Terbinafine

Terbinafine (TDT 067) is an antifungal medication used to treat fungal infections. It is a potent non-competitive inhibitor of squalene epoxidase from Candida with a Ki of 30 nM.

Solid

Terbinafine is a tertiary amine that is N-methyl-1-naphthalenemethylamine in which the amino hydrogen is replaced by a 3-(tertbutylethynyl)allyl group. An antifungal agent administered orally (generally as the hydrochloride salt) for the treatment of skin and nail infections. It has a role as an EC 1.14.13.132 (squalene monooxygenase) inhibitor, a P450 inhibitor and a sterol biosynthesis inhibitor. It is a tertiary amine, an acetylenic compound, a member of naphthalenes, an enyne and an allylamine antifungal drug. It is a conjugate base of a terbinafine(1+).|Terbinafine hydrochloride (Lamisil) is a synthetic allylamine antifungal. It is highly lipophilic in nature and tends to accumulate in skin, nails, and fatty tissues. Like other allylamines, terbinafine inhibits ergosterol synthesis by inhibiting the fungal squalene monooxygenase (also called squalene epoxidase), an enzyme that is part of the fungal cell wall synthesis pathway. Terbinafine hydrochloride was granted FDA approval on 30 December 1992.|Terbinafine is an Allylamine Antifungal.|Terbinafine is an orally and topically active allylamine fungicidal agent which is used to treat superficial fungal infections of the skin and nails. Terbinafine has been clearly linked to rare instances of acute liver injury that can be severe and sometimes fatal.|Terbinafine is a synthetic allylamine derivative with antifungal activity. Terbinafine exerts its effect through inhibition of squalene epoxidase, thereby blocking the biosynthesis of ergosterol, an important component of fungal cell membranes. As a result, this agent disrupts fungal cell membrane synthesis and inhibits fungal growth.|A naphthalene derivative that inhibits fungal SQUALENE EPOXIDASE and is used to treat DERMATOMYCOSES of the skin and nails.

