* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With hydrogenchloride; trichlorophosphate In methanol at 0 - 20℃; for 20 - 24 h; Stage #2: at 80℃; Stage #3: With hydrogenchloride In dichloromethane; water at 20℃;
In a four necked 2 Lit round bottom flask fitted with overhead mechanical stirrer, double surface condenser, thermometer pocket, and pressure equalizing funnel placed 'in the plastic tub, top of the condenser is connected with nitrogen inlet, THF 300ml, magnesium turnings (29.0grm. 1.208moles.) were charged . The flow of nitrogen was started and small amount (crystal) of iodine approximately 50.0 mgs. and 5ml of ethyl bromide was charged . The reaction starts with disappearance of brownish color, . Ethyl bromide (133.Ogrm..1.22 moles) mixed with THF (50ml ) were charged in pressure equalizing tunnel and started the addition of ethyl bromide slowly. The reaction flask was cooled with ice water and the temperature was maintained at 25-30°c. The cooling bath was replaced with water bath after the ethyl bromide addition was completed. The temperature was raised slowly up to 73-75°c. The reaction mixture was kept under reflux for 1 to 2 hours. The water bath was removed and the reaction flask was kept in a cooling bath replacing the condenser.with nitrogen inlet. The reaction mass was cooled to 0-5°c and t-butylacetylene (100grm. 1.219 moles) mixed with THF (50ml) was. charged through the funnel. The addition of t-butyl acetylene was started slowly at 0-5°c with stirring for some time at 0-5°c. Arolein (68: 0grm 1.22moles) mixed with THF (50ml) was charged through the funnel. The reaction mass was kept at 0-5°c, and stirred further for 2 to 3 hours at the same temperature and the temperature was raised to room temperature and stirred - for 18 to 20 hours and checked the completion of the reaction on gas chromatography. The reaction mixture is quenched with dil HCI and water, and the pH was adjusted to 2 to 2.5. The layers are separated and the aqueous phase is extracted with methylene chloride. The combined organic phase is washed with water to neutrality. The organic phase is dried and solvent stripped to give 6,6-dimethyl-hept-l-ene-4-yne-3=ol in 65.4percent yield with purity of 97.2percent .This is dissolved in methanol (300ml) and cooled to 0-5°C and mixture of phosphorous oxychloride (35.0grm 0.33mole), Hydrochloric acid (300ml) is charged slowly at 0-5°c. The reaction mixture was stirred at 0-5°c for 2' to 4 hours and the temperature was raised to room temperature and further stirred for several hours 18 to 20 hours . The completion of the reaction is checked on gas chromatography. After the reaction is completed; n-hexane (300ml) was charged , stirred for 30 min, and the phases were separated. The, aqueous phase was re-extracted with n-hexane (100ml) and the combined organic phase was washed with water to neutrality. The organic solvent was smpped and to the residue, N- (1-napthylmethyl) methylamine and caustic soda flakes are charged . The reaction mixture was heated up to 80°c and maintained at this temperature until reaction is completed. The reaction mass is cooled to room temperature and hydrochloric acid (400ml), methylene chloride 400ml are charged and stirred . The phases are separated, the organic-phase washed with water until neutrality. The methylene chloride was recovered and ethyl acetate is added. The -separated Terbinafine, HCl is filtered- and-washed with..ethyl a(at)(at)t(at) (at)nd dried to give 134 (at) (at)(81 percent yielc(at)(at)(at)terbir(at)afine hydrochloride with 99percent of purity having no cis (Z) isomer.
With hydrogenchloride In water; butanone at 20 - 30℃; for 0.25 h;
169.9 g (0.420 mol theoretical) crude terbinafine (example 22) is dissolved in 306 ml methyl ethyl ketone (MEK) at 20/25°C; then 41.3 ml (1 eq. ) of 32percent aqueous HCl are added dropwise at 20/30°C. Crystallisation of the product takes place during addition. The suspension is stirred for 15 minutes and then concentrated to a small volume under vacuum at 40°C to azeotropically eliminate the water present, it is subsequently made up twice with MEK and again concentrated to a small volume under vacuum at 40°C and finally diluted with MEK to restore it to the initial volume. The suspension is then cooled to -10°C and stirred for 3 hours. The precipitate is filtered, washed with 2x69 ml cold MEK and dried to constant weight under vacuum at 40°C. 103.3 g (0.317 mol, 75percent yield) terbinafine hydrochloride are obtained as a white crystalline solid with purity of 99.8percent (HPLC Apercent) and a melting point of 207°C-208°C.
66.4%
With hydrogenchloride In water; butanone at 0 - 20℃; for 2.5 h;
14.1 g crude terbinafine (39.9 mmol theoretical, example 6) is dissolved in 94 ml methyl ethyl ketone (MEK) and then 3.9 ml (0.0399 mol) of 32percent aqueous hydrochloric acid is added dropwise. The resulting suspension is stirred for 30 minutes and then concentrated to a small volume, using a rotavapor to azeotropically distil off the water. The initial volume is restored with chilled MEK. After stirring for 2 hours at 20°C, the precipitate is filtered, washed with 2x11 ml MEK and dried to constant weight under a heat lamp. 8.7 g (66.4percent yield) of terbinafine-HCl are obtained as a white solid with purity of 99.3percent (HPLC Apercent).
63%
With hydrogenchloride In isopropyl alcohol at 0 - 20℃; for 0.5 h;
14.2 g crude terbinafine base (40.0 mmol theoretical, example 6) is dissolved in 24 ml isopropanol and then 17.2 g (1.1 eq. ) of 9.35percent hydrochloric acid in isopropanol are added dropwise. The resulting solution is stirred for 30 minutes, then concentrated to a small volume using a rotavapor, and then taken up with 24 ml chilled isopropanol. 71 ml diisopropyl ether is then added dropwise at 20/25°C; the crystallisation of the product is observed following the addition of approx. half of the amount of ether. Following stirring for 8 hours at 20°C, the precipitate is filtered, washed with 2x14 ml of an iPrOH/diisopropyl ether mixture (1/3 by volume) and dried to constant weight at 40°C in a vacuum oven. 8.3 g (63percent yield) terbinafine-HCl is obtained as a white solid with purity of 95.0percent (HPLC Apercent).
29.7%
With hydrogenchloride In water; acetone at -5 - 20℃; for 2 - 3 h;
19.2 g crude terbinafine base (57.2 mmol theoretical, example 6) is dissolved in 83 ml acetone and then 6.2 ml (0.0631 mol) of 32percent aqueous hydrochloric acid is added dropwise. The resulting suspension is stirred for 30 minutes at 20°C and then cooled to-5°/-10°C and stirred for a further 2.5 hours. The precipitate is filtered, washed with 16 ml cold acetone and dried to constant weight at 40°C in a vacuum oven. 10.8 g (57.5percent yield) terbinafine-HCl is obtained as a white solid with purity in excess of 99.8percent (HPLC Apercent).' EXAMPLE 18: Terbinafine (1) hydrochloride 17.6 g crude terbinafine base (56.6 mmol theoretical, example 13) is dissolved in 80 ml (4.5 vol.) of acetone and 6.8 ml (1.1 eq. ) of 32percent aqueous hydrochloric acid are added. The resulting suspension is cooled to -20°C and stirred for 2 hours. The precipitate is filtered, washed with 20 ml acetone and dried at 40°C in a vacuum oven to give 4.9 g (29.7percent yield) of Terbinafine hydrochloride as a white solid with purity in excess of 99.9percent (HPLC Apercent).
With sodium hydroxide; sodium borohydrid In ethyl acetate; isopropyl alcohol; toluene
EXAMPLE 30 17.1 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one tosyl hydrazone (53.4 mmol) prepared in Example 1 and 2.4 g of sodium hydroxide (60.0 mmol) were added to 57 ml of toluene. The reaction mixture was stirred for two hours at 90° C., cooled to room temperature, and washed with 90 ml of distilled water. 2.8 g of N-methyl-1-naphthalenemethylamine hydrochloride (13.5 mmol) and 0.98 g of sodium borohydride (25.9 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 15 ml of isopropanol was added to the reaction mixture, which was then stirred for twenty-four hours at room temperature, washed with 50 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 40 ml of ethyl acetate was added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 40 ml of ethyl acetate, and then dried in vacuo to give 2.2 g of terbinafine hydrochloride (yield: 50.3percent).
