CN102898314B - Preparation method of terbinafine hydrochloride - Google Patents
Preparation method of terbinafine hydrochloride Download PDFInfo
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- CN102898314B CN102898314B CN201210454165.7A CN201210454165A CN102898314B CN 102898314 B CN102898314 B CN 102898314B CN 201210454165 A CN201210454165 A CN 201210454165A CN 102898314 B CN102898314 B CN 102898314B
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Abstract
The invention discloses a preparation method of terbinafine hydrochloride, and belongs to the technical field of medicine. According to the method, a monomethylamine aqueous solution and (E)-1, 3 dichloropropene are taken as materials to react to obtain (E)-1-methylamino-3-chlorine-propylene; then (E)-1-methylamino-3-chlorine-propylene reacts with tertiary butyl acetylene to obtain (E)-N-(6, 6-dimethyl-2-heptylene-4-alkynyl) methylamine; and then the (E)-N-(6, 6-dimethyl-2-heptylene-4-alkynyl) methylamine reacts with 1-chlorine-methylnaphthalene to obtain terbinafine, and hydrochloric acid is added for salification to obtain terbinafine hydrochloride. According to the method, materials are easy to get, the cost is low, the preparation method is simple, the yield is high, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of Terbinafine Hcl, belong to medical technical field.
Background technology
Terbinafine Hcl, chemical name is: (E)-N-(6,6-dimethyl hept-2-ene"-4-alkynyl)-N-methyl isophthalic acid-naphthalene methylamine hydrochloric salt (English name: N, 6,6-Trimethyl-N-(naphthalen-1-ylmethyl) hept-2-en-4-yn-1-amine hydrochloride), molecular formula C
21h
25nHCl.Its structural formula is as follows.
Terbinafine Hcl belongs to propylamine antifungal drug, is one of seven new synthetic antifunguses things of the listing nineties in 20th century.Because of its has a broad antifungal spectrum, can sterilization, curative effect is high, and toxic side effects is low, and is caught people's attention.Be mainly used in treating onychomycosis, tinea pedis, the tinea manuum, ringworm of the body, jock itch and tinea versicolor, the diseases such as vaginal candida infection.Terbinafine entered China market in 1993, after synthesized Terbinafine Hcl raw material by Shandong Qilu Pharmaceutical Factory in nineteen ninety-five, and carried out declaring of raw material and ointment formulation by two kind new medicines, and obtain the approval of national correlation department, within 1997, transfer accurate font size to.Along with popularization and the deep exploitation in market, clinical application is increasingly extensive, has obtained good economic benefit and social benefit.
The domestic and international patent of synthetic route and the document of Terbinafine Hcl all have report, sum up and mainly contain following several synthetic routes:
(1) after reacting with organolithium reagent or Grignard reagent taking tert-butyl acetylene as raw material, make 6 with acrolein reaction again, 6 dimethyl-1-heptene-4-alkynes-3-alcohol, obtain 1 halogen-6 through halogenating reaction again, 6 dimethyl-2-heptene-4-alkynes, react with N-methyl isophthalic acid-naphthalene methylamine again, make Terbinafine Hcl with hydrochloric acid salify.Synthesizing of concrete visible patent CN031139198.7(Terbinafine hydrochloride), reaction formula is as follows:
(2) 6, the esterification of 6 dimethyl-1-heptene-4-alkynes-3-alcohol generates 6,6 dimethyl-1-heptene-4-alkynes-3-alcohol acetic ester, and then reacts and obtain Terbinafine with N-methyl isophthalic acid-naphthalene methylamine.
(3) under formaldehyde and sodium borohydride existence, naphthylamines and 6,6 dimethyl-2 heptene-4-alkynes-1-aldehyde reduction amination are made to Terbinafine.
(4) react with chloro methyloxypropane taking N-methyl isophthalic acid-naphthalene methylamine hydrochloric salt as starting raw material and make intermediate N methyl isophthalic acid menaphthyl-2,3 propylene oxide, then react to obtain Terbinafine with tert-butyl acetylene lithium.
(5) N-methyl isophthalic acid-naphthalene methylamine and propine obtain propine derivative under butyllithium exists, then obtain iodopropylene sulfonamide derivatives with Iod R, then make Terbinafine with the reaction of 3,3 neohexenes-1-pink salt.
(6) N-methyl isophthalic acid-naphthalene methylamine obtains (E)-N-(3-chloro-2-propene with the reaction of (E)-1,3 dichloropropylene)-N-methyl isophthalic acid-naphthalene methylamine, then under palladium, cuprous chloride catalysis, make Terbinafine with tert-butyl acetylene.
In above synthetic route, or yield is low, or raw material is rare, and production cost is high, is not suitable for suitability for industrialized production.
Summary of the invention
Technical problem solved by the invention is to provide a kind of preparation method of Terbinafine Hcl.The method raw material is easily purchased, cheap, and preparation method is simple, and yield is high, has the market competitiveness.
For solving the problems of the technologies described above, the technical solution used in the present invention is: a kind of preparation method of Terbinafine Hcl, it is characterized in that, be that raw material reacts and obtains the chloro-propylene of (E)-1-methylamino-3-with monomethylamine aqueous solution and (E)-1,3 dichloropropylene; Then the chloro-propylene of (E)-1-methylamino-3-reacts with tert-butyl acetylene and obtains (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine; Then (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine reacts and obtains Terbinafine with the chloro-methylnaphthalene of 1-again, then obtains Terbinafine Hcl after adding hydrochloric acid salify.
Comprise the steps:
Step 1, (E)-chloro-propylene of 1-methylamino-3-synthetic
Monomethylamine aqueous solution is added in reaction flask, stir borehole cooling to 0～5 DEG C, drip (E)-1,3 dichloropropylenes, dropwise, and naturally rise to room temperature and carry out, react the reaction ratio to 2% following (conventionally reacting 5～6 hours) to vapor detection (E)-1,3 dichloropropylene; After reaction solution layering, organic phase obtains the chloro-propylene of (E)-1-methylamino-3-after washing, dry, suction filtration, and wherein the mol ratio of (E)-1,3 dichloropropylene and Monomethylamine is 1:3～5.
Preferably, the concentration of described monomethylamine aqueous solution is 20 ~ 50%, more preferably 30%.
Step 2, (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine synthetic
The chloro-propylene of (E)-1-methylamino-3-is joined in the mixing solutions of tetrahydrofuran (THF) and n-Butyl Amine 99, add Palladous chloride and cuprous iodide, triphenylphosphine, drip tert-butyl acetylene, 50～60 DEG C of insulations, vapor detection tert-butyl acetylene reaction ratio to 2% following (approximately reacting 15 hours), evaporate to dryness tetrahydrofuran (THF), add n-hexane dissolution, ammonia scrubbing, evaporate to dryness normal hexane.Underpressure distillation can obtain content more than 97%.The wherein chloro-propylene of (E)-1-methylamino-3-: mol ratio=1:0.98～1.01 of tert-butyl acetylene.
Preferably, the mass ratio of described tetrahydrofuran (THF) and n-Butyl Amine 99 is 1.5 ~ 2.5:1; The mass ratio of described Palladous chloride, cuprous iodide and triphenylphosphine is 1:10 ~ 20:3 ~ 8; In the quality of the chloro-propylene of (E)-1-methylamino-3-, the add-on of described n-Butyl Amine 99 is 60 ~ 120%, and the add-on of described Palladous chloride is 0.01 ~ 0.5%.
Step 3, Terbinafine Hcl synthetic
Chloro-1-methylnaphthalene is joined in wet chemical, add phase-transfer catalyst PVOH 400-600, drip (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine, 50～55 DEG C of reaction to samplings detect the chloro-methylnaphthalene of 1-and (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) reaction ratio of methylamine, two kinds of residual controls of reactant (reaction times is generally 4～5 hours) below 0.5%.Reaction solution adds chloroform to stir, layering, and organic phase is washed rear dropping dilute hydrochloric acid to PH=2; Branch vibration layer, washing organic phase is to neutral, and evaporate to dryness chloroform adds ethyl acetate reflux 20～40 minutes, centrifugal the Terbinafine Hcl crude product of lowering the temperature, then use Virahol dissolving crystallized, and suction filtration, oven dry gets product.The chloro-methylnaphthalene of described 1-is 1:0.98～1.02 with the mol ratio of (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine.
Preferably, in the quality of the chloro-methylnaphthalene of 1-, the add-on of described PVOH 400-600 is 0.1 ~ 5%.Preferably, in described wet chemical, the mass ratio of salt of wormwood and water is 1:2 ~ 3.
Beneficial effect; With Monomethylamine, (E)-1,3 dichloropropylene, n-Butyl Amine 99 and the chloro-methylnaphthalene of 1-, for raw material, raw material is simple and easy to get, and low price.Production stage of the present invention is simple, and yield is high, and suitability for industrialized is produced.
Embodiment
Embodiment 1
Step 1:(E)-chloro-the propylene of 1-methylamino-3-synthetic
200 grams of monomethylamine aqueous solutions (30%) are joined in 500ml reaction flask, open and stir, be cooled to 0 DEG C, add 0.5 gram of tributyl brometo de amonio, drip 50 grams of (E)-1,3 dichloropropylenes, slowly rise to 20 DEG C, react 4 hours, the chloro-propylene of monitoring (E)-1-methylamino-3-residual 3%, continue to rise to 25 DEG C of reactions 2 hours, residual 1.3%, layering.Product, in lower floor, is washed residual Monomethylamine, then adds 5 grams, siccative sodium sulfate, and dry, suction filtration obtains 45 grams of products, content 97.5%, yield 92.5%.The reaction of this step, requires reaction vessel sealing property to get well.
Step 2:(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine synthetic
By in 45 grams of input reaction flasks of the chloro-propylene of (E)-1-methylamino-3-of step 1, add 100 grams of tetrahydrofuran (THF)s, 50 grams of n-Butyl Amine 99s, 0.2 gram of Palladous chloride, 3 grams of cuprous iodides, 1 gram of triphenyl phosphorus, 40 DEG C drip 34 grams of tert-butyl acetylenes, within 30 minutes, dropwise, slowly be warming up to 55 DEG C, insulation reaction samples detection after 15 hours, E) the chloro-propylene residual quantity 1.5% of 1-methylamino-3-, tert-butyl acetylene residual 0.7%, reaction reaches requirement, evaporated under reduced pressure tetrahydrofuran (THF), water-bath is below 70 DEG C, after evaporate to dryness, be cooled to below 30 DEG C, add normal hexane 200ml, stir and within 15 minutes, add again 30 milliliters of washings of ammoniacal liquor (ammoniacal liquor recovery preservation, reclaim Palladous chloride), reclaim under reduced pressure normal hexane, then rectifying obtains faint yellow transparent E)-N-(6, 6-dimethyl-2-heptene-4-alkynyl) 58 grams of methylamines, content 97.5%, yield 90.2%.
Step 3, Terbinafine Hcl synthetic
65 grams of chloro-1-methylnaphthalenes are joined in 120 grams of water, add 50 grams of salt of wormwood, add 2 grams of phase-transfer catalyst PVOHs 400, drip (the E)-N-(6 of 58 grams of steps 2,6-dimethyl-2-heptene-4-alkynyl) methylamine, 50～55 DEG C are reacted 4 hours, and sampling detects the chloro-methylnaphthalene of 1-residual 0.35%, (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine residual 0.4%.Add 200 grams of chloroforms to stir, add 100 grams of washings, organic layer drips 150 grams of dilute hydrochloric acid (50 grams of concentrated hydrochloric acid+100 gram water), to PH=2 again, branch vibration layer, be washed to neutrality, evaporate to dryness chloroform adds 200 grams of ethyl acetate backflow 30 minutes, the centrifugal Terbinafine Hcl crude product that obtains of lowering the temperature, use again 300 grams of Virahols dissolving crystallized, suction filtration, oven dry gets product, 98 grams.Yield 80.5%.
Embodiment 2
Step 1:(E)-chloro-the propylene of 1-methylamino-3-synthetic
380 grams of monomethylamine aqueous solutions (30%) are joined in 1000ml reaction flask, open and stir, be cooled to 2 DEG C, add 1.0 grams of tributyl brometo de amonios, drip 100 grams of (E)-1,3 dichloropropylenes, slowly rise to 20 DEG C, react 3 hours, the chloro-propylene of monitoring (E)-1-methylamino-3-residual 3.8%, continue to rise to 25 DEG C of reactions 2.5 hours, residual 1.2%, layering, product is in lower floor, wash residual Monomethylamine, then add 10 grams, siccative sodium sulfate, dry, suction filtration obtains 90.5 grams of products, content 97.3%, yield 92.7%.The reaction of this step, requires reaction vessel sealing property to get well.
Step 2:(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine synthetic
By in 90.5 grams of input reaction flasks of the chloro-propylene of (E)-1-methylamino-3-of step 1, add 190 grams of tetrahydrofuran (THF)s, 95 grams of n-Butyl Amine 99s, 0.35 gram of Palladous chloride, 5 grams of cuprous iodides, 2 grams of triphenyl phosphorus, 40 DEG C drip 68 grams of tert-butyl acetylenes, within 30 minutes, dropwise, slowly be warming up to 57 DEG C, insulation reaction samples detection after 15 hours, E) the chloro-propylene residual quantity 1.3% of 1-methylamino-3-, tert-butyl acetylene residual 0.6%, reaction reaches requirement, evaporated under reduced pressure tetrahydrofuran (THF), water-bath is below 70 DEG C, after evaporate to dryness, be cooled to below 30 DEG C, add normal hexane 350ml, stir and within 15 minutes, add again 50 milliliters of washings of ammoniacal liquor (ammoniacal liquor recovery preservation, reclaim Palladous chloride), reclaim under reduced pressure normal hexane, then rectifying obtains faint yellow transparent E)-N-(6, 6-dimethyl-2-heptene-4-alkynyl) 117 grams of methylamines, content 97.7%, yield 91.0%.
Step 3, Terbinafine Hcl synthetic
130 grams of chloro-1-methylnaphthalenes are joined in 230 grams of water, add 95 grams of salt of wormwood, add 3 grams of phase-transfer catalyst PVOHs 600, drip (the E)-N-(6 of 116 grams of steps 2,6-dimethyl-2-heptene-4-alkynyl) methylamine, 50～55 DEG C are reacted 4.5 hours, and sampling detects the chloro-methylnaphthalene of 1-residual 0.35%, (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine residual 0.3%.Add 350 grams of chloroforms to stir, add 180 grams of washings, organic layer drips 270 grams of dilute hydrochloric acid (90 grams of concentrated hydrochloric acid+180 gram water), to PH=2 again, branch vibration layer, be washed to neutrality, evaporate to dryness chloroform adds 380 grams of ethyl acetate backflow 30 minutes, the centrifugal Terbinafine Hcl crude product that obtains of lowering the temperature, use again 500 grams of Virahols dissolving crystallized, suction filtration, oven dry gets product, 200 grams.Yield 82.0%.
