CN111606811A - Preparation method of terbinafine hydrochloride - Google Patents
Preparation method of terbinafine hydrochloride Download PDFInfo
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Abstract
The invention provides a preparation method of terbinafine hydrochloride, which comprises the following steps: in an acid-binding agent A, carrying out substitution reaction on N-methyl-1-naphthylmethylamine (II) and (E) -1, 3-dichloropropene (III) to obtain N- (3-chloroallyl-1) -methyl-1-naphthylmethylamine (IV) reaction liquid; carrying out condensation reaction on N- (3-chloroallyl-1) -methyl-1-naphthylmethylamine (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-naphthylmethylamine (VI); the reaction solution is treated by ammonia complexing and water washing to obtain oily matter; then forming salt in a hydrochloric acid aqueous solution to obtain a terbinafine hydrochloride crude product, and recrystallizing to obtain terbinafine hydrochloride. The preparation method of the invention does not use organic solvent, is environment-friendly, has low cost and simple operation, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of terbinafine hydrochloride, belonging to the technical field of pharmaceutical chemical synthesis.
Background
Terbinafine hydrochloride is an allylamine medicine with broad-spectrum antifungal activity, can specifically interfere the synthesis of fungal cell walls, and can destroy and die cell membranes, thereby achieving the effect of killing or inhibiting fungi. Terbinafine hydrochloride is suitable for tinea manuum, tinea pedis, tinea corporis, tinea unguium, tinea versicolor, etc. Terbinafine hydrochloride (terbinafine hydrochloride) is a white or white-like powder chemical with the chemical name of (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine hydrochloride and the structural formula is shown in the following formula I.
In the prior art, there are reports about the preparation method of terbinafine hydrochloride, such as: chinese patent document CN110423200A provides a preparation method for improving the purity of terbinafine hydrochloride, which comprises adding an acid-binding agent into water, stirring for dissolving, adding N-methyl-1-naphthylmethylamine and 1-chloro-6, 6-dimethyl-2-heptene-4-alkyne for reaction, and cooling to room temperature; adding ethyl acetate for extraction, filtering, adding a hydrochloric acid aqueous solution, stirring, and filtering to obtain a terbinafine hydrochloride crude product; and then purifying the crude product to obtain the terbinafine hydrochloride. Chinese patent document CN101870655A provides a method for preparing terbinafine hydrochloride, which comprises dissolving a certain amount of catalyst in an organic solvent, adding 1-chloro-6, 6-dimethyl-2-heptene-4-alkyne, sequentially adding alkali and N-methyl-1-naphthylmethylamine hydrochloride, condensing at 10-40 ℃, salifying the obtained product with hydrogen chloride in an alcohol system to obtain terbinafine hydrochloride, and recrystallizing with an alcohol-water mixed solution to obtain a qualified product. Chinese patent document CN108017544A provides a method for synthesizing terbinafine, which uses water as solvent, and makes monomethylamine, 1-chloromethyl naphthalene, and 1-chloro-6, 6-dimethyl-2-heptene-4-alkyne undergo the process of one-step reaction to produce terbinafine.
However, in the above reaction scheme, terbinafine is prepared by reaction in a solvent, a large amount of waste liquid is generated, the cost is high, and the intermediate product is subjected to next reaction after post-treatment, and the preparation steps are complex.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of terbinafine hydrochloride, which does not use organic solvent, has low cost, is environment-friendly, is simple to operate and is suitable for industrial production.
Description of terms:
a compound of formula I: terbinafine hydrochloride, chemical name: (E) -N- (6, 6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine hydrochloride;
a compound of formula II: n-methyl-1-naphthalenemethylamine;
a compound of formula III: (E) -1, 3-dichloropropene;
a compound of formula IV: n- (3-chloroallyl-1) -methyl-1-naphthylmethylamine;
a compound of formula V: 3, 3-dimethyl-1-butyne;
a compound of formula VI: (E) -N- (6, 6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthalenemethylamine;
the compound number and the structural formula number have the same reference relationship, and the structural formula is taken as the basis.
