CN1362400A - Synthesis of terbinafine hydrochloride - Google Patents
Synthesis of terbinafine hydrochloride Download PDFInfo
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- CN1362400A CN1362400A CN 01139198 CN01139198A CN1362400A CN 1362400 A CN1362400 A CN 1362400A CN 01139198 CN01139198 CN 01139198 CN 01139198 A CN01139198 A CN 01139198A CN 1362400 A CN1362400 A CN 1362400A
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Abstract
The method for synthesizing terbinafine hydrochloride includes the following steps: using tert-butyl acetylene as raw material, converting it into 3,3-dimethyl-1-butyne litihium or 3,3-dimethyl-1-butyne Grignard reagent, then synthesizing intermediate 1-halo-6,6-diemthyl-2-hepten-4-acetylene, heating said intermediate and N-methyl-1-naphthoamine and making them produce condensation reaction in alkaline system, using HCl to form salt to obtain the invented product.
Description
Technical field
The present invention relates to the synthetic route of a kind of Terbinafine hydrochloride (Terbinafine Hydrochloride).
Background technology
Terbinafine hydrochloride is as a kind of allylic amines antifungal drug, it can effective single-minded inhibition squalene cyclooxygenase, and in the fungus breeding process, the biosynthesizing of ergosterol needs the effect of squalene cyclooxygenase, so suppress just effective kill fungi of squalene cyclooxygenase, thereby healing is because of being subjected to the caused disease of fungi infestation.Therefore Terbinafine hydrochloride has the bigger market requirement, and its molecular formula is:
The synthetic route of Terbinafine has multiple: 1. (Tetra.Lett.1979 such as W.Granitzer, 34,3145.) in toluene solution, can optionally dialkyne be reduced to trans-formula eneyne with Dibal (diisobutylaluminum hydride), reaction formula is as follows:
2. in the presence of formaldehyde and sodium borohydride, A.Stutz (Canadian Patent 1157023) is with naphthylamines and trans-6, and 6-dimethyl hept-2-ene"-4-alkynes-1-aldehyde reduction amination can obtain Terbinafine, and reaction formula is as follows:
3. K.Karimian etc. (US Patent 5817875) is a starting raw material with N-methyl isophthalic acid-naphthalene methylamine hydrochloric salt, by forming intermediate 2, and 3-epoxypropane, addition reaction and anhydrating has obtained Terbinafine, and reaction formula is as follows:
4. K.Karimian etc. (US Patent 5817875) has reported that also application Wittig reacts to synthesize Terbinafine, and reaction formula is as follows:
5. in the presence of palladium catalyst, Gotteland etc. (SYNLETT, 1995,931.Tetra.Lett.1996,37 (1), 57.) can be stereoselective with vinyl chloride and end-group alkyne coupling, the synthetic Terbinafine of high yield, and reaction scheme is as follows:
More than each route be not that yield is not high, raw material is rare, is exactly that intermediate is difficult for preparation, perhaps catalyzer costliness and incompatibility suitability for industrialized production.
Summary of the invention
The problem to be solved in the present invention provides a kind of high-efficient simple synthetic intermediate 1-halogen-6, and 6-dimethyl-2-heptan is rare-4-alkynes, and then prepares the method for Terbinafine hydrochloride.
The present invention is a raw material with tertiary butyl acetylene, is converted into 3,3-dimethyl-ethyl acetylene base lithium or 3, and 3-dimethyl-ethyl acetylene base Grignard reagent, resynthesis intermediate 1-halogen-6,6-dimethyl-2-heptan is rare-4-alkynes; Above-mentioned intermediate 1-halogen-6,6-dimethyl-2-heptan is rare-and 4-alkynes and N-methyl isophthalic acid-naphthalene methylamine after adding thermal condensation, get the product Terbinafine hydrochloride with the HCl salify in alkaline system.