The crude N- (3-CHLORO-2-PROPENYL)-N-METHYL-1-NAPHTHALENEMETHANAMINE (12.0 mmoles) (E/Z=98/2), 0.27 g of Pt/C 10% (about 50% umidity) (0.069 mmoles), 0.027 g of CuI (0.14 mmoles), 3.11 g of piperidine (36 mmoles) at room temperature. The mixture is heated under stirring to approx. 80C inner temperature for 30', then cooled to about 40C and 1.29 g OF T-BUTYLACETYLENE (16 mmoles) is dropped therein. The reaction mixture is heated at 80C and is kept in these conditions for 3 hours, then is cooled at r. t. and diluted with 40 ml of toluene and 80 ml of water. Stirring is continued for about 15', then the mixture is filtered through CELITE and filtration mother liquors are acidified under stirring with 3.1 g of 37% HC1 (31.6 mmoles). The phases are separated and the toluene phase is evaporated under vacuum at 50C to obtain 3.60 g of an oily residue consisting of 3.42 g of 10.0 g (0.0858 mol) tert-butyl-2-chloro-acetylene and 50 ml toluene are introduced into a reactor. The resulting solution is heated at 80C, and then over a period of 30 minutes, 35.5 ml of 25% n-butyllithium (1.15 eq. ) in heptane are added. Upon complete addition, the resulting white suspension is stirred for 2 hours at 80 C. A mixture of toluene and chlorobutane, reaction by-product, is then subsequently distilled at atmospheric pressure under a flow of nitrogen, at the same time adding toluene in order to keep the initial volume constant. The mixture is cooled to 50C and 15.5 g (0.0572 mol) crude N-(trans-3-chloro-2-propenyl)-N-inethyl-1- naphthalene-methylamine, 20 ml THF and 74 mg NiCl2 (0.77 molar percent) introduced. The reaction mixture is heated at 90-95C for 1 hour, cooled to 20/25C and 130 ml of a 2.5% (w/v) aqueous solution of EDTA disodium salt added, the phases are separated and the aqueous phase re- extracted with 70 ml chilled toluene. The combined organic phases are washed with 2x90 ml water and concentrated to a residue, thus giving 18.2 g (greater than theoretical yield) The reaction described in is repeated, using a mixture of 77 mg of NiC12 (0.7% mol) and 300 mg of triphenylphosphine as a catalyst. The reaction mixture is heated at 90-95C for 1 hour. Following the work-up described in example 8, 19.2 g (greater than theoretical yield) of The reaction described in is repeated, using 600 mg of PdCl2(PPh3) (1.4 molar percent) as a catalyst. The reaction mixture is heated at 90-95C for 1 hour and subsequently cooled to 20-25C. Following the work-up described in example 8, 19.2 g (greater than the theoretical yield), of 1.5 g (0.216 mol) lithium granules which are then covered with 40 ml tetrahydrofuran are introduced into an inertised reactor. The suspension is heated to 50C and subsequently a solution consisting of 10 g (0.085 mol) tert-butyl-2-chloroacetylene and 10 ml THF is added dropwise over a period of 40 minutes. The reaction mixture is refluxed for two hours until the complete consumption of the reagent. 110 mg (0.085mmol) NiC12, 10 ml THF and 13.9 g (0.0566 mol, 0.66 eq. ) crude N-(trans-3-chloro-2- propenyl)-N-methyl-1-naphthalenemethanamine are introduced into an inertised reactor under nitrogen; the suspension is then poured into the reactor mentioned above. The mixture is refluxed for 5 hours, after which time, it is cooled to room temperature and then 10 ml water, 50 ml of a 5% aqueous EDTA solution and 50 ml toluene are added. The suspension is stirred and the phases separated. The organic phase is washed a further three times with 50 ml of a 5% EDTA solution adjusted to pH 9 with NH40H and finally, concentrated to residue to give 17.5 g of crude 1.5 g (0.216 mol) lithium granules which are then covered with 40 ml tetrahydrofuran are introduced into an inertised reactor. The suspension is heated to 50C and subsequently a solution consisting of 10 g (0.085 mol) ' tert-butyl-2-chloroacetylene and 10 ml THF is added dropwise over a period of 40 minutes. The reaction mixture is refluxed for two hours until the complete consumption of the reagent. 