CN110256387A - A kind of preparation method of high-purity medicine intermediate - Google Patents
A kind of preparation method of high-purity medicine intermediate Download PDFInfo
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- CN110256387A CN110256387A CN201910576647.1A CN201910576647A CN110256387A CN 110256387 A CN110256387 A CN 110256387A CN 201910576647 A CN201910576647 A CN 201910576647A CN 110256387 A CN110256387 A CN 110256387A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
Abstract
The invention discloses a kind of preparation methods of high-purity medicine intermediate, belong to pharmaceutical chemistry technical field.The preparation method of medicine intermediate provided by the invention is using dehydroactic acid and aromatic amine as raw material, with 1,3,6- naphthalene trisulfonic acid is catalyst, condensation reaction is carried out in isopropanol water solution reaction dissolvent, 4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyran-2-one derivative of high-purity is directly prepared, is not necessarily to further purification processes.Production process of the present invention is simple, the product purity height and high income of synthesis.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical fields, more specifically to a kind of preparation of high-purity medicine intermediate
Method.
Background technique
As one of Schiff class compound, pyrone derivative is widely distributed in nature, is many days
Right product molecule or the intermediate or basic framework of pharmaceutical drug substance synthesis, have numerous physiological activity, to various physiological processes
It plays an important role, for example analgesic activity, antifungal activity, antiviral activity, anticancer activity, resists the invasion of other organisms
Characteristic and diuretic activity etc..Based on above-mentioned characteristic, pyrone derivative is critically important biosynthesis in biological medicine
Intermediate.And 4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- in pyrone derivative containing pyranone structure
Pyran-2-one derivative is also a kind of important medicine intermediate being applied in terms of pharmacology and bioactivity.
The preparation of Schiff class compound is often by series of steps such as condensation, addition, rearrangement, cancellation, couplings
Composition, and alkaloid compound in general sense is usually the product generated by aldehydes or ketones and primary amine condensation.With scientific skill
The progress of art, people start to select different reaction raw materials according to actual needs, different to achieve the purpose that.For example, in recent years,
Researcher starts that 4- is prepared by the way that coupling reaction occurs using dehydroactic acid and amine and its derivative as reaction raw materials
Hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyran-2-one derivative generally requires organic base in preparation process
Or acid is used as catalyst.
Antonio J.Demuner etc. is using dehydroactic acid (alpha, gamma-dehydroacetic acid) and aromatic amine as reaction
Raw material, it is a series of as catalysts, Isosorbide-5-Nitrae-dioxacyclohexanes as having synthesized under conditions of reaction dissolvent using triethylamine
4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyran-2-one derivative (Preparation of achiral
And chiral (E)-enaminopyran-2,4-diones and their phytotoxic activity [J],
Journal of Agricultural and Food Chemistry, 2009,57:1399~1405).But this method exists
Following problems: first is that the preparation process reaction time is long, it is up to 16h；Second is that the product purity being prepared is low, need further
Purification operations；Third is that catalysts and solvent can not be recycled, it is in practical applications to be restricted more.
Then, Zang Hongjun etc. still using dehydroactic acid using with aromatic amine as raw material, still, using acidic ion liquid [BMIM-
SO3H]HSO4It is assisted as catalyst, and under 40 DEG C of water-baths using ultrasonic radiation, after reaction terminating, then it is organic through revolving removing
Solvent, the residue ethanol washing that will be obtained, to obtain net product, reaction is prepared for silica gel column chromatography purified product when necessary
A series of 4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyran-2-one derivative, substantially reduces reaction
Time, and product yield high, reusable (the ionic liquid-catalyzed synthesis 4- hydroxyl -6- methyl-under Ultrasonic Radiation of catalyst
[1- (phenylimino) ethyl] -2H- pyran-2-one derivative [J], organic chemistry, 2012,32:2193~2197).But
This method still has following problem: first is that products therefrom, which still needs to be further processed, could improve purity；Second is that can recycle
The substance of recycling is limited, can only realize the recycling of catalyst, and the removal process of catalyst is complicated, Expenses Cost is higher；Three
Be at present for the acidic ion liquid containing precursor structures such as imidazoles, pyridines, itself preparation cost with regard to relatively high, and
Biological degradability is poor, in addition, also found with further studying ionic liquid, the ionic liquid of this type also has centainly
Toxicity.
