CN108929273A - A kind of preparation method of imidazole ethyl vanillic acid ether sodium salt - Google Patents
A kind of preparation method of imidazole ethyl vanillic acid ether sodium salt Download PDFInfo
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- CN108929273A CN108929273A CN201810675480.XA CN201810675480A CN108929273A CN 108929273 A CN108929273 A CN 108929273A CN 201810675480 A CN201810675480 A CN 201810675480A CN 108929273 A CN108929273 A CN 108929273A
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- VUQUOGPMUUJORT-UHFFFAOYSA-N Cc(cc1)ccc1S(OC)(=O)=O Chemical compound Cc(cc1)ccc1S(OC)(=O)=O VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
Abstract
The present invention relates to field of medicinal chemistry, and in particular to a kind of preparation method of imidazole ethyl vanillic acid ether sodium salt.It is characterized in that: using imidazoles for starting material, condensation reaction is carried out under normal condition after highly basic activates, can high yield acquisition midbody compound；It is reacted under base catalysis with vanillic acid methyl esters again；Then imidazole ethyl vanillic acid ether sodium salt can be prepared by salt by sodium hydroxide hydrolysis.Preparation method reaction condition of the invention is mild, and post-processing is easy, the yield of condensation step, the reaction yield being apparently higher than in existing literature at the yield of ether step；Means of purification without additional post chromatography etc. simultaneously, can be such that the preparation cost of product is greatly reduced.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of preparation method of imidazole ethyl vanillic acid ether sodium salt.
Background technique
Imidazole ethyl vanillic acid ether sodium salt is a kind of drug with antiplatelet aggregative activity, can be used for treating thrombotic
The heart, cerebral ischemia or infarct.
Chinese patent CN 101851209A discloses a kind of preparation method of imidazole ethyl vanillic acid ether, with vanillic acid first
Ester is starting material, is reacted with 1,2- Bromofume at ether, is then condensed again with imidazoles, by after basic hydrolysis with hydrochloric acid
The hydrochloride of imidazole ethyl vanillic acid ether is made at salt.Specific synthetic route is as follows:
The technique has used a kind of more special and expensive methyl tributanoximo silane to make during reacting at ether
For catalyst, while because of reactant 1, the activity of two bromine atoms is identical in 2- Bromofume, causes in reaction process very
Difficult to control to generate mono-substituted title intermediate, impurity is more, and post-processing need to use column chromatographic purifying, and yield is only 59%；Contracting
During closing reaction, use sodium hydride for alkali, reaction temperature is 95 DEG C, and condition is excessively violent, and impurity is caused to increase, and is post-processed
It is needed in the process using column chromatographic purifying, yield is only 55%.It will lead to simultaneously using above-mentioned process route most main in entire technique
Midbody compound (II) need to could be made by the reaction of two low yielding steps in the raw material vanillic acid methyl esters wanted, mole receipts
Rate is only 32.45%, and unit consumption is larger, also results in product cost and obviously rises.
Use the hydrochloride of imidazole ethyl vanillic acid ether as target product in above-mentioned patent simultaneously, in subsequent middle need
The sodium salt that imidazole ethyl vanillic acid ether is generated after sodium hydroxide neutralizes is administered, complex, therefore it is directly prepared
It is more conducive to be administered for sodium salt.
Summary of the invention
The invention discloses a kind of preparation methods for preparing imidazole ethyl vanillic acid ether sodium salt, use imidazoles former for starting
Material, condensation reaction is carried out under normal condition after highly basic activates, can high yield acquisition midbody compound (III)；Again with perfume (or spice)
Methyl oxalate reacts under base catalysis can be prepared by midbody compound (II)；Then it can be made by sodium hydroxide hydrolysis at salt
It obtains compound (I).Specific reaction is as follows:
Wherein R=-Br ,-OSO2CH3Or
R preferably-Br.
Wherein starting material imidazoles preferably first carries out condensation reaction with (IV) again after highly basic activates.
The preferred sodium hydride of highly basic, potassium tert-butoxide, sodium methoxide, potassium hydroxide or sodium hydroxide.