The technical scheme of the invention is as follows:
a preparation method of terbinafine hydrochloride comprises the following steps:
(1) in an acid-binding agent A, carrying out substitution reaction on a compound shown in a formula II and a compound shown in a formula III to obtain a reaction solution of a compound shown in a formula IV; directly carrying out the next reaction without processing the reaction solution;
(2) directly carrying out condensation reaction on the reaction liquid of the compound of the formula IV obtained in the step (1) and a compound of the formula V under the action of a composite catalyst and an acid-binding agent B to obtain a reaction liquid of a compound of the formula VI; the reaction solution is processed by ammonia water complexing and washing, and the obtained upper oily substance is used for the next reaction;
(3) forming a salt of the compound shown in the formula VI in the oily matter obtained in the step (2) in a hydrochloric acid aqueous solution to obtain a terbinafine hydrochloride crude product;
(4) and (4) recrystallizing the crude terbinafine hydrochloride obtained in the step (3) to obtain terbinafine hydrochloride.
According to the invention, in the step (1), the acid-binding agent A is n-butylamine, isobutylamine or triethylamine, and the molar ratio of the acid-binding agent A to the compound of formula II is 1.2-1.4: 1.0.
According to a preferred embodiment of the invention, the molar ratio of the compound of formula II to the compound of formula III in step (1) is 1.0:1.1 to 1.3.
Preferably, according to the present invention, the substitution reaction in step (1) comprises the steps of: mixing the compound of the formula II with an acid-binding agent A, controlling the temperature to 10-20 ℃, dropwise adding the compound of the formula III into the system, and heating to 50-55 ℃ after dropwise adding to react for 10-12 h.
According to the invention, the composite catalyst in the step (2) is a mixture of palladium chloride, cuprous iodide and triphenylphosphine, wherein the mass ratio of the palladium chloride to the cuprous iodide to the triphenylphosphine is 1:10-15:3-5, and the mass of the composite catalyst is 3.0-3.5% of that of the compound shown in the formula II.
According to the invention, in the step (2), the acid-binding agent B is n-butylamine, isobutylamine or triethylamine, and the molar ratio of the acid-binding agent B to the compound of the formula II is 1.2-1.4: 1.0.
According to a preferred embodiment of the invention, the molar ratio of the compound of the formula V to the compound of the formula II in step (2) is from 1.1 to 1.3: 1.0.
Preferably, according to the present invention, the condensation reaction in step (2) comprises the steps of: and (2) cooling the reaction liquid obtained in the step (1) to 20-25 ℃, adding an acid-binding agent B and a composite catalyst, dropwise adding the compound of the formula V into the system, and heating to 60-65 ℃ to react for 20-25h after dropwise adding.
According to the invention, the ammonia water complexing and washing treatment step in the step (2) is preferably as follows: concentrating the reaction solution to 93-94% of the original mass, adding concentrated ammonia water and water into the concentrated solution for complexing and washing for 0.5-1h, standing and layering to obtain an upper oily substance; the mass ratio of the added volume of the water to the compound of the formula II is 3-4mL:1 g; the mass fraction of the strong ammonia water is 22-25%, and the adding volume of the strong ammonia water is that the mass ratio of the compound of the formula II is 0.20-0.25mL:1 g.
Preferably according to the invention, the salification step in step (3) is: adding water and concentrated hydrochloric acid into the obtained oily substance, heating to 85-90 deg.C, salifying for 0.5-1h, cooling to 0-5 deg.C, filtering, and washing with water to obtain terbinafine hydrochloride crude product; the mass ratio of the added volume of the water to the compound of the formula II is 18-20mL:1 g; the mass fraction of the concentrated hydrochloric acid is 36-38%, and the adding volume of the concentrated hydrochloric acid is that the mass ratio of the compound of the formula II is 0.6-0.8mL:1 g.
Preferably according to the present invention, the recrystallization step in step (4) is: adding water into the obtained terbinafine hydrochloride crude product, heating to 85-90 ℃ for recrystallization, cooling to 0-5 ℃, filtering, washing with water, and drying to obtain terbinafine hydrochloride; the mass ratio of the added volume of the water to the wet terbinafine hydrochloride crude product is 7-9mL:1 g.
