CN117645533B - Synthesis method of 4- (trifluoromethyl) cyclohexanone - Google Patents
Synthesis method of 4- (trifluoromethyl) cyclohexanone Download PDFInfo
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- CN117645533B CN117645533B CN202311361627.5A CN202311361627A CN117645533B CN 117645533 B CN117645533 B CN 117645533B CN 202311361627 A CN202311361627 A CN 202311361627A CN 117645533 B CN117645533 B CN 117645533B
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- Prior art keywords
- trifluoromethyl
- cyclohexanedione
- cyclohexanone
- hydrazone
- toluenesulfonyl
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- IPQDZFUZVJKAKZ-UHFFFAOYSA-N 4-(trifluoromethyl)cyclohexan-1-one Chemical compound FC(F)(F)C1CCC(=O)CC1 IPQDZFUZVJKAKZ-UHFFFAOYSA-N 0.000 title claims abstract 9
- 238000001308 synthesis method Methods 0.000 title claims abstract 4
- -1 1, 4-cyclohexanedione-toluenesulfonyl hydrazone Chemical compound 0.000 claims abstract 5
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 claims abstract 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract 3
- DCZFGQYXRKMVFG-UHFFFAOYSA-N cyclohexane-1,4-dione Chemical compound O=C1CCC(=O)CC1 DCZFGQYXRKMVFG-UHFFFAOYSA-N 0.000 claims abstract 3
- 229910052700 potassium Inorganic materials 0.000 claims abstract 3
- 239000011591 potassium Substances 0.000 claims abstract 3
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 claims abstract 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract 3
- 230000008878 coupling Effects 0.000 claims abstract 2
- 238000010168 coupling process Methods 0.000 claims abstract 2
- 238000005859 coupling reaction Methods 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims 4
- 239000003960 organic solvent Substances 0.000 claims 4
- 230000002194 synthesizing effect Effects 0.000 claims 4
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- 229910052796 boron Inorganic materials 0.000 claims 3
- 239000003054 catalyst Substances 0.000 claims 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 238000005286 illumination Methods 0.000 claims 2
- 150000007530 organic bases Chemical class 0.000 claims 2
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 239000012973 diazabicyclooctane Substances 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical group COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 claims 1
- 150000007857 hydrazones Chemical class 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of 4- (trifluoromethyl) cyclohexanone, belonging to the field of medical intermediates. The invention is divided into two steps: the first step: condensing 1, 4-cyclohexanedione with p-toluenesulfonyl hydrazine to obtain 1, 4-cyclohexanedione-toluenesulfonyl hydrazone; and a second step of: the 1, 4-cyclohexanedione-toluene sulfonyl hydrazone and the potassium trifluoromethyl trifluoroborate are subjected to light coupling under alkaline conditions to obtain the 4- (trifluoromethyl) cyclohexanone. The synthesis method has the characteristics of few steps, simple and stable operation, high yield and the like.
Description
Technical Field
The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a synthetic method of 4- (trifluoromethyl) cyclohexanone.
Background
The 4- (trifluoromethyl) cyclohexanone can be used as an excellent organic solvent and an organic intermediate, and compared with a compound without fluorine, the 4- (trifluoromethyl) cyclohexanone has better stability, bioactivity and fat solubility, is widely applied to the fields of microelectronics industry, medicines, new materials and the like, and is an important intermediate and monomer for synthesizing liquid crystal materials in the microelectronics field, and has important application value; in the medical field, it is an important segment of organic building blocks, and can be introduced into cyclohexyl trifluoromethyl, for example, 4- (trifluoromethyl) cyclohexanone is used as an intermediate to synthesize an agonist of a melanocortin receptor (WO 2008/7930,2008, A1) for treating corresponding cancers and the like.
