78628-80-5 Usage
Uses
Used in Pharmaceutical Industry:
Terbinafine hydrochloride is used as an antimycotic allylamine for the treatment of dermatophyte infections of the toenail/fingernail, ringworm, and jock itch. It acts as a specific inhibitor of squalene epoxidase, a key enzyme in fungal ergosterol biosynthesis.
Used in Research and Development:
Terbinafine hydrochloride is used in adsorption, partition, and stability studies to understand its properties and behavior in various conditions.
Used in Quality Control and Analysis:
Terbinafine hydrochloride may be used as a pharmaceutical reference standard for the determination of the analyte in drug dosage forms by UV spectrophotometry and high-performance thin layer chromatography (HPTLC).
Dermatologist Broad-spectrum Antifungal Drugs
Terbinafine hydrochloride is a kind of broad-spectrum dermatologist allyl amine antifungal drugs. It is developed by Swiss Novartis in the 1980 s, and appeared in the market of UK for the first time in 1991. Approved by FDA of the United States for OTC drugs in 1996, and appeared in the market of the United States in the same year. At present, the drug is been sold in more than 90 countries of the word. It can specificity trouble the late biological decomposition of fungus sterol, selectively inhibit the activity of fungal squalene ring oxidase, and inhibit the squalene epoxidation in the formation of ungal cell membrane, thus to kill or inhibit the active of the fungus. Suitable for treatment of candidiasis skin, such as tinea manuum, tinea, tinea, ringworm of the body, tinea versicolor, it is also the best medicine for the treatment of onychomycosis.
Terbinafine hydrochloride entered the the first batch of country announced OTC directory in 2000. This product belongs to antifungal drugs. It has strong effect on shallow fungal infection, and can cure most of the fungal skin diseases through external use.
Pharmacokinetics
According to reports in the literatures, after 250 mg of Terbinafine hydrochloride been taken orally, it reaches peak plasma concentration of 0.97 m ug/ml within 2 hours. The absorption half-life is 0.8 hours, spread half-life is 4.6 hours, the degree of biological application is slightly affected by eating, but not used for dose adjustments. The combination rate of drugs and plasma protein is 99%, and can quickly disperse and concentrate in the lipophilic corneous layer through the dermis. Terbinafine hydrochloride can be spread in the skin, therefore, a very high concentration can be reached in the hair follicle, hair and skin layers of fat, and it can enter in the deck in the last few weeks of healing. The metabolites after the bioconversion have no antifungal activity, then discharged through urine. The half-life is 17 hours, no accumulation in the body, and its steady blood drug concentration is not affected by age. But the alleviation rate can reduce for people with liver and kidney disorders, thus triggers blood drug concentration decreasing.
Indications
1.Skin, hair and nail infection caused by Btrichophyta (white hair versicolor bacterium, Trichophyton mentagrophytes, Trichophyton verrucosum, trichophyton tonsurans and Trichophyton violaceum, etc.), microsporum canis, epidermophyton floccosum, ect.
2.Skin yeast infections caused by all kinds of tinea disease (ringworm of the body, tinea, tinea manus and tinea capitis, etc.) and candida (candida albicans, etc.).
3.Onychomycosis (nail fungus infection) caused by molds.
Indications
Terbinafine Hydrochloride is a synthetic allylamine antifungal
agent, structurally related to naftifine. It inhibits fungal sterol biosynthesis
by inhibiting the enzyme squalene 2,3-epoxidase. The deficiency of
ergosterol and concomitant accumulation of squalene within the fungal
cell results in cell death. It can be fungicidal or fungistatic, depending on
the concentration used, and is effective against dermatophytes, Aspergillus,
blastomycosis, and histoplasmosis. It is only minimally effective against
Candida.
Usage and Dosage
Local external use: apply adequate amount to the affected area and its surrounding, 1-2 times a day. Ringworm of the body, 2-4 weeks, tinea of feet and hands, tinea versicolor, 4 to 6 weeks.
Oral: 0.25 grams each time for adult, once per day, period of treatment is as follows:
Skin infection treatment: tinea of feet and hands [toe (means) and plantar]: 2~6 weeks; Ringworm of the body, tinea, 2~4 weeks.
Skin candidiasis: 2~4 weeks. normal skin appearance and loss of infection can only be visible in a few weeks for curing.
Hair and scalp infection treatment: tinea capitis: 4 weeks, tinea capitis most happen in children.
Onychomycosis: The most treatment course of patients is 6 weeks to three months. Young patients with normal growth can shorten the treatment course, and less than 3 months of treatment may be enough in addition to the thumb (foot) armour.