45.5%
With sodium hydroxide; sodium borohydrid In ethanol; ethyl acetate; toluene
EXAMPLE 29 11.4 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one tosyl hydrazone (35.6 mmol) prepared in Example 1 and 1.6 g of sodium hydroxide (40.0 mmol) were added to 57 ml of toluene. The reaction mixture was stirred for two hours at 90° C., cooled to room temperature, and washed with 60 ml of distilled water. 2.8 g of N-methyl-1-naphthalenemethylamine hydrochloride (13.5 mmol) and 0.98 g of sodium borohydride (25.9 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 30 ml of ethanol was added to the reaction mixture, which was then stirred for twenty-four hours at room temperature, washed with 50 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 40 ml of ethyl acetate were added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 40 ml of ethyl acetate, and then dried in vacuo to give 2.0 g of terbinafine hydrochloride (yield: 45.5percent).
19%
With sodium hydroxide; sodium borohydrid In ethyl acetate; toluene; <i>tert</i>-butyl alcohol
EXAMPLE 28 5.7 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one tosyl hydrazone (17.8 mmol) prepared in Example 1 and 0.8 g of sodium hydroxide (20.0 mmol) were added to 57 ml of toluene. The reaction mixture was stirred for two hours at 90° C., cooled to room temperature, and washed with 30 ml of distilled water and 30 ml of 2N-hydrochloric acid. 2.8 g of N-methyl-1-naphthalenemethylamine hydrochloride (13.5 mmol) and 0.43 g of sodium borohydride (11.3 mmol). were added to the reaction mixture, which was then stirred for an hour at room temperature. 15 ml of t-butanol was added to the reaction mixture, which was then stirred for twenty-four hours at 60° C., washed with 50 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 25 ml of ethyl acetate was added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 25 ml of ethyl acetate, and then dried in vacuo to give 0.84 g of terbinafine hydrochloride (yield: 19.0percent).
With sodium hydroxide; sodium borohydrid; acetic acid In ethyl acetate; toluene; <i>tert</i>-butyl alcohol
EXAMPLE 27 5.7 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one tosyl hydrazone (17.8 mmol) prepared in Example 1 and 0.89 of sodium hydroxide (20.0 mmol) were added to 57 ml of toluene. The reaction mixture was stirred for two hours at 90° C., cooled to room temperature, and washed with 30 ml of distilled water and 30 ml of 2N-hydrochloric acid. 2.8 g of N-methyl-1-naphthalenemethylamine hydrochloride (13.5 mmol), 0.8 ml of acetic acid and 0.43 g of sodium borohydride (11.3 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 15 ml of t-butanol was added to the reaction mixture, which was then stirred for twenty-four hours at room temperature, washed with 50 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 25 ml of ethyl acetate was added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 25 ml of ethyl acetate, and then dried in vacuo to give 0.77 g of terbinafine hydrochloride (yield: 17.4percent).
Reference：
[1] Patent: US2003/130530, 2003, A1,
6
[ 556811-67-7 ]
[ 65473-13-4 ]
[ 78628-80-5 ]
Yield
Reaction Conditions
Operation in experiment
18.6%
With sodium hydroxide; sodium borohydrid In ethyl acetate; isopropyl alcohol; toluene
EXAMPLE 15 7 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one benzenesulfonyl hydrazone (22.9 mmol) prepared in Example 2 and 1.0 g of sodium hydroxide (25.0 mmol) were added to 35 ml of toluene. The reaction mixture was stirred for two hours at 90° C., cooled to room temperature and washed with 35 ml of distilled water and 35 ml of 2N-hydrochloride acid (twice). 3.5 g of N-methyl-1-naphthalenemethylamine hydrochloride (16.9 mmol) and 0.54 g of sodium borohydride (14.3 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 19 ml of isopropanol were added to the reaction mixture, which was then stirred for thirty-five hours at room temperature, washed with 35 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 35 ml of ethyl acetate were added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 35 ml of ethyl acetate, and then dried in vacuo to give 1.03 g of terbinafine hydrochloride (yield: 18.6percent).
With sodium hydroxide; sodium borohydrid In methanol; ethyl acetate; toluene
EXAMPLE 14 5.7 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one tosyl hydrazone (17.8 mmol) prepared in Example 1 and 0.8 g of sodium hydroxide (20.0 mmol) were added to 57 ml of toluene. The reaction mixture was stirred for two hours at 90° C., cooled to room temperature, and washed with 35 ml of distilled water and 35 ml of 2N-hydrochloride acid (twice). 2.8 g of N-methyl-1-naphthalenemethylamine hydrochloride (13.5 mmol) and 0.43 g of sodium borohydride (NaBH4, 11.3 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 15 ml of methanol was added to the reaction mixture, which was then stirred for fifteen hours at room temperature, washed with 50 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 25 ml of ethyl acetate was added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 25 ml of ethyl acetate, and then dried in vacuo to give 0.46 g of terbinafine hydrochloride (yield: 10.4percent) 1H NMR (δ, CDCl3) 12.78(s, 1H), 8.13-8.06(m, 2H), 7.97-7.92(m, 2H), 7.65-7.63(m, 1H), 7.59-7.57(m, 2H), 6.39-6.35(m, 1H), 5.89-5.85(d, 1H), 4.78-4.75(m, 1H), 4.62-4.63(m, 1H), 3.88-3.87(m, 1H), 3.66-3.65(m, 1H), 2.63(s, 3H), 1.24(s, 9H)
Reference：
[1] Patent: US2003/130530, 2003, A1,
9
[ 556811-69-9 ]
[ 65473-13-4 ]
[ 78628-80-5 ]
Yield
Reaction Conditions
Operation in experiment
11.7%
With sodium hydroxide; sodium borohydrid In ethyl acetate; isopropyl alcohol; toluene
EXAMPLE 18 8.0 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one 4-methoxybenzenesulfonyl hydrazone (23.0 mmol) prepared in Example 5 and 1.0 g of sodium hydroxide (25.3 mmol) were added to 40 ml of toluene. The reaction mixture was stirred for two hours at 90° C., cooled to room temperature, and washed with 40 ml of distilled water and 40 ml of 2N-hydrochloride acid twice. 3.5 g of N-methyl-1-naphthalenemethylamine hydrochloride (18.3 mmol) and 0.54 g of sodium borohydride (14.2 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 19 ml of isopropanol was added to the reaction mixture, which was then stirred for thirty-six hours at room temperature, washed with 40 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 40 ml of ethyl acetate was added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 35 ml of ethyl acetate, and then dried in vacuo to give 0.7 g of terbinafine hydrochloride (yield: 11.7percent).
Reference：
[1] Patent: US2003/130530, 2003, A1,
10
[ 556811-66-6 ]
[ 65473-13-4 ]
[ 78628-80-5 ]
Yield
Reaction Conditions
Operation in experiment
10.9%
With sodium hydroxide; sodium borohydrid In ethyl acetate; isopropyl alcohol; toluene
EXAMPLE 17 7.7 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one methanesulfonyl hydrazone (31.5 mmol) prepared in Example 4 and 1.4 g of sodium hydroxide (34.7 mmol) were added to 40 ml of toluene. The reaction mixture was stirred for two hours at 90° C., cooled to room temperature, and washed with 40 ml of distilled water and 40 ml of 2N-hydrochloride acid (twice). 5.2 g of N-methyl-1-naphthalenemethylamine hydrochloride (25.2 mmol) and 0.95 g of sodium borohydride (25.2 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 20 ml of isopropanol was added to the reaction mixture, which was then stirred for thirty-six hours at room temperature, washed with 40 ml of 2N-hydrochloric acid twice, concentrated under a reduced pressure. 40 ml of ethyl acetate were added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 40 ml of ethyl acetate, and then dried in vacuo to give 0.9 g of terbinafine hydrochloride (yield: 10.9percent).
