CN108610318A - A kind of preparation method of trifluoromethyl pyran derivate - Google Patents
A kind of preparation method of trifluoromethyl pyran derivate Download PDFInfo
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- CN108610318A CN108610318A CN201611142089.0A CN201611142089A CN108610318A CN 108610318 A CN108610318 A CN 108610318A CN 201611142089 A CN201611142089 A CN 201611142089A CN 108610318 A CN108610318 A CN 108610318A
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- prepare compound
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- 0 CCOC(Cc(c(C(F)(F)F)ccc1)c1OC*)=O Chemical compound CCOC(Cc(c(C(F)(F)F)ccc1)c1OC*)=O 0.000 description 2
- NFODMEIUJBDFIN-UHFFFAOYSA-N CCOC(C1c(c(C(F)(F)F)ccc2)c2OCC1=O)=O Chemical compound CCOC(C1c(c(C(F)(F)F)ccc2)c2OCC1=O)=O NFODMEIUJBDFIN-UHFFFAOYSA-N 0.000 description 1
- BIQBTEPMLFSQNH-UHFFFAOYSA-M CCOC(Cc(c(C(F)(F)F)ccc1)c1[O-])=O Chemical compound CCOC(Cc(c(C(F)(F)F)ccc1)c1[O-])=O BIQBTEPMLFSQNH-UHFFFAOYSA-M 0.000 description 1
- WSFJDCMTIUVOTD-UHFFFAOYSA-N O=C(C1)COc2c1c(C(F)(F)F)ccc2 Chemical compound O=C(C1)COc2c1c(C(F)(F)F)ccc2 WSFJDCMTIUVOTD-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
Abstract
The invention discloses a kind of 5 trifluoromethyl N methyl 3 of trifluoromethyl pyran derivate, the preparation method of 4 dihydro 2H pyrans, 3 amine, using 2 (6 trifluoromethyl, 2 hydroxy phenyl) methyl acetates as starting material, target product 5 is obtained by etherificate, cyclization, decarboxylation, ammonification reduction reaction, product of the present invention synthesizes diversified compound library as template small molecule.
Description
Technical field
The present invention relates to a kind of novel processing step of medicine intermediate, more particularly to a kind of trifluoromethyl pyran derivate
The preparation method of 5- trifluoromethyl-N- methyl -3,4- dihydro -2H- pyrans -3- amine.
Technical background
Compound 5- trifluoromethyl-N- methyl -3,4- dihydro -2H- pyrans -3- amine, structural formula are：
This compound 5- trifluoromethyl-N- methyl -3,4- dihydro -2H- pyrans -3- amine and relevant derivative are in drug
There is extensive use in and organic synthesis.The synthesis of 5- trifluoromethyls-N- methyl -3,4- dihydros -2H- pyrans -3- amine at present
It is more difficult.It is easy to operate therefore, it is necessary to develop a raw material to be easy to get, react easily controllable, the overall yield suitably side of synthesis
Method.
Invention content
The invention discloses a kind of trifluoromethyl pyran derivate 5- trifluoromethyls-N- methyl -3,4- dihydro -2H- pyrans -
The preparation method of 3- amine by etherificate, cyclization, takes off using 2- (6- trifluoromethyl -2- hydroxy phenyls) methyl acetate as starting material
Carboxylic, ammonification reduction reaction obtain target product 5, and synthesis step is as follows：
(1), as starting material, 2 are obtained by etherification reaction using 2- (6- trifluoromethyl -2- hydroxy phenyls) methyl acetate,
(2) ring closure reaction is carried out 2, obtains 3,
(3) 3 progress decarboxylic reactions are obtained 4,
(4) 4 progress ammonification reduction reactions are obtained 5,
In a preferred embodiment, the reagent used in the etherification reaction prepare compound 2 is selected from bromoacetic acid second
Ester；Reagent used in the ring closure reaction prepare compound 3 is selected from sodium ethoxide；4 institute of decarboxylic reaction prepare compound
Reducing agent is selected from sodium hydroxide；Reducing agent used in the ammonification reduction reaction prepare compound 5 is selected from methylamine hydrochloric acid
Salt.
In a preferred embodiment, the solvent used in the etherification reaction prepare compound 2 is selected from N, N- diformazans
Base formamide；Solvent used in the ring closure reaction prepare compound 3 is selected from ethyl alcohol；The decarboxylic reaction prepare compound
Solvent used in 4 is selected from N,N-dimethylformamide；Solvent used in the ammonification reduction reaction prepare compound 5 is selected from first
Alcohol.
In a preferred embodiment, the reaction temperature used in the etherification reaction prepare compound 2 is solvent
Reflux temperature；Temperature used in the ring closure reaction prepare compound 3 is 0 DEG C of reflux temperature to solvent；The decarboxylation
Temperature used in reaction prepare compound 4 is the reflux temperature of solvent；Used in the ammonification reduction reaction prepare compound 5
Temperature is room temperature.
The present invention relates to a kind of trifluoromethyl pyran derivate 5- trifluoromethyls-N- methyl -3,4- dihydro -2H- pyrans -3-
The preparation method of amine is reported currently without other Patents documents.