In other cases, the treatment is usually 3 months. Some patients, especially whose thumb (toe) infected, may take 6 months or longer. The treatment may take more than 3 months if the nail grew slowly in the first week. In healing of mycology and stopping for a few months after treatment, the continuous improvement of nail appearance then completely normal can be seen, this is because that the healthy tissue growth needs time.
Originator
Sandoz (Switzerland)
Manufacturing Process
To an ice-cooled solution of N-methyl-1-naphthalenemethylamine
hydrochloride (2.1 g) in methanol (40 ml) and water (10 ml) was added
sodium hydroxide powder (2 g) followed by dropwise addition of
epichlorohydrin (8 ml). The mixture was heated at 60°C for 3 h, then cooled
to room temperature. Volatile materials were removed in vacuo and the
residue was taken up in ethyl acetate and washed with water. The organic
phase was collected, dried over sodium sulfate, filtered and evaporated to
dryness. The crude mixture was purified by flash chromatrography on silica
gel (grade 9385, Merck, 230-400 mesh, 60 A) using a solvent gradient of a
mixture of hexane and ethyl acetate (95:5, 90:10 and 85:15) as eluent,
affording the N-methyl-N-naphthylmethyl-2,3-epoxypropane (1.85 g, 81.5%)
as an oil.To a solution of 3,3-dimethylbutyne (2.95 ml) in dry THF (50 ml) at -78°C
was added a 2.5 M solution of n-BuLi in hexane (10 ml) dropwise. The
mixture was allowed to warm to room temperature over 15 min and stirred at
that temparature for a further 15 min, then was cooled back to -78°C and
BF3OEt2 (3 ml) was added dropwise. The mixture was stirred for 15 min and
1.8 g of N-methyl-N-naphthylmethyl-2,3-epoxypropane, dissolved in THF (10
ml), was added dropwise. After stirring at -78°C for 2 h, saturated sodium
bicarbonate solution (15 ml) was added, and the reaction mixture was allowed
to warm to room temperature. The mixture was extracted with ethyl acetate
(2 times 25 ml), and the combined organic fractions was dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was purified by flash
chromatrography on silica gel (grade 9385, Merck, 230-400 mesh, 60 a) using
a mixture of hexane and ethyl acetate (85:15) as eluent, thereby affording
the N-methyl-N-(1-naphthylmethyl)-2-hydroxy-heptan-4-ynyl-1-amine as an
oil (1.95 g, 79%).To an ice-cooled solution of N-methyl-N-(1-naphthylmethyl)-2-hydroxyheptan-
4-ynyl-1-amine (155 mg) in THF (10 ml) was added Et3N (0.35 ml)
followed by methanesulfonyl chloride (0.075 ml). The resulting mixture was
stirred at 0°C for 3 h, then filtered. The filtrate was concentrated in vacuo,
dissolved in toluene (10 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
(0.37 ml) was added. The resulting mixture was heated at 80°C for 4 h,
cooled to room temperature then poured onto a silica gel column and eluted
with hexane (100%) followed by a mixture of hexane and ethyl acetate
(95:5). Thus, a mixture of E- and Z-isomers of N-methyl-N-(1-
naphthylmethyl)-6,6-dimethylhept-2-en-4-ynyl)-1-amine were obtained in a
ratio of 2:5 (95 mg, 66%).
Therapeutic Function
Antifungal
Biochem/physiol Actions
Mode of Action: Inhibits squalene epoxidase, preventing biosynthesis of ergosterol.Antimicrobial spectrum: Antifungal and antimycotic. Fungicidal against dermatopytes and some yeasts; fungistatic against Candida albicans.
Clinical Use
Terbinafine hydrochloride (Lamisil) is available for
topical and systemic use (oral tablet) in the treatment of
dermatophyte skin and nail infections. Terbinafine also
exhibits in vitro activity against filamentous and dimorphic
fungi, but its clinical utility in treating infections
with these organisms has not yet been established. It is
used most commonly in the treatment of onychomycosis;
in this setting, terbinafine is superior to griseofulvin
and at least equivalent to itraconazole.When given systemically,
terbinafine is 99% protein bound and accumulates
in fat, skin, and nails, persisting for weeks.
Cerebrospinal fluid penetration is less than 10%.
Dosage reductions are required with renal or hepatic
insufficiency. Although terbinafine has little effect on
hepatic cytochrome P450 enzyme systems, it does minimally
enhance cyclosporine clearance. Oral terbinafine
is generally well tolerated but occasionally causes gastric
distress and liver enzyme elevation.
