CN105461680B - A kind of synthetic method of 2- (4- fluorophenyls) thiophene - Google Patents
A kind of synthetic method of 2- (4- fluorophenyls) thiophene Download PDFInfo
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- CN105461680B CN105461680B CN201511009947.XA CN201511009947A CN105461680B CN 105461680 B CN105461680 B CN 105461680B CN 201511009947 A CN201511009947 A CN 201511009947A CN 105461680 B CN105461680 B CN 105461680B
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- thiophene
- fluorophenyls
- synthetic method
- solvent
- fluorophenyl
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- IEYRYHZNHGOZKM-UHFFFAOYSA-N C=[Br](c(cc1)ccc1F)=C Chemical compound C=[Br](c(cc1)ccc1F)=C IEYRYHZNHGOZKM-UHFFFAOYSA-N 0.000 description 1
- HRXNWVIVXSAHLG-UHFFFAOYSA-N Fc1ccc(C2SC=CC2)cc1 Chemical compound Fc1ccc(C2SC=CC2)cc1 HRXNWVIVXSAHLG-UHFFFAOYSA-N 0.000 description 1
- SGZUDSSDAUABAV-UHFFFAOYSA-N OS(c1ccc[s]1)O Chemical compound OS(c1ccc[s]1)O SGZUDSSDAUABAV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a kind of synthetic methods of 2 (4 fluorophenyl) thiophene, including 1), 4 fluoro acetophenones are in Solid triphosgene and N, Vilsmeier Haack reactions occur under the action of N dimethylformamides, obtain 3 chlorine 3 (4 fluorophenyl) methacrylaldehyde;2), with ethyl thioglycolate ring closure reaction occurs for 3 chlorine 3 (4 fluorophenyl) methacrylaldehyde in the presence of alkali, obtains 5 (4 fluorophenyl) thiophene, 2 carboxylic acid, ethyl ester;3), ester hydrolysis occurs in the presence of alkali for 5 (4 fluorophenyl) thiophene, 2 carboxylic acid, ethyl ester, obtains 5 (4 fluorophenyl) thiophene, 2 formic acid;4), 2 (4 fluorophenyl) thiophene are made under copper powder catalysis in 5 (4 fluorophenyl) thiophene, 2 formic acid.The present invention provides that a kind of raw material is cheap and easy to get for the synthesis of 2 (4 fluorophenyl) thiophene, the mild synthetic method of reaction condition, entirely reacts to equipment and reaction condition without particular/special requirement, and the yield of product is higher;Safety that is easy to operate, can ensureing operating personnel has good market prospects.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to novel diabetes medicine canagliflozin was synthesized
The preparation of Cheng Suoxu key intermediates, especially a kind of new method and purposes for preparing 2- (4- fluorophenyls) thiophene.
Background technology
Canagliflozin (Canagliflozin, trade name Invokana) is first granted sodium glucose cotransport egg
White 2 (SGLT2) inhibitor obtains the approval of U.S. FDA in March, 2013 and is treated for diabetes B.Its structural formula is as follows
It is shown:
Patent US20100099883A1 reports preparation method, as shown below:
Compound 2- shown in structural formula 5 (4- fluorophenyls) thiophene is intermediate needed for Canagliflozin synthesis, at present
Its synthesis mode of report has following several:
Method 1:
Method 2:
Method 3:
Method 4:
But above 4 kinds of production methods have a certain drawbacks, and in method 1 and 2, the boric acid raw material 2- thienyl boric acids used
Or 4- fluorobenzoic boric acids, production need low temperature (<- 50 DEG C) condition, and the hazardous agents such as butyl lithium are used, to equipment and operation
Personnel requirement is high, is not easy large-scale production and so that product itself is expensive, increases production cost.Secondly, it is mostly used in reaction
To metal Pd precious metal, equally increase production cost.In method 3 and 4, the preparation of Grignard Reagent has been all referred to.Grignard is tried
The preparation of agent, needs anhydrous and oxygen-free, and the requirement to equipment is high.Itself activity is high, operates easy initiation safety accident not in place.
It is above-mentioned to solve the problems, such as, a kind of safe operation, simplicity are found, the cheap and easily-available production method of raw material has very much
It is necessary.
Invention content
Synthetic method the technical problem to be solved by the present invention is to overcome existing 2- (4- fluorophenyls) thiophene is former to reaction
The defects of material or harsh reaction condition requirement, provides a kind of synthetic method of 2- (4- fluorophenyls) thiophene.
