CN102887872B - Method for preparing amorolfine hydrochloride - Google Patents
Method for preparing amorolfine hydrochloride Download PDFInfo
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Abstract
The invention relates to a method for preparing amorolfine hydrochloride. The method comprises the following steps of: reacting 4-iodo-tert-amylbenzene with 2-methylallyl alcohol by taking N-methylpyrrolidone as a solvent in the presence of a palladium catalyst and alkali to obtain 3-tert-pentylphenyl-2-methyl propanal; performing reductive amination reaction of the obtained 3-tert-pentylphenyl-2-methyl propanal and cis-2,6-dimethylmorpholine by taking sodium triacetoxyborohydride as a reducing agent in the presence of glacial acetic acid to obtain amorolfine; and transforming the amorolfine into the amorolfine hydrochloride. The invention has the advantages that the process is reasonable, is beneficial to the environment, health, and safety (EHS), and is suitable for industrialized production, wastewater is easy to biodegrade, the reaction selectivity is high, the high-yield high-purity product is obtained, and the like.
Description
Technical field
The present invention relates to the preparation method of hydrochloric acid amorolfine.
Background technology
Hydrochloric acid amorolfine (amorolfine hydrochloride), chemical name is cis-4-[3-[4-(1,1-Dimethyl-propyl) phenyl]-2-methyl-propyl]-2,6-Dimethyl-morpholin hydrochloride, CAS registration number is 78613-38-4, and chemical structural formula is as follows:
Hydrochloric acid amorolfine is a kind of antifungal drug, is developed by Roche Holding Ag, and listing in 1991, commodity are called Leceryl.About the synthesis technique of hydrochloric acid amorolfine, prior art is existing to be described:
The synthetic route that US Patent No. 7795425B2 discloses hydrochloric acid amorolfine is as follows:
US7795425B2 synthetic route: (1) 2-methyl cinnamic aldehyde and cis-2, the condensation reaction of 6-thebaine obtains cis-4-(3-phenyl-2-methyl-propyl)-2,6-Dimethyl-morpholin hydrochloride, (2) cis-4-(3-phenyl-2-methyl-propyl)-2,6-Dimethyl-morpholin hydrochloride again with 2-methyl-Sec-Butyl Chloride, by acid catalysis, there is Heck reaction, obtain amorolfine.In step (1), need palladium carbon shortening, thus cost is higher; In addition, step may have multiple rearrangement reaction in (2), and by product is many, and purifying products difficulty, final product quality is not high and yield is low, and needs the low-temp reaction equipment of-40 ~-65 DEG C, and energy consumption is large.
International patent application WO2007113218A1 improves the synthetic method of hydrochloric acid amorolfine, the first step Heck reacts, under palladium catalyst and alkali exist, 4-iodo tert.-amylbenzene and 2-methallyl alcohol are obtained by reacting 3-tert-pentyl phenyl-2 methyl propanal, reaction solvent is selected from DMF (being abbreviated as DMF), polar aprotic solvent or non-polar solvent; Second step reductive amination process, 3-tert-pentyl phenyl-2 methyl propanal and cis-2,6-thebaines are obtained by reacting amorolfine, and reductive agent is selected from palladium chtalyst hydrogenation or metal borohydride; And then obtain hydrochloric acid amorolfine.Synthetic route is as follows:
WO2007113218A1 technique still existing defects: (1) the first step Heck reacts, and reaction solvent DMF has moderate toxicity, international cancer research institution (IARC) thinks that it may be carcinogens.DMF stable chemical nature, can long-term existence in waste water, large to water pollution, is difficult to biological degradation, its BOD5/COD value=0.065 (BOD5/COD is the index of waste water bio-degradable, and 0.3 is the lower value of waste water bio-degradable).During large production, cost for wastewater treatment is high.Although DMF boiling point is 154 DEG C, unstable under alkaline condition particularly high temperature, more than 100 DEG C just start there is decomposition.Polar aprotic solvent, lower alcohol as described in that patent, can not meet pyroreaction requirement, and poorly soluble to palladium catalyst of high boiling polar aprotic solvent, is difficult to react.Non-polar solvent does not dissolve palladium catalyst substantially, and thus using value is little.(2) second step reductive amination process, adopt the cost of noble metal palladium chtalyst hydrogenation higher, high pressure reactor is dangerous; Adopt metal borohydride reduction easily to produce a large amount of hydrogen, cause potential safety hazard, also 3-tert-pentyl phenyl-2 methyl propanal can be reduced to corresponding alcohol and increase impurity; The reduction by product of metal Cyanoborohydride is violent in toxicity.(3) product yield is on the low side, and the total recovery of embodiment product is about 50%.The purity of product and intermediate is not all disclosed.
Thus this area needs the preparation method that develops a kind of improving technique, decreasing pollution, raising productive rate and quality product, be suitable for the hydrochloric acid amorolfine of suitability for industrialized production.
Summary of the invention
Object of the present invention is exactly to overcome the deficiencies in the prior art, provides a kind of rational technology, environmentally friendly, cost is low, yield is high, product purity is high, and be suitable for the preparation method of the hydrochloric acid amorolfine of suitability for industrialized production.
For achieving the above object, the invention provides following technical scheme:
The method of the hydrochloric acid amorolfine shown in a kind of preparation formula (Ib),
Comprise the steps:
(1) with N-Methyl pyrrolidone (being abbreviated as NMP) for solvent, under the existence of palladium catalyst and alkali, make formula (II) compound:
React with 2-methallyl alcohol, obtain formula (III) compound:
(2) in organic solvent, under Glacial acetic acid exists, take sodium triacetoxy borohydride as reductive agent, formula (III) compound and cis-2 that step (1) is obtained, 6-thebaine carries out reductive amination process, obtains formula (Ia) compound;
(3) formula (Ia) compound that step (2) obtains is changed into hydrochloric acid amorolfine.