With hydrogenchloride; In water; butanone; at 20 - 30℃; for 0.25h;
169.9 g (0.420 mol theoretical) crude terbinafine (example 22) is dissolved in 306 ml methyl ethyl ketone (MEK) at 20/25C; then 41.3 ml (1 eq. ) of 32% aqueous HCl are added dropwise at 20/30C. Crystallisation of the product takes place during addition. The suspension is stirred for 15 minutes and then concentrated to a small volume under vacuum at 40C to azeotropically eliminate the water present, it is subsequently made up twice with MEK and again concentrated to a small volume under vacuum at 40C and finally diluted with MEK to restore it to the initial volume. The suspension is then cooled to -10C and stirred for 3 hours. The precipitate is filtered, washed with 2x69 ml cold MEK and dried to constant weight under vacuum at 40C. 103.3 g (0.317 mol, 75% yield) terbinafine hydrochloride are obtained as a white crystalline solid with purity of 99.8% (HPLC A%) and a melting point of 207C-208C.
66.4%
With hydrogenchloride; In water; butanone; at 0 - 20℃; for 2.5h;Product distribution / selectivity;
14.1 g crude terbinafine (39.9 mmol theoretical, example 6) is dissolved in 94 ml methyl ethyl ketone (MEK) and then 3.9 ml (0.0399 mol) of 32% aqueous hydrochloric acid is added dropwise. The resulting suspension is stirred for 30 minutes and then concentrated to a small volume, using a rotavapor to azeotropically distil off the water. The initial volume is restored with chilled MEK. After stirring for 2 hours at 20C, the precipitate is filtered, washed with 2x11 ml MEK and dried to constant weight under a heat lamp. 8.7 g (66.4% yield) of terbinafine-HCl are obtained as a white solid with purity of 99.3% (HPLC A%).
63.0%
With hydrogenchloride; In isopropyl alcohol; at 0 - 20℃; for 0.5h;Product distribution / selectivity;
14.2 g crude terbinafine base (40.0 mmol theoretical, example 6) is dissolved in 24 ml isopropanol and then 17.2 g (1.1 eq. ) of 9.35% hydrochloric acid in isopropanol are added dropwise. The resulting solution is stirred for 30 minutes, then concentrated to a small volume using a rotavapor, and then taken up with 24 ml chilled isopropanol. 71 ml diisopropyl ether is then added dropwise at 20/25C; the crystallisation of the product is observed following the addition of approx. half of the amount of ether. Following stirring for 8 hours at 20C, the precipitate is filtered, washed with 2x14 ml of an iPrOH/diisopropyl ether mixture (1/3 by volume) and dried to constant weight at 40C in a vacuum oven. 8.3 g (63% yield) terbinafine-HCl is obtained as a white solid with purity of 95.0% (HPLC A%).
29.7 - 57.5%
With hydrogenchloride; In water; acetone; at -5 - 20℃; for 2 - 3h;Product distribution / selectivity;
19.2 g crude terbinafine base (57.2 mmol theoretical, example 6) is dissolved in 83 ml acetone and then 6.2 ml (0.0631 mol) of 32% aqueous hydrochloric acid is added dropwise. The resulting suspension is stirred for 30 minutes at 20C and then cooled to-5/-10C and stirred for a further 2.5 hours. The precipitate is filtered, washed with 16 ml cold acetone and dried to constant weight at 40C in a vacuum oven. 10.8 g (57.5% yield) terbinafine-HCl is obtained as a white solid with purity in excess of 99.8% (HPLC A%).' EXAMPLE 18: Terbinafine (1) hydrochloride 17.6 g crude terbinafine base (56.6 mmol theoretical, example 13) is dissolved in 80 ml (4.5 vol.) of acetone and 6.8 ml (1.1 eq. ) of 32% aqueous hydrochloric acid are added. The resulting suspension is cooled to -20C and stirred for 2 hours. The precipitate is filtered, washed with 20 ml acetone and dried at 40C in a vacuum oven to give 4.9 g (29.7% yield) of Terbinafine hydrochloride as a white solid with purity in excess of 99.9% (HPLC A%).
With hydrogenchloride; In water; ethyl acetate; at 0 - 5℃; for 1h;pH 1.5 - 2;Product distribution / selectivity;
Ethyl acetate (4 volumes) was added to the product of Example 1. The solution was cooled to a temperature ranging from about 0 C. to about 5 C. The pH of the reaction mass was adjusted to about 1.5 to about 2 with 5N hydrochloric acid. The reaction mass was maintained for one hour. The reaction mass was then filtered and washed with ethyle acetate (2 volumes). The product was dried at a temperature of about 60 C. Yield=1.5 g.
With hydrogenchloride; In propane;
Terbinafine Hydrochloride is prepared by precipitation of a Terbinafine base dissolved in 2 propane or 1-I saturated, equivalent to dry 1-HCl. Afterwards, n-heptane is added. The final product is obtained.
With hydrogenchloride; In water; acetone;
Terbinafine as obtained according to one of the above examples is reacted in acetone with a stoichiometric amount of 37% molar hydrochloric acid. Crystallization is obtained by seeding with pure terbinafine hydrochloride, cooling TO-10C. After one hour, the mixture is filtered and the solid is washed with acetone, then dried to obtain pure terbinafine hydrochloride as a white solid having 99.9% HPLC purity (E/Z = 100: 0) and a content of catalyst residues lower than 1 p. p. m.
N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthylmethyl amine hydrochloride[ No CAS ]
[ 91161-71-6 ]
[ 78628-81-6 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In tetrahydrofuran; water; acetonitrile;pH 6.5;Aqueous phosphate buffer;
100 grams of the product from Example 2, containing the hydrochloride salt of Terbinafine (I) and the cis isomer (II) was dissolved in 500 ml isopropanol at reflux temperature. The solution was cooled to 25 C. and the mixture was stirred for 4 hours. The resulting suspension was filtered using Whatman No. 1 filter paper and the cake washed with 60 ml isopropyl alcohol. After 4 hours drying at 50 C., 80 grams of <strong>[78628-80-5]Terbinafine hydrochloride</strong> were obtained, having a purity greater than 99.5%, as determined by HPLC analysis as follows: A mobile phase comprising 200 ml THF, 400 ml acetonitrile and 400 ml of an aqueous buffer solution (6 g sodium dihydrogen phosphate dihydrate in 1 liter of water and adjusted to pH 6.5 using 1.0 N NaOH) was prepared. 30 mg of product was dissolved in 100.0 ml of the mobile phase. A 10 mul sample of the thus prepared product-containing solution into an HPLC using a UV detector at 220 nm on a 250×4.6 mm Luna C8(2) column (5 micron, available from Phenomenex Cat. Nr. 00G-4249-EO). The conditions used for chromatographic separation were: 45 C. oven temperature, flow rate of 1.0 ml min-1 using the mobile phase described above. Under these conditions, Terbinafine (I) was observed to have a retention time of 27.6 minutes and the respective cis isomer (II) was observed to have a relative retention time of 0.89. Other potential impurities include 4-methyl Terbinafine (relative retention time) 1.21 and beta-Terbinafine (0.82). The ratio of the areas of the detected peaks was taken to represent the relative amounts in the sample of the respective compounds.