In order to solve the above technical problem, the present invention provides following technical solutions:
A kind of synthetic method of 2- (4- fluorophenyls) thiophene, including following steps:
1), under the action of Solid triphosgene and N,N-dimethylformamide Vilsmeier- occurs for 4- fluoro acetophenones
Haack reacts, and by adding water stratification, alkalizes, filters, be dried to obtain the chloro- 3- of 3- (4- fluorophenyls) methacrylaldehyde;
Further, the molar ratio of 4- fluoro acetophenones, Solid triphosgene and n,N-Dimethylformamide is:1:0.4~
1.0:1.2~3.0.
Further, the solvent of 5~15 times of 4- fluoro acetophenone quality, wherein solvent are further included in the reaction system:4-
Fluoro acetophenone quality=mL:G, the solvent are any one in dichloromethane, chloroform, carbon tetrachloride and 1,2- dichloroethanes.
Further, Triphosgene/DMF reagents used in reaction can also use POCl3/DMF, (COCl) 2/DMF,
The reagents such as SOCl2/DMF replace carrying out Vilsmeier-Haack reactions;
Further, reaction temperature is 0 DEG C~25 DEG C.
2), with ethyl thioglycolate ring closure reaction occurs for the chloro- 3- of 3- (4- fluorophenyls) methacrylaldehyde in the presence of alkali, through adding
Water filters, obtains 5- (4- fluorophenyls) thiophene-2-carboxylic acid ethyl ester;
Further, the Ester groups of the ethyl thioglycolate in the reaction can be by the straight chain of C1~C5 or containing branch
Alcohol replaces, and the mole dosage of ethyl thioglycolate or the substituted ethyl thioglycolate of Ester groups is 3- chloro- 3- (4- fluorobenzene
Base) 1~1.5 times of methacrylaldehyde.
Further, the mole dosage of alkali is 1~3 times of the chloro- 3- of 3- (4- fluorophenyls) methacrylaldehyde.Alkali can be inorganic
Alkali, such as sodium carbonate, potassium carbonate, sodium ethoxide, sodium methoxide, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium tert-butoxide, the tert-butyl alcohol
Potassium, sodium tert-amyl alcohol, tert-pentyl alcohol potassium etc.;Can also be organic base such as triethylamine, pyridine etc..
Further, which further includes the solvent of 3~10 times of chloro- 3- of 3- (4- fluorophenyls) methacrylaldehyde quality,
Wherein solvent:The chloro- 3- of 3- (4- fluorophenyls) methacrylaldehyde quality=mL:G, the solvent for NMP, DMF, DMAc, pyridine, acetonitrile,
Any one of acetone, 1,4- dioxane, tetrahydrofuran, methanol, ethyl alcohol and isopropanol.
Further, the temperature of the reaction is 30 DEG C~80 DEG C.
3), ester hydrolysis occurs in the presence of alkali for 5- (4- fluorophenyls) thiophene-2-carboxylic acid ethyl ester, through adding water, is acidified, takes out
5- (4- fluorophenyls) thiophene -2-carboxylic acid is made in filter, drying;
Further, inorganic base of the alkali for 1.0~2.0 times of 5- (4- fluorophenyls) thiophene-2-carboxylic acid ethyl ester molal quantitys, can
Think any one or a few in lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
Further, 3~10 times of 5- (4- fluorophenyls) thiophene-2-carboxylic acid ethyl ester is further included in the reaction system of step 3)
The solvent of quality, wherein solvent:5- (4- fluorophenyls) thiophene fluorophenyl) thiophene-2-carboxylic acid ethyl ester quality=mL:G, described is molten
Agent is any one of methanol, ethyl alcohol, isopropanol, propyl alcohol, 1,4- dioxane.
4), 5- (4- fluorophenyls) thiophene -2-carboxylic acids heat decarboxylation under copper powder catalysis, and filtered, crystallization is filtered, tied again
Obtained 2- (4- fluorophenyls) thiophene of crystalline substance.
Further, the dosage of copper powder is the 10% of 5- (4- fluorophenyls) thiophene -2-carboxylic acid quality.
Further, which includes dimethyl sulfoxide, sulfolane, quinoline etc.;Its volumetric usage is substrate matter
2-10 times of amount;
Further, 160 DEG C -250 DEG C of temperature used in reaction.
The present invention provides that a kind of raw material is cheap and easy to get for the synthesis of 2- (4- fluorophenyls) thiophene, the mild conjunction of reaction condition
Into method, entire reaction is to equipment and reaction condition without particular/special requirement, and the yield of product is higher;It is easy to operate, can be with
Ensure the safety of operating personnel, there are good market prospects.
Description of the drawings
Attached drawing is used to provide further understanding of the present invention, and a part for constitution instruction, the reality with the present invention
Example is applied together for explaining the present invention, is not construed as limiting the invention.In the accompanying drawings:
Fig. 1 is the flow chart that the present invention reacts.