Therefore, develop a kind of green, efficiently, conveniently and efficiently high-purity medicine intermediate 4- hydroxyl -6- methyl-[1- (benzene
Base imino group) ethyl] -2H- pyran-2-one derivative synthetic method have practical practical significance.
Summary of the invention
1. to solve the problems, such as
It is derivative for 4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyran-2-one is prepared in the prior art
Yield is low for the method tool of object, reaction dissolvent can not reuse, what the product prepared need to be purified by other technologies means asks
Topic, the present invention provide a kind of high-purity medicine intermediate 4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyrans -
The preparation method of 2- ketone derivatives.
2. technical solution
To solve the above-mentioned problems, the technical solution adopted in the present invention is as follows:
A kind of preparation method of high-purity medicine intermediate, it is water-soluble in isopropanol using dehydroactic acid and aromatic amine as raw material
It in liquid, is condensed through catalyst, it is derivative to obtain 4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyran-2-one
Object.Reaction process only has micro by-product production, directly forms 4- hydroxyl -6- methyl-[1- (benzene of high-purity after reaction
Base imino group) ethyl] -2H- pyran-2-one derivative, without further being purified by silica gel column chromatography, and the yield of product
It is high；Remnants are obtained after 4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyran-2-one derivative is separated
Filtrate carries out next round condensation reaction after being directly added into raw material, can simply, easily realize without carrying out any processing
The circulating and recovering of filtrate (isopropanol water solution solvent and catalyst).
Preferably, isopropanol in the isopropanol water solution: the volume by volume concentration of water is 46%~55%.
Preferably, isopropanol in the isopropanol water solution: the volume by volume concentration of water is 50%~54%.
Preferably, isopropanol in the isopropanol water solution: the volume by volume concentration of water is 41%~53%.
Preferably, isopropanol in the isopropanol water solution: the volume by volume concentration of water is 52%~53%.
Further, the preparation method of the medicine intermediate, the specific steps are as follows: by dehydroactic acid, aromatic amine and
Catalyst is added in isopropanol water solution, is mixed, and 50~100min of processing is heated to reflux, and direct cooling and standings can be precipitated solid
Solid product separating, washing is dried in vacuo 4- hydroxyl -6- methyl-[1- (phenylimino) to get high-purity by body product
Ethyl] -2H- pyran-2-one derivative.It is not necessary that further by silica gel column chromatography or recrystallization etc., other means are purified,
Simplify experimental procedure.
In order to further remove impurity, guarantees product purity, the solid product separated is carried out using dehydrated alcohol
Washing.
Filtrate is obtained after solid product is separated, gained filtrate can be recycled.By-product is few in reaction process, therefore
Almost without residual impurity in filtrate, next round reaction can will not be had an impact because of impurity with direct reuse；In addition, reacting
The loss of solvent and catalyst can almost be disregarded in journey, will not react because of quantity of solvent and catalyst concn variation next round
It has an impact；And it is made through the verifying of multiple circulation experiment as can be seen that filtrate repeats and after continuous recycling and reusing 5 or 6 time
Standby obtained 4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyran-2-one derivative purity is still greater than 98%,
Yield is still higher than 60%.
Further, used catalyst 1,3,6- naphthalene trisulfonic acids.1,3,6- naphthalene trisulfonic acid and isopropanol water solution are common
Constitutive material carries out chemically synthesized reaction-catalysis dicyandiamide solution, and the two generates synergistic effect, and isopropanol water solution can change
The catalytic way of 1,3,6- naphthalene trisulfonic acid (gives H+Mode), the by-product in reaction process is reduced, and 1,3,6- naphthalene trisulfonic acid can
To provide enough active catalytic groups, product yield is improved.
Raw material proportioning, catalyst type, catalyst amount, reaction dissolvent etc. together constitute final reaction system, and
It often pulls one hair and move the whole body for any chemical synthesis or production, the change of any of them one side can all cause the later period
The purity of product, yield reduce and reaction process in the production quantity of by-product increase, and then impact effect is based on this:
Preferably, the addition molar ratio of the aromatic amine and dehydroactic acid is (1.0~1.2): 1.
Preferably, the volume that isopropanol water solution is counted using milliliter as dehydroactic acid by mM in terms of substance amount 7
~10 times.
Preferably, 1, the addition molar ratio of 3,6- naphthalene trisulfonic acids and dehydroactic acid is (0.04~0.07): 1.