Chemical equation of the present invention is expressed as follows:
(1) Heck reaction
(2) reductive amination process
(3) salify
" Heck reaction " of the present invention refers to that He Ke reacts, also claiming ditch Lv Mu-He Ke reaction (Mizoroki-Heck Reaction), is the linked reaction that halohydrocarbon (or triflate) and alkene generate substituted olefine under alkali and palladium chtalyst.
" reductive amination process " of the present invention, also known as Bao Qi reduction (Borch reduction), is a kind of method easily aldehyde ketone being converted to amine.First be amine and Carbonyl addition, condensation, generate the analog west not alkali (Schiff Base) of carbonyl, the hydrogen transmission that the latter accepts hydrogen donor generates final product amine.
In step of the present invention (1), palladium catalyst comprises the organic complex of palladium salt or palladium, such as palladium, palladous sulfate, Palladous nitrate, Palladous chloride, palladium bromide, palladium iodide, four (triphenyl phosphorus) palladium, bi triphenyl phosphorus palladium chloride, two benzonitrile Palladous chloride; Preferred palladium, palladous sulfate, Palladous nitrate or Palladous chloride; More preferably palladium or Palladous chloride.
Alkali described in step of the present invention (1) is selected from alkaline carbonate, alkali metal hydrocarbonate, alkali metal acetate, alkali metal phosphate, alkali metal hydrogen phosphate disalt or their mixture; Preferred sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium acetate, potassium acetate, sodium phosphate, potassiumphosphate, Sodium phosphate dibasic, dipotassium hydrogen phosphate or their mixture; More preferably sodium bicarbonate or Sodium phosphate dibasic.
In step of the present invention (1), formula (II) compound: 2-methallyl alcohol: palladium catalyst: the mol ratio of alkali is 1.0: (1.0 ~ 5.0): (0.003 ~ 0.2): (1.0 ~ 3.0); Be preferably 1.0: (1.5 ~ 2.5): (0.005 ~ 0.05): (1.0 ~ 2.0).React in above-mentioned preferred proportional range, under the high yield of guarantee and highly purified situation, can reduce costs.Wherein, formula (II) compound (i.e. 4-iodo tert.-amylbenzene) can prepare with reference to the method for the embodiment 1 of WO2007113218A1, and the associated viscera of the document is incorporated in specification sheets of the present invention.
In step of the present invention (1), range of reaction temperature is 80-160 DEG C, is preferably 90-130 DEG C.Reaction times is 1 ~ 24 hour.
Step of the present invention (1) is carried out under protection of inert gas, and rare gas element is generally nitrogen or argon gas.Reaction end is controlled by the content of 4-iodo tert.-amylbenzene in gas-chromatography (GC) assaying reaction system.
Formula (III) compound (i.e. 3-tert-pentyl phenyl-2 methyl propanal) that step of the present invention (1) obtains can not be separated, and adopts " one kettle way " technique to be directly used in the reductive amination process of step (2).
3-tert-pentyl phenyl-2 methyl propanal that step of the present invention (1) obtains also can be separated, such as: reaction residual liquor is by filtering, and removing insolubles, adds water and organic solvent in filtrate, extracting and separating, the machine that leaves passes through distillating recovering solvent mutually.
Preferably, the crude product of 3-tert-pentyl phenyl-2 methyl propanal that step (1) obtains can be further purified, before step (2), such as also comprise the purification step of formula (III) compound: formula (III) compound step (1) obtained and saturated aqueous solution of sodium bisulfite generation addition reaction, gained adduct again with acid-respons, obtain formula (III) compound of purifying.More specifically, can the crude product of 3-tert-pentyl phenyl-2 methyl propanal be joined in the saturated aqueous solution of sodium bisulfite of 10 ~ 40 DEG C, there is addition reaction, stir and separate out solid, filter, solid organic solvent washing, solid suspension is in acid afterwards, in 0 ~ 25 DEG C of reaction 3 ~ 20 hours, finally by extraction, isolate 3-tert-pentyl phenyl-2 methyl propanal sterling, its GC purity can reach more than 98%.In aforesaid operations, described acid is selected from the hydrochloric acid or sulfuric acid that concentration is 1 ~ 3 mol/L.
In addition, the crude product of the 3-tert-pentyl phenyl-2 methyl propanal obtained also can improve purity by rectifying.
The reaction process of step of the present invention (2) is: 3-tert-pentyl phenyl-2 methyl propanal and cis-2 that step (1) obtains, the reaction under Glacial acetic acid exists of 6-thebaine generates west not alkali, temperature of reaction is 10-25 DEG C, reaction times 30-60 minute; West not alkali again with sodium triacetoxy borohydride generation redox reaction, obtain formula (Ia) compound, i.e. amorolfine.Temperature of reaction is 0-25 DEG C, reaction times 2-5 hour.Reaction end is controlled by the content of 3-tert-pentyl phenyl-2 methyl propanal in GC assaying reaction system.
In step of the present invention (2), organic solvent is selected from methyl alcohol, Virahol, methylene dichloride, trichloromethane, ethylene dichloride, methyl acetate, ethyl acetate, propyl acetate, butylacetate, toluene or tetrahydrofuran (THF), is preferably methyl alcohol, methylene dichloride, ethyl acetate or butylacetate.
In step of the present invention (2), the mol ratio of each material is formula (III) compound: cis-2,6-thebaine: Glacial acetic acid: sodium triacetoxy borohydride=1.0: (1.0 ~ 4.0): (1.0 ~ 3.0): (1.0 ~ 2.5), preferred formula (III) compound: cis-2,6-thebaines: Glacial acetic acid: sodium triacetoxy borohydride=1.0: (1.0 ~ 2.0): (1.0 ~ 2.0): (1.0 ~ 1.5).React in above-mentioned preferred proportional range, under the high yield of guarantee and highly purified situation, can reduce costs.
The amorolfine that step of the present invention (2) obtains can be separated, by adding water and organic solvent carries out extracting and separating in reaction residual liquor, stay organic phase by distillating recovering solvent and further distillation obtain amorolfine, also can carry out next step reaction with the above-mentioned organic extractant phase liquid containing amorolfine.
