CN110372730A - A kind of preparation method of 2- methylthiophene simultaneously [2,3-d] thiazole - Google Patents
A kind of preparation method of 2- methylthiophene simultaneously [2,3-d] thiazole Download PDFInfo
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- CN110372730A CN110372730A CN201910510910.7A CN201910510910A CN110372730A CN 110372730 A CN110372730 A CN 110372730A CN 201910510910 A CN201910510910 A CN 201910510910A CN 110372730 A CN110372730 A CN 110372730A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
The present invention relates to compounds process for production thereof fields, more particularly to a kind of 2- methylthiophene simultaneously [2,3-d] thiazole preparation method, it is reacted using compound shown in formula A as raw material, product purity made from preparation method in through the invention is high, and catalyst and solvent can be recycled, and reaction is mild, it is easily controllable, it is suitble to industrialized production.
Description
Technical field
The present invention relates to the systems of compounds process for production thereof field more particularly to a kind of 2- methylthiophene simultaneously [2,3-d] thiazole
Preparation Method.
Background technique
The method that traditional handicraft prepares 2- methylthiophene simultaneously [2,3-d] thiazole is complicated, at high cost, and it is low to prepare product yield.
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- methylthiophene is provided
And the preparation method of [2,3-d] thiazole
The present invention is to be achieved by the following technical programs:
A kind of preparation method of 2- methylthiophene simultaneously [2,3-d] thiazole, which comprises the following steps:
A. compound shown in preparation formula S-22A:
Compound and aceticanhydride shown in formula A are added in reaction flask, stirring is cooled to 15 DEG C, and concentrated nitric acid, 15 DEG C of temperature are added dropwise
Lower heat preservation 1 hour, sampling carry out TLC to monitoring raw material end of reaction, add water and stir 1 hour, suction filtration obtains crude product；
Crude product is dissolved in ethyl acetate, anhydrous sodium sulfate dries, filters, and organic phase is concentrated under reduced pressure into a small amount of solvent, takes advantage of
Thermal conductivity enters in petroleum ether, is cooled to 20 DEG C, filtering dries to obtain compound shown in formula S-22A；
B. compound shown in preparation formula S-22B:
Water, sulphur and vulcanized sodium are added in reaction flask, is heated to 75 DEG C and stirs 3 hours, obtain mixed solution；
Compound shown in methanol and formula S-22A is added in a kettle, is heated to 60 DEG C, mixed solution is added dropwise, drips
It flows back 3 hours after finishing, control is cooled to 20 DEG C, centrifugation obtains chemical combination shown in formula S-22B to monitoring raw material end of reaction in sampling
Object；
C. compound shown in preparation formula S-22C:
Compound and aceticanhydride shown in acetic acid, formula S-22B are added in a kettle, is heated with stirring to 90 DEG C, iron powder is added,
Insulation reaction 10 hours at a temperature of 100 DEG C, sampling HPLC detection are cooled to 60 DEG C up to raw material end of reaction, add water, stirring 1
Hour, 20 degrees Celsius of centrifugations are cooled to, crude product is obtained；
THF and crude product are added in a kettle, is heated to reflux 2 hours, filters while hot, second is added after being concentrated and dried in filtrate
Solid is precipitated in alcohol, freezing, filters drying, and solid is precipitated in freezing, filters drying and obtains the first fine work of compound shown in formula S-22C；
The first fine work of compound shown in addition DMF, atlapulgite and formula S-22C in a kettle is heated to 50 DEG C, heat preservation
Stirring 30 minutes filters, and filtrate is poured into water, and solid is precipitated, and filters drying, obtains compound shown in formula S-22C；
D. compound shown in preparation formula S-22:
Compound, acetic acid and p-methyl benzenesulfonic acid shown in formula S-22C are added in reaction flask, is heated with stirring to 105 DEG C, heat preservation
3 hours, until TLC monitors raw material end of reaction, 60 DEG C are cooled to, water is added, extracted 3 times using t-butyl methyl ether, organic layer is used
In 25% sodium hydroxide solution and acetic acid, organic layer anhydrous sodium sulfate drying are concentrated to get crude product；
Crude product rectifying is obtained into compound shown in formula S-22.