Preferably, 1,3,6- above-mentioned naphthalene trisulfonic acids, structural formula are as follows:
4- hydroxyl -6- methyl-[1- (phenyl imido is prepared using 1,3,6- naphthalene trisulfonic acid catalytic dehydrogenation acetic acid and aromatic amine
Base) ethyl] -2H- pyran-2-one derivative reaction equation it is as follows:
Wherein aromatic amine is 4- nitroaniline, benzene methanamine, 4- chloroaniline, 2- chloroaniline, 3- chloroaniline, 4- fluoroaniline, 4-
Any one of methyl -3- chloroaniline, 4- methylaniline, 4- aminoanisole.
3. beneficial effect
Compared with the prior art, the invention has the benefit that
(1) preparation method of high-purity medicine intermediate provided by the invention, using isopropanol water solution as reaction dissolvent,
It can change the catalytic way of catalyst, reduce the by-product generated in reaction process, on the one hand can guarantee that raw material arrives in this way
Product efficiently generates rate, on the other hand product yield high can be improved product purity, mentions without further chromatographing or recrystallizing
It is pure；
(2) preparation method of high-purity medicine intermediate provided by the invention, the filtrate after separation product can be recycled back to
With, it is environmentally protective, and repeatedly circulating and recovering remains to ensure the yield and purity of product, without doing any processing i.e. when filtrate recycle
It can be recycled, recycling and reusing is simple；
(3) preparation method of high-purity medicine intermediate provided by the invention, with 1,3,6- naphthalene trisulfonic acid for catalyst, with
Isopropanol water solution collectively constitutes catalytic reaction system, and the two generates synergistic effect, and isopropanol water solution changes 1,3,6- naphthalenes three
The catalytic way of sulfonic acid (gives H+Mode), the by-product in reaction process is reduced, the selectivity of product is improved, in raw material dosage
More products, entire preparation method economical and efficient, green can be obtained in identical situation (using dehydroactic acid as mete-wand)
Environmental protection.
Detailed description of the invention
Fig. 1 is that the catalyst system of 1,3,6- naphthalene trisulfonic acids and isopropanol water solution composition is being catalyzed in the embodiment of the present invention 10
It prepares when being recycled in the reaction of 3- [1- (4- nitrobenzophenone imino group) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one
Product yield variation diagram；
Fig. 2 is that the catalyst system of 1,3,6- naphthalene trisulfonic acids and isopropanol water solution composition is being catalyzed in the embodiment of the present invention 11
Prepare product when being recycled in the reaction of 3- [1- (benzyl imino group) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one
Yield variation diagram；
Fig. 3 is that the catalyst system of 1,3,6- naphthalene trisulfonic acids and isopropanol water solution composition is being catalyzed in the embodiment of the present invention 12
It is recycled in preparation 3- [1- (3- chlorine 4- methylphenylimino) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one reaction
When product yield variation diagram.
Specific embodiment
Substantive features and remarkable result of the invention can be emerged from from following embodiments, but they not to this
Invention imposes any restrictions, and those skilled in the art's content according to the present invention makes some nonessential modifications and adaptations,
It belongs to the scope of protection of the present invention.
Below by specific embodiment, the present invention is further illustrated, wherein in embodiment reaction product infrared light
Spectrum test characterization uses 55 infrared spectrometer of model EQUINOX (KBr tabletting) of German Bruker company；Hydrogen composes core
Magnetic resonance characterizes the Nuclear Magnetic Resonance of the model AVANCE 300MHz using German Bruker company；Reaction product
Fusing point is measured using capillary tube method.
Embodiment 1
To the 50ml single port with condenser pipe and stirring magneton for the isopropanol water solution for filling 9ml volume by volume concentration 52%
1,3,6- naphthalene trisulfonic acid catalyst of 1.2mmol 4- nitroaniline, 1.0mmol dehydroactic acid and 0.07mmol, room are added in bottle
The lower magnetic agitation of temperature mixes.It being heated to reflux to generate, has maintained the reflux for a length of 91min when reaction, TLC (thin plate chromatography) is detected,
Raw material point disappears, and reaction, which terminates to be cooled to room temperature, is precipitated a large amount of solids, stands, filters, filter residue is washed using the dehydrated alcohol of 3mL
3- [1- (4- nitrobenzophenone imino group) ethyl] -4- hydroxyl -6- methyl-is obtained after being dried in vacuo at 3 times (3ml × 3), 80 DEG C
2H- pyran-2-one, it is 98.9% that high performance liquid chromatography, which measures its purity, calculated yield 72%.4- nitre is directly added into filtrate
It is reused after base aniline and dehydroactic acid.