At ether react in midbody compound (III) with vanillic acid methyl esters preferably react under alkaline condition be made intermediate
Compound (II).The preferred potassium carbonate of alkali or cesium carbonate.
Preferred preparation method, comprising: imidazoles is added in solvent and be dissolved, add after highly basic dehydrogenation be added (IV) into
Row condensation reaction is evaporated under reduced pressure removes solvent after completion of the reaction, and ethyl acetate and water is added, and extraction, washing divide and take organic layer dry
Vacuum distillation removes ethyl acetate and obtains midbody compound (III) after dry；Dimethylformamide dissolution is added, adds vanilla
Sour methyl esters and alkali reaction, are filtered to remove insoluble matter after completion of the reaction, and vacuum distillation removes dimethylformamide, and ethyl acetate is added
With water extraction, washing, vacuum distillation after taking organic layer dry is divided to remove ethyl acetate, and is beaten purifying by methyl tertiary butyl ether(MTBE)
After obtain midbody compound (II)；Alcohol and water dissolution is added, sodium hydroxide reaction is then added, is evaporated under reduced pressure after completion of the reaction
Alcohol is removed, acetone crystallization is added and obtains target compound (I).
Wherein dissolve the preferred dimethylformamide of solvent or acetonitrile of imidazoles.
The preferred methanol of alcohol, ethyl alcohol or isopropanol.
The temperature of condensation reaction of the present invention is preferably 50~80 DEG C.
Preparation method of the invention, reaction condition is mild, and post-processing is easy, and the yield of condensation step is about 70%, at ether
The yield of step is about 80%, hence it is evident that higher than the reaction yield in existing literature；Purifying hand without additional post chromatography etc. simultaneously
Section, the molar yield for preparing the process primary raw material vanillic acid methyl esters of midbody compound (II) can be improved by 32.45% to about
80%, while the use of methyl tributanoximo silane costly is also avoided, the preparation cost of product can be made substantially to drop
It is low.
Specific embodiment
Embodiment 1
Imidazoles (6.8g, 100mmol) is added in 20ml anhydrous acetonitrile (or dimethylformamide), ice water after stirring and dissolving
Bath is cooled to 0~10 DEG C, and 60% sodium hydride (4.2g, 105mmol) is added portionwise under nitrogen protection, finishes insulation reaction for 24 hours.
Then the chloro- 2- bromoethane (35.8g, 250mmol) of 1- is added, is warming up to 50~80 DEG C after completion of the reaction.Vacuum distillation removes second
Nitrile (or dimethylformamide), is added water 20ml, and the extracting and washing of ethyl acetate 50ml × 3 merges organic layer and saturated common salt is added
Water 20ml washing divides and takes organic layer that the drying of 10g anhydrous sodium sulfate is added, and removes acetic acid second using reduced pressure after filter, washing
Ester and the chloro- 2- bromoethane of excessive 1- obtain midbody compound (I) 9.8g, yield 75.0%, purity 97.6%.
Embodiment 2
The chloro- 2- bromoethane of 1- in above-described embodiment 1 is changed to 2- chloroethyl methanesulfonates (39.6g, 250mmol),
Yield 80.7%, purity 98.5%.
Embodiment 3
By the chloro- 2- bromoethane of 1- in above-described embodiment 1 be changed to 2- chloroethyl p-methyl benzenesulfonic acid ester (250mmol,
58.7g), yield 66.3%, purity 98.2%.
Embodiment 4
Imidazoles (6.8g, 100mmol) is added in 20ml anhydrous methanol (or tert-butyl alcohol), sodium methoxide is added after stirring and dissolving
Or potassium tert-butoxide (100mmol, respectively 5.4g, 11.2g), it finishes and is warming up to 50~80 DEG C of 5~6h of reaction, recycling is concentrated under reduced pressure
Methanol or the tert-butyl alcohol are to dry.20ml anhydrous acetonitrile (or dimethylformamide) dissolution is added, the chloro- 2- bromoethane of 1- is then added
(35.8g, 250mmol) is finished and is warming up to 50~80 DEG C after completion of the reaction.Vacuum distillation removing acetonitrile (or dimethyl formyl
Amine), water 20ml is added, the extracting and washing of ethyl acetate 50ml × 3 merges organic layer and saturated salt solution 20ml washing is added, divides and take
The drying of 10g anhydrous sodium sulfate is added in organic layer, removes ethyl acetate using reduced pressure after filter, washing and excessive 1- is chloro-
2- bromoethane obtains midbody compound (I) 9.3g, yield 71.2%, purity 96.3%.
