CN111606811B - Preparation method of terbinafine hydrochloride - Google Patents
Preparation method of terbinafine hydrochloride Download PDFInfo
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- CN111606811B CN111606811B CN202010500582.5A CN202010500582A CN111606811B CN 111606811 B CN111606811 B CN 111606811B CN 202010500582 A CN202010500582 A CN 202010500582A CN 111606811 B CN111606811 B CN 111606811B
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- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 title claims abstract description 82
- 229960000699 terbinafine hydrochloride Drugs 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000000243 solution Substances 0.000 claims abstract description 30
- 238000005406 washing Methods 0.000 claims abstract description 28
- 239000002253 acid Substances 0.000 claims abstract description 20
- 239000011230 binding agent Substances 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 239000002131 composite material Substances 0.000 claims abstract description 15
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 14
- 230000000536 complexating effect Effects 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 41
- 238000010438 heat treatment Methods 0.000 claims description 31
- 238000001816 cooling Methods 0.000 claims description 30
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 20
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 16
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 10
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 10
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 10
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000010668 complexation reaction Methods 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- MQRIUFVBEVFILS-UHFFFAOYSA-N n-methyl-1-naphthalen-1-ylmethanamine Chemical compound C1=CC=C2C(CNC)=CC=CC2=C1 MQRIUFVBEVFILS-UHFFFAOYSA-N 0.000 abstract description 23
- UOORRWUZONOOLO-OWOJBTEDSA-N (E)-1,3-dichloropropene Chemical compound ClC\C=C\Cl UOORRWUZONOOLO-OWOJBTEDSA-N 0.000 abstract description 17
- PPWNCLVNXGCGAF-UHFFFAOYSA-N 3,3-dimethylbut-1-yne Chemical compound CC(C)(C)C#C PPWNCLVNXGCGAF-UHFFFAOYSA-N 0.000 abstract description 9
- UOORRWUZONOOLO-UHFFFAOYSA-N telone II Natural products ClCC=CCl UOORRWUZONOOLO-UHFFFAOYSA-N 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 3
- 229910021529 ammonia Inorganic materials 0.000 abstract 1
- 239000012065 filter cake Substances 0.000 description 17
- 239000002994 raw material Substances 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- 229960002722 terbinafine Drugs 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XMWGTKZEDLCVIG-UHFFFAOYSA-N 1-(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1 XMWGTKZEDLCVIG-UHFFFAOYSA-N 0.000 description 1
- 206010005913 Body tinea Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 208000007712 Tinea Versicolor Diseases 0.000 description 1
- 206010067197 Tinea manuum Diseases 0.000 description 1
- 206010056131 Tinea versicolour Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- ACHJACAEYOYEBF-UHFFFAOYSA-N n-(4-aminophenyl)-3-methylbutanamide Chemical compound CC(C)CC(=O)NC1=CC=C(N)C=C1 ACHJACAEYOYEBF-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- BWMISRWJRUSYEX-SZKNIZGXSA-N terbinafine hydrochloride Chemical compound Cl.C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-SZKNIZGXSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 201000003875 tinea corporis Diseases 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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 crude terbinafine hydrochloride product; and then purifying the crude product to obtain the terbinafine hydrochloride. Chinese patent document CN101870655A provides a preparation method of 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-naphthylamine 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 synthesis method of terbinafine, which uses water as solvent, and makes monomethylamine, 1-chloromethyl naphthalene, and 1-chloro-6, 6-dimethyl-2-heptene-4-alkyne produce terbinafine through one-step reaction.
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 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 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 matter, heating to 85-90 ℃, salifying for 0.5-1h, then cooling to 0-5 ℃, filtering, washing with water to obtain crude terbinafine hydrochloride; 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 obtained 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 is finished, keeping the temperature for reaction for 12h, 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 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 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 155.3g, 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), 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 reacting for 22h, detecting that the raw material IV completely reacts by TLC, concentrating under reduced pressure to 154.6g, 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-heptylene-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 has 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), 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) and (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), 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 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 (9)
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; the acid-binding agent A is n-butylamine, isobutylamine and triethylamine, and the molar ratio of the acid-binding agent A to the compound of the formula II is 1.2-1.4: 1.0;
(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-layer oily matter is used for the next reaction; the acid-binding agent B is n-butylamine, isobutylamine and 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;
(3) forming 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 crude terbinafine hydrochloride product; the salifying step comprises the following steps: adding water and concentrated hydrochloric acid into the obtained oily matter, heating to 85-90 ℃, salifying for 0.5-1h, then cooling to 0-5 ℃, filtering, washing with water to obtain crude terbinafine hydrochloride;
(4) recrystallizing the crude terbinafine hydrochloride obtained in the step (3) to obtain terbinafine hydrochloride; in the preparation process of the terbinafine hydrochloride, no organic solvent is added except reactants and water.
2. 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.
3. The process for preparing terbinafine hydrochloride of claim 1, wherein the step of said substitution reaction in step (1) is: 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.
4. 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.
5. The process for preparing terbinafine hydrochloride in claim 1, wherein the molar ratio of the compound of formula v to the compound of formula ii in step (2) is 1.1-1.3: 1.0.
6. 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.
7. 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-layer 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.
8. The method for preparing terbinafine hydrochloride according to claim 1, wherein the mass ratio of the volume of water added in step (3) to the compound of 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.
9. 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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