Reaction formula is described below:
Principal reaction step of the present invention is as follows:
1) synthetic 1-halogen-6,6-dimethyl-2-heptene-4-alkynes:
In the time of-10～60 ℃, in organic solvent, with tertiary butyl acetylene is raw material, by the mol ratio with alkyl Ge Shi (R-MgX) reagent or lithium reagent (RLi) is 1: 0.5～3, be recommended as 1: 0.8～and 1.5, reacted 0.5～36 hour, be converted into 3,3-dimethyl-ethyl acetylene base lithium or 3,3-dimethyl-ethyl acetylene base Grignard reagent, described R base is C
1～C
10The straight or branched alkyl, for example: methyl, vinyl, just/sec.-propyl, the just/tertiary butyl, n-hexyl etc., described X is halogen atom such as Cl and Br etc.The R base is recommended alkyl such as normal-butyl in the lithium reagent (RLi);
In the time of-20～40 ℃, in organic solvent, above-mentioned reaction product again with acrolein reaction 1～30 hour, generate 6,6-dimethyl-1-heptene-4-alkynes-3-alcohol, wherein the consumption mol ratio of propenal is 0.5～5 times of tertiary butyl acetylene, is recommended as 0.8～1.5 times;
At ZnCl
2Under the catalysis, under-20 ℃～reflux temperature, in organic solvent, reset with the halide reagent halogenation, halide reagent consumption mol ratio is 1～6 times of tertiary butyl acetylene, is recommended as 1: 1～2.4 times, reacted 0.5～30 hour, get 1-halogen-6,6-dimethyl-2-heptene-4-alkynes, described halogen atom is Cl, Br etc.Catalyzer ZnCl wherein
2The consumption mol ratio be tertiary butyl acetylene 0.2-4 doubly, described halide reagent is PCl
5, POCl
3, PBr
3/ HBr, sulfur oxychloride or dichloride sulfone etc.
2) synthetic Terbinafine hydrochloride:
N-alkyl-1-naphthalene methylamine and 1-halogen-6,6-dimethyl-2-heptene-4-alkynes is in organic solvent, acting on 10～140 ℃ and carry out condensation by alkali, then in the system of alcohol, get the product Terbinafine hydrochloride with the HCl salify, obtain satisfactory qualified product by recrystallization at last, content＞99% (HPLC).Described alkali such as Na
2CO
3, NaHCO
3, K
2CO
3Or KHCO
3And organic bases pyridine, triethylamine or Tributylamine etc.Described alcohol is C
1～C
10The alcohol of straight or branched, for example: methyl alcohol, ethanol, Virahol etc.
The prolongation reaction times helps reaction in the above-mentioned reaction.Described organic solvent is alcohol, ether, hexanaphthene, tetrahydrofuran (THF) (THF), the N of toluene, benzene, low carbon chain, dinethylformamide (DMF), tetracol phenixin, methylene dichloride, sherwood oil, acetone, trichloromethane, normal hexane, normal heptane or dioxane etc.Intermediate can not purified and just do not purified as far as possible in the above-mentioned reaction process.
Remarkable advantage of the present invention is: at synthetic 1-halogen-6,6-dimethyl-2-heptan is rare-4-alkynes in, overcome the security and the industrial limitation that has of expensive problem, operation, and reduced loss, improved yield.In addition in reaction process if the intermediate product 6 of not purifying, 6-dimethyl-1-heptene-4-alkynes-3-alcohol is all favourable in reaction and operation, we use ZnCl in the halogenation rearrangement reaction
2As catalyzer, make that the ratio of pros-and-cons type product can reach about 1: 7 in the reactant, we can obtain content＞95% of trans product by rectifying, and total recovery reaches more than 60%.
In synthetic Terbinafine hydrochloride, make the yield in this step to reach more than 90%.
Adopt method of the present invention to synthesize Terbinafine hydrochloride, reaction is control and relatively more succinct easily, and raw material is easy to get, and is easy to operate.In the building-up process, do not influencing under the situation of yield, intermediate can not purified and just do not purified as far as possible, has reduced the intermediary operation link so as far as possible, and the result shows that yield all increases, so the inventive method is a kind of method of suitable suitability for industrialized production.
Embodiment
The present invention will be helped to understand by following embodiment, but content of the present invention can not be limited.
Embodiment one
One, the 1-bromo-6, and 6-dimethyl-2-heptan is rare-4-alkynes
The 1000ml reaction flask is at N
2Protection adds 150mlTHF, 24.8g tertiary butyl acetylene down.Cooling, dropping butyllithium cyclohexane solution 180ml (2.0M) drips and finishes back insulation 2 hours, is warming up under the faint reflux state and reacts 4 hours.Be cooled to-10～0 ℃.
