CN107011283A - A kind of methyl mercapto replaces the preparation method of benzo [d] oxazole derivatives - Google Patents
A kind of methyl mercapto replaces the preparation method of benzo [d] oxazole derivatives Download PDFInfo
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- CN107011283A CN107011283A CN201710400933.3A CN201710400933A CN107011283A CN 107011283 A CN107011283 A CN 107011283A CN 201710400933 A CN201710400933 A CN 201710400933A CN 107011283 A CN107011283 A CN 107011283A
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- prepare compound
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- benzo
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- SSWZUOXLFTXIEZ-UHFFFAOYSA-N Cc(cc1N2)ccc1OC2=S Chemical compound Cc(cc1N2)ccc1OC2=S SSWZUOXLFTXIEZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
Abstract
The invention discloses the preparation method that a kind of methyl mercapto replaces benzo [d] oxazole derivatives 5 methyl 2 (methyl mercapto) benzo [d] oxazole, using the methylphenol of 2 nitro 4 as initiation material, by reduction, cyclization, methylating obtains target product, and the compound is important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of methyl mercapto substitution benzo [d]
The preparation method of oxazole derivatives 5- methyl -2- (methyl mercapto) benzo [d] oxazole.
Technical background
Compound methyl mercapto replaces benzo [d] oxazole derivatives 5- methyl -2- (methyl mercapto) benzo [d] oxazole, structural formula
For：
This compound methyl mercapto replaces benzo [d] oxazole derivatives 5- methyl -2- (methyl mercapto) benzo [d] oxazole and correlation
Derivative in pharmaceutical chemistry and organic synthesis have extensive use.Current methyl mercapto substitution benzo [d] oxazole derivatives
Synthesis is more difficult.It is easy to get accordingly, it would be desirable to develop a raw material, it is easy to operate, react easily controllable, overall yield is suitably closed
Into method.
The content of the invention
Methyl mercapto substitution benzo [d] oxazole derivatives 5- methyl -2- (methyl mercapto) benzo is prepared the invention discloses one kind
The method of [d] oxazole, using 2- nitro-4-methyls phenol as initiation material, by reduction, cyclization, methylating obtains target product
4.Synthesis step is as follows：
(1) using 2- nitro-4-methyls phenol as initiation material, 2 are obtained by reduction reaction；
(2) ring closure reaction is carried out 2, obtains 3；
(3) 3 progress methylation reactions are obtained 4；
In a preferred embodiment, the reducing agent used in described reduction reaction prepare compound 2 is selected from hydrogen；Institute
The reagent used in ring closure reaction prepare compound 3 stated is selected from ehtyl potassium xanthate；Described methylation reaction prepare compound 4
Reagent used is selected from dimethyl suflfate.
In a preferred embodiment, the solvent used in described reduction reaction prepare compound 2 is selected from methanol；It is described
Ring closure reaction prepare compound 3 used in solvent be selected from pyridine；Solvent used in described methylation reaction prepare compound 4
Selected from water.
In a preferred embodiment, the reaction temperature used in described reduction reaction prepare compound 2 is room temperature；Institute
The temperature used in ring closure reaction prepare compound 3 stated is the reflux temperature of solvent；Described methylation reaction prepare compound 4
Temperature used is the backflow of solvent.
Beneficial effects of the present invention：In the present invention examination that methylates is used as using dimethyl suflfate instead of traditional iodomethane
Agent, because the volatility of iodomethane is more much bigger than dimethyl suflfate, so using health effect ratio of the iodomethane for operator
Dimethyl suflfate is big, and iodomethane is expensive and dimethyl suflfate is cheap, so being conducive to industrial amplification production.Institute
To be reduction of the security risk and production cost of operation.
The present invention is further described by the following embodiment, and these descriptions are not present invention to be made into one
The restriction of step.It should be understood by those skilled in the art that the equivalent substitution made to the technical characteristic of the present invention, or change accordingly
Enter, still fall within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 2- amidos -4- methylphenols
15g 2- nitro-4-methyls phenol and the palladium carbons of 1g 10% are added in 120ml methanol, hydrogen is passed through, room temperature is stirred
Mix 8 hours, filter, collect filtrate, concentration obtains 13g 2- amido -4- methylphenols.
(2) synthesis of 5- methyl benzo [d] oxazole -2- (3H)-thiophene ketone
12g 2- amido -4- methylphenols and 18g ehtyl potassium xanthates are added in 180ml pyridines, are heated to reflux stirring
Mix 3 hours, be cooled to room temperature, add 10% hydrochloric acid, add ethyl acetate, extraction point liquid is collected organic phase, dried, concentration,
Isolated 9g 5- methyl benzo [d] oxazole -2- (the 3H)-thiophene ketone of silicagel column on residue.
(3) synthesis of 5- methyl -2- (methyl mercapto) benzo [d] oxazole
8g 5- methyl benzo [d] oxazole -2- (3H)-thiophene ketone is added in 110ml water, 4g sodium hydroxides are added, then add
Enter 12g dimethyl suflfates, be heated to reflux stirring 4 hours, cooling has solid precipitation, filters, 7.1g is obtained with re-crystallizing in ethyl acetate
5- methyl -2- (methyl mercapto) benzo [d] oxazole.