Formula (Ia) compound amorolfine can be changed into formula (Ib) compound hydrochloric acid amorolfine according to common method.Such as: be dissolved in acetone or ethyl acetate by formula (Ia) compound, add hydrochloric acid, formula (Ib) compound is obtained.
Compared with prior art, the present invention has the following advantages:
The reaction solvent of step of the present invention (1) is N-Methyl pyrrolidone (NMP), and NMP boiling point is 202 ~ 204 DEG C, and chemical stability is good, and Heat stability is good is suitable for pyroreaction, is conducive to improving reaction efficiency.NMP biodegradability strong (its BOD5/COD value=1.71), the process of reaction waste readily biodegradable, to environment, healthy and helpful.NMP boiling point is high, dissolving power strong, stable chemical nature, good thermal stability, is conducive to improving temperature of reaction, Reaction time shorten, reduces catalyst levels, reduce costs.
Reductive amination process is reductive agent with sodium triacetoxy borohydride, avoids the use of precious metal catalyst, high pressure reactor and poisonous reagent.Experiment shows, the reaction preference of sodium triacetoxy borohydride is better than sodium borohydride or precious metal catalyst high-pressure hydrogenation, 3-tert-pentyl phenyl 2 methyl propanal can not be reduced to corresponding alcohol, side reaction is few, reaction conditions is gentle, is easy to control, and security is good, convenient post-treatment, the yield of reductive amination process and salt-forming reaction reaches more than 83%.
Whole piece technological design is reasonable, good reaction selectivity, and reaction efficiency improves, and the purity of product hydrochloric acid amorolfine is high, and HPLC purity reaches more than 99.5%, and total recovery is high, is suitable for suitability for industrialized production.
Embodiment
Following examples will contribute to explaining the present invention further, but be not used in restriction content of the present invention.
In the present invention, raw materials and reagent are commercially available prod.
Detecting instrument:
Agilent gas chromatograph, model Agilent 7890A, Agilent company.
Shimadzu high performance liquid chromatograph, model Shimadzu LC-20A, Shimadzu Corporation.
400MHz FT-NMR nuclear magnetic resonance spectrometer, model Bruker Avance 400, Bruker company.
Embodiment 1
Diacetyl oxide 2600mL is added in the reactor of 10L cleaning, Glacial acetic acid 5200mL, sodium periodate 350g, iodine 1236g, is cooled to 5 DEG C, drips 810mL sulfuric acid, control to dropwise in 1 hour, then add 1130g tert.-amylbenzene, stirring at room temperature more than 16 hours, it is complete that thin-layer chromatography detects raw material reaction.Reaction solution is poured in 8L water and 4L methylene dichloride mixed solution, extracting and demixing, organic layer 25% sodium sulfite aqueous solution 4L washs once, organic over anhydrous dried over sodium sulfate, steaming desolventizes methylene dichloride, obtaining resistates is 4-iodo tert.-amylbenzene 2013g, yield: 96%, GC purity 94.2%.1H-NMR modal data: (400MHz, CDCl
3): 0.73 (3H, t, J=7.4Hz), 1.31 (6H, s), 1.67 (2H, q, J=7.4Hz), 7.13 (2H, d, J=8.56Hz), 7.66 (2H, d, J=8.56Hz).
Embodiment 2
The 4-iodo tert.-amylbenzene 2kg prepared according to embodiment 1 method is added in the reactor of 10L cleaning; N-Methyl pyrrolidone 6L; logical nitrogen protection; start stirring, add palladium 300g, sodium bicarbonate 1.7kg; finally add 2-methallyl alcohol 2.5kg; be warming up to 105 DEG C of reactions, the GC content detecting 4-iodo tert.-amylbenzene monitors reaction process, reacts end in 2 hours.Be chilled to room temperature, filter, filtrate concentrates, resistates adds 12L acetic acid ethyl dissolution, uses 20L water washing, organic phase rectifying, collect 125-128 DEG C of cut (vacuum tightness≤-0.099Mpa), obtain 3-tert-pentyl phenyl-2 methyl propanal 1.41kg, yield: 88.6%, GC purity: 93.5%.1H-NMR modal data: (400MHz, CDCl
3): 0.69 (3H, t, J=7.45Hz), 1.11 (3H, d, J=6.87Hz), 1.29 (6H, s), 1.65 (2H, q, J=7.43Hz), 2.60 (1H, dd, J=13.52Hz), 2.69 (1H, J=7.06Hz), 3.08 (1H, dd, J=13.54Hz), 7.12 (2H, d, J=8.27Hz), 7.27 (2H, d, J=8.27Hz), 9.75 (1H, s).
In 10L reactor, add above-mentioned 3-tert-pentyl phenyl-2 methyl propanal 1kg, 5L ethyl acetate, logical nitrogen protection, is cooled to 10 DEG C, drips 600g 2,6-thebaine, within about 30 minutes, adds.Then drip 300mL Glacial acetic acid, temperature remains on 15 DEG C, dropwises, and is warmed up to 18 DEG C of insulations 30 minutes.Be cooled to 10 DEG C again, add 1.3kg sodium triacetoxy borohydride, 18 DEG C of insulations after adding, the GC content detecting 3-tert-pentyl phenyl-2 methyl propanal monitors reaction process, reacts end in 2 hours.Being cooled to less than 10 DEG C, is 10 with sodium hydroxide solution adjust pH, stratification, and organic layer 4L tap water washs.Organic phase adds concentrated hydrochloric acid, and adjust pH is 2, filters, and filter cake, 65 DEG C of drying under reduced pressure 14 hours, obtains hydrochloric acid amorolfine 1.39kg, yield: 85.6%, HPLC purity: 99.6%.1H-NMR modal data: 1H NMR (400MHz, CD
3oD) δ: 0.64 (3H, t, J=7.2Hz), 1.03 (3H, d, J=6.8Hz), 1.15 (6H, d, J=6.0Hz), 1.25 (6H, s), 1.64 (2H, m, J=7.6Hz), 2.34 (1H, d, J=6.8Hz), 2.48 (2H, d, J=6.8Hz), 2.75 (2H, d, J=6.0Hz), 3.1 (2H, d, J=8.8Hz), 3.4 (2H, d, J=11.2Hz), 3.9 (2H, m), 7.16 (2H, dd, J=8.4Hz), 7.27 (2H, dd, J=8.4Hz).