Claims (5)
1. a preparation method for Terbinafine Hcl, is characterized in that, is that raw material reacts and obtains the chloro-propylene of (E)-1-methylamino-3-with monomethylamine aqueous solution and (E)-1,3 dichloropropylene; Then the chloro-propylene of (E)-1-methylamino-3-reacts with tert-butyl acetylene and obtains (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine; Then (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine reacts and obtains Terbinafine with the chloro-methylnaphthalene of 1-again, then obtains Terbinafine Hcl after adding hydrochloric acid salify, specifically comprises the following steps:
(1) synthesizing of (E)-chloro-propylene of 1-methylamino-3-
Monomethylamine aqueous solution is added in reaction flask, stir borehole cooling to 0～5 DEG C, drip (E)-1,3 dichloropropylenes, dropwise, and naturally rise to room temperature and react, react to the reaction ratio to 2% of vapor detection (E)-1,3 dichloropropylene; After reaction solution layering, organic phase obtains the chloro-propylene of (E)-1-methylamino-3-after washing, dry, suction filtration; Wherein the mol ratio of (E)-1,3 dichloropropylene and Monomethylamine is 1:3～5;
(2) synthesizing of (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine
The chloro-propylene of (E)-1-methylamino-3-is joined in the mixing solutions of tetrahydrofuran (THF) and n-Butyl Amine 99, add Palladous chloride, cuprous iodide and triphenylphosphine, drip tert-butyl acetylene, 50～60 DEG C of insulation reaction are to vapor detection tert-butyl acetylene reaction ratio to 2%; Reaction solution evaporate to dryness tetrahydrofuran (THF), add n-hexane dissolution, ammonia scrubbing, after evaporate to dryness normal hexane, obtain (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine, the wherein chloro-propylene of (E)-1-methylamino-3-: mol ratio=1:0.98～1.01 of tert-butyl acetylene;
(3) Terbinafine Hcl is synthetic
Chloro-1-methylnaphthalene is joined in wet chemical, add phase-transfer catalyst PVOH 400-600, drip (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine, 50～55 DEG C of reaction to samplings detect the chloro-methylnaphthalene of 1-and (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) reaction ratio of methylamine, two kinds of residual controls of reactant are below 0.5%; Reaction solution obtains Terbinafine Hcl again through aftertreatment after adding hydrochloric acid salify; The chloro-methylnaphthalene of described 1-is 1:0.98～1.02 with the mol ratio of (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine.
2. the preparation method of a kind of Terbinafine Hcl as claimed in claim 1, it is characterized in that, the reaction solution of described step (3) obtains Terbinafine Hcl again through aftertreatment after adding hydrochloric acid salify: reaction solution adds chloroform to stir, layering, organic phase is washed rear dropping dilute hydrochloric acid to PH=2; Branch vibration layer, washing organic phase is to neutral, and evaporate to dryness chloroform adds ethyl acetate reflux 20～40 minutes, centrifugal the Terbinafine Hcl crude product of lowering the temperature, then use Virahol dissolving crystallized, suction filtration, dries the Terbinafine Hcl that gets product.
3. the preparation method of a kind of Terbinafine Hcl as claimed in claim 1 or 2, is characterized in that, in described step (2), the mass ratio of tetrahydrofuran (THF) and n-Butyl Amine 99 is 1.5 ~ 2.5:1; The mass ratio of described Palladous chloride, cuprous iodide and triphenylphosphine is 1:10 ~ 20:3 ~ 8; In the quality of the chloro-propylene of (E)-1-methylamino-3-, the add-on of described n-Butyl Amine 99 is 60 ~ 120%, and the add-on of described Palladous chloride is 0.01 ~ 0.5%.
4. the preparation method of a kind of Terbinafine Hcl as claimed in claim 1 or 2, is characterized in that, in described step (3), in the quality of the chloro-methylnaphthalene of 1-, the add-on of described PVOH 400-600 is 0.1 ~ 5%; In described wet chemical, the mass ratio of salt of wormwood and water is 1:2 ~ 3.
5. the preparation method of a kind of Terbinafine Hcl as claimed in claim 1 or 2, is characterized in that, the concentration of described step (1) monomethylamine aqueous solution is 20 ~ 50%.
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| CN110423200B (en) * | 2019-08-29 | 2022-03-25 | 成都奥邦药业有限公司 | Method for improving purity of terbinafine hydrochloride |
| CN114380696B (en) * | 2021-12-23 | 2022-11-25 | 山东诚汇双达药业有限公司 | Preparation method of terbinafine hydrochloride |
| CN114773138B (en) * | 2022-03-09 | 2023-03-28 | 湖北骐盛医药科技有限公司 | Preparation method and application of tert-butyl acetylene |
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