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CAS No. : | 65473-13-4 |
Formula : | C12H14ClN |
M.W : | 207.70 |
SMILES Code : | Cl.CNCC1=CC=CC2=C1C=CC=C2 |
MDL No. : | MFCD00012555 |
InChI Key : | BVJVHPKFDIYQOU-UHFFFAOYSA-N |
Pubchem ID : | 16211748 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In polyethylene glycol-400 (PEG-400); at 25 - 40℃; for 5h; | In a 3-necked round bottom flask, N-methyl-naphthylmethylamine hydrochloride (2 g) and PEG-400 (15 ml) were added at room temperature (about 25 C. to about 30 C.) and stirred for about 15 minutes. Trans-1-chloro-6,6-dimethyl-2-heptene-4-yne (2 g) was added to the round bottom flask. A first lot of potassium hydroxide powder (0.2 g) was added to the flask at room temperature and maintained for about 1 hour. A second lot of potassium hydroxide powder (0.4 g) was added to the flask and maintained for about 1 hour. A third lot of potassium hydroxide powder (0.4 g) was added to the flask and the contents of the flask were heated to a temperature ranging from about 35 C. to about 40 C. for about 3 hours. The completion of the reaction was monitored by TLC. After completion of the reaction as determined by TLC, water (150 ml) was added to the flask. The terbinafine was extracted from the flask with toluene (4 volumes). The toluene layer was washed with 2% tartaric acid solution. The toluene was distilled off under a vacuum and the contents were cooled to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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. |
Tags: Terbinafine Related Compound A | Benzene Compounds | Aryls | Organic Building Blocks | 65473-13-4
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