CN115340448A - Method for synthesizing monofluoroolefin by using ketone derivative as raw material - Google Patents
Method for synthesizing monofluoroolefin by using ketone derivative as raw material Download PDFInfo
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- CN115340448A CN115340448A CN202211114363.9A CN202211114363A CN115340448A CN 115340448 A CN115340448 A CN 115340448A CN 202211114363 A CN202211114363 A CN 202211114363A CN 115340448 A CN115340448 A CN 115340448A
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 239000002994 raw material Substances 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 15
- 150000002576 ketones Chemical class 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- -1 ketone compounds Chemical class 0.000 claims abstract description 23
- SJGALSBBFTYSBA-UHFFFAOYSA-N oxaziridine Chemical compound C1NO1 SJGALSBBFTYSBA-UHFFFAOYSA-N 0.000 claims abstract description 14
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims abstract description 10
- TYCFGHUTYSLISP-UHFFFAOYSA-N 2-fluoroprop-2-enoic acid Chemical class OC(=O)C(F)=C TYCFGHUTYSLISP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000463 material Substances 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 239000010949 copper Substances 0.000 claims description 11
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 9
- 229910052802 copper Inorganic materials 0.000 claims description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 150000001336 alkenes Chemical class 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 abstract 1
- 239000003446 ligand Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000012043 crude product Substances 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000006880 cross-coupling reaction Methods 0.000 description 3
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- UIQGEWJEWJMQSL-UHFFFAOYSA-N 2,2,4,4-tetramethylpentan-3-one Chemical compound CC(C)(C)C(=O)C(C)(C)C UIQGEWJEWJMQSL-UHFFFAOYSA-N 0.000 description 2
- NOJXPGXFDASWEI-UHFFFAOYSA-N 3-ethylsulfanylprop-1-ene Chemical compound CCSCC=C NOJXPGXFDASWEI-UHFFFAOYSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- UJXJAFOYAIWOFY-UHFFFAOYSA-N 3-fluoro-3-phenylprop-2-enoic acid Chemical compound OC(=O)C=C(F)C1=CC=CC=C1 UJXJAFOYAIWOFY-UHFFFAOYSA-N 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000006908 Julia-Kocienski olefination reaction Methods 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000006115 defluorination reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
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- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
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- C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
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Abstract
The invention belongs to the field of organic synthesis, and relates to a method for synthesizing monofluoro-olefin by using derivatives of ketone compounds as raw materials. Taking fluoroacrylic acid and ketone compound derivative oxaziridine as raw materials, taking copper hexachlorophosphate tetraethyl cyanide as a catalyst and 1, 10-phenanthroline as a ligand to perform model reaction to obtain the Z-configuration monofluoro olefin compound with the general formula (I). The method has the advantages of cheap and easily obtained reaction raw materials, simple reaction feeding mode, high stereoselectivity of products and high synthetic economic value. Provides an efficient, convenient and economic preparation method for synthesizing monofluoroolefin with important value from cheap ketone compounds as raw materials.
Description
Technical Field
The invention relates to compound preparation, and belongs to the field of organic synthesis. In particular to a method for synthesizing monofluoro olefin by taking derivatives of ketone compounds as raw materials.
Background
The insertion of fluorine atoms or fluorine-containing fragments into organic molecules can cause the change of properties of lipophilicity, metabolic stability, membrane permeability, bioavailability, binding capacity with biological targets and the like in physical, chemical and biological activities. Therefore, fluorine-containing organic compounds are widely used in the fields of medicine, agricultural chemicals, material science, and the like. It is statistically counted that about 40% of the pesticide molecules and about 25% of the pharmaceutical molecules on the market contain at least one fluorine atom. In particular, the monofluoroolefin and the peptide bond in the fluorine-containing organic compound are bioisosteres, and have strong stability to peptidase and stable spatial conformation. Thus, monofluoroolefins are ideal peptide bond mimetics in the fields of medicinal chemistry and materials. Further, monofluoroolefins have been widely used in the fields of biomedicine, drug research, and the like (formula 1).
In view of the importance of monofluoroolefins in chemical medicine and materials, many practical synthetic strategies have recently been reported by international and domestic groups of subjects. For example, carbene insertion reaction, wittig reaction, julia-Kocienski olefination reaction, ring-opening cross-coupling reaction of metadifluorocyclopropane, cross-coupling reaction of metafluorohaloolefin, and defluorination cross-coupling reaction of metadifluoroolefin (formula 2). The ketone compound is a cheap and easily available chemical. Moreover, ketone compounds are widely present in a variety of active molecules. However, no examples of synthesizing monofluoroolefins from ketones or their derivatives have been reported. Therefore, the synthesis of monofluoroolefin by using ketone compounds or derivatives thereof as raw materials has important synthesis application value.