The mixed solution that adds 17.9g propenal and 100mlTHF, room temperature reaction 3～5 hours.The cooling reaction solution, and transfer pH value to 5～6, organic phase is told in the reaction solution layering, and the water ethyl acetate extraction merges organic phase.With saturated NaCl solution washing, drying, concentrated, get 66.6g (GC content: 51.5%).
Add 10g Zinc Chloride Anhydrous, N in the reaction flask of 3000ml
2Protection adds 165gPBr down
3, be heated to 80～90 ℃ 0.5 hour.Cooling adds 1000ml hexanaphthene and 500mlTHF, adds the 66.6g concentrated solution of above-mentioned gained and the mixed solution of 200ml hexanaphthene, room temperature reaction 5 hours under 0～5 ℃.
The cooling reaction solution is poured in the frozen water, tells organic phase, and water is with 1, the 2-ethylene dichloride extracts, and merges organic phase with saturated NaCl solution washing, drying, concentrated, gets the 104g brown liquid, GC content: 33.4% (trans), 6.37% (cis), anti-/ suitable=5.24: 1.
Rectifying gets: 36.5g weak yellow liquid, GC content: 90.15% (trans), 2.75% (cis).
Bp：51-55℃/1～2mmHg
Theoretical yield: 60.3g,
Actual output: 36.5g.
Actual recovery: 60.5%
Embodiment two
One, the 1-chloro-6, and 6-dimethyl-2-heptan is rare-4-alkynes
The 1000ml reaction flask is at N
2Protection adds 150mlTHF, 24.8g tertiary butyl acetylene down.The THF solution 245ml (1.43M) that adds ethylmagnesium bromide is warming up under the faint reflux state and reacted 4 hours.Be cooled to-10～0 ℃.
The mixed solution that adds 17.9g propenal and 100mlTHF, room temperature reaction 3～5 hours.The cooling reaction solution, and transfer pH value to 5～6, organic phase is told in the reaction solution layering, and the water ethyl acetate extraction merges organic phase.With saturated NaCl solution washing, drying, concentrated, get 60.2g (GC content: 57.6%).
Add 10g Zinc Chloride Anhydrous, N in the reaction flask of 3000ml
2Protection adds 70gSOCl down
2, refluxed 0.5 hour.Cooling adds 1000ml hexanaphthene and 500mlTHF, adds the 60.2g concentrated solution of above-mentioned gained and the mixed solution of 200ml hexanaphthene, room temperature reaction 5 hours under 0～5 ℃.
The cooling reaction solution, reaction solution is poured in the frozen water, tells organic phase, and water is with 1, the 2-ethylene dichloride extracts, and merges organic phase with saturated NaCl solution washing, drying, concentrated, gets the 87.6g brown liquid, GC content: 39.34% (trans), 5.47% (cis), anti-/ suitable=6.08: 1.
Rectifying gets: 29.8g weak yellow liquid, GC content: 92.36% (trans), 2.17% (cis).
Bp:64～68 ℃/10mmHg (trans), 59～64 ℃/10mmHg (cis).
Theoretical yield: 47.2g,
Actual output: 28.2g.
Actual recovery: 59.7%
Two, Terbinafine hydrochloride is synthetic
In the 500ml reaction flask, add 40gN-methylnaphthalene methylamine, 24.8g yellow soda ash, 250mlDMF is cooled to-5 ℃, adds 38.5g 1-chloro-6, and 6-dimethyl-2-heptan is rare-4-alkynes, reacted 0.5 hour.Be heated to 80～100 ℃ of reactions then, detect with TLC, to raw material 1-chloro-6,6-dimethyl-2-heptan is rare-and 4-alkynes disappears, and reaction finishes.
Remove by filter the solid in the reaction solution, the filtrate drying, concentrate Vandyke brown liquid 69.7g, add the 354ml anhydrous diethyl ether, mix with concentrated solution, add the suitable quantity of water washing again, divide the phase of anhydrating, organic phase is through washing, dry, concentrate 65g brown thick liquid.Use the 650ml anhydrous alcohol solution, stir down, slowly add 35mlC
2H
5The OH-HCl saturated solution, stirring at room 20 minutes is concentrated into dried 94.4g khaki color solid.