In the prior art methods of 4- (trifluoromethyl) cyclohexanone intermediates, there are mainly two synthetic methods:
Route a: literature [ Journal ofOrganic Chemistry,2011, vol.76, #19, p.7706-7719] takes 1, 4-cyclohexanedione monoethylene glycol ketal as a starting material, products are obtained through four-step synthesis, 8-hydroxy-8- (trifluoromethyl) -1, 4-dioxaspiro [4.5] decane is firstly obtained through reaction with (trifluoromethyl) trimethylsilane under the action of tetrabutylammonium fluoride serving as a phase transfer catalyst, then 4-trifluoromethyl-3-cyclohexenone vinyl ketal is obtained through elimination under the action of thionyl chloride, DMAP and pyridine, 4-trifluoromethyl cyclohexanone vinyl ketal is obtained through subsequent platinum-carbon catalytic hydrogenation addition, and finally 4- (trifluoromethyl) cyclohexanone is obtained through hydrochloric acid deprotection, wherein the total yield is about 14.3 percent and the purity is 90 percent. The method has longer operation steps, lower yield and relatively higher cost. The reaction equation is as follows:
Route B: the European Union patent WO2008/7930,2008, A1 takes 4-trifluoromethyl phenol as an initiator, and the product is obtained through two-step synthesis, firstly, platinum dioxide is catalyzed, hydrogenated and added in a high-temperature and high-pressure resistant stainless steel kettle to obtain 4- (trifluoromethyl) cyclohexanol, then, 4- (trifluoromethyl) cyclohexanone is obtained through oxidation by using a dess-Martin oxidant, the total yield is up to 82.3 percent, the steps of the method are short, but the requirement on equipment is high, and the price of an oxidizing reagent is high. The reaction equation is as follows:
Aiming at the defects of the reaction route, the invention adopts the coupling reaction of the p-toluenesulfonyl hydrazone and the potassium trifluoromethyl trifluoroborate under the irradiation of visible light, thereby not only reducing the cost and improving the stability, but also being capable of carrying out industrialized production and further meeting the increasing demands.
Disclosure of Invention
In order to solve the technical problems, the invention discloses a synthesis method of 4- (trifluoromethyl) cyclohexanone. The synthesis method comprises two steps: the first step: condensing 1, 4-cyclohexanedione with p-toluenesulfonyl hydrazine to obtain 1, 4-cyclohexanedione-toluenesulfonyl hydrazone; and a second step of: the 1, 4-cyclohexanedione-toluene sulfonyl hydrazone and the potassium trifluoromethyl trifluoroborate are subjected to light coupling under alkaline conditions to obtain the 4- (trifluoromethyl) cyclohexanone. The synthesis method has the characteristics of few steps, simple and stable operation, high yield and the like.
The invention relates to a synthesis method of 4- (trifluoromethyl) cyclohexanone, which has the following reaction equation:
The first step: heating and condensing 1, 4-cyclohexanedione, p-toluenesulfonyl hydrazine, a boron-containing catalyst and an organic solvent to obtain 1, 4-cyclohexanedione-toluenesulfonyl hydrazone;
and a second step of: coupling 1, 4-cyclohexanedione mono toluene sulfonyl hydrazone, trifluoromethyl potassium trifluoroborate, organic base and organic solvent under the illumination to obtain 4- (trifluoromethyl) cyclohexanone.
Further, in the above technical scheme, the boron-containing catalyst in the first step is selected from trimethyl borate and triisopropyl borate.
Further, in the above technical scheme, the organic solvent in the first step is selected from tetrahydrofuran, methanol, ethanol or isopropanol.
Further, in the technical scheme, the molar ratio of the 1, 4-cyclohexanedione, the p-toluenesulfonyl hydrazine and the boron-containing catalyst in the first step is 1.02-1.05:1:0.3-1.0.
Further, in the above technical scheme, in the second step, the base is selected from DBU or DAB CO; the base is preferably DBU.
Further, in the above technical scheme, the organic solvent in the second step is selected from 1, 4-dioxane or benzotrifluoride.
Further, in the technical scheme, in the second step, the molar ratio of the 1, 4-cyclohexanedione monomethylsulfonyl hydrazone to the potassium trifluoromethyl trifluoroborate to the organic base is 1.01-1.03:1:1-1.2.
Further, in the above technical solution, in the second step, the illumination is selected from blue 450nm light sources.
The invention has the beneficial effects that:
1. The first step adopts the addition of a catalytic amount of boron-containing catalyst, ensures that no double substitution byproducts (reaction products of two ketones in cyclohexanedione and p-toluenesulfonyl hydrazine) are generated in a reaction system, and the monoazone product can be obtained after the reaction is finished and pulping is carried out.