Embodiment 3
The 4-iodo tert.-amylbenzene 2kg prepared according to embodiment 1 method is added in the reactor of 10L cleaning; N-Methyl pyrrolidone 6L; logical nitrogen protection; start stirring, add palladium 150g, dipotassium hydrogen phosphate 2.5kg; finally add 2-methallyl alcohol 1.8kg; be warming up to 130 DEG C of reactions, the GC content detecting 4-iodo tert.-amylbenzene controls reaction process, reacts end in 10 hours.Be chilled to room temperature, filter, filtrate concentrates, resistates adds 12L acetic acid ethyl dissolution, 20L washes, organic phase concentrates, reclaim ethyl acetate, resistates is at room temperature added drop-wise in the saturated sodium sulfite solution of 10L, separate out solid, stir 6 hours, filter, filter cake 5L ethyl acetate is washed, solid dispersal is in the hydrochloric acid of 10L1 mol/L, stirred at ambient temperature 5 hours, reaction solution 10L extraction into ethyl acetate, anhydrous magnesium sulfate drying, filter, filtrate concentrates dry ethyl acetate, obtain 3-tert-pentyl phenyl-2 methyl propanal 1.40kg, yield: 87.9%, GC purity: 98.5%.1H-NMR modal data: (400MHz, CDCl
3): 0.69 (3H, t, J=7.45Hz), 1.11 (3H, d, J=6.87Hz), 1.29 (6H, s), 1.65 (2H, q, J=7.43Hz), 2.60 (1H, dd, J=13.52Hz), 2.69 (1H, J=7.06Hz), 3.08 (1H, dd, J=13.54Hz), 7.12 (2H, d, J=8.27Hz), 7.27 (2H, d, J=8.27Hz), 9.75 (1H, s).
In 10L reactor, add above-mentioned 3-tert-pentyl phenyl-2 methyl propanal 1kg, 5L ethyl acetate, logical nitrogen protection, is cooled to 10 DEG C, drips 1.2kg 2,6-thebaine, within 40 minutes, adds.Then drip 780mL Glacial acetic acid, temperature remains on 15 DEG C, dropwises, and is warmed up to 20 DEG C of insulations 60 minutes.Be cooled to 10 DEG C again, add 2.3kg sodium triacetoxy borohydride, 25 DEG C of insulations after adding, the GC content detecting 3-tert-pentyl phenyl-2 methyl propanal monitors reaction process, reacts end in 2 hours.Being cooled to less than 10 DEG C, is 11 with sodium hydroxide solution adjust pH, stratification, and organic layer 4L tap water washs, organic phase adds concentrated hydrochloric acid, and adjust pH is 2, filters, and filter cake was 70 DEG C of drying under reduced pressure 14 hours, obtain hydrochloric acid amorolfine 1.37kg, yield: 84.6%, HPLC purity: 99.7%.1H-NMR modal data: 1H NMR (400MHz, CD
3oD) δ: 0.64 (3H, t, J=7.2Hz), 1.03 (3H, d, J=6.8Hz), 1.15 (6H, d, J=6.0Hz), 1.25 (6H, s), 1.64 (2H, m, J=7.6Hz), 2.34 (1H, d, J=6.8Hz), 2.48 (2H, d, J=6.8Hz), 2.75 (2H, d, J=6.0Hz), 3.1 (2H, d, J=8.8Hz), 3.4 (2H, d, J=11.2Hz), 3.9 (2H, m), 7.16 (2H, dd, J=8.4Hz), 7.27 (2H, dd, J=8.4Hz).
Embodiment 4
The 4-iodo tert.-amylbenzene 2kg prepared according to embodiment 1 method is added in the reactor of 10L cleaning; N-Methyl pyrrolidone 4L; logical nitrogen protection; start stirring, add Palladous nitrate 6g, sodium acetate 627g; finally add 2-methallyl alcohol 592g; be warming up to 140 DEG C of reactions, the GC content detecting 4-iodo tert.-amylbenzene monitors reaction process, reacts end in 24 hours.Be chilled to room temperature, filter, filtrate concentrates, and resistates adds 8L acetic acid ethyl dissolution, 16L washes, and organic phase rectifying, collects 125-128 DEG C of cut (vacuum tightness≤-0.099Mpa), obtain 3-tert-pentyl phenyl-2 methyl propanal 1.37kg, yield: 86%, GC purity: 93.0%.1H-NMR modal data: (400MHz, CDCl
3): 0.69 (3H, t, J=7.45Hz), 1.11 (3H, d, J=6.87Hz), 1.29 (6H, s), 1.65 (2H, q, J=7.43Hz), 2.60 (1H, dd, J=13.52Hz), 2.69 (1H, J=7.06Hz), 3.08 (1H, dd, J=13.54Hz), 7.12 (2H, d, J=8.27Hz), 7.27 (2H, d, J=8.27Hz), 9.75 (1H, s).
In 10L reactor, add above-mentioned 3-tert-pentyl phenyl-2 methyl propanal 1kg, 5L methylene dichloride, logical nitrogen protection, is cooled to 10 DEG C, drips 1.6Kg 2,6-thebaine, within 45 minutes, adds.Then drip 300mL Glacial acetic acid, temperature remains on 15 DEG C, dropwises, and is warmed up to 23 DEG C of insulations 60 minutes.Be cooled to 10 DEG C again, add 1.6Kg sodium triacetoxy borohydride, 23 DEG C of insulations after adding, the GC content detecting 3-tert-pentyl phenyl-2 methyl propanal monitors reaction process, reacts end in 2 hours.Being cooled to less than 10 DEG C, is 10 with sodium hydroxide solution adjust pH, stratification, and organic layer 4L tap water washs, organic phase adds concentrated hydrochloric acid, and adjust pH is 1, filters, and filter cake was 70 DEG C of drying under reduced pressure 14 hours, obtain hydrochloric acid amorolfine 1.36Kg, yield: 83.6%, HPLC purity: 99.6%.1H-NMR modal data: 1H NMR (400MHz, CD
3oD) δ: 0.64 (3H, t, J=7.2Hz), 1.03 (3H, d, J=6.8Hz), 1.15 (6H, d, J=6.0Hz), 1.25 (6H, s), 1.64 (2H, m, J=7.6Hz), 2.34 (1H, d, J=6.8Hz), 2.48 (2H, d, J=6.8Hz), 2.75 (2H, d, J=6.0Hz), 3.1 (2H, d, J=8.8Hz), 3.4 (2H, d, J=11.2Hz), 3.9 (2H, m), 7.16 (2H, dd, J=8.4Hz), 7.27 (2H, dd, J=8.4Hz).