3- [1- (4- nitrobenzophenone imino group) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one: white solid；
M.p.154~156 DEG C；IR (KBr) ν: 3396,3033,2925,1698,1647,1562,1468,1379,1066,942,835,
762cm-1；1H NMR (300MHz, CDCl3): δ=2.18 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.55 (s, 3H, CH3),
5.73 (s, 1H, CH), 7.02 (d, J=6.5Hz, 2H, ArH), 7.21 (d, J=6.1Hz, 2H, ArH), 15.64 (s, 1H, OH).
Embodiment 2
To the 50ml single port with condenser pipe and stirring magneton for the isopropanol water solution for filling 7ml volume by volume concentration 46%
1,3,6- naphthalene trisulfonic acid catalyst of 1.0mmol benzene methanamine, 1.0mmol dehydroactic acid and 0.04mmol are added in bottle, at room temperature
Magnetic agitation mixes.It has been heated to reflux to generate, has maintained the reflux for a length of 54min when reaction, TLC (thin plate chromatography) detection, raw material
Point disappears, and reaction, which terminates to be cooled to room temperature, is precipitated a large amount of solids, stands, filters, filter residue washs (3ml × 3), 80 through dehydrated alcohol
3- [1- (benzyl imino group) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one, efficient liquid are obtained after being dried in vacuo at DEG C
Its purity of phase chromatographic determination is 98.6%, calculated yield 86%.It is carried out after being directly added into benzene methanamine and dehydroactic acid in filtrate
It reuses.
3- [1- (benzyl imino group) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one: faint yellow solid；m.p.79
~81 DEG C；IR (KBr) ν: 3439,3055,2914,1696,1641,1568,1470,1384,1057,993,872,725cm-1；1H NMR (300MHz, CDCl3): δ=2.14 (s, 3H, CH3), 2.66 (s, 3H, CH3), 4.65 (d, J=5.4Hz, 2H, CH2),
5.69 (s, 1H, CH), 7.24~7.29 (m, 2H, ArH), 7.35 (d, J=6.6Hz, 1H, ArH), 7.37 (t, J=7.5Hz,
2H, ArH), 14.52 (s, 1H, OH).
Embodiment 3
To the 50ml single port with condenser pipe and stirring magneton for the isopropanol water solution for filling 8ml volume by volume concentration 50%
1,3,6- naphthalene trisulfonic acid catalyst of 1.1mmol 4- chloroaniline, 1.0mmol dehydroactic acid and 0.06mmol, room temperature are added in bottle
Lower magnetic agitation mixes.It has been heated to reflux to generate, has maintained the reflux for a length of 79min when reaction, TLC (thin plate chromatography) detection is former
Shots disappear, and reaction, which terminates to be cooled to room temperature, is precipitated a large amount of solids, stand, filter, filter residue through dehydrated alcohol washing (3ml × 3),
3- [1- (4- chlorophenylimino) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one is obtained after being dried in vacuo at 80 DEG C, it is high
It is 99.1% that effect liquid phase chromatogram, which measures its purity, calculated yield 79%.4- chloroaniline and dehydroactic acid are directly added into filtrate
After reused.
3- [1- (4- chlorophenylimino) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one: white solid；
M.p.138~140 DEG C；IR (KBr) ν: 3401,3077,2723,1714,1649,1563,1462,1326,1088,947,839,
716cm-1；1H NMR (300MHz, CDCl3): δ=2.11 (s, 3H, CH3), 2.46 (s, 3H, CH3), 5.75 (s, 1H, CH),
7.39 (d, J=8.5Hz, 2H, ArH), 7.52 (d, J=8.5Hz, 2H, ArH), 15.69 (s, 1H, OH)
Embodiment 4
To the 50ml single port with condenser pipe and stirring magneton for the isopropanol water solution for filling 8ml volume by volume concentration 50%
1,3,6- naphthalene trisulfonic acid catalyst of 1.1mmol 2- chloroaniline, 1.0mmol dehydroactic acid and 0.07mmol, room temperature are added in bottle
Lower magnetic agitation mixes.It has been heated to reflux to generate, has maintained the reflux for a length of 84min when reaction, TLC (thin plate chromatography) detection is former
Shots disappear, and reaction, which terminates to be cooled to room temperature, is precipitated a large amount of solids, stand, filter, filter residue through dehydrated alcohol washing (3ml × 3),
3- [1- (2- chlorophenylimino) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one is obtained after being dried in vacuo at 80 DEG C, it is high
It is 99.2% that effect liquid phase chromatogram, which measures its purity, calculated yield 74%.2- chloroaniline and dehydroactic acid are directly added into filtrate
After reused.