N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthylmethyl amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
124.8 grams (0.601 mole) N-methyl-1-naphthylmethyl amine (III) HCl followed by 120 grams (1.1 mole) sodium carbonate were added to 720 ml tap water in a three-necked reactor with stirring at 300-350 rpm. The reaction mixture was heated to 77-83 C. 93.6 grams (0.598 mole) 1-chloro-6,6-dimethyl-2-heptene-4-yne (IVb), obtained as described above were added over a four-hour period. After 4 additional hours at 80 C., stirring was ceased, leading to an immediate appearance of two phases. The lower aqueous phase was removed from the reactor and washed with toluene (2×100 ml). The two toluene washes and an additional 720 ml toluene were added to the reactor. The toluene solution was allowed to cool to room temperature. 66 ml of a 32% aqueous HCl solution were added to the toluene solution so as to acidify the solution to a pH of about 0.5-1.5 as measured using a Gel Pressure Electrode, produced by Mettler-Toledo International. After 20 minutes, 200 ml water were added, and the resulting suspension was stirred at 20-30 C. for 15 minutes and then filtered using Whatman No. 1 filter paper. The cake was washed with toluene (3×120 ml) and with water (1×150 ml). The damp cake was dried at 50 C. for 5 hours, to give 174 gram of a mixture containing the hydrochloride salts of Terbinafine (I) and the Terbinafine cis isomer (II) (0.555 mole, 93.8% yield relative to IVb).; 124.8 grams (0.601 mole) N-methyl-1-naphthylmethyl amine (III) HCl followed by 120 grams (1.1 mole) sodium carbonate were added to 720 ml tap water in a three-necked reactor with stirring at 300-350 rpm. The reaction mixture was heated to 77-83 C. 93.6 grams (0.598 mole) 1-chloro-6,6-dimethyl-2-heptene-4-yne (IVb) (3.5:1 trans/cis ratio) were added over a four-hour period. After 4 additional hours at 80 C., stirring was ceased, leading to an immediate appearance of two phases. The lower aqueous phase was removed from the reactor and washed with toluene (2×100 ml). The two toluene washes and an additional 720 ml toluene were added to the reactor. The toluene solution was allowed to cool to room temperature. Gaseous HCl was bubbled through the solution over a period of 20 minutes until the pH reached 1.5 as measured using a Gel Pressure Electrode, produced by Mettler-Toledo International. The reaction was exothermic, the temperature of the solution rising from 30 C. to 50 C. in 30 minutes. The reaction was allowed to cool to room temperature. After 20 minutes, 200 ml water were added, and the resulting suspension was stirred at 20-30 C. for 15 minutes and then filtered using Whatman No. 1 filter paper. The cake was washed with toluene (3×120 ml) and water (1×150 ml). The damp cake was dried at 50 C. for 5 hours, to give 182 grams of a mixture containing the hydrochloride salts of Terbinafine (I) and the Terbinafine cis isomer (II) (0.580 mole, 97.1% yield relative to IVb).; Example 5 Large-Scale Preparation of Terbinafine HCl 100 kilograms (482 mole) N-methyl-1-naphthylmethyl amine (III) HCl followed by 95 kilograms (800 mole) sodium carbonate were added to 550 liter tap water in a 1000 liter reactor with stirring. The reaction mixture was heated to 77-83 C. 75 kilogram (479 mole) 1-chloro-6,6-dimethyl-2-heptene-4-yne (IVb) (4:1 trans/cis ratio) were added over a four hour period. After 2 additional hours at 77-83 C., stirring was ceased, leading to the appearance of two phases. The lower aqueous phase was removed, 570 liters toluene were added to the reactor, mixed for 15 minutes, and removed. The aqueous phase was returned to the reactor and mixed with 80 liters toluene for 15 minutes. After an additional 15 minutes, the aqueous phase was removed and the previously removed product-containing toluene solution returned to the reactor. The toluene solution was allowed to cool to 20 C.-25 C. 60 liters of a 32% aqueous HCl solution were added to the toluene solution, so as to acidify the solution over a period of two hours while the temperature was maintained at 20 C.-25 C. Once the addition of HCl was completed, it was confirmed that the pH of the solution was less than 1.5, and mixing continued for an additional 15 minutes. The suspension was then filtered (using a filter pressure). The cake was washed with 100 liters toluene, then with 200 liters water and then with another 100 liters toluene. The damp cake was dried at 50 C. for 12 hours under a nitrogen stream to obtain 140 kilogram of a mixture containing the hydrochloride salts of Terbinafine (I) and the Terbinafine cis isomer (II) (446 mole, 93.1% yield relative to IVb).
In a round bottom flask equipped with a nitrogen inlet and guard tube, N-methyl-naphthylmethylamine hydrochloride (100 g), dimethylsulfoxide (500 ml) and potassium carbonate (136 g) were added at room temperature (about 25 C. to about 30 C.). Trans-1-chloro-6,6-dimethyl-2-heptene-4-yne (116 g) was added to the round bottom flask over a period of about 15 to about 30 minutes. (Due to the exothermic reaction the temperature rises to about 60 C.). Cool the reaction mass to room temperature and stir for about 4 to about 5 hours. The completion of the reaction was monitored by TLC (RLC mobile phase chloroform:methanol:ammonia at 9:1:one drop of ammonia). If the reaction is not complete, stir for another hour and check again. After completion of the reaction as determined by TLC, ethyl acetate (400 ml) was added to the flask, followed by an addition of water (3 L). The layers were separated. The aqueous layer was extracted with ethyl acetate (2×300 ml). A 2% tartaric acid solution (400 ml) was added to the combined organic extract wash. The organic layer was washed with water (2×500 ml). Carbon (5 g) was added to the organic layer and stirred at room temperature for about 20 minutes. The reaction mass was filtered with a Celite bed. The Celite bed was washed with ethyl acetate (100 ml). The ethyl acetate was distilled out which resulted in about 350 to about 450 ml of reaction mass. The pH of the organic layer was adjusted to about 1.5 to about 2.0 using 5N hydrochloric acid at a temperature ranging from about 0 C. to about 10 C. using a pH meter. The solution was stirred for about 30 minutes. The compound was filtered and washed with chilled ethyl acetate (100 ml). The crude wet terbinafine was placed in a flask with ethyl acetate (200 ml). The reaction mass was heated to a temperature ranging from about 65 C. to about 75 C. and stirred for about 30 minutes. The compound was filtered and washed with chilled ethyl acetate (50 ml). The compound was slurry-washed with demineralized water (2×300 ml). The compound was dried in an oven at a temperature ranging from about 55 C. to about 60 C. until the moisture content was less than 1%. Yield 80 g. EXAMPLE 4 Preparation of Terbinafine Hydrochloride Acetonitrile (720 ml) was added to the product (80 g) of Example 3 in a round bottom flask equipped with a condenser. The contents were heated to a temperature ranging from about 82 C. to about 87 C. to get a clear solution. The solution was filtered. The reaction mass was cooled to a temperature ranging from about 0 C. to about 5 C. The solution was stirred for about 30 to about 45 minutes. The solution was filtered and washed with chilled acetonitrile (100 ml). The compound was dried at a temperature ranging from about 55 C. to about 60 C. Yield 64 g.
In a round bottom flask, N-methyl-naphthylmethylamine hydrochloride (50 g), toluene (300 ml), water (100 ml), trans-1-chloro-6,6-dimethyl-2-heptene-4-yne (70 g), sodium hydroxide (10.6 g) and tetra butyl ammonium bromide (10 g) were added at room temperature. The reaction mixture was heated to a temperature ranging from about 70 C. to about 80 C. and maintained for about 4 to 5 hours. The completion of the reaction was monitored by TLC (RLC mobile phase chloroform:methanol:ammonia at 9:1:one drop of ammonia). After completion of the reaction as determined by TLC, the aqueous and organic layers were separated. The aqueous layer was extracted with toluene (200 ml). The combined organic layer was washed with water. Toluene from the organic layer was evaporated completely under vacuum and ethyl acetate (150 ml) was added. A 50% hydrochloric acid solution was added to obtain a pH ranging from about 1.0 to about 2.0 at a temperature ranging from about 0 C. to about 5 C. The crystallized hydrochloride salt was filtered and washed with chilled ethyl acetate (100 ml). The compound was dried in an oven at a temperature ranging from about 55 C. to about 60 C. until the moisture content was less than 1%. Yield=25 g.
N-methyl-n-naphthylmethylamine hydrochloride (20 g), dimethyl acetamide (150 ml) and potassium carbonate (K2CO3, 45 g) were taken in a dry round bottom flask at room temperature. Trans-1-chloro-6,6-dimethyl-2-heptene-4-yne (20 g) was added to the reaction mixture followed by potassium iodide (KI, 20 g) at a temperature of about 25 C. The reaction mass was stirred for 24 hours. The completion of the reaction was monitored by TLC (RLC mobile phase chloroform:methanol:ammonia at 9:1:one drop of ammonia). After completion of the reaction as determined by TLC, water (1500 ml) was added and the product was extracted with ethyl acetate (4×20 ml). After the layer separation the combined organic layer was washed with 2% tartaric acid solution followed by water. The layer was cooled to a temperature ranging from about 0 C. to about 5 C. The pH was adjusted to a range between about 1.5 and 2.0 with a 5N HCL solution. The solution was stirred for a period of about 1 hour at a temperature ranging from about 0 C. to about 5 C. The solution was filtered and washed with chilled ethyl acetate (40 ml) and dried in an oven at a temperature ranging from about 55 C. to about 60 C. until the moisture content was less than 1%. Yield=15 g.