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 includes the following steps
A. S-22A is prepared
Compound and 60kg aceticanhydride shown in formula A, stirring are added in 100L reaction flask, frozen cooling starts to drip to 15 DEG C
Add 10.7kg concentrated nitric acid, nitric acid temperature is added dropwise in the present embodiment should not be too low, is kept for 20 DEG C or so, drips off heat preservation 1 hour, sampling
TLC (PE:EA=6:1), raw material has reacted, and is put into 300L water, stirs 1 hour, filters to obtain wet product: 19kg.
Wet product is dissolved in 40kg ethyl acetate, anhydrous sodium sulfate dries, filters, and organic phase is concentrated under reduced pressure into a small amount of molten
Agent is poured into while hot in 40L petroleum ether, is cooled to 20 DEG C, filtering is dried: compound shown in 8.4kg formula S-22A, HPLC:
99%.
B. S-22B is prepared
4.8kg water, 765g sulphur and 5.74kg vulcanized sodium are added in 10L reaction flask, is heated to 75 DEG C and stirs 3 hours,
Solution M is made
Compound shown in 27kg methanol and 8.4kg formula S-22A is added in 100L reaction kettle, is heated to 60 DEG C, starts to drip
Solubilization liquid M drips off reflux 3 hours, controls in sampling, raw material has reacted, and is cooled to 20 DEG C, is centrifuged: 6kg formula S-22B shownization
Close object.
C. S-22C is prepared
44kg acetic acid, compound shown in 6kg formula S-22B and 24kg aceticanhydride are added in 100L reaction kettle, is heated with stirring to
90 DEG C, 11.2kg iron powder is added portionwise, iron powder will be slowly added in batches, otherwise react acutely easy slug, and it is anti-to add 100 DEG C of heat preservations
It answers 10 hours, sampling HPLC detection, raw material has reacted, and is cooled to 60 DEG C, adds water 100kg, stirs 1 hour, and 20 DEG C start to be centrifuged,
Obtain crude compound shown in formula S-22C: 10.6kg；
S-22C purification: crude compound shown in 80kgTHF and 10.6kg formula S-22 is added in a kettle, is heated to reflux 2
Hour, it filters while hot, after filtrate concentration is dry plus solid is precipitated in 2kg ethyl alcohol, freezing, filters drying, filter cake obtains 9kg formula S-22C institute
Show the first fine work of compound；
Compound shown in addition 27kg DMF in a kettle, 1.1327kg atlapulgite and 9kg formula S-22C is smart for the first time
Product are heated to 50 DEG C, insulated and stirred 30 minutes, filter, and filtrate is poured into 30kg water, and solid is precipitated, and filters drying: 1.39kg formula
Compound shown in S-22C.
D. S-22 is prepared
Compound, 8.5kg acetic acid and 542g p-methyl benzenesulfonic acid shown in 900g formula S-22C are added in reaction flask, stirring adds
Heat keeps the temperature 3 hours to 105 DEG C, and TLC detection, raw material has reacted, has been cooled to 60 DEG C, adds water 5kg, stirs, with 15kg tert-butyl first
Ether extracts 3 times, organic layer 22kg, and in 25% sodium hydroxide solution and acetic acid, organic layer anhydrous sodium sulfate drying, concentration are dry
Crude product is obtained, merges rectifying and obtains: compound shown in 1049g formula S-22, GC: > 98%HPLC: > 99%, the present embodiment Chinese style S-22 institute
Show and wants inflated with nitrogen after compound rectifying comes out, it is stored refrigerated.