3- [1- (2- chlorophenylimino) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one: white solid；
M.p.159~161 DEG C；IR (KBr) ν: 3430,3079,2925,1696,1644,1567,1459,1362,1060,945,857,
754cm-1；1H NMR (300MHz, CDCl3): δ=2.15 (s, 3H, CH3), 2.49 (s, 3H, CH3), 5.77 (s, 1H, CH),
7.23 (t, J=7.5Hz, 1H, ArH), 7.29~7.35 (m, 2H, ArH), 7.55 (dd, J1=1.5Hz, J2=7.1Hz, 1H,
ArH), 15.93 (s, 1H, OH)
Embodiment 5
To the 50ml single port with condenser pipe and stirring magneton for the isopropanol water solution for filling 9ml volume by volume concentration 52%
1,3,6- naphthalene trisulfonic acid catalyst of 1.1mmol 3- chloroaniline, 1.0mmol dehydroactic acid and 0.06mmol, room temperature are added in bottle
Lower magnetic agitation mixes.It has been heated to reflux to generate, has maintained the reflux for a length of 68min when reaction, TLC (thin plate chromatography) detection is former
Shots disappear, and reaction, which terminates to be cooled to room temperature, is precipitated a large amount of solids, stand, filter, filter residue through dehydrated alcohol washing (3ml × 3),
3- [1- (3- chlorophenylimino) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one is obtained after being dried in vacuo at 80 DEG C, it is high
It is 98.9% that effect liquid phase chromatogram, which measures its purity, calculated yield 80%.3- chloroaniline and dehydroactic acid are directly added into filtrate
After reused.
3- [1- (3- chlorophenylimino) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one: white solid；
M.p.116~118 DEG C；IR (KBr) ν: 3427,3061,2644,1703,1651,1564,1462,1383,1068,996,837,
792cm-1；1H NMR (300MHz, CDCl3): δ=2.13 (s, 3H, CH3), 2.56 (s, 3H, CH3), 5.75 (s, 1H, CH),
7.04 (d, J=7.5Hz, 1H, ArH), 7.18 (s, 1H, ArH), 7.31~7.38 (m, 2H, ArH), 15.90 (s, 1H, OH)
Embodiment 6
To the 50ml single port with condenser pipe and stirring magneton for the isopropanol water solution for filling 9ml volume by volume concentration 52%
1,3,6- naphthalene trisulfonic acid catalyst of 1.1mmol 4- fluoroaniline, 1.0mmol dehydroactic acid and 0.06mmol, room temperature are added in bottle
Lower magnetic agitation mixes.It has been heated to reflux to generate, has maintained the reflux for a length of 81min when reaction, TLC (thin plate chromatography) detection is former
Shots disappear, and reaction, which terminates to be cooled to room temperature, is precipitated a large amount of solids, stand, filter, filter residue through dehydrated alcohol washing (3ml × 3),
3- [1- (4- fluorophenyl imino group) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one is obtained after being dried in vacuo at 80 DEG C, it is high
It is 98.7% that effect liquid phase chromatogram, which measures its purity, calculated yield 76%.4- fluoroaniline and dehydroactic acid are directly added into filtrate
After reused.
3- [1- (4- fluorophenyl imino group) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one: white solid；
M.p.146~148 DEG C；IR (KBr) ν: 3425,3083,2929,1728,1664,1579,1481,1333,1067,1005,
836,774cm-1；1H NMR (300MHz, CDCl3): δ=2.14 (s, 3H, CH3), 2.55 (s, 3H, CH3), 5.76 (s, 1H,
CH), 7.17 (d, J=6.5Hz, 4H, ArH), 15.73 (s, 1H, OH)
Embodiment 7
To the 50ml single port with condenser pipe and stirring magneton for the isopropanol water solution for filling 9ml volume by volume concentration 52%
1,3, the 6- naphthalene trisulfonic acids catalysis of 1.0mmol 4- methyl -3- chloroaniline, 1.0mmol dehydroactic acid and 0.05mmol are added in bottle
Agent, magnetic agitation mixes at room temperature.It has been heated to reflux to generate, has maintained the reflux for a length of 59min, TLC (thin plate chromatography) when reaction
Detection, raw material point disappear, and reaction, which terminates to be cooled to room temperature, is precipitated a large amount of solids, stand, filter, filter residue is washed through dehydrated alcohol
(3ml × 3) obtain 3- [1- (3- chlorine 4- methylphenylimino) ethyl] -4- hydroxyl -6- methyl-after being dried in vacuo at 80 DEG C
2H- pyran-2-one, it is 98.4% that high performance liquid chromatography, which measures its purity, calculated yield 84%.4- first is directly added into filtrate
It is reused after base -3- chloroaniline and dehydroactic acid.