Embodiment 5
The chloro- 2- bromoethane of 1- in above-described embodiment 4 is changed to 2- chloroethyl methanesulfonates (39.6g, 250mmol),
Yield 72.7%, purity 97.4%.
Embodiment 6
By the chloro- 2- bromoethane of 1- in above-described embodiment 4 be changed to 2- chloroethyl p-methyl benzenesulfonic acid ester (250mmol,
58.7g), yield 67.1%, purity 97.5%.
Embodiment 7
Imidazoles (6.8g, 100mmol) is added to aqueous solution (100mmol, the difference of 35% sodium hydroxide or potassium hydroxide
For in 11.4g, 16.0g), stirring is warming up to back flow reaction 30min, recycle-water is concentrated under reduced pressure to dry, and further pass through drying
Remove remaining a small amount of water.20ml anhydrous acetonitrile (or dimethylformamide) dissolution is added, adds the chloro- 2- bromoethane of 1-
(35.8g, 250mmol) is finished and is warming up to 50~80 DEG C after completion of the reaction.Vacuum distillation removing acetonitrile (or dimethyl formyl
Amine), water 20ml is added, the extracting and washing of ethyl acetate 50ml × 3 merges organic layer and saturated salt solution 20ml washing is added, divides and take
The drying of 10g anhydrous sodium sulfate is added in organic layer, removes ethyl acetate using reduced pressure after filter, washing and excessive 1- is chloro-
2- bromoethane obtains midbody compound (I) 9.7g, yield 74.3%, purity 98.1%.
Embodiment 8
The chloro- 2- bromoethane of 1- in above-described embodiment 7 is changed to 2- chloroethyl methanesulfonates (39.6g, 250mmol),
Yield 77.1%, purity 98.4%.
Embodiment 9
By the chloro- 2- bromoethane of 1- in above-described embodiment 7 be changed to 2- chloroethyl p-methyl benzenesulfonic acid ester (250mmol,
58.7g), yield 68.0%, purity 98.8%.
Embodiment 10
By midbody compound (I) (19.5g, 0.15mol are made according to 7 method of above-described embodiment), vanillic acid methyl esters
(18.2g, 0.1mol) is added in 80ml dimethylformamide after stirring and dissolving, is added potassium carbonate (27.6g, 0.2mol), heating
After completion of the reaction to 50~80 DEG C.It is down to room temperature, is filtered to remove insoluble matter, residual filtrate vacuum distillation removes dimethyl formyl
Amine, is added water 20ml, and the extracting and washing of ethyl acetate 100ml × 3 merges organic layer and saturated salt solution 20ml washing is added, divides and take
The drying of 20g anhydrous sodium sulfate is added in organic layer, removes ethyl acetate using being concentrated under reduced pressure after filter, washing.First is added in residue
Be beaten after purification under base tertbutyl ether 80ml reflux temperature, be down to room temperature, be filtered, washed, dry after obtain midbody compound
(II) 21.8g, yield 79.0%, purity 99.1%.
Embodiment 11
Potassium carbonate in above-described embodiment 10 is changed to cesium carbonate, yield 82.2%, purity 98.7%.
Embodiment 12
By midbody compound obtained in above-described embodiment 10 (II) (13.8g, 50mmol), sodium hydroxide (4.0g,
100mol) it is added in methanol (or ethyl alcohol, isopropanol) aqueous solution (alcohol 75ml, water 25ml), after fully reacting is stirred at room temperature, reaction
Liquid vacuum distillation removes alcohol, and acetone 250ml is then added, crystallization is stirred at room temperature, is filtered, washed, target is obtained after filtration cakes torrefaction
Compound (I) 11.5g, yield 81.0%, purity 99.3%.1H-NMR(D2O, 500MHz) δ: 7.70 (s, 1H, Imidazole
H), 7.47 (s, 1H, ArH), 7.45 (d, 1H, ArH), 7.18 (s, 1H, Imidazole H), 6.97 (s, 1H, Imidazole
H), 6.92 (d, 1H, ArH), 4.39 (s, 4H, CH2-CH2), 3.82 (s, 3H, OCH3)；ESI-Ms(+C) m/z:263.0 (M-Na+
2H)。
Claims (10)
1. a kind of preparation method of the imidazole ethyl vanillic acid ether sodium salt of formula (I), comprising:
2. the preparation method of claim 1, wherein R is Br.
