CN112110803B - Preparation method of 3',5' -dichloro-2, 2, 2-trifluoro acetophenone - Google Patents
Preparation method of 3',5' -dichloro-2, 2, 2-trifluoro acetophenone Download PDFInfo
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Abstract
The application relates to the technical field of chemical pharmacy, in particular to a preparation method of 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, which takes 3' -chloro-2, 2, 2-trifluoroacetophenone as a raw material and prepares the 3',5' -dichloro-2, 2, 2-trifluoroacetophenone by four steps of nitration, reduction, chlorination and deamination.
Description
Technical Field
The application relates to the technical field of chemical pharmacy, in particular to a preparation method of 3',5' -dichloro-2, 2, 2-trifluoro acetophenone.
Background
3',5' -dichloro-2, 2, 2-trifluoro acetophenone is one important intermediate for synthesizing pesticide and veterinary medicine.
In the prior art, the synthesis methods of 3',5' -dichloro-2, 2, 2-trifluoro acetophenone mainly include the following methods:
1. PCT patent application No. WO2018009751 discloses a preparation method using 3, 5-dichlorobromobenzene and methyl trifluoroacetate as starting materials, using tetrahydrofuran as a solvent, preparing grignard reagent by reacting 3, 5-dichlorobromobenzene with isopropyl magnesium chloride-lithium chloride, and then reacting with methyl trifluoroacetate.
2. The Chinese patent with the publication number of CN107353189A discloses a preparation method for obtaining 3, 5-dichlorobromobenzene and methyl trifluoroacetate by taking 3, 5-dichlorobromobenzene as a raw material and reacting with trifluoroacetyl compound under the action of butyl lithium.
In the two prior arts, the raw materials are expensive and the reaction conditions are severe, and some of the raw materials which are inflammable, explosive and expensive are used in the reaction process, which increases the cost of industrial production and has poor economic effect in large-scale production.
Disclosure of Invention
Aiming at the defects in the prior art, the application aims to provide the preparation method of the 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, which selects the raw materials with low price and mild reaction conditions to realize the preparation of the 3',5' -dichloro-2, 2, 2-trifluoroacetophenone and has better economic effect.
In one embodiment, the present application provides a method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, comprising the steps of:
s1, carrying out nitration reaction on the compound I and a nitration reagent under the catalysis of acid I to obtain a composition of a compound II and a compound III;
s2, carrying out nitro reduction reaction on the compound II and compound III composition obtained in the step S1 to obtain a compound IV and compound V composition;
s3, carrying out chlorination reaction on the compound IV and compound V composition obtained in the step S2 through a chlorination reagent to obtain a compound VI and compound VII composition;
s4, carrying out diazotization elimination reaction on the compound VI and the compound VII obtained in the step S3 to obtain 3',5' -dichloro-2, 2, 2-trifluoroacetophenone;
in step S1, the acid i is one of phosphoric acid, polyphosphoric acid, methanesulfonic acid, chlorosulfonic acid, trifluoromethanesulfonic anhydride, acetic acid, acetic anhydride, boron trifluoride diethyl etherate, perchloric acid, phosphomolybdic acid, strong acid resin, fuming sulfuric acid, and 80% -98% sulfuric acid, or a stable mixed system formed by any two or more of the above acids; the nitrating reagent is any one or more of nitric acid, fuming nitric acid, sodium nitrate, potassium nitrate, ammonium nitrate, lead nitrate, aluminum nitrate, barium nitrate, dinitrogen pentoxide and nitrogen dioxide; the reaction temperature during nitration is 0-80 ℃;
in step S3, one or more of chlorine, sulfuryl chloride, trichloroisocyanuric acid, and NCS is selected for chlorination.
The compound I is a common chemical raw material, is simple and easy to obtain, can be directly purchased and has low price. After the compound I is nitrified, under the action of a chloride ion substitution effect, two compounds of a compound II and a compound III can be generated, and the compound II and the compound III are directly put into the next reaction without separation. In step S2, the nitro group is reduced to an amino group to give a mixture of compound IV and compound V, which is then fed to the next step without isolation. In the step S3, amino is a strong electron-donating group and has a good ortho-para positioning effect, so that the compound IV and the compound V only have a halogenation reaction on the 5' position of a benzene ring in the chlorination process, the reaction is easy to occur, and harsh reaction conditions are not needed. After the reaction is finished, removing amino through diazotization reaction to obtain the 3',5' -dichloro-2, 2, 2-trifluoro acetophenone.