3- [1- (3- chlorine 4- methylphenylimino) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one: light yellow solid
Body；M.p.167~169 DEG C；IR (KBr) ν: 3437,3078,2981,1704,1652,1559,1468,1356,1063,950,
832,763cm-1；1H NMR (300MHz, CDCl3): δ=2.12 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.52 (s, 3H,
CH3), 5.70 (s, 1H, CH), 6.93 (d, J=8.0Hz, 1H, ArH), 7.13 (s, 1H, ArH), 7.24 (d, J=8.0Hz, 1H,
ArH), 15.74 (s, 1H, OH)
Embodiment 8
To the 50ml single port with condenser pipe and stirring magneton for the isopropanol water solution for filling 9ml volume by volume concentration 54%
1,3,6- naphthalene trisulfonic acid catalyst of 1.1mmol 4- methylaniline, 1.0mmol dehydroactic acid and 0.06mmol, room are added in bottle
The lower magnetic agitation of temperature mixes.It being heated to reflux to generate, has maintained the reflux for a length of 66min when reaction, TLC (thin plate chromatography) is detected,
Raw material point disappears, and reaction, which terminates to be cooled to room temperature, is precipitated a large amount of solids, stands, filters, filter residue wash through dehydrated alcohol (3ml ×
3) 3- [1- (4- methylphenylimino) ethyl] -4- hydroxyl -6- methyl -2H- pyrans -2- is obtained after, being dried in vacuo at 80 DEG C
Ketone, it is 99.0% that high performance liquid chromatography, which measures its purity, calculated yield 81%.It is directly added into 4- methylaniline in filtrate and takes off
It is reused after hydroacetic acid.
3- [1- (4- methylphenylimino) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one: white solid；
M.p.154~156 DEG C；IR (KBr) ν: 3402,3038,2932,1704,1655,1569,1477,1386,1071,950,841,
768cm-1；1H NMR (300MHz, CDCl3): δ=2.15 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.56 (s, 3H, CH3),
5.71 (s, 1H, CH), 7.01 (d, J=6.2Hz, 2H, ArH), 7.20 (d, J=6.1Hz, 2H, ArH), 15.63 (s, 1H, OH)
Embodiment 9
The 50ml with condenser pipe and stirring magneton to the isopropanol water solution for filling 10ml volume by volume concentration 55% is mono-
1,3, the 6- naphthalene trisulfonic acids catalysis of the 4- aminoanisole, 1.0mmol dehydroactic acid and 0.07mmol of 1.2mmol is added in mouth bottle
Agent, magnetic agitation mixes at room temperature.It has been heated to reflux to generate, has maintained the reflux for a length of 87min, TLC (thin plate chromatography) when reaction
Detection, raw material point disappear, and reaction, which terminates to be cooled to room temperature, is precipitated a large amount of solids, stand, filter, filter residue is washed through dehydrated alcohol
(3ml × 3) obtain 3- [1- (4- methoxyphenyl imino group) ethyl] -4- hydroxyl -6- methyl -2H- after being dried in vacuo at 80 DEG C
Pyran-2-one, it is 98.8% that high performance liquid chromatography, which measures its purity, calculated yield 72%.4- methoxy is directly added into filtrate
It is reused after base aniline and dehydroactic acid.
4- [1- (4- methoxyphenyl imino group) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one: yellow solid；
M.p.180~182 DEG C；IR (KBr) ν: 3437,3085,2927,1692,1615,1561,1474,1328,1066,942,830,
712cm-1；1H NMR (300MHz, CDCl3): δ=2.17 (s, 3H, CH3), 2.54 (s, 3H, CH3), 3.81 (s, 3H, CH3),
5.74 (s, 1H, CH), 6.93 (d, J=8.6Hz, 2H, ArH), 7.08 (d, J=8.6Hz, 2H, ArH), 15.56 (s, 1H, OH)
Embodiment 10
After reaction, filtrate is without any processing according to the additional amount and reaction condition of raw material in embodiment 1 for embodiment 1
Next batch preparation reaction is carried out, is repeated in this way 6 times, product 3- [1- (4- nitrobenzophenone imino group) ethyl] -4- hydroxyl -
The liquid chromatogram purity of 6- methyl -2H- pyran-2-one is all larger than 98.5%, and Fig. 1 is shown in calculated yield variation.