Embodiment 5
The 4-iodo tert.-amylbenzene 2kg prepared according to embodiment 1 method is added in the reactor of 10L cleaning; N-Methyl pyrrolidone 4L; logical nitrogen protection; start stirring, add Palladous chloride 30g, sodium bicarbonate 750g; finally add 2-methallyl alcohol 1.3kg; be warming up to 120 DEG C of reactions, the GC content detecting 4-iodo tert.-amylbenzene controls reaction process, reacts end in 13 hours.Be chilled to room temperature, filter, filtrate concentrates, resistates adds 8L chloroform and dissolves, 16L washes, organic phase concentrates, reclaim ethyl acetate, resistates is at room temperature added drop-wise in the saturated sodium sulfite solution of 10L, separate out solid, stir 6 hours, filter, filter cake 5L ethyl acetate is washed, solid dispersal is in the sulfuric acid of 3L 3 mol/L, stirred at ambient temperature 5 hours, reaction solution 10L extraction into ethyl acetate, anhydrous magnesium sulfate drying, filter, filtrate concentrates dry ethyl acetate, obtain 3-tert-pentyl phenyl-2 methyl propanal 1.46kg, yield: 91.7%, GC purity: 98.8%.1H-NMR modal data: (400MHz, CDCl
3): 0.69 (3H, t, J=7.45Hz), 1.11 (3H, d, J=6.87Hz), 1.29 (6H, s), 1.65 (2H, q, J=7.43Hz), 2.60 (1H, dd, J=13.52Hz), 2.69 (1H, J=7.06Hz), 3.08 (1H, dd, J=13.54Hz), 7.12 (2H, d, J=8.27Hz), 7.27 (2H, d, J=8.27Hz), 9.75 (1H, s).
In 10L reactor, add above-mentioned 3-tert-pentyl phenyl-2 methyl propanal 1kg, 5L dehydrated alcohol, logical nitrogen protection, is cooled to 10 DEG C, drips 600g 2,6-thebaine, within 30 minutes, adds.Then drip 500mL Glacial acetic acid, temperature remains on 15 DEG C, dropwises, and is warmed up to 23 DEG C of insulations 60 minutes.Be cooled to 10 DEG C again, add 1.2kg sodium triacetoxy borohydride, 10 DEG C of insulations after adding, the GC content detecting 3-tert-pentyl phenyl-2 methyl propanal monitors reaction process, reacts end in 5 hours.Be 11 with sodium hydroxide solution adjust pH at 10 DEG C, add 3L methylene dichloride, stratification, organic layer 4L tap water washing, organic phase adds concentrated hydrochloric acid, adjust pH is 2, filter, filter cake, 70 DEG C of drying under reduced pressure 14 hours, obtains hydrochloric acid amorolfine 1.41kg, yield: 87.0%, HPLC purity: 99.7%.1H-NMR modal data: 1H NMR (400MHz, CD
3oD) δ: 0.64 (3H, t, J=7.2Hz), 1.03 (3H, d, J=6.8Hz), 1.15 (6H, d, J=6.0Hz), 1.25 (6H, s), 1.64 (2H, m, J=7.6Hz), 2.34 (1H, d, J=6.8Hz), 2.48 (2H, d, J=6.8Hz), 2.75 (2H, d, J=6.0Hz), 3.1 (2H, d, J=8.8Hz), 3.4 (2H, d, J=11.2Hz), 3.9 (2H, m), 7.16 (2H, dd, J=8.4Hz), 7.27 (2H, dd, J=8.4Hz).
Embodiment 6
The 4-iodo tert.-amylbenzene 2kg prepared according to embodiment 1 method is added in the reactor of 10L cleaning; N-Methyl pyrrolidone 4L; logical nitrogen protection; start stirring, add palladium 10g, salt of wormwood 800g; finally add 2-methallyl alcohol 1.1kg; be warming up to 80 DEG C of reactions, the GC content detecting 4-iodo tert.-amylbenzene controls reaction process, reacts end in 24 hours.Be chilled to room temperature, filter, filtrate concentrates, and resistates adds 8L chloroform and dissolves, 16L washes, and organic phase rectifying, collects 125-128 DEG C of cut (vacuum tightness≤-0.099Mpa), obtain 3-tert-pentyl phenyl-2 methyl propanal 1.42kg, yield: 89.2%, GC purity: 92.5%.1H-NMR modal data: (400MHz, CDCl
3): 0.69 (3H, t, J=7.45Hz), 1.11 (3H, d, J=6.87Hz), 1.29 (6H, s), 1.65 (2H, q, J=7.43Hz), 2.60 (1H, dd, J=13.52Hz), 2.69 (1H, J=7.06Hz), 3.08 (1H, dd, J=13.54Hz), 7.12 (2H, d, J=8.27Hz), 7.27 (2H, d, J=8.27Hz), 9.75 (1H, s).