Clinical Use
(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalene-methanamine hydrochloride (Lamisil) is an off-whitecrystalline material that is soluble in polar organic solventssuch as methanol, ethanol, and methylene chloride but isonly slightly soluble in water. The highly lipophilic freebase is insoluble in water. Terbinafine hydrochloride isavailable in a 1% cream for topical administration for thetreatment of tinea pedis, tinea corporis, and tinea cruris.Terbinafine is more potent than naftifine and has alsodemonstrated oral activity against onychomycosis (ringwormof the nails). It has not been approved in the UnitedStates for oral administration.
Side effects
Adverse reactions include lens and retinal disturbances (red/green visual
perception), metallic taste disturbance that may last up to 4 weeks after
medication discontinuation, hepatoxicity, and pancytopenia. Five percent of
patients will experience delayed gastric emptying with symptoms of nausea,
fullness, and/or dyspepsia. Terbinafine does not appear to have any effect on
the cytochrome P-450 systems (Check baseline CBC and LFTs; repeat if taken
for >6 weeks).
Veterinary Drugs and Treatments
Terbinafine may be useful for treating dermatophytic and other
fungal infections in dogs and cats.
Terbinafine may also be useful for treating birds for systemic
mycotic (e.g., aspergillosis) infections.
Check Digit Verification of cas no
The CAS Registry Mumber 78628-80-5 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 7,8,6,2 and 8 respectively; the second part has 2 digits, 8 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 78628-80:
(7*7)+(6*8)+(5*6)+(4*2)+(3*8)+(2*8)+(1*0)=175
175 % 10 = 5
So 78628-80-5 is a valid CAS Registry Number.
InChI:InChI=1/C21H25N/c1-21(2,3)15-8-5-9-16-22(4)17-19-13-10-12-18-11-6-7-14-20(18)19/h5-7,9-14H,16-17H2,1-4H3/b9-5+
78628-80-5Relevant articles and documents
Preparation method of terbinafine hydrochloride
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Paragraph 0041; 0044-0048; 0051-0055; 0058-0062; 0065-0068, (2020/09/12)
The invention provides a preparation method of terbinafine hydrochloride, which comprises the steps of: carrying out a substitution reaction on N-methyl-1-naphthylamine (II) and (E)-1, 3-dichloropropene (III) in an acid-binding agent A to obtain an N-(3-chloroallyl-1)-methyl-1-naphthylamine (IV) reaction liquid; carrying out condensation reaction on N-(3-chloroallyl-1)-methyl-1-naphthylamine (IV)and 3, 3-dimethyl-1-butyne (V) in the reaction solution under the action of a composite catalyst and an acid-binding agent B to obtain a reaction solution of (E)-N-(6, 6-dimethyl-2-heptene-4-alkynyl)-N-methyl-1-naphthylamine (VI); complexing and washing the reaction solution with ammonia water to obtain an oily substance; and salifying the oily substance in a hydrochloric acid aqueous solution toobtain crude terbinafine hydrochloride, and recrystallizing the crude terbinafine hydrochloride to obtain terbinafine hydrochloride. The preparation method disclosed by the invention does not use an organic solvent, is environment-friendly, low in cost and simple to operate, and is suitable for industrial production.
Preparation method for improving purity of terbinafine hydrochloride
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Paragraph 0023-0037, (2019/11/21)
The invention discloses a preparation method for improving the purity of terbinafine hydrochloride, and the method comprises the following steps: 1) adding an acid binding agent into water, stirring and dissolving, adding N-methylnaphthylamine and 1-chlorine-6,6-dimethyl-2-heptene-4-alkyne, and cooling to room temperature; adding ethyl acetate for extraction, filtering, adding a hydrochloric acidaqueous solution, stirring, and filtering to obtain crude terbinafine hydrochloride; and 2) purifying the terbinafine hydrochloride, namely adding the crude terbinafine hydrochloride in the step 1) and purified water into a reaction kettle, heating and refluxing to dissolve, cooling to room temperature, and filtering to obtain a finished product of the terbinafine hydrochloride. According to the preparation method of the terbinafine hydrochloride, only water is used as a crystallization solvent and no toxic solvent is used in the final step reaction of the bulk drug, so that potential harm oftoxic organic solvents to human bodies is avoided; moreover, the solvent amount is extremely small, the cost is low, the generated waste liquid is less, the pollution to the environment is reduced, the product purity and yield are high, the reaction operation is simple, the control is easy, the production period is short, and commercial production is facilitated.