2. The second step adopts p-toluenesulfonyl hydrazone and trifluoromethyl potassium trifluoroborate to carry out coupling reaction under the irradiation of visible light, so that the method has the advantages of high efficiency, easy operation and safety; heavy metal catalysts such as traditional palladium and copper catalysts are avoided.
Drawings
FIG. 1 shows the HNMR spectrum of the 4- (trifluoromethyl) cyclohexanone product obtained in example 4.
Detailed Description
The present invention will be further described in detail by the following examples, but the present invention is not limited to the following examples.
Example 1
In a four-necked flask, 1, 4-cyclohexanedione (117.7 g,1.05 mol) and trimethyl borate (20.8 g,0.2 mol) and methanol 600mL were added; heating to 40-50deg.C, adding dropwise a mixed solution of p-toluenesulfonyl hydrazine (186.2 g,1 mol) and methanol 450mL, maintaining the temperature and stirring for 2 hr, heating to reflux for 1 hr, and performing HPLC to control the reaction of p-toluenesulfonyl hydrazine completely. Removing methanol by reduced pressure distillation, adding ethyl acetate, washing with water, concentrating the organic layer under reduced pressure, pulping with n-heptane, and oven drying to obtain 271.4g of 1, 4-cyclohexanedione monomethylsulfonyl hydrazone with yield 96.8％,HPLC 97.5％.1HNMR(400MHz,DMSO-d6):9.78(s,1H),7.68-7.65(m,2H),7.40-7.37(m,2H),2.38(s,3H),2.14-2.02(m,4H),1.94-1.82(m,4H).
Example 2
In a four-necked flask, 1, 4-cyclohexanedione (117.7 g,1.05 mol) and trimethyl borate (31.2 g,0.3 mol) and tetrahydrofuran (600 mL) were added; heating to 40-50deg.C, adding dropwise a mixed solution of p-toluenesulfonyl hydrazine (186.2 g,1 mol) and tetrahydrofuran (450 mL), maintaining the temperature and stirring for 3 hr, heating to reflux for 1 hr, and performing HPLC to completely react the p-toluenesulfonyl hydrazine. Ethanol was distilled off under reduced pressure, ethyl acetate was added, then water was washed, the organic layer was concentrated under reduced pressure, and n-heptane was slurried and dried to give 259.6g of 1, 4-cyclohexanedione monomethylenesulfonylhydrazone, yield 92.6%, 99.4% by HPLC.
Example 3:
The four-mouth bottle with magnetic stirring is added with 0.01mol of 1, 4-cyclohexanedione mono toluene sulfonyl hydrazone, 0.01mol of trifluoromethyl potassium trifluoroborate, 0.01mol of alkali and organic solvent, under the protection of nitrogen, light sources with different wavelengths are irradiated, the temperature is controlled to be 30-35 ℃, the reaction is stopped after 2 hours, the GC is performed, and the yield condition is judged by an internal standard method, as shown in the table 1.
TABLE 1 influence of different solvents, bases and light conditions on the reaction
Note that: some representative experimental data are shown in the table.
Example 4
1, 4-Cyclohexanedione (28.9 g,0.103 mol), potassium trifluormethyl trifluoroborate (17.6 g,0.1 mol), DBU (15.2 g,0.1 mol) and benzotrifluoride (140 mL) are sequentially added into a four-mouth bottle with magnetic stirring, after nitrogen replacement, a blue light LED (light-emitting diode) with a wavelength of 450nm is irradiated, the temperature is controlled to be 30-35 ℃ for reaction for 2 hours, TLC (thin layer chromatography) is used for rapidly detecting the potassium trifluormethyl trifluoroborate, the light source is withdrawn, the crude product is obtained by reduced pressure distillation at room temperature, and then 11.3g of 4- (trifluoromethyl) cyclohexanone is obtained by rectification; yield is good 68.1％,HPLC 99.1％.1HNMR(400MHz,CDCl3):2.48-2.40(m,3H),2.36-2.28(m,2H),2.23-2.17(m,2H),1.80-1.73(m,2H).