In 10L reactor, add above-mentioned 3-tert-pentyl phenyl-2 methyl propanal 1kg, 5L methyl alcohol, nitrogen protection, is cooled to 10 DEG C, drips 600g 2,6-thebaine, within 30 minutes, adds.Then drip 500mL Glacial acetic acid, temperature remains on 10 DEG C, dropwises, and is warmed up to 20 DEG C of insulations 60 minutes.Be cooled to 10 DEG C again, add 1.2kg sodium triacetoxy borohydride, 23 DEG C of insulations after adding, the GC content detecting 3-tert-pentyl phenyl-2 methyl propanal monitors reaction process, reacts end in 2 hours.Be cooled to 10 DEG C, be 10 with sodium hydroxide solution adjust pH, add 3L methylene dichloride, stratification, organic layer 4L tap water washs, organic phase adds concentrated hydrochloric acid, and adjust pH is 1.5, filters, filter cake was 65 DEG C of drying under reduced pressure 15 hours, obtain hydrochloric acid amorolfine 1.46kg, yield: 90.1%, HPLC purity: 99.8%.1H-NMR modal data: 1H NMR (400MHz, CD
3oD) δ: 0.64 (3H, t, J=7.2Hz), 1.03 (3H, d, J=6.8Hz), 1.15 (6H, d, J=6.0Hz), 1.25 (6H, s), 1.64 (2H, m, J=7.6Hz), 2.34 (1H, d, J=6.8Hz), 2.48 (2H, d, J=6.8Hz), 2.75 (2H, d, J=6.0Hz), 3.1 (2H, d, J=8.8Hz), 3.4 (2H, d, J=11.2Hz), 3.9 (2H, m), 7.16 (2H, dd, J=8.4Hz), 7.27 (2H, dd, J=8.4Hz).
Embodiment 7
The 4-iodo tert.-amylbenzene 2kg prepared according to embodiment 1 method is added in the reactor of 10L cleaning; N-Methyl pyrrolidone 6L; logical nitrogen protection; start stirring, add palladium 75g, Sodium phosphate dibasic 2.0kg; finally add 2-methallyl alcohol 780g; be warming up to 125 DEG C of reactions, the GC content detecting 4-iodo tert.-amylbenzene controls reaction process, reacts end in 8 hours.Be chilled to room temperature, filter, filtrate concentrates, resistates adds 12L acetic acid ethyl dissolution, 20L washes, organic phase concentrates, reclaim ethyl acetate, resistates is at room temperature added drop-wise in the saturated sodium sulfite solution of 10L, separate out solid, stir 6 hours, filter, filter cake 5L ethyl acetate is washed, solid dispersal is in the hydrochloric acid of 10L2 mol/L, stirred at ambient temperature 5 hours, reaction solution 10L extraction into ethyl acetate, anhydrous magnesium sulfate drying, filter, filtrate concentrates dry ethyl acetate, obtain 3-tert-pentyl phenyl-2 methyl propanal 1.45kg, yield: 91.0%, GC purity: 97.8%.1H-NMR modal data: (400MHz, CDCl
3): 0.69 (3H, t, J=7.45Hz), 1.11 (3H, d, J=6.87Hz), 1.29 (6H, s), 1.65 (2H, q, J=7.43Hz), 2.60 (1H, dd, J=13.52Hz), 2.69 (1H, J=7.06Hz), 3.08 (1H, dd, J=13.54Hz), 7.12 (2H, d, J=8.27Hz), 7.27 (2H, d, J=8.27Hz), 9.75 (1H, s).
Above-mentioned 3-tert-pentyl phenyl-2 methyl propanal 1kg, 5L toluene is added, logical nitrogen protection in 10L reactor; be cooled to 10 DEG C, drip 700g 2,6-thebaine; then add 280mL Glacial acetic acid, temperature remains on 15 DEG C, is then warmed up to 23 DEG C of insulations 60 minutes.Be cooled to 10 DEG C again, add 1.0kg sodium triacetoxy borohydride, be incubated at adding latter 20 DEG C, the GC content detecting 3-tert-pentyl phenyl-2 methyl propanal monitors reaction process, reacts end in 3 hours.Being cooled to less than 10 DEG C, is 11 with sodium hydroxide solution adjust pH, stratification, and organic layer 4L tap water washs, organic phase adds concentrated hydrochloric acid, and adjust pH is 1, filters, and filter cake was 70 DEG C of drying under reduced pressure 14 hours, obtain hydrochloric acid amorolfine 1.36kg, yield: 83.8%, HPLC purity: 99.6%.1H-NMR modal data: 1H NMR (400MHz, CD
3oD) δ: 0.64 (3H, t, J=7.2Hz), 1.03 (3H, d, J=6.8Hz), 1.15 (6H, d, J=6.0Hz), 1.25 (6H, s), 1.64 (2H, m, J=7.6Hz), 2.34 (1H, d, J=6.8Hz), 2.48 (2H, d, J=6.8Hz), 2.75 (2H, d, J=6.0Hz), 3.1 (2H, d, J=8.8Hz), 3.4 (2H, d, J=11.2Hz), 3.9 (2H, m), 7.16 (2H, dd, J=8.4Hz), 7.27 (2H, dd, J=8.4Hz).
Embodiment 8
The 3-tert-pentyl phenyl-2 methyl propanal 1kg prepared by embodiment 5 method is added in 10L reactor; 5L methylene dichloride; logical nitrogen protection; be cooled to 10 DEG C; drip 1000g 2,6-thebaine, then add 400mL Glacial acetic acid; temperature remains on 15 DEG C, is then warmed up to 20 DEG C of insulations 60 minutes.Be cooled to 0 DEG C again, add 1.5kg sodium triacetoxy borohydride, add rear 6 DEG C of insulations, the GC content detecting 3-tert-pentyl phenyl-2 methyl propanal monitors reaction process, reacts end in 5 hours.Be 10 with sodium hydroxide solution adjust pH at 6 DEG C, stratification, organic layer 4L tap water washing, organic phase adds concentrated hydrochloric acid, adjust pH is 2, filters, and filter cake was 65 DEG C of drying under reduced pressure 14 hours, obtain hydrochloric acid amorolfine 1.48kg, yield: 91.2%, HPLC purity: 99.7%.1H-NMR modal data: 1H NMR (400MHz, CD
3oD) δ: 0.64 (3H, t, J=7.2Hz), 1.03 (3H, d, J=6.8Hz), 1.15 (6H, d, J=6.0Hz), 1.25 (6H, s), 1.64 (2H, m, J=7.6Hz), 2.34 (1H, d, J=6.8Hz), 2.48 (2H, d, J=6.8Hz), 2.75 (2H, d, J=6.0Hz), 3.1 (2H, d, J=8.8Hz), 3.4 (2H, d, J=11.2Hz), 3.9 (2H, m), 7.16 (2H, dd, J=8.4Hz), 7.27 (2H, dd, J=8.4Hz).