110 mg (0.085mmol) NiCl2, 455 mg triphenylphosphine and 10 ml THF are introduced into a second inertised reactor under nitrogen. The mixture is heated until a yellow precipitate is obtained, then 13.9 g (0.0566 mol) crude N-(trans-3- chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine are added. The resulting suspension is poured into the first reactor and the mixture refluxed for 2 hours until complete conversion, and then cooled to room temperature. By following the same work-up as example 13, 17.0 g (greater than theoretical yield) crude Terbinafine is obtained with a purity of 74.5%.The reaction described in example 6 is repeated, using 421 mg PdCl2(PPh3) (1.4 mol%) as a catalyst. The reaction mixture is heated at 90-95C for 4 hours and subsequently cooled to 20-25C. Following the work-up described in example 6, 14.2 g (greater than the theoretical yield), of crude Into a reactor in an inert atmosphere are introduced 1.58 g (0.228 mol) of lithium granules and 40 ml tetrahydrofuran. The suspension is heated at 50C and subsequently a solution consisting of 10 g (0.065 mol) 1, 1-dichloro-3, 3-dimethylbutene 5 and 10 ml THF added dropwise over a period of 40 minutes. The reaction mixture is refluxed for three hours until the complete consumption of the reagent. Then 10.6 g (0.043 mol) crude N-(trans-3-chloro-2-propenyl)-N- methyl-1-naphthalene-methanamine, 80 mg (0.61 mmol) NiCl2 and 10 ml THF are added. The mixture is kept refluxing for 6 hours and then cooled to 20C. 10 ml water, 50 ml of a 5 % (w/v) solution of EDTA disodium salt and 50 ml toluene are added to the reaction mixture. The suspension is stirred and the phases separated. The organic phase is washed with 3 x 50 ml of a 5% EDTA solution adjusted to pH 9 with NH40H and finally, concentrated to residue to give 12.5 g of crude 50.0 g (0.321 mol) of 1, 1-dichloro-3, 3- dimethylbutene and 250 ml toluene are introduced into a reactor. The resulting solution is heated at 80C, and then 242.5 ml 25% n-butyllithium (2.1 eq. ) in heptane is added over a period of 45 minutes at 80-90 C. Upon complete addition, the resulting white suspension is stirred for 2 hours at 80 C. A mixture of toluene, heptane and chlorobutane, reaction by-product, is then subsequently distilled at atmospheric pressure under a flow of nitrogen, at the same time adding toluene in order to keep the initial volume constant. The suspension is cooled to 80C and 66.7 g (0.247 mol, 0.8 eq. , titre HPLC A% 91.0%), of crude N-(trans-3- chloro-2-propenyl)-N-methyl-l-naphthalenemethanamine, 100 ml THF and 480 mg NiCl2 (3.7 mmol, 0.011 eq. ) added. The reaction mixture is heated at 90-95C for 1 hour and then cooled to 20-25C. 400 ml water and 100 ml of 30% aqueous ammonia are added; the phases are separated and the aqueous phase re-extracted with 250 ml toluene. The combined organic phases are washed with 2x250 ml water and subsequently treated with 3.5 g of acticarbon. After stirring for 30 minutes at 20/25C, the carbon is filtered, washing the filter with 100 ml toluene. The organic phase is concentrated to residue, thus giving 62.8 g (0.215 mol, 87.0% yield) of crude 10.0 g (0.06 mol) 1, 1-dichloro-3, 3-dimethylbutene and 50 ml toluene are introduced into a reactor. The resulting solution is heated at 80C, and then 45.5 ml 25% n-butyllithium (2.1 eq. ) in heptane are added over a period of 30 minutes. Upon complete addition, the resulting white suspension is stirred for 2 hours at 80 C. A mixture of toluene and chlorobutane, reaction by- product, is then subsequently distilled at atmospheric pressure under a flow of nitrogen, at the same time adding toluene in order to keep the initial volume constant. The suspension is cooled to 50C and 10.8 g (0.04 mol, 0.66 eq. ) of crude N-(trans-3-chloro-2-propenyl)-N- methyl-1-naphthalenemethanamine, 20 ml THF, 52 mg NiCl2 (0.7 molar percent) and 210 mg triphenylphosphine added. The reaction mixture is heated at 90-95C for 4 hours. The mixture is cooled and, at 20/25C, 100 ml of a 2.5% aqueous EDTA disodium salt solution added, the phases are separated and the aqueous phase re-extracted with 75 ml toluene. Finally, the combined organic phases are washed with 2x80 ml water. The organic phase is concentrated to residue, thus giving 15.1 g (in excess of theoretical yield) crude

Allylamine antifungal drugs have a wider antibacterial spectrum than naftifine and higher antifungal activity. It can inhibit the squalene cyclooxygenase of the fungus with high selectivity, so that the squalene epoxidation reaction is blocked during the formation of the fungal cell membrane, and the formation of the fungal cell membrane is destroyed, so as to kill or inhibit the fungus. Safe, low toxicity, small side effects, good tolerance for oral and external use, no teratogenicity or embryo toxicity. Clinically used for various skin fungal infections (tinea pedis, jock itch and body ringworm) and nail fungal infections.

Molecular Weight:291.4
XLogP3:5.6
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:5
Exact Mass:291.198699802
Monoisotopic Mass:291.198699802
Topological Polar Surface Area:3.2
Heavy Atom Count:22
Complexity:428
Defined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes