CN102898314A - Preparation method of terbinafine hydrochloride - Google Patents
Preparation method of terbinafine hydrochloride Download PDFInfo
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- CN102898314A CN102898314A CN2012104541657A CN201210454165A CN102898314A CN 102898314 A CN102898314 A CN 102898314A CN 2012104541657 A CN2012104541657 A CN 2012104541657A CN 201210454165 A CN201210454165 A CN 201210454165A CN 102898314 A CN102898314 A CN 102898314A
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- chloro
- dimethyl
- methylamine
- terbinafine hcl
- methylamino
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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 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229960000699 terbinafine hydrochloride Drugs 0.000 title abstract description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 74
- 229960002722 terbinafine Drugs 0.000 claims abstract description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
- UOORRWUZONOOLO-OWOJBTEDSA-N (E)-1,3-dichloropropene Chemical compound ClC\C=C\Cl UOORRWUZONOOLO-OWOJBTEDSA-N 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- XMWGTKZEDLCVIG-UHFFFAOYSA-N 1-(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1 XMWGTKZEDLCVIG-UHFFFAOYSA-N 0.000 claims description 16
- NSZIPUZEOBXRIE-DUXPYHPUSA-N (E)-3-chloro-N-methylprop-1-en-1-amine Chemical group CN/C=C/CCl NSZIPUZEOBXRIE-DUXPYHPUSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- PPWNCLVNXGCGAF-UHFFFAOYSA-N 3,3-dimethylbut-1-yne Chemical group CC(C)(C)C#C PPWNCLVNXGCGAF-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 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 10
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 6
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 6
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000009413 insulation Methods 0.000 claims description 4
- 239000003444 phase transfer catalyst Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 238000005070 sampling Methods 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000005201 scrubbing Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 2
- CGHIBGNXEGJPQZ-UHFFFAOYSA-N 1-hexyne Chemical group CCCCC#C CGHIBGNXEGJPQZ-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- UOORRWUZONOOLO-UHFFFAOYSA-N telone II Natural products ClCC=CCl UOORRWUZONOOLO-UHFFFAOYSA-N 0.000 abstract 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- -1 iodopropylene sulfonamide Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- VKFAUCPBMAGVRG-UHFFFAOYSA-N dipivefrin hydrochloride Chemical compound [Cl-].C[NH2+]CC(O)C1=CC=C(OC(=O)C(C)(C)C)C(OC(=O)C(C)(C)C)=C1 VKFAUCPBMAGVRG-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- YROGWJLGNLJNOK-UHFFFAOYSA-N 1-chloro-1-methoxypropane Chemical compound CCC(Cl)OC YROGWJLGNLJNOK-UHFFFAOYSA-N 0.000 description 1
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 208000002474 Tinea Diseases 0.000 description 1
- 208000007712 Tinea Versicolor Diseases 0.000 description 1
- 201000010618 Tinea cruris Diseases 0.000 description 1
- 206010067197 Tinea manuum Diseases 0.000 description 1
- 206010056131 Tinea versicolour Diseases 0.000 description 1
- 241000893966 Trichophyton verrucosum Species 0.000 description 1
- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 description 1
- IHJICFFGQVAWEV-UHFFFAOYSA-N [Li].CC(C)(C)C#C Chemical compound [Li].CC(C)(C)C#C IHJICFFGQVAWEV-UHFFFAOYSA-N 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- BWMISRWJRUSYEX-UHFFFAOYSA-N hydron;n,6,6-trimethyl-n-(naphthalen-1-ylmethyl)hept-2-en-4-yn-1-amine;chloride Chemical compound Cl.C1=CC=C2C(CN(CC=CC#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000005002 naphthylamines Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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)-and 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 the 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, but 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, synthesized the Terbinafine Hcl raw material by Shandong Qilu Pharmaceutical Factory in nineteen ninety-five afterwards, and carried out declaring of raw material and ointment formulation by two kind new medicines, and obtained the approval of national correlation department, transferred accurate font size in 1997 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 the synthetic route of Terbinafine Hcl and document all have report, sum up to mainly contain following several synthetic routes:
(1) take tert-butyl acetylene as raw material and after organolithium reagent or the Grignard reagent reaction, 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, with N-methyl isophthalic acid-naphthalene methylamine reaction, make Terbinafine Hcl with the hydrochloric acid salify again.Synthesizing of concrete visible patent CN031139198.7(Terbinafine hydrochloride), reaction formula is as follows:
(2) 6,6 dimethyl-1-heptene-4-alkynes-3-alcohol esterification generates 6,6 dimethyl-1-heptene-4-alkynes-3-alcohol acetic ester, and then obtains Terbinafine with N-methyl isophthalic acid-naphthalene methylamine reaction.
(3) in the presence of formaldehyde and sodium borohydride, naphthylamines and 6,6 dimethyl-2 heptene-4-alkynes-1-aldehyde reduction amination are made Terbinafine.
(4) take N-methyl isophthalic acid-naphthalene methylamine hydrochloric salt as starting raw material and chloro methyloxypropane reaction make intermediate N methyl isophthalic acid menaphthyl-2,3 propylene oxide, react to get Terbinafine with the tert-butyl acetylene lithium again.
(5) N-methyl isophthalic acid-naphthalene methylamine and propine obtain the propine derivative in the presence of butyllithium, get the iodopropylene sulfonamide derivatives with Iod R again, make Terbinafine with 3,3 neohexenes-1-pink salt reaction again.
(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, under palladium, cuprous chloride catalysis, make Terbinafine with tert-butyl acetylene again.
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 provides a kind of preparation method of Terbinafine Hcl.The method raw material is easily purchased, and is cheap, and the 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 (E)-1-methylamino-3-chloro-propylene with monomethylamine aqueous solution and (E)-1,3 dichloropropylene; Then (E)-1-methylamino-3-chloro-propylene and tert-butyl acetylene react and obtain (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine; Then (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine reacts with 1-chloro-methylnaphthalene and obtains Terbinafine, obtains Terbinafine Hcl after adding the hydrochloric acid salify again.
Comprise the steps:
Step 1, (E)-1-methylamino-3-chloro-propylene synthetic
Monomethylamine aqueous solution is added in the reaction flask, stir borehole cooling to 0～5 ℃, drip (E)-1,3 dichloropropylenes dropwise, and naturally rise to room temperature and carry out, react the reaction ratio to 2% following (usually reacting 5～6 hours) to vapor detection (E)-1,3 dichloropropylene; After the reaction solution layering, organic phase obtains (E)-1-methylamino-3-chloro-propylene behind washing, drying, 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
(E)-1-methylamino-3-chloro-propylene 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 ℃ of insulations, vapor detection tert-butyl acetylene reaction ratio to 2% following (reacting approximately 15 hours), the evaporate to dryness tetrahydrofuran (THF), add n-hexane dissolution, ammonia scrubbing, evaporate to dryness normal hexane.Underpressure distillation can get content more than 97%.(E)-1-methylamino-3-chloro-propylene wherein: the mol ratio=1:0.98 of tert-butyl acetylene～1.01.
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 (E)-1-methylamino-3-chloro-propylene, 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
1-chloro-methylnaphthalene is joined in the wet chemical, add phase-transfer catalyst PVOH 400-600, drip (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine, 50～55 ℃ of reactions to sampling detects 1-chloro-methylnaphthalene 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 and stirs, layering, and organic phase is washed rear dropping dilute hydrochloric acid to PH=2; Branch vibration layer, the washing organic phase is to neutral, and the evaporate to dryness chloroform added the ethyl acetate reflux 20～40 minutes, and the centrifugal Terbinafine Hcl crude product that gets of lowering the temperature uses Virahol dissolving crystallized again, suction filtration, oven dry gets product.Described 1-chloro-methylnaphthalene with (E)-mol ratio of N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine is 1:0.98～1.02.
Preferably, in the quality of 1-chloro-methylnaphthalene, the add-on of described PVOH 400-600 is 0.1 ~ 5%.Preferably, the mass ratio of salt of wormwood and water is 1:2 ~ 3 in the described wet chemical.
Beneficial effect; Be raw material with Monomethylamine, (E)-1,3 dichloropropylene, n-Butyl Amine 99 and 1-chloro-methylnaphthalene, raw material is simple and easy to, and low price.Production stage of the present invention is simple, and yield is high, suitability for industrialized production.
Embodiment
Embodiment 1
Step 1:(E)-1-methylamino-3-chloro-propylene synthetic
200 gram monomethylamine aqueous solutions (30%) are joined in the 500ml reaction flask, open and stir, be cooled to 0 ℃, add 0.5 gram tributyl brometo de amonio, drip 50 gram (E)-1,3 dichloropropylenes slowly rise to 20 ℃, react 4 hours, monitoring (E)-1-methylamino-3-chloro-propylene residual 3%, continue to rise to 25 ℃ of reactions 2 hours, residual 1.3%, layering.Product is washed residual Monomethylamine in lower floor, then adds siccative sodium sulfate 5 grams, drying, and suction filtration gets product 45 grams, content 97.5%, yield 92.5%.The reaction of this step requires the reaction vessel sealing property to get well.
Step 2:(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine synthetic
(E)-1-methylamino of step 1-3-chloro-propylene 45 grams are dropped in the reaction flasks, add 100 gram tetrahydrofuran (THF)s, 50 gram n-Butyl Amine 99s, Palladous chloride 0.2 gram, cuprous iodide 3 grams, triphenyl phosphorus 1 gram, 40 ℃ drip tert-butyl acetylene 34 grams, dropwised in 30 minutes, slowly be warming up to 55 ℃, the insulation reaction detection of taking a sample after 15 hours, E) 1-methylamino-3-chloro-propylene residual quantity 1.5%, tert-butyl acetylene residual 0.7%, reaction reaches requirement, evaporated under reduced pressure tetrahydrofuran (THF), water-bath are cooled to behind the evaporate to dryness below 30 ℃ below 70 ℃, add normal hexane 200ml, stir and added again 30 milliliters of washings of ammoniacal liquor (ammoniacal liquor reclaims and preserves, and reclaims Palladous chloride), reclaim under reduced pressure normal hexane in 15 minutes, then rectifying gets faint yellow transparent E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine 58 grams, content 97.5%, yield 90.2%.
Step 3, Terbinafine Hcl synthetic
1-chloro-methylnaphthalene 65 grams are joined in the 120 gram water, add 50 gram salt of wormwood, add 2 gram phase-transfer catalyst PVOHs 400, drip (the E)-N-(6 of 58 gram steps 2,6-dimethyl-2-heptene-4-alkynyl) methylamine, 50～55 ℃ were reacted 4 hours, and sampling detects 1-chloro-methylnaphthalene residual 0.35%, (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine residual 0.4%.Adding 200 gram chloroforms stirs, add 100 gram washings, organic layer drips 150 gram dilute hydrochloric acid (50 gram concentrated hydrochloric acids+100 gram water), to PH=2 again, branch vibration layer, be washed to neutrality, the evaporate to dryness chloroform adds 200 gram ethyl acetate backflow 30 minutes, the centrifugal Terbinafine Hcl crude product that gets of lowering the temperature, dissolving crystallized with 300 gram Virahols again, suction filtration, oven dry gets product, 98 grams.Yield 80.5%.
Embodiment 2
Step 1:(E)-1-methylamino-3-chloro-propylene synthetic
380 gram monomethylamine aqueous solutions (30%) are joined in the 1000ml reaction flask, open and stir, be cooled to 2 ℃, add 1.0 gram tributyl brometo de amonios, drip 100 gram (E)-1,3 dichloropropylenes, slowly rise to 20 ℃, reacted 3 hours, monitoring (E)-1-methylamino-3-chloro-propylene residual 3.8%, continue to rise to 25 ℃ of reactions 2.5 hours, residual 1.2%, layering, product is in lower floor, wash residual Monomethylamine, then add siccative sodium sulfate 10 grams, drying, suction filtration gets product 90.5 grams, content 97.3%, yield 92.7%.The reaction of this step requires the reaction vessel sealing property to get well.
Step 2:(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine synthetic
(E)-1-methylamino of step 1-3-chloro-propylene 90.5 grams are dropped in the reaction flasks, add 190 gram tetrahydrofuran (THF)s, 95 gram n-Butyl Amine 99s, Palladous chloride 0.35 gram, cuprous iodide 5 grams, triphenyl phosphorus 2 grams, 40 ℃ drip tert-butyl acetylene 68 grams, dropwised in 30 minutes, slowly be warming up to 57 ℃, the insulation reaction detection of taking a sample after 15 hours, E) 1-methylamino-3-chloro-propylene residual quantity 1.3%, tert-butyl acetylene residual 0.6%, reaction reaches requirement, evaporated under reduced pressure tetrahydrofuran (THF), water-bath are cooled to behind the evaporate to dryness below 30 ℃ below 70 ℃, add normal hexane 350ml, stir and added again 50 milliliters of washings of ammoniacal liquor (ammoniacal liquor reclaims and preserves, and reclaims Palladous chloride), reclaim under reduced pressure normal hexane in 15 minutes, then rectifying gets faint yellow transparent E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine 117 grams, content 97.7%, yield 91.0%.
Step 3, Terbinafine Hcl synthetic
1-chloro-methylnaphthalene 130 grams are joined in the 230 gram water, add 95 gram salt of wormwood, add 3 gram phase-transfer catalyst PVOHs 600, drip (the E)-N-(6 of 116 gram steps 2,6-dimethyl-2-heptene-4-alkynyl) methylamine, 50～55 ℃ were reacted 4.5 hours, and sampling detects 1-chloro-methylnaphthalene residual 0.35%, (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine residual 0.3%.Adding 350 gram chloroforms stirs, add 180 gram washings, organic layer drips 270 gram dilute hydrochloric acid (90 gram concentrated hydrochloric acids+180 gram water), to PH=2 again, branch vibration layer, be washed to neutrality, the evaporate to dryness chloroform adds 380 gram ethyl acetate backflow 30 minutes, the centrifugal Terbinafine Hcl crude product that gets of lowering the temperature, dissolving crystallized with 500 gram Virahols again, suction filtration, oven dry gets product, 200 grams.Yield 82.0%.
Claims (6)
1. the preparation method of a Terbinafine Hcl is characterized in that, is that raw material reacts and obtains (E)-1-methylamino-3-chloro-propylene with monomethylamine aqueous solution and (E)-1,3 dichloropropylene; Then (E)-1-methylamino-3-chloro-propylene and tert-butyl acetylene react and obtain (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine; Then (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine reacts with 1-chloro-methylnaphthalene and obtains Terbinafine, obtains Terbinafine Hcl after adding the hydrochloric acid salify again.
2. the preparation method of a kind of Terbinafine Hcl as claimed in claim 1 is characterized in that, may further comprise the steps:
(1) (E)-1-methylamino-3-chloro-propylene synthetic
Monomethylamine aqueous solution is added in the reaction flask, stir borehole cooling to 0～5 ℃, drip (E)-1,3 dichloropropylene, dropwise, naturally rise to room temperature and react, react to the reaction ratio to 2% of vapor detection (E)-1,3 dichloropropylene; After the reaction solution layering, organic phase obtains (E)-1-methylamino-3-chloro-propylene behind washing, drying, suction filtration; Wherein the mol ratio of (E)-1,3 dichloropropylene and Monomethylamine is 1:3～5;
(2) (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine synthetic
(E)-1-methylamino-3-chloro-propylene 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 ℃ 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 obtains (E)-N-(6 behind the evaporate to dryness normal hexane, 6-dimethyl-2-heptene-4-alkynyl) methylamine, wherein (E)-1-methylamino-3-chloro-propylene: the mol ratio=1:0.98 of tert-butyl acetylene～1.01;
(3) Terbinafine Hcl is synthetic
1-chloro-methylnaphthalene is joined in the wet chemical, add phase-transfer catalyst PVOH 400-600, drip (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine, 50～55 ℃ of reactions to sampling detects 1-chloro-methylnaphthalene 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 the hydrochloric acid salify; Described 1-chloro-methylnaphthalene with (E)-mol ratio of N-(6,6-dimethyl-2-heptene-4-alkynyl) methylamine is 1:0.98～1.02.
3. the preparation method of a kind of Terbinafine Hcl as claimed in claim 2, it is characterized in that, the reaction solution of described step (3) obtains Terbinafine Hcl again through aftertreatment after adding the hydrochloric acid salify: reaction solution adds chloroform and stirs, layering, organic phase are washed rear dropping dilute hydrochloric acid to PH=2; Branch vibration layer, the washing organic phase is to neutral, and the evaporate to dryness chloroform added the ethyl acetate reflux 20～40 minutes, and the centrifugal Terbinafine Hcl crude product that gets of lowering the temperature uses Virahol dissolving crystallized again, and suction filtration is dried the Terbinafine Hcl that gets product.
4. a kind of preparation method of Terbinafine Hcl as claimed in claim 2 or claim 3 is characterized in that, the mass ratio of tetrahydrofuran (THF) and n-Butyl Amine 99 is 1.5 ~ 2.5:1 in the described step (2); The mass ratio of described Palladous chloride, cuprous iodide and triphenylphosphine is 1:10 ~ 20:3 ~ 8; In the quality of (E)-1-methylamino-3-chloro-propylene, 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%.
5. a kind of preparation method of Terbinafine Hcl as claimed in claim 2 or claim 3 is characterized in that in the quality of 1-chloro-methylnaphthalene, the add-on of described PVOH 400-600 is 0.1 ~ 5% in the described step (3); The mass ratio of salt of wormwood and water is 1:2 ~ 3 in the described wet chemical.
6. a kind of preparation method of Terbinafine Hcl as claimed in claim 2 or claim 3 is characterized in that the concentration of described step (1) monomethylamine aqueous solution is 20 ~ 50%.
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| CN110423200A (en) * | 2019-08-29 | 2019-11-08 | 成都奥邦药业有限公司 | A kind of preparation method improving terbinafine HCl purity |
| CN114380696A (en) * | 2021-12-23 | 2022-04-22 | 山东诚汇双达药业有限公司 | Preparation method of terbinafine hydrochloride |
| CN114773138A (en) * | 2022-03-09 | 2022-07-22 | 湖北骐盛医药科技有限公司 | Preparation method and application of tert-butyl acetylene |
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| CN110423200A (en) * | 2019-08-29 | 2019-11-08 | 成都奥邦药业有限公司 | A kind of preparation method improving terbinafine HCl purity |
| CN114380696A (en) * | 2021-12-23 | 2022-04-22 | 山东诚汇双达药业有限公司 | Preparation method of terbinafine hydrochloride |
| CN114773138A (en) * | 2022-03-09 | 2022-07-22 | 湖北骐盛医药科技有限公司 | Preparation method and application of tert-butyl acetylene |
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