The present invention is further described by the following embodiment, these descriptions are not to make the content of present invention into one
The restriction of step.It should be understood by those skilled in the art that equivalent replacement made by technical characteristic of the invention, or change accordingly
Into still falling within protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) synthesis of 2- (6- trifluoromethyl -2- phenoxyethanoic acids ethyl ester) ethyl acetate
17g 2- (6- trifluoromethyl -2- hydroxy phenyls) methyl acetate is added to 130ml N,N-dimethylformamides
In, 15g bromoacetates and 12g potassium carbonate is added, heating stirring reflux is cooled to room temperature, and water and ethyl acetate, extraction is added
Organic phase is collected in liquid separation, dry, and concentration obtains 10g 2- (6- trifluoromethyl -2- phenoxyethanoic acids ethyl ester) ethyl acetate.
(2) synthesis of 5- trifluoromethyls -3- oxos -3,4- dihydros -2H- chromene -4- Ethyl formates
10g 2- (5- trifluoromethyl -2- phenoxyethanoic acids ethyl ester) ethyl acetate is added in 70ml ethyl alcohol, is cooled to 0
DEG C, 8g sodium ethoxides are added, heating stirring back flow reaction 3 hours, cooling room temperature, concentration, is added water and ethyl acetate extracts liquid separation,
Organic phase is collected, it is dry, it is concentrated to give bromo- 3- oxos -3, the 4- dihydro -2H- chromenes -4- Ethyl formates of 7g 6-.
(3) synthesis of 6- trifluoromethyls -2H- chromenes -3 (4H) -one
7g 6- trifluoromethyl -3- oxo -3,4- dihydro -2H- chromene -4- Ethyl formates are added to 80mlN, N- diformazans
In base formamide, 5g sodium hydroxides are added, are heated to reflux stirring 24 hours, filtering adds water and ethyl acetate, extraction point
Liquid collects organic phase, dry, concentration, and silica gel post separation obtains -3 (4H) -one of 4g 6- trifluoromethyl -2H- chromenes on residue.
(4) synthesis of 6- trifluoromethyls-N- methyl -3,4- dihydros -2H- pyrans -3- amine
4g 6- trifluoromethyl -3- oxo -3,4- dihydro -2H- chromene -4- Ethyl formates are added in 30ml methanol, are added
Enter 3g methylamine hydrochlorides, be stirred at room temperature 20 hours, add 4g sodium borohydrides, be stirred at room temperature 3 hours, filter, add water and
Ethyl acetate extracts liquid separation, collects organic phase, dry, concentration, and silica gel post separation obtains 2.1g 6- trifluoromethyls-N- on residue
Methyl -3,4- dihydro -2H- pyrans -3- amine.
Claims (5)
1. a kind of preparation side of trifluoromethyl pyran derivate 5- trifluoromethyls-N- methyl -3,4- dihydro -2H- pyrans -3- amine
Method is restored using 2- (6- trifluoromethyl -2- hydroxy phenyls) methyl acetate as starting material by etherificate, cyclization, decarboxylation, ammonification
Target product 5 is obtained by the reaction, synthetic route is as follows：
2. the method according to claim 1, it is characterized in that the 4 steps reaction is,
(1), as starting material, 2 are obtained by etherification reaction using 2- (6- trifluoromethyl -2- hydroxy phenyls) methyl acetate,
(2) ring closure reaction is carried out 2, obtains 3,
(3) 3 progress decarboxylic reactions are obtained 4,
(4) 4 progress ammonification reduction reactions are obtained 5,
3. the method according to claim 1, which is characterized in that the reagent used in the etherification reaction prepare compound 2 is selected from
Bromoacetate；Reagent used in the ring closure reaction prepare compound 3 is selected from sodium ethoxide；The decarboxylic reaction preparationization
Close the mixture that the reducing agent used in object 4 is selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate；The ammonia
Change the reducing agent used in reduction reaction prepare compound 5 and is selected from methylamine hydrochloride.
4. the method according to claim 1, which is characterized in that the solvent used in the etherification reaction prepare compound 2 is selected from
Tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, N, N- dimethyl
The mixture of one or more of acetamide, acetonitrile；Solvent used in the ring closure reaction prepare compound 3 is selected from first
Alcohol, ethyl alcohol, normal propyl alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N, N-
The mixture of one or more of dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile；The decarboxylic reaction preparationization
It closes the solvent used in object 4 and is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, three
In chloromethanes, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide
One or more of mixtures；Solvent used in the ammonification reduction reaction prepare compound 5 is selected from methanol, ethyl alcohol, positive third
Alcohol, isopropanol, tetrahydrofuran, dichloromethane, toluene, ortho-xylene, paraxylene, meta-xylene, N,N-dimethylformamide,
The mixture of one or more of DMAC N,N' dimethyl acetamide, acetonitrile.
5. the method according to claim 1, which is characterized in that the reaction temperature used in the etherification reaction prepare compound 2
It is the reflux temperature of solvent；Temperature used in the ring closure reaction prepare compound 3 is 0 DEG C of reflux temperature to solvent；Institute
The temperature used in decarboxylic reaction prepare compound 4 stated is reflux temperature of the room temperature to solvent；The ammonification reduction reaction system
Temperature used in standby compound 5 is room temperature.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926775A (en) * | 2015-05-07 | 2015-09-23 | 湖南华腾制药有限公司 | Preparation method of fluorine-containing pyran derivative |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926775A (en) * | 2015-05-07 | 2015-09-23 | 湖南华腾制药有限公司 | Preparation method of fluorine-containing pyran derivative |
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Application publication date: 20181002 |