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- methylthiophene simultaneously [2,3-d] thiazole, which comprises the following steps:
A. compound shown in preparation formula S-22A:
Compound and aceticanhydride shown in formula A are added in reaction flask, stirring is cooled to 15 DEG C, and concentrated nitric acid is added dropwise, protects at a temperature of 15 DEG C
Temperature 1 hour, sampling carry out TLC to monitoring raw material end of reaction, add water and stir 1 hour, suction filtration obtains crude product；
Crude product is dissolved in ethyl acetate, anhydrous sodium sulfate dries, filters, and organic phase is concentrated under reduced pressure into a small amount of solvent, leads while hot
Enter in petroleum ether, is cooled to 20 DEG C, filtering dries to obtain compound shown in formula S-22A；
B. compound shown in preparation formula S-22B:
Water, sulphur and vulcanized sodium are added in reaction flask, is heated to 75 DEG C and stirs 3 hours, obtain mixed solution；
Compound shown in methanol and formula S-22A is added in a kettle, is heated to 60 DEG C, mixed solution is added dropwise, after being added dropwise
Reflux 3 hours, control is cooled to 20 DEG C, centrifugation obtains compound shown in formula S-22B to monitoring raw material end of reaction in sampling；
C. compound shown in preparation formula S-22C:
Acetic acid, compound and aceticanhydride shown in formula S-22B are added in a kettle, is heated with stirring to 90 DEG C, is added iron powder, 100 DEG C
At a temperature of insulation reaction 10 hours, sampling HPLC detection is cooled to 60 DEG C, adds water, stir 1 hour until raw material end of reaction,
20 degrees Celsius of centrifugations are cooled to, crude product is obtained；
THF and crude product are added in a kettle, is heated to reflux 2 hours, filters while hot, ethyl alcohol is added after being concentrated and dried in filtrate, cold
Freezeout goes out solid, filters drying, and solid is precipitated in freezing, filters drying and obtains the first fine work of compound shown in formula S-22C；
The first fine work of compound shown in addition DMF, atlapulgite and formula S-22C in a kettle, is heated to 50 DEG C, insulated and stirred
It 30 minutes, filters, filtrate is poured into water, and solid is precipitated, and filters drying, obtains compound shown in formula S-22C；
D. compound shown in preparation formula S-22:
Compound, acetic acid and p-methyl benzenesulfonic acid shown in formula S-22C are added in reaction flask, is heated with stirring to 105 DEG C, heat preservation 3 is small
When, until TLC monitors raw material end of reaction, 60 DEG C are cooled to, water is added, extracted 3 times using t-butyl methyl ether, organic layer is with 25%
In sodium hydroxide solution and acetic acid, organic layer anhydrous sodium sulfate drying are concentrated to get crude product；
Crude product rectifying is obtained into compound shown in formula S-22.
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| CN201910510910.7A CN110372730A (en) | 2019-06-13 | 2019-06-13 | A kind of preparation method of 2- methylthiophene simultaneously [2,3-d] thiazole |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002145886A (en) * | 2000-06-26 | 2002-05-22 | Fuji Photo Film Co Ltd | Method for producing heterocyclic compound |
| JP2004168679A (en) * | 2002-11-18 | 2004-06-17 | Fuji Photo Film Co Ltd | Method for producing aromatic compound |
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2019
- 2019-06-13 CN CN201910510910.7A patent/CN110372730A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002145886A (en) * | 2000-06-26 | 2002-05-22 | Fuji Photo Film Co Ltd | Method for producing heterocyclic compound |
| JP2004168679A (en) * | 2002-11-18 | 2004-06-17 | Fuji Photo Film Co Ltd | Method for producing aromatic compound |
Non-Patent Citations (3)
| Title |
|---|
| ASTRAKHANTSEVA, N. I.: "Synthesis of 2-mercapto derivatives of thieno[2,3-d]thiazole and benzothieno[3,2-d]thiazole", 《KHIMIYA GETEROTSIKLICHESKIKH SOEDINENII》 * |
| CLAUDE PAULMIER, FRANCIS OUTURQUIN: "Thienyl- and selenienylthiocyanates and selenocyanates. 4. Synthesis of thieno[2,3-d]thiazoles, thieno[2,3-e]thiazines and several selenophene analogs", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
| LUCA SARTORI, ET AL.: "Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 1: High-Throughput Screening and Preliminary Exploration", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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