CN110256324A - A kind of preparation method of 2- methyl -5-OHi - Google Patents
A kind of preparation method of 2- methyl -5-OHi Download PDFInfo
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- CN110256324A CN110256324A CN201910510893.7A CN201910510893A CN110256324A CN 110256324 A CN110256324 A CN 110256324A CN 201910510893 A CN201910510893 A CN 201910510893A CN 110256324 A CN110256324 A CN 110256324A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Abstract
The present invention relates to compounds process for production thereof fields, more particularly to a kind of preparation method of 2- methyl -5-OHi, it the use of 3- amino ethyl crotonate is that raw material is reacted, product purity made from preparation method in through the invention is high, catalyst and solvent can be recycled, reaction is mild, easily controllable, is suitble to industrialized production.
Description
Technical field
The present invention relates to compounds process for production thereof field more particularly to a kind of 2- methyl -5-OHi preparation methods.
Background technique
Conventional method prepares 2- methyl -5-OHi method complexity, and cost of material is high, and product yield is low, and purity is low.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the deficiencies in the prior art, a kind of 2- methyl -5- is provided
The preparation method of oxyindole.
The present invention is to be achieved by the following technical programs:
A kind of preparation method of 2- methyl -5-OHi, which comprises the following steps:
A. preparation formula B compound represented:
It is pumped into glacial acetic acid in a kettle, benzoquinone is added, stirs and is cooled to 20-25 DEG C；
3- amino ethyl crotonate, glacial acetic acid is added dropwise, maintains temperature of reaction system at 15-25 DEG C during being added dropwise, is added dropwise
After, it is stirred 2-3 hours at a temperature of 15 DEG C；
Freezing is extruded, is warmed to room temperature and is stirred overnight naturally；
Next day, TLC monitor 3- amino ethyl crotonate end of reaction, are cooled to 10-15 DEG C, filter, and are centrifuged, and washing obtains
To crude product；
Crude product and toluene are put into reaction kettle, 85 DEG C of stirrings 2-3 hours are warming up to, is cooled to 5-10 DEG C later, is filtered,
Toluene is washed, and formula B compound represented wet product is obtained；
B. preparation formula C compound represented:
Formula B compound represented wet product obtained in addition concentrated hydrochloric acid, ethyl alcohol and step a, slowly heats up in reaction flask
Reflux, separates ethyl alcohol；
100 DEG C of reactions 4-5 hours are warming up to, until TLC monitors raw material end of reaction；
10 DEG C are cooled to, PH to 5-6 is adjusted with 30% NaOH aqueous solution, interior temperature is kept to be not higher than 30 in adjustment process
℃；
5 DEG C are cooled to, filters, obtains crude product；
Dichloroethanes and crude product are added in reaction flask, flow back 2h, is cooled to 40-50 DEG C, it filters, filtrate stratification,
Organic layer adds water, active carbon, and flow back 2h, is cooled to 40-50 DEG C, filters, stratification, and concentration freezes crystallization, obtains formula C institute
The compound shown.
The beneficial effects of the present invention are:
Product purity made from preparation method in through the invention is high, and catalyst and solvent can be recycled, reaction temperature
With, it is easily controllable, it is suitble to industrialized production.
Detailed description of the invention
Fig. 1 is reaction principle figure of the invention.
Specific embodiment
In order to make those skilled in the art more fully understand technical solution of the present invention, with reference to the accompanying drawing and most
The present invention is described in further detail for good embodiment.
As shown, the present invention the following steps are included:
A. preparation formula B compound represented:
Charge ratio:
It is pumped into glacial acetic acid in 5L reaction kettle, benzoquinone is added, stirs and is cooled to 20-25 DEG C；
3- amino ethyl crotonate+100g glacial acetic acid is added dropwise, and during controlling dropwise addition, reaction system
Temperature is at 15-25 DEG C；
Be added dropwise, 15 DEG C stirring 2-3 hours；
Freezing is extruded, is warmed to room temperature and is stirred overnight naturally；
Next day TLC (PE:AcOEt=1:1) 3- amino ethyl crotonate end of reaction is cooled to 10-15 DEG C, filters, from
The heart, washing.Obtain formula B compound represented crude product 900g, HPLC product 70.5% (benzoquinone 26.9%)；
4000g toluene is added in 5L reaction kettle, formula B compound represented crude product is added, heats up 85 DEG C and stirs 2-3 hours,
It is cooled to 5-10 DEG C, is filtered, toluene is washed, and 600g formula B compound represented crude product wet product, HPLC 94.2% are obtained.