Embodiment 9
3-tert-pentyl phenyl-2 methyl propanal 1kg, the 4L tetrahydrofuran (THF) prepared by embodiment 2 method is added, logical nitrogen protection in 10L reactor; be cooled to 10 DEG C, drip 820g 2,6-thebaine; then add 380mL Glacial acetic acid, temperature remains on 15 DEG C, then incubated at room temperature 60 minutes.Be cooled to 10 DEG C again, add 1.8kg sodium triacetoxy borohydride, add rear 10 DEG C of insulations, the GC content detecting 3-tert-pentyl phenyl-2 methyl propanal monitors reaction process, reacts end in 5 hours.Be 10 with sodium hydroxide solution adjust pH at 10 DEG C, stratification, organic layer 4L tap water washing, organic phase adds concentrated hydrochloric acid, adjust pH is 2, filters, and filter cake was 65 DEG C of drying under reduced pressure 14 hours, obtain hydrochloric acid amorolfine 1.41kg, yield: 87.1%, HPLC purity: 99.8%.1H-NMR modal data: 1H NMR (400MHz, CD
3oD) δ: 0.64 (3H, t, J=7.2Hz), 1.03 (3H, d, J=6.8Hz), 1.15 (6H, d, J=6.0Hz), 1.25 (6H, s), 1.64 (2H, m, J=7.6Hz), 2.34 (1H, d, J=6.8Hz), 2.48 (2H, d, J=6.8Hz), 2.75 (2H, d, J=6.0Hz), 3.1 (2H, d, J=8.8Hz), 3.4 (2H, d, J=11.2Hz), 3.9 (2H, m), 7.16 (2H, dd, J=8.4Hz), 7.27 (2H, dd, J=8.4Hz).
Comparative example 1
The 4-iodo tert.-amylbenzene 137g prepared according to embodiment 1 method is added in 1000mL four-hole boiling flask, 1.12g palladium, 50.4g sodium bicarbonate, N, dinethylformamide 500mL, nitrogen protection, add 2-methallyl alcohol 54g, be warmed up to 100 DEG C of insulations 10 hours, cool to room temperature, filter, filter cake N, dinethylformamide 300mL washs, merging filtrate, pour in the mixture of 2000mL saturated aqueous common salt and 1000mL ethyl acetate and extract, organic phase is washed, with anhydrous magnesium sulfate drying, filter, concentrated dry solvent, residue vacuum distills, collect 125-128 DEG C of cut (vacuum tightness≤-0.099Mpa), obtain 3-tert-pentyl phenyl-2 methyl propanal 84g, yield: 77%, GC purity: 88.0%.1H-NMR modal data: (400MHz, CDCl
3): 0.69 (3H, t, J=7.45Hz), 1.11 (3H, d, J=6.87Hz), 1.29 (6H, s), 1.65 (2H, q, J=7.43Hz), 2.60 (1H, dd, J=13.52Hz), 2.69 (1H, J=7.06Hz), 3.08 (1H, dd, J=13.54Hz), 7.12 (2H, d, J=8.27Hz), 7.27 (2H, d, J=8.27Hz), 9.75 (1H, s).
Above-mentioned for 109g 3-tert-pentyl phenyl-2 methyl propanal and 500mL ethanol are joined in 1000mL four-hole boiling flask, be cooled to 0 DEG C, add 30mL Glacial acetic acid and 69g 2, 6-thebaine, stirring at room temperature 30 minutes, be cooled to-15 DEG C, 15.93g sodium borohydride is added in 1 hour, 0 DEG C of insulation 2 hours are warmed up to after adding, by reaction solution with 25% sodium hydroxide solution adjust pH be 12, add 2000mL saturated aqueous common salt and 1000mL ethyl acetate extracts, organic phase is washed, concentrated dry, the resistates obtained adds 500mL isopropyl ether, logical hydrogen chloride gas is 2 to pH, stirring at room temperature 2 hours, filter, isopropyl ether washs, filter cake was 70 DEG C of drying under reduced pressure 14 hours, obtain hydrochloric acid amorolfine 119g, yield: 67%, HPLC purity: 97.1%.1H-NMR modal data: 1HNMR (400MHz, CD
3oD) δ: 0.64 (3H, t, J=7.2Hz), 1.03 (3H, d, J=6.8Hz), 1.15 (6H, d, J=6.0Hz), 1.25 (6H, s), 1.64 (2H, m, J=7.6Hz), 2.34 (1H, d, J=6.8Hz), 2.48 (2H, d, J=6.8Hz), 2.75 (2H, d, J=6.0Hz), 3.1 (2H, d, J=8.8Hz), 3.4 (2H, d, J=11.2Hz), 3.9 (2H, m), 7.16 (2H, dd, J=8.4Hz), 7.27 (2H, dd, J=8.4Hz).