Specific embodiment
The preferred embodiment of the present invention is illustrated below in conjunction with attached drawing, it should be understood that preferred reality described herein
It applies example to be merely to illustrate and explain the present invention, be not intended to limit the present invention.
Embodiment
A kind of synthetic method of 2- (4- fluorophenyls) thiophene, including following steps:
1) in 500mL four-hole bottles, 40mL dichloromethane is added in as solvent, then adds in n,N-Dimethylformamide
(21.9g, 3.0mmol, 3.0eq.) is cooled to 0~5 DEG C;
Solid triphosgene (29.7g, 1.0mmol, 1.0eq.) is dissolved in 110mL dichloromethane, is added dropwise in reaction bulb,
Temperature control is no more than 10 DEG C, finishes, and stirs 10 minutes;
0-10 DEG C of temperature control is added dropwise 4- fluoro acetophenones (13.8g, 1.0mmol, 1.0eq.), finishes, and stirs 1h, heats up later
To back flow reaction 5h, stop reaction and be cooled to room temperature;
Reaction solution is poured into 200mL ice water, is stirred, stratification;Water layer potassium carbonate tune pH to 6-7 has a large amount of solid
Body generates.It filters, dry the chloro- 3- of brown solid 3- (4- fluorophenyls) methacrylaldehyde 10g, yield:58.1%.
2) by the chloro- 3- of 3- (4- fluorophenyls) methacrylaldehyde (10.0g, 57.9mmol, 1.0eq.) and potassium carbonate (9.6g,
69.5mmol, 1.2eq.) it is added in 30mL acetonitriles, and be heated to 65 DEG C;
It in being added dropwise to ethyl thioglycolate (7.6g, 63.7mmol, 1.1eq.) in 10 minutes, finishes, the reaction was continued 5h stops
It only reacts, is cooled to room temperature;
Under stirring, 150mL water is slowly added into reaction, there is solid precipitation;10 points of stirring filters, dry solid 5-
(4- fluorophenyls) thiophene-2-carboxylic acid ethyl ester 11.9g, yield:88.1%.This step can not also dry the 5- (4- that will directly obtain
Fluorophenyl) thiophene-2-carboxylic acid ethyl ester is for reacting in next step;
3) 5- (4- fluorophenyls) thiophene-2-carboxylic acid ethyl esters (8.4g, 33.5mmol, 1.0eq.) are added in 33mL ethyl alcohol, and
It is heated to 70 DEG C;
Sodium hydroxide (2.0g, 50.3mmol, 1.5eq.) is dissolved in 25mL water, is added dropwise in above-mentioned reaction solution, finishes,
Insulation reaction 3h stops reaction, is cooled to room temperature, concentrated hydrochloric acid tune pH2-3;
It adds in the 100mL water of stirring, is filtered after 10 points, filtration cakes torrefaction obtains 6.5g off-white powders, yield by reacting:
87.1%;
4) 5- (4- fluorophenyls) thiophene -2-carboxylic acid (5.0g, 22.5mmol, 1.0eq.) and copper powder (0.5g, 7.8mmol,
It 0.35eq.) is added in 15mL sulfolane, reacts and react 2h at 200 DEG C, stop reaction, be cooled to room temperature.Suction filtration removes copper
Powder is added in reacting in the 100mL water of stirring, there is the precipitation of white solid 2- (4- fluorophenyls) thiophene.After 10 points of stirring, filter,
Dry solid 2.9g, yield:72%.
This example demonstrates that synthetic method of the invention not only mild condition, raw material is cheap, and the yield of product compared with
Height has good market prospects.
Finally it should be noted that:The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention,
Although the present invention is described in detail referring to the foregoing embodiments, for those skilled in the art, still may be used
To modify to the technical solution recorded in foregoing embodiments or carry out equivalent replacement to which part technical characteristic.
All within the spirits and principles of the present invention, any modification, equivalent replacement, improvement and so on should be included in the present invention's
Within protection domain.
Claims (10)
1. a kind of synthetic method of 2- (4- fluorophenyls) thiophene, which is characterized in that including following steps:
1), Vilsmeier-Haack occurs under the action of Solid triphosgene and N,N-dimethylformamide for 4- fluoro acetophenones anti-
Should, by adding water stratification, alkalize, filter, be dried to obtain the chloro- 3- of 3- (4- fluorophenyls) methacrylaldehyde;
2), with ethyl thioglycolate ring closure reaction occurs for the chloro- 3- of 3- (4- fluorophenyls) methacrylaldehyde in the presence of alkali, through adding water,
It filters, obtains 5- (4- fluorophenyls) thiophene-2-carboxylic acid ethyl ester;
3), ester hydrolysis occurs in the presence of alkali for 5- (4- fluorophenyls) thiophene-2-carboxylic acid ethyl ester, through adding water, is acidified, filters, do
It is dry that 5- (4- fluorophenyls) thiophene -2-carboxylic acid is made;
4), 5- (4- fluorophenyls) thiophene -2-carboxylic acids heat decarboxylation under copper powder catalysis, and filtered, crystallization filters, recrystallization system
Obtain 2- (4- fluorophenyls) thiophene.