The reaction route of the invention is as follows:
the invention has the following technical characteristics and beneficial effects:
1. the invention takes N-methyl-1-naphthylmethylamine and (E) -1, 3-dichloropropene as raw materials to obtain N- (3-chloroallyl-1) -methyl-1-naphthylmethylamine through substitution reaction; then coupling and condensing N- (3-chloroallyl-1) -methyl-1-naphthylmethylamine and 3, 3-dimethyl-1-butyne to obtain terbinafine, and salifying terbinafine in a hydrochloric acid aqueous solution to obtain terbinafine hydrochloride. The method has the advantages of easily available raw materials, low cost and simple preparation method, and the terbinafine can be prepared by the first two-step chemical synthesis 'one-pot method'. The raw materials of the first two steps of reaction are dissolved in the acid-binding agent, so that the concentration of the raw materials is high, and the reaction conversion rate is high; terbinafine hydrochloride obtained by salification can be completely dissolved in water under high temperature condition, the salification is sufficient, and the product yield is high.
2. The preparation method of the invention does not use organic solvent, is environment-friendly and is suitable for industrial production.
Detailed Description
The present invention is further illustrated by, but is not limited to, the following examples.
The methods described in the examples are conventional methods unless otherwise specified; the reagents used are commercially available without further indication.
The yields in the examples are all molar yields.
Example 1
A preparation method of terbinafine hydrochloride comprises the following steps:
(1) adding 50g N-methyl-1-naphthylmethylamine (II) and 25.7g of N-butylamine into a reaction bottle, uniformly stirring, controlling the temperature to be 10-20 ℃, dropwise adding 35.7g of (E) -1, 3-dichloropropene (III) into the system, heating to 50-55 ℃ after dropwise adding, preserving the temperature for reaction for 12 hours, and detecting that a raw material II completely reacts by TLC (thin layer chromatography) to obtain an N- (3-chloroallyl-1) -methyl-1-naphthylmethylamine (IV) reaction solution; directly carrying out the next reaction without processing the reaction solution;
(2) cooling the reaction liquid obtained in the step (1) to 20-25 ℃, adding 25.7g of n-butylamine and 1.72g of composite catalyst (the mass of palladium chloride, cuprous iodide and triphenylphosphine is 0.12g, 1.2g and 0.4g respectively), then dropwise adding 3, 3-dimethyl-1-butyne (V) into the system, after the dropwise adding is finished, heating to 60-65 ℃ for reaction for 20h, detecting that the raw material IV completely reacts by TLC, concentrating under reduced pressure to 155.3g, then cooling the obtained concentrated solution to 20-25 ℃, adding 150mL of water and 10mL of 23% concentrated ammonia water for complexing and washing for 1h, standing for layering, and separating out an upper-layer oily substance to obtain an (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) oily substance;
(3) adding 900mL of water and 30mL of concentrated hydrochloric acid with the mass fraction of 37% into the oily matter of the (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) obtained in the step (2), heating to 85-90 ℃ to form salt for 0.5h, cooling to 0-5 ℃, carrying out suction filtration, and washing a filter cake with 50mL of water to obtain 115.8g of a crude terbinafine hydrochloride wet product;
(4) and (3) adding 926mL of water into the crude terbinafine hydrochloride wet product obtained in the step (3), heating to 85-90 ℃, recrystallizing, cooling to 0-5 ℃, performing suction filtration, washing a filter cake with 50mL of water, and drying the filter cake to obtain 78.5g of terbinafine hydrochloride.
The terbinafine hydrochloride prepared in this example had a purity of 99.6% and a total molar yield of 82.0%.