A PROCESS FOR THE PURIFICATION OF 1-HALO-6,6-DIMETHYL-HEPT-2-ENE-4-YNE
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Page/Page column 7, (2008/06/13)
The invention relates to a process for purification of 1-halo-6,6-dimethyl-hept-2-ene-4-yne of Formula (I), wherein X represents a halogen atom subjecting crude 1-halo-6,6-dimethyl-hept-2-ene-4-yne to distillation under reduced pressure to obtain pure 1-halo-6,6-dimethyl-hept-2-ene-4-yne. This compound is an important intermediate for the production of the widely used antifungal drug Terbinafine.
PROCESS FOR PREPARING TERBINAFINE
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Page/Page column 16; 17, (2010/11/27)
A process for preparing terbinafine or a salt thereof having high purity.
IMPROVED PROCESS FOR THE PREPARATION OF TERBINAFINE HYDROCHLORIDE AND NOVEL CRYSTALLINE FORM OF TERBINAFINE
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Page/Page column 21, (2010/11/28)
Improved process for the preparation of Terbinafme Hydrochloride compound of formula (I): substantially free of Genotoxic impurity compound of formula (II) and Novel crystalline form of Terbinafine.
Preparations for the care nails that contain Terbinafine hydrochloride
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Page/Page column 2, (2008/06/13)
There are provided topical preparations for the care of fingernails and toenails. The preparation is in the form of a varnish solution that contains Terbinafine Hydrochloride as an active ingredient and a vehicle formulated with all or some of the following components: ethyl alcohol, poly (methyl vinyl ether alt maleic acid monobutyl ester) in 50% ethanol solution, and Butylated Hydroxytoluene (BHT). The topical preparation can be applied in such a way as to be spread freely on the fine tissue of the nail. The preparation is comfortable when applied to the patient, and can be applied infrequently, depending on the degree of severity of the infection, and also shows good tolerability.
Process for the preparation of naphthylmethylamine derivatives
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Page/Page column 3, (2008/06/13)
Disclosed is a process for the preparation of a naphthylmethylamine derivative or a pharmaceutically acceptable salt thereof of Formula I wherein R1 is a lower straight or branched alkyl group and R2 is a lower straight or branched alkyl group, aryl group or araylalkyl group, the process comprising reacting a N-alkyl-1-naphthylmethylamine HCl compound of Formula II: wherein R1 has the aforestated meaning, with a compound of Formula III wherein X is a halogen and R2 has the aforestated meaning in the presence of at least one base and in at least one solvent.
Process for the preparation of terbinafine and salts thereof
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Page/Page column 6; 10-11, (2008/06/13)
A process for the preparation of Terbinafine and salts thereof by reacting 1-chloro-6,6-dimethylhept-2-en-4-yne and N-methyl-N-(1-naphthylmethyl)amine in a basic aqueous medium is disclosed. Also disclosed is a process for the preparation of 1-chloro-6,6-dimethylhept-2-en-4-yne.
AN IMPROVED PROCESS FOR THE PREPARATION OF TERBINAFINE HYDROCHLORIDE
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Page/Page column 9-10, (2010/02/14)
The present invention relates to an improved process for preparation of terbinafine hydrochloride ,which is (E) - N- Methyl -N-(1-Naphtylmethyl)-6,6-dimethylhept-2-ene-4-ynyl-1-amine has the formula (I), which comprises reacting t-butylacetylene with ethylmagnesium bromide in THF (ii) adding acrolein at a temperature in the range of 0-10o C to get , 6,6-dimethyl-hept-1-ene-4-yne-3-ol, (iii) reacting it with a mixture of phosphorous oxychloride and hydrochloric acid in methanol (iv) extracting the reaction mass with aliphatic/aromatic solvent and removing the solvent (v) reacting the residue with N-(1-naphtylmethyl)methyl amine in the presence of a base to give Terbinafine (vi) adding hydrochloric acid and extracting the Terbinafine Hcl formed with a chlorinated solvent and (vii) recovering the chlorinated solvent under vacuum and adding ethylacetate to separate Terninafine hydrochloride which is filtered and dried.
A PROCESS FOR THE SYNTHESIS OF TERBINAFINE AND DERIVATIVES THEREOF
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Page/Page column 37-38, (2010/02/15)
The present invention relates to a synthetic method for terbinafine and analogues thereof using metal catalysts, preferably Ni (II) salts and/or complexes.