2. a kind of synthetic method of 2- (4- fluorophenyls) thiophene as described in claim 1, which is characterized in that in the step 1)
The molar ratio of 4- fluoro acetophenones, Solid triphosgene and N,N-dimethylformamide is:1:0.4~1.0:1.2~3.0.
3. a kind of synthetic method of 2- (4- fluorophenyls) thiophene as described in claim 1, which is characterized in that the step 1)
Solvent is further included in reaction system, the volume mass ratio of wherein solvent and 4- fluoro acetophenones is 5~15mL:1g, the solvent are
Any one in dichloromethane, chloroform, carbon tetrachloride and 1,2- dichloroethanes.
4. such as a kind of synthetic method of claim 1-3 any one of them 2- (4- fluorophenyls) thiophene, which is characterized in that described
The reaction temperature of step 1) is 0 DEG C~25 DEG C.
5. a kind of synthetic method of 2- (4- fluorophenyls) thiophene as described in claim 1, which is characterized in that in the step 2)
The mole dosage of ethyl thioglycolate be 1~1.5 times of the chloro- 3- of 3- (4- fluorophenyls) methacrylaldehyde, the mole dosage of alkali is 3-
1~3 times of chloro- 3- (4- fluorophenyls) methacrylaldehyde.
6. a kind of synthetic method of 2- (4- fluorophenyls) thiophene as claimed in claim 5, which is characterized in that in the step 2)
Reaction system further includes solvent, and the volume mass ratio of wherein solvent and the chloro- 3- of 3- (4- fluorophenyls) methacrylaldehyde is 3~10mL:1g,
The solvent is NMP, DMF, DMAC, pyridine, acetonitrile, acetone, 1,4- dioxane, tetrahydrofuran, methanol, ethyl alcohol and isopropanol
Any one of.
7. such as claim 1,5 and the synthetic method of a kind of 2- of 6 any one of them (4- fluorophenyls) thiophene, which is characterized in that
The reaction temperature of the step 2) is 30 DEG C~80 DEG C.
8. a kind of synthetic method of 2- (4- fluorophenyls) thiophene as described in claim 1, which is characterized in that in the step 3)
Inorganic base of the alkali for 1.0~2.0 times of 5- (4- fluorophenyls) thiophene-2-carboxylic acid ethyl ester molal quantitys, the reaction of the step 3)
Solvent is further included in system, the volume mass ratio of wherein solvent and 5- (4- fluorophenyls) thiophene-2-carboxylic acid ethyl ester is 3~10mL:
1g, the solvent are any one of methanol, ethyl alcohol, isopropanol, propyl alcohol, Isosorbide-5-Nitrae-dioxane.
9. a kind of synthetic method of 2- (4- fluorophenyls) thiophene as described in claim 1, which is characterized in that in the step 4)
The dosage of copper powder is the 10% of 5- (4- fluorophenyls) thiophene -2-carboxylic acid quality.
A kind of 10. synthetic method of 2- (4- fluorophenyls) thiophene as described in claim 1, which is characterized in that the step 4)
Reaction temperature be 160 DEG C~250 DEG C.
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103649033A (en) * | 2011-05-26 | 2014-03-19 | Tf化学公司 | Family of aryl, heteroaryl, O-aryl and O-heteroaryl carbasugars |
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CN103649033A (en) * | 2011-05-26 | 2014-03-19 | Tf化学公司 | Family of aryl, heteroaryl, O-aryl and O-heteroaryl carbasugars |
Non-Patent Citations (3)
Title |
---|
Efficient Synthesis of a new type of Baylishillman Adducts and their Stereoselective Bromination;Weihui Zhong et al.;《Synthetic Communications》;20101231;第40卷(第16期);2441-2456 * |
Microwave Assisted Synthesis of 5-Arylthiophene-2-carboxylates;Jagath Reddy et al.;《Heterocyclic Communications》;20041231;第10卷(第6期);411-414 * |
Synthesis and Polymerization of Ethynylthiophenes and Ethynylfurans Containing Trifluoromethyl Groups;Masakazu Nishida et al.;《Journal of Fluorine Chemistry》;19901231;第46卷(第3期);445-459 * |
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