B. preparation formula C compound represented:
Charge ratio:
Concentrated hydrochloric acid is added in 10L reaction flask, ethyl alcohol, intermediate is added, slow temperature rising reflux separates ethyl alcohol；
After ethyl alcohol separates, 100 DEG C of reactions are warming up to, until TLC raw material fully reacting after 4-5 hours；
10 DEG C are cooled to hereinafter, adjusting pH=5-6 with 30%NaOH aqueous solution, and interior temperature in adjustment process is kept to be not higher than
30℃；
Adjusting finishes, and is cooled to 5 DEG C or so, filters, obtains formula C compound represented wet product 800g；
5000g dichloroethanes is added in 5L reaction flask, formula C compound represented wet product is added, flow back 2h, is cooled to 40-
It 50 DEG C, filters, filtrate purification layering, organic layer adds 1000g water, and 50g active carbon, flow back 2h, is cooled to 40-50 DEG C, filters, essence
System layering；Organic layer adds 500g water, and 200g active carbon, flow back 2h, is cooled to 40-50 DEG C, filters, purification layering；
When dichloroethanes merging is concentrated into 1L or so, freezing crystallization obtains 125g formula C compound represented, HPLC
99.05%, mother liquor continues to be concentrated into 300g, and freezing crystallization obtains 10g formula C compound represented, and HPLC 99.1% adds up to
135g。
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (1)
1. a kind of preparation method of 2- methyl -5-OHi, which comprises the following steps:
A. preparation formula B compound represented:
It is pumped into glacial acetic acid in a kettle, benzoquinone is added, stirs and is cooled to 20-25 DEG C；
3- amino ethyl crotonate, glacial acetic acid is added dropwise, maintains temperature of reaction system at 15-25 DEG C during being added dropwise, is added dropwise
Afterwards, it is stirred 2-3 hours at a temperature of 15 DEG C；
Freezing is extruded, is warmed to room temperature and is stirred overnight naturally；
Next day, TLC monitor 3- amino ethyl crotonate end of reaction, are cooled to 10-15 DEG C, filter, and are centrifuged, washing, obtain thick
Product；
Crude product and toluene are put into reaction kettle, 85 DEG C of stirrings 2-3 hours are warming up to, is cooled to 5-10 DEG C later, is filtered, toluene
It washes, obtains formula B compound represented wet product；
B. preparation formula C compound represented:
The formula B compound represented wet product obtained in addition concentrated hydrochloric acid, ethyl alcohol and step a in reaction flask, slow temperature rising reflux,
Separate ethyl alcohol；
100 DEG C of reactions 4-5 hours are warming up to, until TLC monitors raw material end of reaction；
10 DEG C are cooled to, PH to 5-6 is adjusted with 30% NaOH aqueous solution, interior temperature is kept to be not higher than 30 DEG C in adjustment process；
5 DEG C are cooled to, filters, obtains crude product；
Dichloroethanes and crude product are added in reaction flask, flow back 2h, is cooled to 40-50 DEG C, filters, and filtrate stratification is organic
Layer plus water, active carbon, flow back 2h, is cooled to 40-50 DEG C, filters, stratification, and concentration freezes crystallization, obtains shown in formula C
Compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910510893.7A CN110256324A (en) | 2019-06-13 | 2019-06-13 | A kind of preparation method of 2- methyl -5-OHi |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910510893.7A CN110256324A (en) | 2019-06-13 | 2019-06-13 | A kind of preparation method of 2- methyl -5-OHi |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110256324A true CN110256324A (en) | 2019-09-20 |
Family
ID=67917981
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910510893.7A Pending CN110256324A (en) | 2019-06-13 | 2019-06-13 | A kind of preparation method of 2- methyl -5-OHi |
Country Status (1)
| Country | Link |
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| CN (1) | CN110256324A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1344270A (en) * | 1999-01-13 | 2002-04-10 | 千年药品公司 | Functionalized heterocycles as chemokine receptor modulators |
-
2019
- 2019-06-13 CN CN201910510893.7A patent/CN110256324A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1344270A (en) * | 1999-01-13 | 2002-04-10 | 千年药品公司 | Functionalized heterocycles as chemokine receptor modulators |
Non-Patent Citations (5)
| Title |
|---|
| GEORGE R. ALLEN 等: "The Behavior of 2-Carbomethoxy-and 2-Acetyl-l,4-benzoquinone in the Nenitzescu Indole Synthesis", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| JAMES B. PATRICK等: "STUDIES ON THE NENITZESCU SYNTHESIS OF 5-HYDROXYINDOLES", 《TETRAHEDRON LETTERS》 * |
| SUSAN LEPRI 等: "Indole Based Weapons to Fight Antibiotic Resistance: A Structure−Activity Relationship Study", 《J. MED. CHEM.》 * |
| YUN-SHENG HUANG等: "Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole", 《RES CHEM INTERMED》 * |
| 王钝 等: "盐酸阿比朵尔的合成", 《中国医药工业杂志》 * |
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| PB01 | Publication | ||
| PB01 | Publication | ||
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Application publication date: 20190920 |