EXAMPLE 13 (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine hydrochloride (terbinafine) To 33 ml of tetrahydrofuran were added 5.40 g (22 mmol) of (E)-N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine, 210 mg (1.1 mmol) of copper (I) iodide and 356 mg (0.31 mmol) of tetrakis (triphenylphosphine)palladium, and further, 4.35 ml (44 mmol) of n-butylamine and 2.83 ml (23.1 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 17 hours at room temperature. The reaction mixture was concentrated and the residue was subjected to silica gel chromatography (n-hexane?n-hexane/ethyl acetate=9/1?4/1). The desired fractions were put together and concentrated under reduced pressure. The oily residue was dissolved in 6 ml of ethanol and 6 ml of 23% hydrogen chloride methanol solution was added thereto. The solvent and excess hydrogen chloride were distilled off. The resulting crystals were suspended in diisopropyl ether, filtered, washed with diisopropyl ether and dried to obtain 6.41 g (yield: 89%) of the above identified compound as white crystalline powder. Melting point: 205 C.. IR(KBr cm-1: 2970, 2440, 1465, 1410, 1360, 955, 805, 770. NMR(CDCl3 +D2 O)delta: 1.23(9 H, s), 2.60(3 H, s), 3.72(2 H, d, 7.5 Hz), 4.62(2 H, s), 5.87(1 H, d, 15 Hz), 6.37(1 H, dt, 15 Hz, 7.5 Hz), 7.5-8.2(7 H, m).
80%
EXAMPLE 6 Preparation of Terbinafine Hydrochloride A solution of crude terbinafine (example 1, ~7.7 mmoles) in acetone (16 mL) is added with a 37% w/w hydrochloric acid solution (0.76 g, 7.7 mmoles). Crystallization is obtained by seeding with pure terbinafine hydrochloride while cooling -10 C. After 1 hour the mixture is filtered and the solid is washed with acetone, then dried to obtain 2.0 g of pure terbinafine hydrochloride as a white solid (80% yield starting from vinyl chloride II).
80%
Example 6 : Preparation of terbinafine hydrochloride A solution of crude terbinafine (example 1, ~ 7.7 mmoles) in acetone (16 mL) is added with a 37% w/w hydrochloric acid solution (0.76 g, 7.7 mmoles). Crystallization is obtained by seeding with pure terbinafine hydrochloride while cooling -10C. After 1 hour the mixture is filtered and the solid is washed with acetone, then dried to obtain 2.0 g of pure terbinafine hydrochloride as a white solid (80% yield starting from vinyl chloride II).
54.2%
EXAMPLE 36 The same procedures as described in Example 30 were repeated, except that the reaction mixture was stirred for thirty-two hours at about -5 C. instead of being stirred for twenty-four hours at room temperature, to give 2.4 g of terbinafine hydrochloride (yield: 54.2%).
53.0%
EXAMPLE 37 The same procedures as described in Example 30 were repeated, except that the reaction mixture was stirred for twenty-eight hours at about 3 C. instead of being stirred for twenty-four hours at room temperature, to give 2.4 g of terbinafine hydrochloride (yield: 53.0%).
35.7%
EXAMPLE 21 The same procedures as described in Example 14 were repeated, except that t-butanol was used instead of methanol and then reacted for sixty-three hours, to give 1.58 g of terbinafine hydrochloride (yield: 35.7%).
30.0%
EXAMPLE 22 The same procedures as described in Example 14 were repeated, except that sodium triacetoxyborohydride was used instead of sodium borohydride, to give 1.32 g of terbinafine hydrochloride (yield: 30.0%).
27.1%
EXAMPLE 23 The same procedures as described in Example 14 were repeated, except that sodium cyanoborohydride was used instead of sodium borohydride, to give 1.2 g of terbinafine hydrochloride (yield: 27.1%).
23.0%
EXAMPLE 20 The same procedures as described in Example 14 were repeated, except that isopropanol was added to the reaction mixture instead of methanol and then reacted for thirty-nine hours, to give 1.02 g of terbinafine hydrochloride (yield: 23.0%).
16.9%
EXAMPLE 19 The same procedures as described in Example 14 were repeated, except that ethanol was used instead of methanol, to give 0.75 g of terbinafine hydrochloride (yield: 16.9%).
10.8%
EXAMPLE 25 The same procedures as described in Example 14 were repeated, except that sodium hydride was used instead of sodium hydroxide, to give 0.48 g of terbinafine hydrochloride (yield: 10.8%).
10.6%
EXAMPLE 31 The same procedures as described in Example 14 were repeated, except that potassium hydroxide was used instead of sodium hydroxide, to give 0.47 g of terbinafine hydrochloride (yield: 10.6%).
10.8%
EXAMPLE 33 The same procedures as described in Example 14 were repeated, except that benzene was used instead of toluene, to give 0.48 g of terbinafine hydrochloride (yield: 10.8%).
9.5%
EXAMPLE 26 The same procedures as described in Example 14 were repeated, except that acetonitrile was used instead of toluene, to give 0.42 g of terbinafine hydrochloride (yield: 9.5%).
9.9%
EXAMPLE 32 The same procedures as described in Example 14 were repeated, except that potassium t-butoxide was used instead of sodium hydroxide, to give 0.44 g of terbinafine hydrochloride (yield: 9.9%).
9.9%
EXAMPLE 34 The same procedures as described in Example 14 were repeated, except that xylene was used instead of toluene, to give 0.44 g of terbinafine hydrochloride (yield: 9.9%).
9.5%
EXAMPLE 35 The same procedures as described in Example 14 were repeated, except that decahydronaphthalene was used instead of toluene, to give 0.42 g of terbinafine hydrochloride (yield: 9.5%).
8.8%
EXAMPLE 24 The same procedures as described in Example 14 were repeated, except that N-methyl-1-naphthalenemethylamine was used instead of N-methyl-1-naphthalenemethylamine hydrochloride, to give 0.39 g of terbinafine hydrochloride (yield: 8.8%).
27.4 kg of crude terbinafine hydrochloride was taken into a clean reactor containing 100 liters of dichloromethane under stirring. The contents were stirred for 25 minutes and then 40 liters of water was added. The mass was stirred for 10 minutes and the organic layer was separated. The organic layer was again washed with 40 liters of water. Final organic layer was heated and solvent distilled completely under vacuum below 45 0C. 15 liters of acetone was the added to the residue and distilled completely under vacuum below 65 0C. The residue was EPO <DP n="19"/>cooled to 30 0C and then 25 liters of acetone was charged. The mixture was then heated to reflux and maintained for 30 minutes, then cooled to 5 0C and stirred for 60 minutes. The material was centrifuged and the solid washed with 25 liters of chilled acetone. The solid was dried at 74 C for 3 hours, 30 minutes and subjected to multi-milling using a 40 mesh screen at 30 C. The milled material was then sieved through a 40-mesh sieve yielding 16.8 kg of the pure terbinafine hydrochloride as a white crystalline solid.Purity by HPLC: 99.93 %.Genotoxic impurity: less than 2.5 ppm by HPLC.