Solid 278ml Virahol, the 100ml anhydrous diethyl ether after the heating for dissolving, is cooled to room temperature, adds the 500ml ether again, the cooling separate out solid, filter 68g white powder (HPLC content:＞99%).
Theoretical yield: 80.8g,
Actual output: 68.0g,
Actual recovery: 84.15%.
Embodiment three
One, the 1-chloro-6, and 6-dimethyl-2-heptan is rare-4-alkynes
The 1000ml reaction flask is at N
2Protection adds 150mlTHF, 25.6g tertiary butyl acetylene down.The THF solution 250ml (1.52M) that adds vinyl bromination magnesium is warming up under the faint reflux state and reacted 4～6 hours.Be cooled to-10～5 ℃.
The mixed solution that adds 17.9g propenal and 100mlTHF, room temperature reaction 2～4 hours.The cooling reaction solution, and transfer pH value to 5～6, organic phase is told in the reaction solution layering, and the water ethyl acetate extraction merges organic phase.With saturated NaCl solution washing, drying, concentrated, get 63.2g (GC content: 57.6%).
Add 10g Zinc Chloride Anhydrous, N in the reaction flask of 3000ml
2Protection adds 70gSOCl down
2, refluxed 0.5 hour.Cooling adds 1000ml hexanaphthene and 500mlTHF, adds the 63.2g concentrated solution of above-mentioned gained and the mixed solution of 200ml hexanaphthene, room temperature reaction 5～7 hours under 0～5 ℃.
The cooling reaction solution, reaction solution is poured in the frozen water, tells organic phase, and water is with 1, the 2-ethylene dichloride extracts, and merges organic phase with saturated NaCl solution washing, drying, concentrated, gets the 85.3g brown liquid, GC content: 38.26% (trans), 5.44% (cis), anti-/ suitable=7.03: 1.
Rectifying gets: 30.2g weak yellow liquid, GC content: 91.53% (trans), 2.05% (cis).
Bp:64～68 ℃/10mmHg (trans), 59～64 ℃/10mmHg (cis).
Theoretical yield: 48.7g,
Actual output: 30.2g.
Actual recovery: 62.01%
Embodiment four
One, the 1-chloro-6, and 6-dimethyl-2-heptan is rare-4-alkynes
In the 1000ml reaction flask, at N
2Protection adds 150mlTHF, 28.7g tertiary butyl acetylene down.Under the room temperature, drip the THF solution 310ml (1.32M) of n-hexyl magnesium bromide, keep temperature of reaction and be no more than 35 ℃, 53 ℃ were reacted 5 hours to faint reflux state.Be cooled to-10～0 ℃.
Begin to drip the mixed solution of 21.0g propenal and 100mlTHF, room temperature reaction 3～5 hours.The cooling reaction solution, and transfer pH value to 5～6, organic phase is told in the reaction solution layering, and the water ethyl acetate extraction merges organic phase.With saturated NaCl solution washing, drying, concentrated, get 71.5g (GC content: 57.6%).
Add the 15g Zinc Chloride Anhydrous in the reaction flask of 3000ml, at N
2Protection adds 83.6gSOCl down
2, refluxed 0.5 hour.Cooling adds 1000ml hexanaphthene and 500mlTHF, and 0～5 ℃ drips the 71.5g concentrated solution of above-mentioned gained and the mixed solution of 200ml hexanaphthene, room temperature reaction 3～6 hours down.
Reaction solution is poured in the frozen water, told organic phase, water is with 1, the 2-ethylene dichloride extracts, and merges organic phase with saturated NaCl solution washing, drying, concentrated, gets the 100.3g brown liquid, GC content: 38.53% (trans), 7.11% (cis), anti-/ suitable=5.42: 1.
Rectifying gets: 30.5g weak yellow liquid, GC content: 91.52% (trans), 2.01% (cis).
Bp:64～68 ℃/10mmHg (trans), 59～64 ℃/10mmHg (cis).