Embodiment 11
After reaction, filtrate is without any processing according to the additional amount and reaction condition of raw material in embodiment 2 for embodiment 2
Next batch preparation reaction is carried out, is repeated in this way 5 times, product 3- [1- (benzyl imino group) ethyl] -4- hydroxyl -6- first
The liquid chromatogram purity of base -2H- pyran-2-one is all larger than 98.2%, and Fig. 2 is shown in calculated yield variation.
Embodiment 12
After reaction, filtrate is without any processing according to the additional amount and reaction condition of raw material in embodiment 7 for embodiment 7
Next batch preparation reaction is carried out, is repeated in this way 6 times, product 3- [1- (3- chlorine 4- methylphenylimino) ethyl] -4-
The liquid chromatogram purity of hydroxyl -6- methyl -2H- pyran-2-one is all larger than 98.0%, and Fig. 3 is shown in calculated yield variation.
Comparative example 1
It is added into the 50ml single port bottle with condenser pipe and stirring magneton for the analytically pure isopropanol for filling 9ml
1,3,6- naphthalene trisulfonic acid catalyst of 1.2mmol4- nitroaniline, 1.0mmol dehydroactic acid and 0.07mmol, at room temperature magnetic force
It stirs and evenly mixs.It has been heated to reflux to generate, has maintained the reflux for a length of 91min when reaction, TLC (thin plate chromatography) detection is sent out through detection
Existing, the raw material point of synthetic product still has.Reaction terminates do not have solid precipitation but after being cooled to room temperature.Then, hair is probed into
Existing, product has been dissolved in reaction solution (filtrate), and carries out detection discovery 3- [1- to reaction solution using high performance liquid chromatography
(4- nitrobenzophenone imino group) ethyl] content of -4- hydroxyl -6- methyl -2H- pyran-2-one is only 43.3% (external standard method), warp
Calculated yield is only 24%.
Comparative example 2
To the 50ml single port bottle with condenser pipe and stirring magneton for the ethanol water for filling 9ml volume by volume concentration 52%
Middle 1,3, the 6- naphthalene trisulfonic acid catalyst that 1.2mmol 4- nitroaniline, 1.0mmol dehydroactic acid and 0.07mmol is added, room temperature
Lower magnetic agitation mixes.It has been heated to reflux to generate, has maintained the reflux for a length of 91min when reaction, TLC (thin plate chromatography) detection is former
Shots do not completely disappear, and reaction terminates to be cooled to room temperature that a small amount of solid is only precipitated, and stands, and filter, filter residue is through dehydrated alcohol
Washing (3ml × 3) obtains 3- [1- (4- nitrobenzophenone imino group) ethyl] -4- hydroxyl -6- methyl-after being dried in vacuo at 80 DEG C
2H- pyran-2-one, it is 92.4% that high performance liquid chromatography, which measures its purity, and calculated yield is only 38%.
Comparative example 3
To the 50ml single port with condenser pipe and stirring magneton for the isopropanol water solution for filling 9ml volume by volume concentration 26%
1,3,6- naphthalene trisulfonic acid catalyst of 1.2mmol 4- nitroaniline, 1.0mmol dehydroactic acid and 0.07mmol are added in bottle, it is former
Material can not be completely dissolved, and magnetic agitation mixes at room temperature.It has been heated to reflux to generate, has maintained the reflux for a length of 91min when reaction,
TLC (thin plate chromatography) detection, raw material point do not completely disappear, and reaction terminates to be cooled to room temperature a large amount of solids, stands, and filter,
Filter residue obtains faint yellow solid after being dried in vacuo at dehydrated alcohol washing (3ml × 3), 80 DEG C, and high performance liquid chromatography measures
The content of 3- [1- (4- nitrobenzophenone imino group) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one is only 78.6% (external standard
Method), calculated yield 43%.