6
2N-hydrochloric acid[ No CAS ]
2N-hydrochloride acid[ No CAS ]
[ 556811-68-8 ]
[ 65473-13-4 ]
[ 78628-80-5 ]
Yield
Reaction Conditions
Operation in experiment
10.4%
With sodium hydroxide; sodium borohydrid; In methanol; ethyl acetate; toluene;
EXAMPLE 14 5.7 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one tosyl hydrazone (17.8 mmol) prepared in Example 1 and 0.8 g of sodium hydroxide (20.0 mmol) were added to 57 ml of toluene. The reaction mixture was stirred for two hours at 90 C., cooled to room temperature, and washed with 35 ml of distilled water and 35 ml of 2N-hydrochloride acid (twice). 2.8 g of <strong>[65473-13-4]N-methyl-1-naphthalenemethylamine hydrochloride</strong> (13.5 mmol) and 0.43 g of sodium borohydride (NaBH4, 11.3 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 15 ml of methanol was added to the reaction mixture, which was then stirred for fifteen hours at room temperature, washed with 50 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 25 ml of ethyl acetate was added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 25 ml of ethyl acetate, and then dried in vacuo to give 0.46 g of terbinafine hydrochloride (yield: 10.4%) 1H NMR (delta, CDCl3) 12.78(s, 1H), 8.13-8.06(m, 2H), 7.97-7.92(m, 2H), 7.65-7.63(m, 1H), 7.59-7.57(m, 2H), 6.39-6.35(m, 1H), 5.89-5.85(d, 1H), 4.78-4.75(m, 1H), 4.62-4.63(m, 1H), 3.88-3.87(m, 1H), 3.66-3.65(m, 1H), 2.63(s, 3H), 1.24(s, 9H)
With sodium hydroxide; sodium borohydrid; In ethyl acetate; isopropyl alcohol; toluene;
EXAMPLE 15 7 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one benzenesulfonyl hydrazone (22.9 mmol) prepared in Example 2 and 1.0 g of sodium hydroxide (25.0 mmol) were added to 35 ml of toluene. The reaction mixture was stirred for two hours at 90 C., cooled to room temperature and washed with 35 ml of distilled water and 35 ml of 2N-hydrochloride acid (twice). 3.5 g of <strong>[65473-13-4]N-methyl-1-naphthalenemethylamine hydrochloride</strong> (16.9 mmol) and 0.54 g of sodium borohydride (14.3 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 19 ml of isopropanol were added to the reaction mixture, which was then stirred for thirty-five hours at room temperature, washed with 35 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 35 ml of ethyl acetate were added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 35 ml of ethyl acetate, and then dried in vacuo to give 1.03 g of terbinafine hydrochloride (yield: 18.6%).
With sodium hydroxide; sodium borohydrid; In ethyl acetate; isopropyl alcohol; toluene;
EXAMPLE 18 8.0 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one 4-methoxybenzenesulfonyl hydrazone (23.0 mmol) prepared in Example 5 and 1.0 g of sodium hydroxide (25.3 mmol) were added to 40 ml of toluene. The reaction mixture was stirred for two hours at 90 C., cooled to room temperature, and washed with 40 ml of distilled water and 40 ml of 2N-hydrochloride acid twice. 3.5 g of <strong>[65473-13-4]N-methyl-1-naphthalenemethylamine hydrochloride</strong> (18.3 mmol) and 0.54 g of sodium borohydride (14.2 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 19 ml of isopropanol was added to the reaction mixture, which was then stirred for thirty-six hours at room temperature, washed with 40 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 40 ml of ethyl acetate was added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 35 ml of ethyl acetate, and then dried in vacuo to give 0.7 g of terbinafine hydrochloride (yield: 11.7%).
With sodium hydroxide; sodium borohydrid; In ethyl acetate; isopropyl alcohol; toluene;
EXAMPLE 17 7.7 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one methanesulfonyl hydrazone (31.5 mmol) prepared in Example 4 and 1.4 g of sodium hydroxide (34.7 mmol) were added to 40 ml of toluene. The reaction mixture was stirred for two hours at 90 C., cooled to room temperature, and washed with 40 ml of distilled water and 40 ml of 2N-hydrochloride acid (twice). 5.2 g of <strong>[65473-13-4]N-methyl-1-naphthalenemethylamine hydrochloride</strong> (25.2 mmol) and 0.95 g of sodium borohydride (25.2 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 20 ml of isopropanol was added to the reaction mixture, which was then stirred for thirty-six hours at room temperature, washed with 40 ml of 2N-hydrochloric acid twice, concentrated under a reduced pressure. 40 ml of ethyl acetate were added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 40 ml of ethyl acetate, and then dried in vacuo to give 0.9 g of terbinafine hydrochloride (yield: 10.9%).
With sodium hydroxide; sodium borohydrid; In ethyl acetate; isopropyl alcohol; toluene;
EXAMPLE 30 17.1 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one tosyl hydrazone (53.4 mmol) prepared in Example 1 and 2.4 g of sodium hydroxide (60.0 mmol) were added to 57 ml of toluene. The reaction mixture was stirred for two hours at 90 C., cooled to room temperature, and washed with 90 ml of distilled water. 2.8 g of <strong>[65473-13-4]N-methyl-1-naphthalenemethylamine hydrochloride</strong> (13.5 mmol) and 0.98 g of sodium borohydride (25.9 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 15 ml of isopropanol was added to the reaction mixture, which was then stirred for twenty-four hours at room temperature, washed with 50 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 40 ml of ethyl acetate was added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 40 ml of ethyl acetate, and then dried in vacuo to give 2.2 g of terbinafine hydrochloride (yield: 50.3%).
45.5%
With sodium hydroxide; sodium borohydrid; In ethanol; ethyl acetate; toluene;
EXAMPLE 29 11.4 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one tosyl hydrazone (35.6 mmol) prepared in Example 1 and 1.6 g of sodium hydroxide (40.0 mmol) were added to 57 ml of toluene. The reaction mixture was stirred for two hours at 90 C., cooled to room temperature, and washed with 60 ml of distilled water. 2.8 g of <strong>[65473-13-4]N-methyl-1-naphthalenemethylamine hydrochloride</strong> (13.5 mmol) and 0.98 g of sodium borohydride (25.9 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 30 ml of ethanol was added to the reaction mixture, which was then stirred for twenty-four hours at room temperature, washed with 50 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 40 ml of ethyl acetate were added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 40 ml of ethyl acetate, and then dried in vacuo to give 2.0 g of terbinafine hydrochloride (yield: 45.5%).
19.0%
With sodium hydroxide; sodium borohydrid; In ethyl acetate; toluene; tert-butyl alcohol;
EXAMPLE 28 5.7 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one tosyl hydrazone (17.8 mmol) prepared in Example 1 and 0.8 g of sodium hydroxide (20.0 mmol) were added to 57 ml of toluene. The reaction mixture was stirred for two hours at 90 C., cooled to room temperature, and washed with 30 ml of distilled water and 30 ml of 2N-hydrochloric acid. 2.8 g of <strong>[65473-13-4]N-methyl-1-naphthalenemethylamine hydrochloride</strong> (13.5 mmol) and 0.43 g of sodium borohydride (11.3 mmol). were added to the reaction mixture, which was then stirred for an hour at room temperature. 15 ml of t-butanol was added to the reaction mixture, which was then stirred for twenty-four hours at 60 C., washed with 50 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 25 ml of ethyl acetate was added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 25 ml of ethyl acetate, and then dried in vacuo to give 0.84 g of terbinafine hydrochloride (yield: 19.0%).
With sodium hydroxide; sodium borohydrid; acetic acid; In ethyl acetate; toluene; tert-butyl alcohol;
EXAMPLE 27 5.7 g of 1-(2'-furyl)-2,2-dimethylpropan-1-one tosyl hydrazone (17.8 mmol) prepared in Example 1 and 0.89 of sodium hydroxide (20.0 mmol) were added to 57 ml of toluene. The reaction mixture was stirred for two hours at 90 C., cooled to room temperature, and washed with 30 ml of distilled water and 30 ml of 2N-hydrochloric acid. 2.8 g of <strong>[65473-13-4]N-methyl-1-naphthalenemethylamine hydrochloride</strong> (13.5 mmol), 0.8 ml of acetic acid and 0.43 g of sodium borohydride (11.3 mmol) were added to the reaction mixture, which was then stirred for an hour at room temperature. 15 ml of t-butanol was added to the reaction mixture, which was then stirred for twenty-four hours at room temperature, washed with 50 ml of 2N-hydrochloric acid twice, and concentrated under a reduced pressure. 25 ml of ethyl acetate was added to the reaction mixture, which was then stirred for an hour to produce a solid. The resulting solid was filtered under a reduced pressure, washed with 25 ml of ethyl acetate, and then dried in vacuo to give 0.77 g of terbinafine hydrochloride (yield: 17.4%).