Formula 2. Synthesis of monofluoroolefins
Disclosure of Invention
The synthesis of monofluoroolefins from ketones or their derivatives has not been achieved. The important synthesis application value of synthesizing monofluoroolefin by cheap and easily obtained ketone compounds. The invention provides a method for efficiently synthesizing Z-configuration monofluoro olefin with high stereoselectivity by using a cheap copper catalyst through ketone compound derivatives.
In order to solve the technical problems, the invention adopts the following technical scheme: a method for synthesizing monofluoro olefin by taking ketone derivatives as raw materials is characterized by comprising the following steps: using fluoroacrylic acid and ketone compound derivative oxaziridine as raw material and using copper tetrakis-cyanide hexafluorophosphate [ Cu (CH) 3 CN) 4 PF 6 ]1, 10-phenanthroline serving as a catalyst and 1, 2-Dichloroethane (DCE) solvent, and reacting according to the following reaction formula to obtain the compound with the general formula (I)Z-monofluoroolefin compound:
preferably, the amount of the material of the copper tetraethyl hexafluorophosphate is 10% of the amount of the material of the oxaziridine.
The amount of the substance of 1, 10-phenanthroline is 10% of the amount of the substance of oxaziridine.
Preferably, the amount of the substance of fluoroacrylic acid is 2 times the amount of the substance of oxaziridine.
Preferably, the reaction temperature is 110 ℃ and the reaction time is 24h.
The method realizes the synthesis of monofluoroolefines by taking the ketone compound derivatives as raw materials with low cost copper as the catalyst, high efficiency and high stereoselectivity for the first time. The reaction raw materials are cheap and easy to obtain, the reaction feeding mode is simple, and the synthesis economic value is high. Provides a high-efficiency, convenient and economic preparation method for synthesizing monofluoroolefin by taking widely-existing ketone compounds as raw materials.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments:
example 1, the reaction formula for this example is shown below:
(1) Tetracetylcopper hexafluorophosphate (10 mol%), 1, 10-phenanthroline (10 mol%), oxaziridine derived from cyclohexylketone (0.15 mmol), and α -fluorocinnamic acid (0.3 mmol) were added to a sealed reactor tube containing magnetons under air, and the reactor tube was purged with argon three times. Under the protection of argon, 1.5mL of 1, 2-dichloroethane was added to the reaction tube, and the reaction tube was stirred in a 110 ℃ oil bath with a piston for 24 hours.
(2) Adding ethyl acetate into the material obtained in the step (1), fully mixing, filtering solid residues by using a short silica gel column, and keeping an organic phase.
(3) And (3) carrying out spin-drying on the solvent in the organic phase obtained in the step (2) to obtain a crude product, and then purifying the crude product by using a silica gel column. The eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 75%, Z/E is more than 30: 1, and the purity of the product is 100%.
Example 2
The reaction formula for this example is shown below:
(1) Under air, copper tetraethyl hexafluorophosphate (10 mol%), 1, 10-phenanthroline (10 mol%), t-butyl ketone-derived oxaziridine (0.15 mmol) and 4-acetamido- α -fluorocinnamic acid (0.3 mmol) were added to a sealed reactor tube containing magnetons and purged with argon three times. 1.5mL of 1, 2-dichloroethane was added to the reaction tube under argon, and the reaction tube was stirred in a 110 ℃ oil bath with a stopper for 24 hours.
(2) Adding ethyl acetate into the material obtained in the step (1), fully mixing, filtering solid residues by using a short silica gel column, and keeping an organic phase.
(3) The solvent in the organic phase obtained in step (2) was spin-dried to obtain a crude product, which was then purified by a silica gel column. The eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 61 percent, Z/E is more than 30: 1, and the purity of the product is 100 percent.
Example 3
The reaction formula for this example is shown below:
(1) Under air, copper tetraethyl hexafluorophosphate (10 mol%), 1, 10-phenanthroline (10 mol%), oxaziridine derived from cyclohexylketone (0.15 mmol) and 4-fluoro-3-chloro-. Alpha. -fluorocinnamic acid (0.3 mmol) were added to a sealed reaction tube containing magnetons with a branch tube, and the reaction tube was purged with argon three times. Under the protection of argon, 1.5mL of 1, 2-dichloroethane was added to the reaction tube, and the reaction tube was stirred in a 110 ℃ oil bath with a piston for 24 hours.
(2) Adding ethyl acetate into the material obtained in the step (1), fully mixing, filtering solid residues by using a short silica gel column, and keeping an organic phase.
(3) And (3) carrying out spin-drying on the solvent in the organic phase obtained in the step (2) to obtain a crude product, and then purifying the crude product by using a silica gel column. The eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 65%, Z/E is more than 30: 1, and the purity of the product is 100%.