Comparative example 2
The 3-tert-pentyl phenyl-2 methyl propanal prepared according to comparative example 1 method by 109g and 500mL methyl alcohol join in 1000mL four-hole boiling flask, be cooled to 0 DEG C, add 30mL Glacial acetic acid and 69g 2,6-thebaine, stirring at room temperature 30 minutes, be cooled to-15 DEG C, nitrogen replacement, add the palladium charcoal of 5g10%, logical hydrogen, reduce under 40 DEG C, 4 normal atmosphere, do not decline to hydrogen pressure, reaction completes.Cool to room temperature, nitrogen replacement, filters, filtrate is 12 with the sodium hydroxide solution adjust pH of 25%, adds 2000mL saturated aqueous common salt and 1000mL ethyl acetate extracts, and organic phase is washed, concentrated dry, the resistates obtained adds 500mL isopropyl ether, and logical hydrogen chloride gas is 2 to pH, stirring at room temperature 2 hours, filters, and isopropyl ether washs, filter cake was 70 DEG C of drying under reduced pressure 14 hours, obtain hydrochloric acid amorolfine 113g, yield: 64%, HPLC purity: 97.8%.1H-NMR modal data: 1H NMR (400MHz, CD
3oD) δ: 0.64 (3H, t, J=7.2Hz), 1.03 (3H, d, J=6.8Hz), 1.15 (6H, d, J=6.0Hz), 1.25 (6H, s), 1.64 (2H, m, J=7.6Hz), 2.34 (1H, d, J=6.8Hz), 2.48 (2H, d, J=6.8Hz), 2.75 (2H, d, J=6.0Hz), 3.1 (2H, d, J=8.8Hz), 3.4 (2H, d, J=11.2Hz), 3.9 (2H, m), 7.16 (2H, dd, J=8.4Hz), 7.27 (2H, dd, J=8.4Hz).
Claims (11)
1. preparation formula (I b) shown in the method for hydrochloric acid amorolfine,
Comprise the steps:
(1) take N-Methyl pyrrolidone as solvent, under the existence of palladium catalyst and alkali, make formula II compound:
React with 2-methallyl alcohol, obtain formula III compound:
Wherein, the mol ratio of formula II compound, 2-methallyl alcohol, palladium catalyst and alkali is 1.0:(1.0 ~ 5.0): (0.003 ~ 0.2): (1.0 ~ 3.0); And the range of reaction temperature of described reaction is 80-160 DEG C;
(2) in organic solvent, under Glacial acetic acid exists, take sodium triacetoxy borohydride as reductive agent, the formula III compound and cis-2 that step (1) is obtained, 6-thebaine carries out reductive amination process, obtains formula (I a) compound;
Wherein, the mol ratio of formula III compound, cis-2,6-thebaines, Glacial acetic acid and sodium triacetoxy borohydride is 1.0:(1.0 ~ 4.0): (1.0 ~ 3.0): (1.0 ~ 2.5);
(3) formula that step (2) obtained (I a) compound change hydrochloric acid amorolfine into.
2. method according to claim 1, it is characterized in that, in step (1), the mol ratio of formula II compound, 2-methallyl alcohol, palladium catalyst and alkali is 1.0:(1.5 ~ 2.5): (0.005 ~ 0.05): (1.0 ~ 2.0).
3. method according to claim 2, it is characterized in that, the mol ratio of the formula III compound of described step (2), cis-2,6-thebaines, Glacial acetic acid and sodium triacetoxy borohydride is 1.0:(1.0 ~ 2.0): (1.0 ~ 2.0): (1.0 ~ 1.5).
4. the method according to any one of claim 1-3, it is characterized in that, the purification step of formula III compound was also comprised: the formula III compound obtain step (1) and saturated aqueous solution of sodium bisulfite generation addition reaction before step (2), gained adduct again with acid-respons, obtain the formula III compound of purifying.
5. method according to claim 4, is characterized in that, described acid is selected from the hydrochloric acid or sulfuric acid that concentration is 1 ~ 3 mol/L.
6. method according to claim 5, it is characterized in that, palladium catalyst described in step (1) is selected from palladium, palladous sulfate, Palladous nitrate or Palladous chloride, and described alkali is selected from alkaline carbonate, alkali metal hydrocarbonate, alkali metal acetate, alkali metal phosphate, alkali metal hydrogen phosphate disalt or their mixture.
7. method according to claim 6, it is characterized in that, palladium catalyst described in step (1) is selected from palladium or Palladous chloride, and described alkali is selected from sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium acetate, potassium acetate, sodium phosphate, potassiumphosphate, Sodium phosphate dibasic, dipotassium hydrogen phosphate or their mixture.
8. method according to claim 7, is characterized in that, the alkali described in step (1) is selected from sodium bicarbonate or Sodium phosphate dibasic.
9. method according to claim 8, is characterized in that, the range of reaction temperature of step (1) is 90-130 DEG C.
10. method according to claim 9, it is characterized in that, the organic solvent of described step (2) is selected from methyl alcohol, Virahol, methylene dichloride, trichloromethane, ethylene dichloride, methyl acetate, ethyl acetate, propyl acetate, butylacetate, toluene or tetrahydrofuran (THF).
11. methods according to claim 10, is characterized in that, the organic solvent of described step (2) is selected from methyl alcohol, methylene dichloride, ethyl acetate or butylacetate.
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| CN104926629B (en) * | 2015-05-30 | 2016-06-22 | 江苏科本医药化学有限公司 | Domino reaction is utilized to prepare the green method of 3,3-diaryl acrylic aldehyde |
| CN105130808B (en) * | 2015-08-13 | 2020-05-19 | 上海瑞博化学有限公司 | Synthesis method of high-purity 2, 5-dimethyl-3, 4-dihydroxy methyl benzoate |
| CN108997246B (en) * | 2017-06-06 | 2021-08-31 | 江苏礼华生物技术有限公司 | Preparation method of amorolfine hydrochloride |
| CN109232458A (en) * | 2018-06-15 | 2019-01-18 | 南通常佑药业科技有限公司 | A kind of preparation method of chirality morpholinium compound |
| CN114907182A (en) * | 2019-09-09 | 2022-08-16 | 武汉诺安药业有限公司 | Clean preparation method of 4-iodo-tert-amylbenzene |
| CN112279749B (en) * | 2020-11-03 | 2022-06-07 | 镇江卡博医药科技有限公司 | Synthetic method of 2-methyl-3- (4-tert-pentylphenyl) propanol |
| CN115093309A (en) * | 2022-06-20 | 2022-09-23 | 浙江海翔药业股份有限公司 | Amorolfine hydrochloride intermediate impurity and preparation method thereof |
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