, cool to below 10°C, slowly add a mixture of 77.0g of the intermediate 13-hydroxy-6,6-dimethyl-1-heptene-4-yne and 90ml of ethanol, and react at room temperature for 1 to 3 hours.

[0035] After the reaction is complete, the mixture is allowed to stand and separated. The organic phase is collected and diluted with 150 ml of n-hexane, washed twice with 300 ml of water, dried over anhydrous sodium sulfate, and concentrated to obtain a light yellow liquid intermediate 2, i.e., a mixture of E / Z-1-bromo-6,6-dimethyl-2-heptene-4-yne, 108.8 g, with a yield of 97.12%.

[0036] Example 3 Synthesis of N-(6,6-dimethylhept-2-en-4-ynyl)-N-methyl-1-naphthylmethylamine

[0037] In a 1000ml glass three-necked flask, add 286.0g of 10% sodium hydroxide solution and 72.5g of N-methyl-1-naphthylamine. Under nitrogen protection, control the temperature at 20-30°C, and drop 100.0g of the mixture of the intermediate 2E / Z-1-bromo-6,6-dimethyl-2-heptene-4-yne. After the dropwise addition, react at room temperature for 3 hours.

[0038] The reaction was terminated when N-methyl-1-naphthylamine disappeared after TLC detection. The reaction solution was extracted with ethyl acetate, allowed to stand, and separated. The organic phase was collected and washed with an appropriate amount of water, and the water phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oil (E / Z)-N-(6,6-dimethylhept-2-ene-4-ynyl)-N-methyl-1-naphthylamine, which was 134.3 g of terbinafine free base E / Z mixture with a yield of 92.7%.

[0039] Example 4 Refining of Terbinafine Hydrochloride Z-Isomer

[0040] In a 1000ml glass three-necked flask, add 100.0g of terbinafine free base E / Z mixture and 400ml of ethyl acetate, stir to dissolve and clarify, control the temperature at 20-30°C, pass 12.5g of hydrogen chloride gas, stir for 3 hours, then slowly cool to -10°C-0°C and keep warm for 3 hours, filter, and concentrate the filtrate under reduced pressure to obtain 47.2g of an oily substance.

[0041] 45.3g of the oily substance was placed in a 500ml three-necked flask, 225ml of methyl tert-butyl ether was added, the temperature was raised to 50°C to dissolve, the temperature was then lowered to 10-15°C, the temperature was kept for 3 hours, filtrated and dried to obtain 42.7g of an off-white compound with a yield of 37.96%. The above-mentioned final product was tested by a nuclear magnetic resonance spectrometer, and the test results confirmed that the substance was the Z-isomer of terbinafine hydrochloride. The nuclear magnetic resonance hydrogen spectrum was tested as shown in FIG. Figure 1 The NMR data are as follows:

[0042] 1 H-HNR (400MHZ, CDCl3) 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)

[0043] Example 5 Purity Detection of Terbinafine Hydrochloride Z-Isomer

[0044] Weigh an appropriate amount of the Z-isomer of terbinafine hydrochloride synthesized in Example 4, dissolve it in a solvent, and perform gradient elution according to the following detection method: use octadecylsilane bonded silica gel as a filler (ZORBAX Eclipse plus C18 3.0 mm*150 mm, 5 um or an equivalent chromatographic column is recommended); triethylamine buffer (take 0.2% triethylamine solution, adjust the pH to 7.5 with glacial acetic acid)-methanol-acetonitrile (30:42:28) as mobile phase A, and triethylamine buffer-methanol-acetonitrile (5:57:38) as mobile phase B; the flow rate is 0.8 ml per minute, the detection wavelength is 280 nm, and gradient elution is performed according to Table 1 below.

[0045] Table 1

[0046]

[0047] The purity of the product is greater than 99.0% after gradient elution according to the above detection method, and the product is suitable for distinguishing the isomers of terbinafine hydrochloride (E / Z).

Claims

1. A method for preparing a terbinafine hydrochloride Z-isomer, wherein the structural formula of the terbinafine hydrochloride Z-isomer is as shown in Formula I: It is characterized in that The preparation method comprises the steps of: 1) Using tert-butylacetylene as a starting material, it is converted into 3,3-dimethyl-1-butynyl lithium through a reaction with n-butyl lithium, and then reacted with acrolein to synthesize the intermediate 1 3-hydroxy-6,6-dimethyl-1-heptene-4-yne; 2) Intermediate 1 is reacted with a halogenating agent to synthesize intermediate 2 E / Z-1-bromo-6,6-dimethyl-2-heptene-4-yne; 3) Intermediate 2 is condensed with N-methyl-1-naphthylmethylamine under alkaline conditions to obtain E / ZN-(6,6-dimethylhept-2-en-4-ynyl)-N-methyl-1-naphthylmethylamine, i.e., terbinafine free base E / Z mixture; 4) In a 1000ml glass three-necked flask, add 100.0g of terbinafine free base E / Z mixture and 400ml of ethyl acetate, stir to dissolve and clarify, control the temperature at 20-30°C, pass 12.5g of hydrogen chloride gas, stir for 3 hours, then slowly cool to -10°C-0°C and keep warm for 3 hours, filter, and concentrate the filtrate under reduced pressure to obtain 47.2g of oil; put 45.3g of the oil in a 500ml three-necked flask, add 225ml of methyl tert-butyl ether, heat to 50°C to dissolve, then cool to 10-15°C, keep warm for 3 hours, filter and dry to obtain 42.7g of an off-white compound; the off-white compound is a high-purity terbinafine hydrochloride isomer (Z)-N-(6,6-dimethylhept-2-ene-4-ynyl)-N-methyl-1-naphthylamine; The route is as follows: 。 2. The method according to claim 1, characterized in that In step 1), the molar ratio of tert-butylacetylene to n-butyllithium is 1:1-3, and the molar ratio of tert-butylacetylene to acrolein is 1:1-5.

3. The method according to claim 1, characterized in that The halogenating agent described in step 2) is hydrobromic acid / phosphorus tribromide.

4. The method according to claim 1, characterized in that The alkaline conditions described in step 3) refer to the presence of sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, diethylamine, triethylamine or pyridine.

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