Example 4
The reaction formula for this example is shown below:
(1) Under air, copper tetraethyl hexafluorophosphate (10 mol%), 1, 10-phenanthroline (10 mol%), t-butyl ketone-derived oxaziridine (0.15 mmol) and estrone-derived α -fluorocinnamic acid (0.3 mmol) were added to a sealed reaction tube containing magnetons with a branch tube, and the reaction tube was purged with argon three times. Under the protection of argon, 1.5mL of 1, 2-dichloroethane was added to the reaction tube, and the reaction tube was stirred in a 110 ℃ oil bath with a piston for 24 hours.
(2) Adding ethyl acetate into the material obtained in the step (1), fully mixing, filtering solid residues by using a short silica gel column, and keeping an organic phase.
(3) And (3) carrying out spin-drying on the solvent in the organic phase obtained in the step (2) to obtain a crude product, and then purifying the crude product by using a silica gel column. The eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 62 percent, Z/E is more than 30: 1, and the purity of the product is 100 percent.
Example 5
The reaction formula for this example is shown below:
(1) Under air, copper tetraethyl hexafluorophosphate (10 mol%), 1, 10-phenanthroline (10 mol%), oxaziridine derived from cyclohexylketone (0.15 mmol) and β -fluorocinnamic acid (0.3 mmol) were added to a sealed reactor tube containing magnetons with a branch tube, and the reactor tube was purged with argon three times. Under the protection of argon, 1.5mL of 1, 2-dichloroethane was added to the reaction tube, and the reaction tube was stirred in a 110 ℃ oil bath with a piston for 24 hours.
(2) Adding ethyl acetate into the material obtained in the step (1), fully mixing, filtering solid residues by using a short silica gel column, and keeping an organic phase.
(3) And (3) carrying out spin-drying on the solvent in the organic phase obtained in the step (2) to obtain a crude product, and then purifying the crude product by using a silica gel column. The eluent is a mixture of petroleum ether and ethyl acetate, the separation yield is 58%, Z/E is more than 30: 1, and the purity of the product is 100%.
The amounts of the substances and the reaction conditions used were experimentally extended as in the examples to demonstrate that the technical solution of the invention has good functional group compatibility.
The present invention has been described in detail, and it should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of product 1 prepared according to the invention;
FIG. 2 is a nuclear magnetic resonance fluorine spectrum of product 1 prepared by the present invention;
FIG. 3 is a NMR carbon spectrum of product 1 prepared according to the invention;
FIG. 4 is a NMR spectrum of product 2 prepared according to the invention;
FIG. 5 is the NMR fluorine spectrum of product 2 prepared by the present invention;
FIG. 6 is a NMR carbon spectrum of product 2 prepared according to the invention;
FIG. 7 is a NMR spectrum of product 3 prepared according to the invention;
FIG. 8 is a nuclear magnetic resonance fluorine spectrum of product 3 prepared by the present invention;
FIG. 9 is a NMR carbon spectrum of product 3 prepared according to the present invention.
Claims (5)
1. A method for synthesizing monofluoro olefin by taking ketone derivatives as raw materials is characterized by comprising the following steps: using fluoroacrylic acid and ketone compound derivative oxaziridine as raw material and using copper tetrakis-cyano hexafluorophosphate [ Cu (CH) 3 CN) 4 PF 6 ]1, 10-phenanthroline as a catalyst and 1, 2-Dichloroethane (DCE) as a solvent, according to the following reaction formula, obtaining the Z-monofluoroolefin compound with the general formula (I): :
2. the method for synthesizing monofluoroolefin according to claim 1, wherein the method comprises the steps of: the amount of the material of the copper tetrakishexafluorophosphate was 10% of the amount of the material of the oxaziridine.
3. The method for synthesizing monofluoroolefin according to claim 1, wherein the method comprises the steps of: the amount of the substance of 1, 10-phenanthroline is 10% of the amount of the substance of oxaziridine.
4. The method for synthesizing monofluoroolefin according to claim 1, wherein said method comprises the steps of: the amount of the substance of fluoroacrylic acid is 2 times the amount of the substance of oxaziridine.
5. The method for synthesizing monofluoroolefin according to claim 1, wherein said method comprises the steps of: the reaction temperature was 110 ℃ and the reaction time was 24 hours.
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| CN111170856A (en) * | 2020-02-08 | 2020-05-19 | 云南民族大学 | Preparation method and application of fluoroolefin |
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| US20020019539A1 (en) * | 2000-03-31 | 2002-02-14 | Bailey Anne E. | Process for the preparation of matrix metalloproteinase inhibitors |
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