Theoretical yield: 55.1g,
Actual output: 30.5g.
Actual recovery: 55.4%
Two, the Terbinafine hydrochloride is synthetic
Add 20g N-methyl isophthalic acid-naphthalene methylamine in the 250ml reaction flask, 130mlDMF, 19.7gKHCO
3, logical nitrogen protection.
Being cooled to-5 ℃, dripping 18.4g 1-chloro-6,6-dimethyl-2-heptan is rare-4-alkynes, be incubated 0.5 hour.Be heated to 80-90 ℃ of reaction 4～6 hours, reacting liquid filtering, concentrate 42g black thick liquid.Add the 50ml ethylene dichloride and make it miscible, respectively water, 2% tartrate, saturated NaHCO
3Solution washing, dry, concentrate 35.4g.
Dissolve concentrated solution with the 140ml Virahol, add 40mlHCl-Virahol saturated solution, stir, filter, concentrate, get the 45.9g solid.
After using 50g Virahol heating for dissolving solid again, solid is separated out in cooling.Wash solid in the spent glycol dme again, get 30.8g white powder (content HPLC＞99%).
Theoretical yield: 33.7g,
Actual output: 30.8g,
Actual recovery: 91.4%.
Embodiment five
One, the 1-chloro-6, and 6-dimethyl-2-heptan is rare-4-alkynes synthetic
The 1000ml reaction flask is at N
2Protection adds 150mlTHF, 24.8g tertiary butyl acetylene down.The THF solution 245ml (1.43M) that adds butyllithium is warming up under the faint reflux state and reacted 4 hours.Cooling.
The mixed solution that adds 17.9g propenal and 100mlTHF, room temperature reaction 3～5 hours.The cooling reaction solution, and transfer pH value to 5～6, organic phase is told in the reaction solution layering, and the water ethyl acetate extraction merges organic phase.With saturated NaCl solution washing, drying, concentrated, get 60.2g (GC content: 57.6%).
Add 10g Zinc Chloride Anhydrous, N in the reaction flask of 3000ml
2Protection adds 70gSOCl down
2, refluxed 0.5 hour.Cooling adds 1000ml hexanaphthene and 500mlTHF, adds the 60.2g concentrated solution of above-mentioned gained and the mixed solution of 200ml hexanaphthene, room temperature reaction 5 hours.
The cooling reaction solution is told organic phase, and water is with 1, and the 2-ethylene dichloride extracts, merge organic phase with saturated NaCl solution washing, drying, concentrate, get the 86.7g brown liquid, GC content: 38.56% (trans), 6.78% (cis), instead/suitable=5.69: 1.
Rectifying gets: 26.7g weak yellow liquid, GC content: 91.54% (trans), 2.56% (cis).
Bp:64～68 ℃/10mmHg (trans), 59～64 ℃/10mmHg (cis).
Theoretical yield: 47.2g,
Actual output: 26.7g.
Actual recovery: 56.6%
Claims (4)
1. the synthetic route of a Terbinafine hydrochloride is characterized in that comprising the steps:
1) synthetic 1-halogen-6,6-dimethyl-2-heptene-4-alkynes:
In the time of-10～60 ℃, in organic solvent, be raw material, with lithium reagent RLi or alkyl with tertiary butyl acetylene
The mol ratio of Grignard reagent RMgX is 1: 0.5～3, reacts 0.5～36 hour, is converted into 3,3-dimethyl-1-
Butynyl lithium or 3,3-dimethyl-ethyl acetylene base Grignard reagent, described R base is C
1～C
10Straight chain or
Saturated or the undersaturated alkyl of chain, X is a halogen atom;
In the time of-20～40 ℃, in organic solvent, above-mentioned product again with acrolein reaction 1～30 hour, generate
6,6-dimethyl-1-heptene-4-alkynes-3-alcohol, wherein the consumption mol ratio of propenal is 0.5～5 of a tertiary butyl acetylene
Doubly;
At catalyzer ZnCl
2Under the catalysis, in organic solvent, under-20 ℃～reflux temperature, use halide reagent halogen
Change rearrangement, halide reagent consumption mol ratio is 1～6 times of tertiary butyl acetylene, reacted 0.5～30 hour,
1-halogen-6,6-dimethyl-2-heptene-4-alkynes, wherein catalyzer ZnCl
2The consumption mol ratio be tertiary butyl acetylene
0.2～4 times, described halide reagent is PCl
5, POCl
3, PBr
3/ HBr, sulfur oxychloride or dichloride sulfone;
2) synthetic Terbinafine hydrochloride:
In organic solvent, N-alkyl-1-naphthalene methylamine and 1-halogen-6,6-dimethyl-2-heptan is rare-4-alkynes, alkaline bar
Carry out condensation at 10～140 ℃ under the part, then get the product Terbinafine hydrochloride with the HCl salify.