With hydrogenchloride; potassium carbonate; In water; dimethyl sulfoxide; ethyl acetate;
EXAMPLE 27 (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine hydrochloride (terbinafine) To a solution of 1.77 g (10 mmol) of 1-chloromethylnaphthalene in 10 ml of dimethyl sulfoxide were added 1.88 g (10 mmol) of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine hydrochloride and 1.66 g (12 mmol) of potassium carbonate under ice cooling. The mixture was stirred for 16 hours at room temperature, poured into 200 ml of ethyl acetate, washed with 100 ml*2 of water, a mixture of 80 ml of water and 10 ml of 2N hydrochloric acid, and 50 ml of saturated sodium chloride aqueous solution respectively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to crystallize. The crystals were suspended in 10 ml of ethyl acetate, cooled, filtered and dried under reduced pressure to obtain 2.95 g (yield: 90%) of the above identified compound as off-white crystalline powder. Melting point, IR and NMR data of the isolated compound agreed with those of Example 13 compound.
29 kg of N-methyl-1 -naphthalene methylamine hydrochloride was charged into a reactor containing 70.4 liters of dimethylformamide and 11 liters of water, under stirring. The contents were stirred for 15 minutes for clear dissolution and 11 kg of sodium carbonate was added to it. The reaction mass was cooled to 13 EPO <DP n="18"/>C and 22 kg of 1-chloro-6,6-dimethyl-2-heptene-4-yne was added slowly at 11 to 14 C. The reaction mixture was stirred at 12 to 14 0C for 60 minutes and then heated to 55 0C. The reaction mass was maintained at 60 C for 5 hours and reaction completion was confirmed by thin layer chromatography. The reaction mass was cooled to room temperature and 99 liters of water was added. Reaction mass was extracted three times with a total of 75 liters of dichloromethane (3x25 liters). Total organic layer was washed twice with 88 liters of water (2x44 liters); 18 liters of water was charged to the final organic layer and was cooled to 13 0C. Reaction mass pH was adjusted to 0.2 by adding 15 liters of 36% aqueous hydrochloric acid and stirring for 30 minutes. The organic layer was separated and washed three times with a total of 267 liters of water (3chi89 liters). Final organic layer was transferred into a reactor and the solvent was distilled completely below 45 C. 11.8 liters of petroleum ether was charged and the solvent distilled completely at below 50 C. Again 68 liters of petroleum ether was charged and heated to reflux. The mass was stirred at reflux for 30 minutes and cooled to 50 C. The solid thus formed was allowed to settle for 60 minutes and the top petroleum ether layer was decanted. The decantation process was repeated two more times. Finally 44 liters of petroleum ether was charged, heated to reflux, maintained for 30 minutes at reflux and then cooled to 25 C. The contents were stirred for 60 minutes at 20 to 25 0C and centrifuged to recover the solid. The centrifuged solid was washed twice with petroleum ether (2x16 liters) and spin- dried for about 60 minutes to get 29.3 kg of crude terbinafine hydrochloride as a semi-dry solid.
Example-3: Preparation of Terbinafine hydrochloride compound of formula- 160 grams of sodium carbonate is added to a solution of 75 grams of N-methyl naphthylmethyl amine hydrochloride in 450 ml of water and 100 ml of dimethyl formamide at an ambient temperature. Stirred the reaction mixture for 45 minutes at ambient temperature. Cooled the mixture to 10-15C and slowly added 34 grams of 6,6-dimethyl-l-chlorohept-2-ene-4-yne. Heated the reaction mixture to 70-750C and stirred for 6 hours. Cooled the reaction mixture to 25-350C. Decomposed the reaction mixture with water. Extracted the reaction mixture thrice with methylene chloride. Combined all the organic phases and washed the organic phase thrice with water. Separated the organic phase and added water then cooled to 10-150C. Slowly added 160.5 ml of hydrochloric acid. Stirred for 30 minutes. Separated the organic phase and washed with water. Distilled the organic phase completely under reduced pressure at below 500C. Hexanes added to the obtained crude and decanted thrice. Isolated the title compound using acetone. The obtained compound purified using acetonitrile as a solvent. Yield 75 grams.Example-4: Preparation of Terbinafine hydrochloride compound of formula- 160 grams of sodium carbonate is added to a solution of 75 grams of N-methyl naphthylmethyl amine hydrochloride in 450 ml of water and 100 ml of dimethylformamide at an ambient temperature. Stirred the reaction mixture for 45 minutes at ambient temperature. Cooled the mixture to 10-150C and slowly added 112.5 grams of 6,6-dimethyl-l-chlorohept-2-ene-4-yne. Heated the reaction mixture to 70-750C and stirred for 6 hours. Cooled the reaction mixture to 25-35C. Decomposed the reaction mixture with water. Extracted the reaction mixture thrice with methylene chloride. Combined all the organic phases and washed the organic phase thrice with water. Separated the organic phase and added water then cooled to 10-150C. Slowly added 160.5 ml hydrochloric acid. Stirred for 30 minutes. Separated the organic phase and washed with water. Distilled the organic phase completely under reduced pressure at below 500C. Isolated the compound using acetone. The obtained compound purified using acetonitrile as a solvent. Yield 75 grams
Example-5: Preparation of Terbinafine hydrochloride compound of formula- 160 grams of sodium carbonate is added to a solution of 75 grams of N-methyl naphthylmethyl amine hydrochloride in 450 ml of water at an ambient temperature. Stirred the reaction mixture for 45 minutes at ambient temperature. Cooled the mixture to 10-15C and slowly added 112.5 grams of 6,6-dimethyl-l-chlorohept-2-ene-4-yne. Heated the reaction mixture to 70-75C and stirred for 6 hours. Cooled the reaction mixture to 25-350C. Decomposed the reaction mixture with water. Extracted the reaction mixture thrice with methylene chloride. Combined all the organic phases and washed the organic phase thrice with water. Separated the organic phase and added water then cooled to 10-15C. Slowly added 160.5 ml hydrochloric acid. Stirred for 30 minutes. Separated the organic phase and washed with water. Distilled the organic phase completely under reduced pressure at below 5O0C. Isolated the compound using acetone. The obtained compound purified using acetonitrile as a solvent. Yield 75 grams
N-Methyl-l-naplithylmethylamine (100 g) was dissolved in water (250 ml). Sodium hydroxide (41.50 g) was dissolved in water (120 ml) and this aqueous sodium hydroxide solution was added to N-Met^yl-I-napththyliriethylatnine solution at 20-400C. The reaction mass was heated to 90-950C and l-chloro-6,6- dimethyl-hept-2-ene-4-yne (96 g, crude viscous oily mass having <n="9"/>chromatographic purity by GC 92.40%, as obtained in Step A) was added at 90- 100C. The reaction mass was stirred at 90-1000C for 2 hrs and then cooled to room temperature. Methylene chloride (400 ml) was added and organic layer separated. The methylene chloride extract was washed with water (150 ml). The washed methylene chloride solution was stirred with 300 ml dilute hydrochloric acid at room temperature for 1 h. The methylene chloride layer was washed with water (100 ml) and treated with carbon (4 g) at room temperature. The methylene chloride was stripped to get a residue. The residue was refluxed for 30 min with ethyl acetate (600 ml). The product slurry was cooled to room temperature and stirred for 30 min. Product was filtered and washed with preheated ethyl acetate (160 ml, 40-450C). Product was dried at 55-600C under reduced pressure for 4 h to yield 104 g of Terbinafne hydrochloride, containing 1087 ppm of impurity of Formula IV.