Example 2
A preparation method of terbinafine hydrochloride comprises the following steps:
(1) adding 50g N-methyl-1-naphthylmethylamine (II) and 27.8g of N-butylamine into a reaction bottle, uniformly stirring, controlling the temperature to be 10-20 ℃, dropwise adding 38.9g of (E) -1, 3-dichloropropene (III) into the system, heating to 50-55 ℃ for reaction after dropwise adding, preserving the temperature for reaction for 11 hours, and detecting that a raw material II completely reacts by TLC (thin layer chromatography) to obtain N- (3-chloroallyl-1) -methyl-1-naphthylmethylamine (IV) reaction liquid; directly carrying out the next reaction without processing the reaction solution;
(2) cooling the reaction liquid obtained in the step (1) to 20-25 ℃, adding 27.8g of n-butylamine and 1.72g of composite catalyst (the mass of palladium chloride, cuprous iodide and triphenylphosphine is 0.12g, 1.2g and 0.4g respectively), then dropwise adding 28.8g of 3, 3-dimethyl-1-butyne (V) into the system, after the dropwise adding is finished, heating to 60-65 ℃ for reaction for 22h, detecting the complete reaction of the raw material IV by TLC, concentrating under reduced pressure to 154.6g, then cooling the obtained concentrated solution to 20-25 ℃, adding 200mL of water and 10mL of 23% concentrated ammonia water for complexing and washing for 1h, standing for layering, and separating out an upper-layer oily substance to obtain an (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) oily substance;
(3) adding 950mL of water and 30mL of concentrated hydrochloric acid with the mass fraction of 37% into the oily matter of the (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) obtained in the step (2), heating to 85-90 ℃ to form salt for 1h, cooling to 0-5 ℃, carrying out suction filtration, washing a filter cake with 50mL of water, and obtaining 117.3g of crude terbinafine hydrochloride wet product;
(4) adding 997mL of water into the crude terbinafine hydrochloride wet product obtained in the step (3), heating to 85-90 ℃, recrystallizing, cooling to 0-5 ℃, performing suction filtration, washing a filter cake with 50mL of water, and drying the filter cake to obtain 78.9g of terbinafine hydrochloride.
The terbinafine hydrochloride prepared in this example had a purity of 99.7% and a total molar yield of 82.4%.
Example 3
A preparation method of terbinafine hydrochloride comprises the following steps:
(1) adding 50g N-methyl-1-naphthylmethylamine (II) and 29.9g of N-butylamine into a reaction bottle, uniformly stirring, controlling the temperature to be 10-20 ℃, dropwise adding 42.1g of (E) -1, 3-dichloropropene (III) into the system, heating to 50-55 ℃ after dropwise adding, preserving the temperature for reaction for 10 hours, and detecting that a raw material II completely reacts by TLC (thin layer chromatography) to obtain an N- (3-chloroallyl-1) -methyl-1-naphthylmethylamine (IV) reaction solution; directly carrying out the next reaction without processing the reaction solution;
(2) cooling the reaction liquid obtained in the step (1) to 20-25 ℃, adding 29.9g of n-butylamine and 1.72g of composite catalyst (the mass of palladium chloride, cuprous iodide and triphenylphosphine is 0.12g, 1.2g and 0.4g respectively), then dropwise adding 28.8g of 3, 3-dimethyl-1-butyne (V) into the system, after the dropwise adding is finished, heating to 60-65 ℃ for reaction for 20h, detecting that the raw material IV completely reacts by TLC, concentrating under reduced pressure to 155.8g, then cooling the obtained concentrated solution to 20-25 ℃, adding 200mL of water and 10mL of 23% concentrated ammonia water for complexing and washing for 1h, standing for layering, and separating out an upper-layer oily substance to obtain an (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) oily substance;
(3) adding 1000mL of water and 30mL of concentrated hydrochloric acid with the mass fraction of 37% into the oily matter of the (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) obtained in the step (2), heating to 85-90 ℃ to form salt for 0.5h, cooling to 0-5 ℃, carrying out suction filtration, and washing a filter cake with 50mL of water to obtain 114.5g of a crude terbinafine hydrochloride wet product;
(4) adding 916mL of water into the crude terbinafine hydrochloride wet product obtained in the step (3), heating to 85-90 ℃, recrystallizing, cooling to 0-5 ℃, performing suction filtration, washing a filter cake with 50mL of water, and drying the filter cake to obtain 79.1g of terbinafine hydrochloride.
The terbinafine hydrochloride prepared in this example has a purity of 99.6% and a total molar yield of 82.6%.