Claims (6)
1. one kind prepares the preparation side that methyl mercapto replaces benzo [d] oxazole derivatives 5- methyl -2- (methyl mercapto) benzo [d] oxazole
Method,
Using 2- nitro-4-methyls phenol as initiation material, by reduction, cyclization, methylating obtains target product 4, synthetic route
It is as follows,
2. method according to claim 1, it is characterized in that described 3 steps reaction is,
(1) using 2- nitro-4-methyls phenol as initiation material, 2 are obtained by reduction reaction；
(2) ring closure reaction is carried out 2, obtains 3；
(3) 3 progress methylation reactions are obtained 4；
3. method according to claim 1, it is characterised in that the reducing agent choosing used in described reduction reaction prepare compound 2
One from iron powder, zinc powder, hydrogen, sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, lithium aluminium hydride, borine
Plant or several mixtures；Reagent used in described ring closure reaction prepare compound 3 is selected from ehtyl potassium xanthate；Described first
Reagent used in glycosylation reaction prepare compound 4 is selected from dimethyl suflfate.
4. method according to claim 1, it is characterised in that the solvent used in described reduction reaction prepare compound 2 is selected from
Methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,
One or more of mixtures in dinethylformamide, DMAC N,N' dimethyl acetamide, triethylamine；Described ring closure reaction system
Solvent used in standby compound 3 is selected from methanol, ethanol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, adjacent diformazan
It is one or more of mixed in benzene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, pyridine
Compound；The described solvent methylated used in anti-prepare compound 4 is selected from water, tetrahydrofuran, dichloromethane, toluene, adjacent diformazan
One or more of mixtures in benzene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.
5. method according to claim 1, it is characterised in that the reaction temperature used in described reduction reaction prepare compound 2
It is the reflux temperature of 0 DEG C~solvent；Temperature used in described ring closure reaction prepare compound 3 is the backflow temperature of 0 DEG C~solvent
Degree；Temperature used in described methylation reaction prepare compound 4 is the reflux temperature of 0 DEG C~solvent.
6. method according to claim 1, it is characterised in that the reaction temperature used in described reduction reaction prepare compound 2
It is room temperature；Temperature used in described ring closure reaction prepare compound 3 is the reflux temperature of solvent；Described methylation reaction system
Temperature used in standby compound 4 is the backflow of solvent.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710400933.3A CN107011283A (en) | 2017-05-31 | 2017-05-31 | A kind of methyl mercapto replaces the preparation method of benzo [d] oxazole derivatives |
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| CN201710400933.3A CN107011283A (en) | 2017-05-31 | 2017-05-31 | A kind of methyl mercapto replaces the preparation method of benzo [d] oxazole derivatives |
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Citations (7)
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|---|---|---|---|---|
| US20020086871A1 (en) * | 2000-12-29 | 2002-07-04 | O'neill Brian Thomas | Pharmaceutical composition for the treatment of CNS and other disorders |
| CN101861311A (en) * | 2007-07-21 | 2010-10-13 | 阿尔巴尼分子研究公司 | The indazole that the 5-pyridone replaces |
| CN103113321A (en) * | 2013-02-27 | 2013-05-22 | 南通大学 | 2-(methylmercapto) benzo [d] oxazole-5-carboxylic acid and preparation method thereof |
| CN104292179A (en) * | 2014-10-19 | 2015-01-21 | 湖南华腾制药有限公司 | Preparation method of 2-chlorobenzo[d]oxazole-5-formaldehyde |
| CN107513043A (en) * | 2016-06-18 | 2017-12-26 | 湖南华腾制药有限公司 | A kind of preparation method of bromine substitution benzoxazoles derivative |
| CN107698534A (en) * | 2016-08-08 | 2018-02-16 | 湖南华腾制药有限公司 | A kind of preparation method of polysubstituted benzo oxazoline compound |
| CN108129413A (en) * | 2016-12-01 | 2018-06-08 | 湖南华腾制药有限公司 | A kind of preparation method of benzo [d] oxazole derivatives |
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2017
- 2017-05-31 CN CN201710400933.3A patent/CN107011283A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020086871A1 (en) * | 2000-12-29 | 2002-07-04 | O'neill Brian Thomas | Pharmaceutical composition for the treatment of CNS and other disorders |
| CN101861311A (en) * | 2007-07-21 | 2010-10-13 | 阿尔巴尼分子研究公司 | The indazole that the 5-pyridone replaces |
| CN103113321A (en) * | 2013-02-27 | 2013-05-22 | 南通大学 | 2-(methylmercapto) benzo [d] oxazole-5-carboxylic acid and preparation method thereof |
| CN104292179A (en) * | 2014-10-19 | 2015-01-21 | 湖南华腾制药有限公司 | Preparation method of 2-chlorobenzo[d]oxazole-5-formaldehyde |
| CN107513043A (en) * | 2016-06-18 | 2017-12-26 | 湖南华腾制药有限公司 | A kind of preparation method of bromine substitution benzoxazoles derivative |
| CN107698534A (en) * | 2016-08-08 | 2018-02-16 | 湖南华腾制药有限公司 | A kind of preparation method of polysubstituted benzo oxazoline compound |
| CN108129413A (en) * | 2016-12-01 | 2018-06-08 | 湖南华腾制药有限公司 | A kind of preparation method of benzo [d] oxazole derivatives |
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| FUERSTENBERG, ALEXANDRE ET AL: "Ultrafast Excited-State Dynamics of DNA Fluorescent Intercalators: New Insight into the Fluorescence Enhancement Mechanism", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
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