Comparative example 4
To the 50ml single port with condenser pipe and stirring magneton for the isopropanol water solution for filling 9ml volume by volume concentration 78%
1,3,6- naphthalene trisulfonic acid catalyst of 1.2mmol 4- nitroaniline, 1.0mmol dehydroactic acid and 0.07mmol are added in bottle, it is former
Material is completely dissolved, and magnetic agitation mixes at room temperature.It has been heated to reflux to generate, it is (thin to maintain the reflux for a length of 91min, TLC when reaction
Plate layer chromatography) it detects, raw material point does not completely disappear, and reaction terminates to be cooled to room temperature do not have solid precipitation.Reaction solution is by efficient
Liquid chromatogram measuring obtains the content of 3- [1- (4- nitrobenzophenone imino group) ethyl] -4- hydroxyl -6- methyl -2H- pyran-2-one only
For 56.9% (external standard method), calculated yield 35%.
Claims (10)
1. a kind of preparation method of high-purity medicine intermediate, the medicine intermediate is body 4- hydroxyl -6- methyl-[1- (benzene
Base imino group) ethyl] -2H- pyran-2-one derivative, it is characterised in that: using dehydroactic acid and aromatic amine as raw material, in isopropyl
It in alcohol solution, is condensed through catalyst, obtains 4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyrans -2-
Ketone derivatives.
2. the preparation method of high-purity medicine intermediate according to claim 1, it is characterised in that: the isopropanol is water-soluble
The volume by volume concentration of liquid is 46%~55%.
3. the preparation method of high-purity medicine intermediate according to claim 2, it is characterised in that: specific step is as follows:
Dehydroactic acid, aromatic amine and catalyst are added in isopropanol water solution, mixes, is heated to reflux, cooling and standings, is isolated solid
Body product is dried in vacuo to get 4- hydroxyl -6- methyl-[1- (phenylimino) ethyl] -2H- pyran-2-one derivative.
4. the preparation method of high-purity medicine intermediate according to claim 2, it is characterised in that: before vacuum drying, benefit
It is washed with dehydrated alcohol to the solid product being precipitated is stood.
5. the preparation method of high-purity medicine intermediate according to claim 2, it is characterised in that: isolate solid product
After obtain filtrate；The filtrate is recycled into use, and when reuse is directly added into raw material in filtrate and carries out next secondary response.
6. the preparation method of high-purity medicine intermediate described in any claim, feature exist according to claim 1~5
In: the catalyst is 1,3,6- naphthalene trisulfonic acids.
7. according to right want 6 described in high-purity medicine intermediate preparation method, it is characterised in that: the aromatic amine and dehydrogenation
The addition molar ratio of acetic acid is (1.0~1.2): 1.
8. the preparation method of high-purity medicine intermediate according to claim 6, it is characterised in that: described 1,3,6- naphthalenes three
The addition molar ratio of sulfonic acid and dehydroactic acid is (0.04~0.07): 1.
9. the preparation method of high-purity medicine intermediate according to claim 6, it is characterised in that: the isopropanol is water-soluble
The volume that liquid is counted using milliliter as dehydroactic acid by mM in terms of 7~10 times of amount of substance.
10. the preparation method of high-purity medicine intermediate according to claim 6, it is characterised in that: the aromatic amine is
4- nitroaniline, benzene methanamine, 4- chloroaniline, 2- chloroaniline, 3- chloroaniline, 4- fluoroaniline, 4- methyl -3- chloroaniline, 4- methyl
Any one of aniline, 4- aminoanisole.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646467A (en) * | 2002-04-02 | 2005-07-27 | 南密西西比研究基金会大学 | Process for making butenyl esters from butadiene |
| CN1683353A (en) * | 2005-03-11 | 2005-10-19 | 河南省科学院化学研究所 | New process for producing liquid methyl tetrahydro phthalic anhydride |
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2019
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646467A (en) * | 2002-04-02 | 2005-07-27 | 南密西西比研究基金会大学 | Process for making butenyl esters from butadiene |
| CN1683353A (en) * | 2005-03-11 | 2005-10-19 | 河南省科学院化学研究所 | New process for producing liquid methyl tetrahydro phthalic anhydride |
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| Title |
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| HUIYAN WANG 等: "A novel and convenient synthesis of 4-hydroxy-6-methyl-3-(1-(phenylimino)ethyl)-2H-pyran-2-one derivatives under ultrasound irradiation", 《ULTRASONICS SONOCHEMISTRY》 * |
| 李大庆 等: "超声波辐射下离子液体催化合成4-羟基-6-甲基-[1-(苯基亚氨基)乙基]-2H吡喃-2-酮衍生物", 《有机化学》 * |
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