Comparative example 1
A preparation method of terbinafine hydrochloride comprises the following steps:
(1) adding 50g of N-methyl-1-naphthylmethylamine (II), 25.7g of N-butylamine and 200mL of acetonitrile into a reaction bottle, uniformly stirring, controlling the temperature to be 10-20 ℃, dropwise adding 35.7g of (E) -1, 3-dichloropropene (III) into the system, heating to 50-55 ℃ after dropwise adding, preserving the temperature for reaction for 12h, and detecting that a raw material II completely reacts by TLC (thin layer chromatography) to obtain an acetonitrile solution of N- (3-chloroallyl-1) -methyl-1-naphthylmethylamine (IV); directly carrying out the next reaction without processing the reaction solution;
(2) cooling the reaction liquid obtained in the step (1) to 20-25 ℃, adding 25.7g of n-butylamine and 1.72g of composite catalyst (the mass of palladium chloride, cuprous iodide and triphenylphosphine is 0.12g, 1.2g and 0.4g respectively), then dropwise adding 3, 3-dimethyl-1-butyne (V) into the system, after the dropwise adding is finished, heating to 60-65 ℃ for reaction for 25h, detecting by TLC that more raw material IV is remained in reaction, continuing the reaction until no obvious change exists in 28h, concentrating under reduced pressure to 155.5g, then cooling the obtained concentrated solution to 20-25 ℃, adding 150mL of water and 10mL of 23% concentrated ammonia water for complexing and washing for 1h, standing for layering, and separating out an upper-layer oily substance to obtain an (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) oily substance;
(3) adding 900mL of water and 30mL of concentrated hydrochloric acid with the mass fraction of 37% into the oily matter of the (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) obtained in the step (2), heating to 85-90 ℃ to form salt for 0.5h, cooling to 0-5 ℃, carrying out suction filtration, washing a filter cake with 50mL of water, and obtaining 73.6g of crude terbinafine hydrochloride wet product;
(4) adding 589mL of water into the crude terbinafine hydrochloride wet product obtained in the step (3), heating to 85-90 ℃, recrystallizing, cooling to 0-5 ℃, performing suction filtration, washing a filter cake with 50mL of water, and drying the filter cake to obtain 58.0g of terbinafine hydrochloride.
The purity of terbinafine hydrochloride prepared by the comparative example is 93.2%, and the total molar yield is 60.6%.
Comparative example 2
A preparation method of terbinafine hydrochloride comprises the following steps:
(1) adding 50g of N-methyl-1-naphthylmethylamine (II), 25.7g of N-butylamine and 200mL of acetonitrile into a reaction bottle, uniformly stirring, controlling the temperature to be 10-20 ℃, dropwise adding 35.7g of (E) -1, 3-dichloropropene (III) into the system, heating to 50-55 ℃ after dropwise adding, carrying out heat preservation reaction for 12h, detecting that a raw material II completely reacts by TLC, and concentrating the reaction solution under reduced pressure to 115.6g to obtain N- (3-chloroallyl-1) -methyl-1-naphthylmethylamine (IV);
(2) cooling the concentrate obtained in the step (1) to 20-25 ℃, adding 200mL of tetrahydrofuran, 25.7g of n-butylamine and 1.72g of composite catalyst (the mass of palladium chloride, the mass of cuprous iodide and the mass of triphenylphosphine are 0.12g, 1.2g and 0.4g respectively), dropwise adding 28.8g of 3, 3-dimethyl-1-butyne (V) into the system, after the dropwise adding is finished, heating to 60-65 ℃ for reaction for 25h, detecting that the raw material IV completely reacts by TLC, concentrating under reduced pressure to 156.2g, then cooling the obtained concentrated solution to 20-25 ℃, adding 200mL of dichloromethane, 150mL of water and 10mL of 23% concentrated ammonia water for complexing and washing for 1h, standing for layering, and separating out a lower organic phase to obtain a dichloromethane solution of (E) -N- (6, 6-dimethyl-2-heptylene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI);
(3) adding 150mL of water and 30mL of concentrated hydrochloric acid with the mass fraction of 37% into the dichloromethane solution of the (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) obtained in the step (2), controlling the temperature to be 20-25 ℃ to salify for 0.5h, standing for layering, and carrying out decompression concentration on the lower organic phase to obtain 103.5g of crude terbinafine hydrochloride concentrate;
(4) and (3) adding 828mL of water into the crude terbinafine hydrochloride concentrate obtained in the step (3), heating to 85-90 ℃, recrystallizing, cooling to 0-5 ℃, performing suction filtration, washing a filter cake with 50mL of water, and drying the filter cake to obtain 73.2g of terbinafine hydrochloride.