3. the preparation method of claim 1, wherein starting material imidazoles first carries out condensation reaction with (IV) again after highly basic activates.
4. the preparation method of claim 3, wherein highly basic is sodium hydride, potassium tert-butoxide, sodium methoxide, potassium hydroxide or hydroxide
Sodium.
5. the preparation method of claim 1, wherein at ether react in midbody compound (III) and vanillic acid methyl esters be in alkalinity
Under the conditions of react be made midbody compound (II).
6. the preparation method of claim 5, wherein alkali is potassium carbonate or cesium carbonate.
7. the preparation method of claim 1, comprising: imidazoles is added in solvent and dissolves, (IV) is added after adding highly basic dehydrogenation
Condensation reaction is carried out, is evaporated under reduced pressure removes solvent after completion of the reaction, ethyl acetate and water is added, extraction, washing divide and take organic layer
Vacuum distillation removes ethyl acetate and obtains midbody compound (III) after drying；Dimethylformamide dissolution is added, adds perfume (or spice)
Methyl oxalate and alkali reaction, are filtered to remove insoluble matter after completion of the reaction, and vacuum distillation removes dimethylformamide, and acetic acid second is added
Ester and water extraction, washing divide vacuum distillation after taking organic layer dry to remove ethyl acetate, and pure by methyl tertiary butyl ether(MTBE) mashing
Midbody compound (II) is obtained after change；Alcohol and water dissolution is added, sodium hydroxide reaction is then added, decompression is steamed after completion of the reaction
Alcohol is removed in distillation, adds acetone crystallization and obtains target compound (I).
8. the preparation method of claim 7, wherein the solvent of dissolution imidazoles is dimethylformamide or acetonitrile.
9. the preparation method of claim 7, wherein alcohol is methanol, ethyl alcohol or isopropanol.
10. the preparation method of any one of claims 1 to 9, wherein the temperature of condensation reaction is 50~80 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114736161A (en) * | 2022-06-13 | 2022-07-12 | 南京医工医药技术有限公司 | Imidazolidinyl vanillic acid ether derivatives and their use |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101481359A (en) * | 1999-04-15 | 2009-07-15 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| CN101851209A (en) * | 2010-06-21 | 2010-10-06 | 合肥医工医药有限公司 | Imidazole ethyl vanillic acid ether, preparation method and medicinal application thereof |
| CN102008459A (en) * | 2006-03-23 | 2011-04-13 | 生物区欧洲有限公司 | Antibacterial agents |
| CN104736530A (en) * | 2012-08-23 | 2015-06-24 | 艾丽奥斯生物制药有限公司 | Compounds for the treatment of paramoxyvirus viral infections |
-
2018
- 2018-06-27 CN CN201810675480.XA patent/CN108929273A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101481359A (en) * | 1999-04-15 | 2009-07-15 | 布里斯托尔-迈尔斯斯奎布公司 | Cyclic protein tyrosine kinase inhibitors |
| CN102008459A (en) * | 2006-03-23 | 2011-04-13 | 生物区欧洲有限公司 | Antibacterial agents |
| CN101851209A (en) * | 2010-06-21 | 2010-10-06 | 合肥医工医药有限公司 | Imidazole ethyl vanillic acid ether, preparation method and medicinal application thereof |
| CN104736530A (en) * | 2012-08-23 | 2015-06-24 | 艾丽奥斯生物制药有限公司 | Compounds for the treatment of paramoxyvirus viral infections |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114736161A (en) * | 2022-06-13 | 2022-07-12 | 南京医工医药技术有限公司 | Imidazolidinyl vanillic acid ether derivatives and their use |
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