Example 5
1, 4-Cyclohexanedione (28.9 g,0.103 mol), potassium trifluormethyl trifluoroborate (17.6 g,0.1 mol), DABCO (11.2 g,0.1 mol) and dioxane (90 mL) were sequentially added into a four-necked flask with magnetic stirring, after nitrogen substitution, a blue LED (light-emitting diode) with a wavelength of 450nm was irradiated, the reaction was carried out for 1 hour at a temperature of 30-35 ℃, TLC was carried out to rapidly detect the potassium trifluormethyl trifluoroborate, the light source was withdrawn, and the crude product was obtained by distillation under reduced pressure at room temperature, followed by rectification to obtain 12.4g of 4- (trifluoromethyl) cyclohexanone. Yield 74.8%, HPLC 99.5%.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should make equivalent substitutions or modifications according to the technical scheme of the present invention and the inventive concept thereof, and should be covered by the scope of the present invention.
Claims (5)
1. A synthesis method of 4- (trifluoromethyl) cyclohexanone is characterized in that the reaction equation is as follows:
the first step: heating and condensing 1, 4-cyclohexanedione, p-toluenesulfonyl hydrazine, a boron-containing catalyst and an organic solvent to obtain 1, 4-cyclohexanedione-toluenesulfonyl hydrazone; the boron-containing catalyst is selected from trimethyl borate or triisopropyl borate;
And a second step of: coupling 1, 4-cyclohexanedione mono-tosyl hydrazone, potassium trifluoromethyl trifluoroborate, organic base and organic solvent under the illumination to obtain 4- (trifluoromethyl) cyclohexanone; the base is selected from DBU or DABCO; the illumination is a blue light 450nm light source.
2. The method for synthesizing 4- (trifluoromethyl) cyclohexanone according to claim 1, wherein: in the first step, the organic solvent is selected from tetrahydrofuran, methanol, ethanol or isopropanol.
3. The method for synthesizing 4- (trifluoromethyl) cyclohexanone according to claim 1, wherein: in the first step, the mol ratio of the 1, 4-cyclohexanedione, the p-toluenesulfonyl hydrazine and the boron-containing catalyst is 1.02-1.05:1:0.3-1.0.
4. The method for synthesizing 4- (trifluoromethyl) cyclohexanone according to claim 1, wherein: in the second step, the organic solvent is selected from 1, 4-dioxane or benzotrifluoride.
5. The method for synthesizing 4- (trifluoromethyl) cyclohexanone according to claim 1, wherein: in the second step, the molar ratio of the 1, 4-cyclohexanedione monomethylsulfonyl hydrazone to the potassium trifluoromethyl trifluoroborate to the organic base is 1.01-1.03:1:1-1.2.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008007930A1 (en) * | 2006-07-14 | 2008-01-17 | Lg Life Sciences Ltd. | Melanocortin receptor agonists |
| CN103145746A (en) * | 2012-12-20 | 2013-06-12 | 大连联化化学有限公司 | Process method for synthesizing cyclopentene/ hexene-1-boronic acid pinacol cyclic ester |
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| CR20230519A (en) * | 2021-05-07 | 2024-01-19 | Merck Sharp & Dohme Llc | Cycloalkyl 3-oxopiperazine carboxamides and cycloheteroalkyl 3-oxopiperazine carboxamides as nav1.8 inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008007930A1 (en) * | 2006-07-14 | 2008-01-17 | Lg Life Sciences Ltd. | Melanocortin receptor agonists |
| CN103145746A (en) * | 2012-12-20 | 2013-06-12 | 大连联化化学有限公司 | Process method for synthesizing cyclopentene/ hexene-1-boronic acid pinacol cyclic ester |
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Inventor after: Li Guowei Inventor after: Yan Haijin Inventor after: Wang Lizhong Inventor after: Sun Guigan Inventor after: Xu Qingyu Inventor after: Li Ning Inventor after: Sun Yulan Inventor after: Lu Keyu Inventor after: Zhao Guoping Inventor before: Li Guowei Inventor before: Sun Guigan Inventor before: Xu Qingyu Inventor before: Li Ning Inventor before: Sun Yulan Inventor before: Lu Keyu Inventor before: Zhao Guoping |
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