With sodium carbonate; In dichloromethane; water; at 15 - 35℃; for 0.25h;pH 7.9;Product distribution / selectivity;
Example-9: Preparation of Form-I of Terbinafme compound of formula-3 from <strong>[78628-80-5]Terbinafine hydrochloride</strong>Dissolved the 200 grams of <strong>[78628-80-5]Terbinafine hydrochloride</strong> in 600 ml of D.M water and 500 ml of methylene chloride at 25-35C. Stirred the reaction mixture for 15 minutes at25-35C. Cooled the reaction mixture to 15-200C. Adjusted the pH of the reaction to 7.9 with sodium carbonate solution. Separated the organic and aqueous layers. Extracted the aqueous layer with methylene chloride. Washed the organic layer with water. Dried the organic layer with sodium sulphate. Distilled the solvent from organic layer completely at below 50C under reduced pressure. Added 100ml of isopropyl alcohol to the above reaction mixture and distilled the solvent completely under reduced pressure at below60C. Cooled the reaction mixture to 25-35C. Added 360 ml of isopropyl alcohol to the above reaction mixture. Heated to reflux and stirred the reaction mixture for 20 minutes at reflux. Cooled the reaction mixture to 0-50C. Stirred the reaction mixture for 60 minutes at 0-5C. Filtered the precipitated solid and washed with chilled isopropyl alcohol. Dried the obtained solid at 30-350C to get form-I of Terbinafine.Yield: 152 gramsM.R: 40C
In a four necked 2 Lit round bottom flask fitted with overhead mechanical stirrer, double surface condenser, thermometer pocket, and pressure equalizing funnel placed 'in the plastic tub, top of the condenser is connected with nitrogen inlet, THF 300ml, magnesium turnings (29.0grm. 1.208moles.) were charged . The flow of nitrogen was started and small amount (crystal) of iodine approximately 50.0 mgs. and 5ml of ethyl bromide was charged . The reaction starts with disappearance of brownish color, . Ethyl bromide (133.Ogrm..1.22 moles) mixed with THF (50ml ) were charged in pressure equalizing tunnel and started the addition of ethyl bromide slowly. The reaction flask was cooled with ice water and the temperature was maintained at 25-30c. The cooling bath was replaced with water bath after the ethyl bromide addition was completed. The temperature was raised slowly up to 73-75c. The reaction mixture was kept under reflux for 1 to 2 hours. The water bath was removed and the reaction flask was kept in a cooling bath replacing the condenser.with nitrogen inlet. The reaction mass was cooled to 0-5c and t-butylacetylene (100grm. 1.219 moles) mixed with THF (50ml) was. charged through the funnel. The addition of t-butyl acetylene was started slowly at 0-5c with stirring for some time at 0-5c. Arolein (68: 0grm 1.22moles) mixed with THF (50ml) was charged through the funnel. The reaction mass was kept at 0-5c, and stirred further for 2 to 3 hours at the same temperature and the temperature was raised to room temperature and stirred - for 18 to 20 hours and checked the completion of the reaction on gas chromatography. The reaction mixture is quenched with dil HCI and water, and the pH was adjusted to 2 to 2.5. The layers are separated and the aqueous phase is extracted with methylene chloride. The combined organic phase is washed with water to neutrality. The organic phase is dried and solvent stripped to give 6,6-dimethyl-hept-l-ene-4-yne-3=ol in 65.4% yield with purity of 97.2% .This is dissolved in methanol (300ml) and cooled to 0-5C and mixture of phosphorous oxychloride (35.0grm 0.33mole), Hydrochloric acid (300ml) is charged slowly at 0-5c. The reaction mixture was stirred at 0-5c for 2' to 4 hours and the temperature was raised to room temperature and further stirred for several hours 18 to 20 hours . The completion of the reaction is checked on gas chromatography. After the reaction is completed; n-hexane (300ml) was charged , stirred for 30 min, and the phases were separated. The, aqueous phase was re-extracted with n-hexane (100ml) and the combined organic phase was washed with water to neutrality. The organic solvent was smpped and to the residue, N- (1-napthylmethyl) methylamine and caustic soda flakes are charged . The reaction mixture was heated up to 80c and maintained at this temperature until reaction is completed. The reaction mass is cooled to room temperature and hydrochloric acid (400ml), methylene chloride 400ml are charged and stirred . The phases are separated, the organic-phase washed with water until neutrality. The methylene chloride was recovered and ethyl acetate is added. The -separated Terbinafine, HCl is filtered- and-washed with..ethyl a(at)(at)t(at) (at)nd dried to give 134 (at) (at)(81 % yielc(at)(at)(at)terbir(at)afine hydrochloride with 99% of purity having no cis (Z) isomer.
Add 62.62L of purified water to a 200L reactor, potassium carbonate (20.36Kg, 146.49mol), stir and dissolve, add N-methylnaphthylmethylamine (25.05Kg, 146.49mol), and then add 1-chloro-6,6- Dimethyl-2-heptene-4-yne (22.85Kg, 146.49mol), heated to 80 C and reacted, after 4 hours, cooled to room temperature, extracted by adding 125L of ethyl acetate, and separated off the ethyl acetate phase and cooled to 0 At -10 C, a 6N aqueous hydrochloric acid solution was added dropwise, the pH was adjusted to 1, stirred for 1-2h, filtered, and the filter cake was dried under vacuum at 70 C for 4h to obtain crude terbinafine hydrochloride (44.07Kg, yield: 92%);Step 2 (purification of crude terbinafine hydrochloride):To the 800L reactor, add crude terbinafine hydrochloride (44.07Kg, 134.77mol), 528.84L of purified water, heat to reflux and dissolve. After cooling to room temperature, cool to 0-10 C in an ice bath, stir for 1h, and filter The filter cake was dried under vacuum at 70 C for 3 h to obtain a finished terbinafine hydrochloride product (40.98 Kg, purity: 99.981%, yield: 93%).
Stage #1: N-(3-chloroallyl)-1-methyl-1-naphthylmethylamine; 3,3-Dimethylbut-1-yne With copper(l) iodide; N-butylamine; triphenylphosphine; palladium dichloride at 60 - 65℃; for 20h;
Stage #2: With hydrogenchloride In water at 85 - 90℃; for 0.5h;
1.2; 1.3; 2.2; 2.3; 3.2; 3.3
(2) Cool the reaction solution obtained in step (1) to 20-25°C, add 29.9g n-butylamine and 1.72g composite catalyst (the masses of palladium chloride, cuprous iodide and triphenylphosphine are 0.12g respectively , 1.2g, 0.4g), and then drop 28.8g of 3,3-dimethyl-1-butyne () into the system. After the addition is complete, the temperature is raised to 60-65°C and reacted for 20 hours. TLC detects the raw material IV. Complete, concentrate under reduced pressure to 155.8g, then cool the resulting concentrated solution to 20-25°C, add 200mL of water and 10mL of 23% concentrated ammonia to wash for 1h, stand for stratification, and separate the upper layer of oil. Obtain (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthylmethylamine (VI) as an oil; (3) (E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthylmethylamine (VI) oil obtained in step (2) Add 1000 mL of water and 30 mL of concentrated hydrochloric acid with a mass fraction of 37%, raise the temperature to 85-90 to form salt for 0.5h, cool to 0-5, filter with suction, and wash the filter cake with 50 mL of water to obtain the crude terbinafine hydrochloride. Product 114.5g;(4) Add 916 mL of water to the crude terbinafine hydrochloride wet product obtained in step (3), raise the temperature to 85-90°C for recrystallization, lower the temperature to 0-5°C, suction filter, wash the filter cake with 50 mL water, and filter The cake was dried to obtain 79.1 g of terbinafine hydrochloride.The purity of the terbinafine hydrochloride prepared in this example was 99.6%, and the total molar yield was 82.6%.
Stage #1: N-methyl-1-naphthalenemethylamine; (E)-6,6-dimethylhept-2-ene-4-yn-1-yl-(4-methylbenzenesulfonate) With potassium carbonate at 60 - 65℃; for 8h; Large scale;
Stage #2: With hydrogenchloride In water monomer Large scale;
1-3
To the methyl isobutyl ketone solution of the above-mentioned (E)-6,6-dimethylhept-2-ene-4-yn-1-yl-(4-methylbenzenesulfonate), add potassium carbonate 120kg and N-methyl-1-naphthylmethylamine 300kg,The temperature was raised to 60-65°C and the reaction was incubated for 8h. After the completion of the reaction, 90kg of water was washed once, the mixed solution of 50kg of purified water and 37kg of 31% concentrated hydrochloric acid was added to the organic layer, and the liquid separation was washed once with purifying 400kg of water, and the liquid separation was carried out.The organic layer was concentrated to dryness under reduced pressure, then 1000 kg of ethyl acetate was added, and the temperature was raised to 75 °C for 2 h. Be cooled to -5°C to 5°C of crystallization filtration to obtain terbinafine hydrochloride crude product, use isopropanol 600kg and ethyl acetate 600kg to be warmed to 75 to dissolve clear,Then cool down to -10°C-5°C for crystallization and centrifugation,Dry to obtain 343.5kg of fine terbinafine hydrochloride, with a molar yield of 72.4% in terms of 6,6-dimethyl-3-hydroxy-4-yne-1-heptene,The purity is 99.5%, and the isomer content is 0.01%.
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