The purity of terbinafine hydrochloride prepared by the comparative example is 99.0%, and the total molar yield is 76.5%.
Comparative example 3
A preparation method of terbinafine hydrochloride comprises the following steps:
(1) adding 50g N-methyl-1-naphthylmethylamine (II) and 25.7g of N-butylamine into a reaction bottle, uniformly stirring, controlling the temperature to be 10-20 ℃, dropwise adding 35.7g of (E) -1, 3-dichloropropene (III) into the system, heating to 50-55 ℃ after dropwise adding, preserving the temperature for reaction for 12 hours, and detecting that a raw material II completely reacts by TLC (thin layer chromatography) to obtain an N- (3-chloroallyl-1) -methyl-1-naphthylmethylamine (IV) reaction solution; directly carrying out the next reaction without processing the reaction solution;
(2) cooling the reaction liquid obtained in the step (1) to 20-25 ℃, adding 25.7g of n-butylamine and 1.72g of composite catalyst (the mass of palladium chloride, cuprous iodide and triphenylphosphine is 0.12g, 1.2g and 0.4g respectively), then dropwise adding 3, 3-dimethyl-1-butyne (V) into the system, after the dropwise adding is finished, heating to 60-65 ℃ for reaction for 20h, detecting that the raw material IV completely reacts by TLC, concentrating under reduced pressure to 154.8g, cooling the obtained concentrated solution to 20-25 ℃, adding 150mL of water and 10mL of 23% concentrated ammonia water for complexing and washing for 1h, standing for layering, and separating out an upper-layer oily substance to obtain an (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) oily substance;
(3) adding 900mL of water and 30mL of concentrated hydrochloric acid with the mass fraction of 37% into the oily matter of the (E) -N- (6, 6-dimethyl-2-heptene-4-alkynyl) -N-methyl-1-naphthylmethylamine (VI) obtained in the step (2), heating to 75-80 ℃, salifying for 0.5h, cooling to 0-5 ℃, carrying out suction filtration, washing a filter cake with 50mL of water, and obtaining 106.3g of crude terbinafine hydrochloride wet product;
(4) and (3) adding 850mL of water into the crude terbinafine hydrochloride wet product obtained in the step (3), heating to 85-90 ℃, recrystallizing, cooling to 0-5 ℃, performing suction filtration, washing a filter cake with 50mL of water, and drying the filter cake to obtain 73.7g of terbinafine hydrochloride.
The comparison example reduces the salt forming temperature, the purity of the prepared terbinafine hydrochloride is 99.4%, the total molar yield is 77.0%, and compared with the invention, the yield is lower.
Claims (10)
1. A preparation method of terbinafine hydrochloride comprises the following steps:
(1) in an acid-binding agent A, carrying out substitution reaction on a compound shown in a formula II and a compound shown in a formula III to obtain a reaction solution of a compound shown in a formula IV; directly carrying out the next reaction without processing the reaction solution;
(2) directly carrying out condensation reaction on the reaction liquid of the compound of the formula IV obtained in the step (1) and a compound of the formula V under the action of a composite catalyst and an acid-binding agent B to obtain a reaction liquid of a compound of the formula VI; the reaction solution is processed by ammonia water complexing and washing, and the obtained upper oily substance is used for the next reaction;
(3) forming a salt of the compound shown in the formula VI in the oily matter obtained in the step (2) in a hydrochloric acid aqueous solution to obtain a terbinafine hydrochloride crude product;
(4) and (4) recrystallizing the crude terbinafine hydrochloride obtained in the step (3) to obtain terbinafine hydrochloride.
2. The method for preparing terbinafine hydrochloride according to claim 1, wherein in step (1), said acid-binding agent A is n-butylamine, isobutylamine, triethylamine, and the molar ratio of said acid-binding agent A to the compound of formula II is 1.2-1.4: 1.0.