2. the synthetic route of a kind of Terbinafine hydrochloride as claimed in claim 1, it is characterized in that described organic solvent is alcohol, ether, hexanaphthene, tetrahydrofuran (THF), the N of toluene, benzene, low carbon chain, dinethylformamide, tetracol phenixin, methylene dichloride, sherwood oil, acetone, trichloromethane, normal hexane, normal heptane or dioxane.
3. the synthetic route of a kind of Terbinafine hydrochloride as claimed in claim 1 is characterized in that described alkali is Na
2CO
3, NaHCO
3, K
2CO
3Or KHCO
3And organic bases pyridine, triethylamine or Tributylamine.
4. the synthetic route of a kind of Terbinafine hydrochloride as claimed in claim 1 is characterized in that intermediate is without purification in the reaction process.
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|---|---|---|---|
| CNB011391987A CN1155557C (en) | 2001-12-25 | 2001-12-25 | Synthesis of terbinafine hydrochloride |
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|---|---|---|---|
| CNB011391987A CN1155557C (en) | 2001-12-25 | 2001-12-25 | Synthesis of terbinafine hydrochloride |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1293037C (en) * | 2004-11-03 | 2007-01-03 | 浙江海正药业股份有限公司 | Process for preparing terbinafine hydrochliride |
| CN101624328B (en) * | 2009-07-31 | 2011-12-14 | 山东铂源化学有限公司 | Method for synthesizing (E)-1-chlorine-6, 6-dimethyl-2-heptylene-4-alkyne |
| CN104725240A (en) * | 2015-02-12 | 2015-06-24 | 吉林修正药业新药开发有限公司 | Method for preparing terbinafine hydrochloride Z-shaped isomer |
| CN113999087A (en) * | 2021-11-25 | 2022-02-01 | 湖州蔚蓝化工有限公司 | Preparation method of E-1-chloro-6, 6-dimethyl-2-heptene-4-alkyne |
| CN115073303A (en) * | 2022-06-28 | 2022-09-20 | 乐泰药业(兰西)有限公司 | Preparation method of terbinafine hydrochloride Z-type isomer |
-
2001
- 2001-12-25 CN CNB011391987A patent/CN1155557C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1293037C (en) * | 2004-11-03 | 2007-01-03 | 浙江海正药业股份有限公司 | Process for preparing terbinafine hydrochliride |
| CN101624328B (en) * | 2009-07-31 | 2011-12-14 | 山东铂源化学有限公司 | Method for synthesizing (E)-1-chlorine-6, 6-dimethyl-2-heptylene-4-alkyne |
| CN104725240A (en) * | 2015-02-12 | 2015-06-24 | 吉林修正药业新药开发有限公司 | Method for preparing terbinafine hydrochloride Z-shaped isomer |
| CN113999087A (en) * | 2021-11-25 | 2022-02-01 | 湖州蔚蓝化工有限公司 | Preparation method of E-1-chloro-6, 6-dimethyl-2-heptene-4-alkyne |
| CN113999087B (en) * | 2021-11-25 | 2024-05-03 | 湖州蔚蓝化工有限公司 | Preparation method of E-1-chloro-6, 6-dimethyl-2-heptylene-4-alkyne |
| CN115073303A (en) * | 2022-06-28 | 2022-09-20 | 乐泰药业(兰西)有限公司 | Preparation method of terbinafine hydrochloride Z-type isomer |
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| Publication number | Publication date |
|---|---|
| CN1155557C (en) | 2004-06-30 |
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