3. The method for preparing terbinafine hydrochloride in accordance with claim 1, wherein the molar ratio of the compound of formula ii to the compound of formula iii in step (1) is 1.0: 1.1-1.3.
4. The method for preparing terbinafine hydrochloride according to claim 1, wherein the substitution reaction in step (1) comprises the steps of: mixing the compound of the formula II with an acid-binding agent A, controlling the temperature to 10-20 ℃, dropwise adding the compound of the formula III into the system, and heating to 50-55 ℃ after dropwise adding to react for 10-12 h.
5. The preparation method of terbinafine hydrochloride according to claim 1, wherein the composite catalyst in step (2) is a mixture of palladium chloride, cuprous iodide and triphenylphosphine, wherein the mass ratio of palladium chloride, cuprous iodide and triphenylphosphine is 1:10-15:3-5, and the mass of the composite catalyst is 3.0-3.5% of the compound of formula ii.
6. The preparation method of terbinafine hydrochloride according to claim 1, wherein in step (2), said acid-binding agent B is n-butylamine, isobutylamine, triethylamine, and the molar ratio of said acid-binding agent B to the compound of formula II is 1.2-1.4: 1.0; the molar ratio of the compound of the formula V to the compound of the formula II is 1.1-1.3: 1.0.
7. The method for preparing terbinafine hydrochloride according to claim 1, wherein the condensation reaction in step (2) comprises the steps of: and (2) cooling the reaction liquid obtained in the step (1) to 20-25 ℃, adding an acid-binding agent B and a composite catalyst, dropwise adding the compound of the formula V into the system, and heating to 60-65 ℃ to react for 20-25h after dropwise adding.
8. The method for preparing terbinafine hydrochloride according to claim 1, wherein the step of aqueous ammonia complexation and washing treatment in step (2) comprises: concentrating the reaction solution to 93-94% of the original mass, adding concentrated ammonia water and water into the concentrated solution for complexing and washing for 0.5-1h, standing and layering to obtain an upper oily substance; the mass ratio of the added volume of the water to the compound of the formula II is 3-4mL:1 g; the mass fraction of the strong ammonia water is 22-25%, and the adding volume of the strong ammonia water is that the mass ratio of the compound of the formula II is 0.20-0.25mL:1 g.
9. The method for preparing terbinafine hydrochloride according to claim 1, wherein the salt formation step in step (3) is: adding water and concentrated hydrochloric acid into the obtained oily substance, heating to 85-90 deg.C, salifying for 0.5-1h, cooling to 0-5 deg.C, filtering, and washing with water to obtain terbinafine hydrochloride crude product; the mass ratio of the added volume of the water to the compound of the formula II is 18-20mL:1 g; the mass fraction of the concentrated hydrochloric acid is 36-38%, and the adding volume of the concentrated hydrochloric acid is that the mass ratio of the compound of the formula II is 0.6-0.8mL:1 g.
10. The method for preparing terbinafine hydrochloride according to claim 1, wherein said recrystallization step in step (4) is: adding water into the obtained terbinafine hydrochloride crude product, heating to 85-90 ℃ for recrystallization, cooling to 0-5 ℃, filtering, washing with water, and drying to obtain terbinafine hydrochloride; the mass ratio of the added volume of the water to the wet terbinafine hydrochloride crude product is 7-9mL:1 g.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5231183A (en) * | 1989-10-02 | 1993-07-27 | Banyu Pharmaceutical Co., Ltd. | Process for producing enyne derivatives |
| CN1993369A (en) * | 2004-06-09 | 2007-07-04 | 意大利合成制造有限公司 | A process for the synthesis of terbinafine and derivatives thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5231183A (en) * | 1989-10-02 | 1993-07-27 | Banyu Pharmaceutical Co., Ltd. | Process for producing enyne derivatives |
| CN1993369A (en) * | 2004-06-09 | 2007-07-04 | 意大利合成制造有限公司 | A process for the synthesis of terbinafine and derivatives thereof |
Non-Patent Citations (1)
| Title |
|---|
| BEUTLER ULRICH等: "The development of a new sustainable process for the production of terbinafine", 《CHIMIA》 * |
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