In the process, the whole reaction has no complex process, and the raw materials are simple and easily-obtained common chemical raw materials, so the production cost is low in the whole production process, and the economic effect is good.
The application may be further configured in a preferred example to: step S1 is specifically as follows:
s1-1, mixing the compound I with an acid I, then dropwise adding a nitration reagent, and fully reacting to obtain an intermediate reaction solution I;
s1-2, adding water and an extracting agent I into the intermediate reaction liquid I after the reaction is finished, and keeping an organic phase I;
s1-3, washing the organic phase I obtained in the step S1-2 and removing the solvent to obtain a composition of a compound II and a compound III;
wherein, the acid I is one of 80-98% sulfuric acid or fuming sulfuric acid, and the nitrating reagent is fuming nitric acid.
Sulfuric acid is selected as a nitrating catalyst, fuming nitric acid is selected, the sulfuric acid is used as an industrial raw material, the supply quantity is large, the price is low, the dissociation degree of the sulfuric acid in a system has the gradient characteristic, more stable hydrogen ion concentration can be provided in the reaction process, the reaction process is more controllable, and the cost is saved. In addition, sulfuric acid is not easy to introduce other groups on a benzene ring, and the purity of a target product is improved.
Fuming nitric acid exists in a liquid state, has good reaction activity, does not need to introduce other solvents during reaction, and reduces the difficulty of post-treatment and separation.
The present application may be further configured in a preferred example to: in step S1-1, after the compound I and the acid I are mixed, heating to 40-60 ℃, and then dropwise adding a nitration reagent for reaction; in step S1-2, the intermediate reaction solution I is first cooled to 0-10 ℃, the intermediate reaction solution I is added dropwise into ice water, and then the extractant I is added.
In the technical scheme, after the compound I and the acid I are mixed, the temperature is raised firstly, the reaction can be rapidly carried out after the temperature is raised, concentrated sulfuric acid is activated for sites on a benzene ring in advance in a preheating mode, and a nitration reagent is added into the system in a dropwise adding mode, so that sufficient materials in the system are nitrated.
The application may be further configured in a preferred example to: in step S2, the nitro group is reduced by hydrogenation reduction under the action of catalyst i, which is any one of platinum carbon, palladium carbon or Raney nickel.
The present application may be further configured in a preferred example to: step S2 is specifically as follows:
s2-1, dissolving the compound II and compound III composition obtained in the step S1 in a solvent I, adding a catalyst, removing air, heating to 40-60 ℃, introducing hydrogen, and fully reacting to obtain an intermediate reaction liquid II;
s2-2, cooling, filtering and concentrating the intermediate reaction liquid II obtained in the step S2-1, further purifying and drying by a recrystallization method to obtain a composition of a compound IV and a compound V;
wherein, the solvent I is any one of the following substances or a homogeneous mixed system formed by any more of the following substances: methanol, ethanol, ethyl acetate, n-butyl acetate, isopropyl acetate, isopropanol, and toluene.
The materials after the reaction are purified and dried by a recrystallization method, the operation is simpler, and the equipment maintenance components are lower. The solution obtained after recrystallization can be recycled after treatment, and the waste of materials is reduced, so that the production cost is further reduced, and the economic effect is improved.
The application may be further configured in a preferred example to: the step S2-2 is specifically as follows: and (3) cooling and filtering the intermediate reaction liquid II obtained in the step (S2-1), adding toluene, heating to 40-50 ℃, fully dissolving, cooling to-30-20 ℃, standing to precipitate a solid, filtering, and drying to obtain the compound IV and compound V composition.
And (3) recrystallizing the intermediate reaction liquid II obtained in the step (S2-1) by using toluene as a solvent, and fully dissolving the solid material in the intermediate reaction liquid II in the toluene by heating first, so that impurities are not easily adsorbed in the residual solid, the impurities in the intermediate reaction liquid II are more fully removed, and the purity of the finally obtained target product is improved.
The present application may be further configured in a preferred example to: step S3 is specifically as follows:
s3-1, dissolving a compound IV and a compound V in a solvent II, heating to 50-60 ℃, adding a chlorination reagent uniformly within 90min after full dissolution, and then carrying out heat preservation and full reaction to obtain an intermediate reaction solution III;
s3-2, cooling the intermediate reaction liquid obtained in the step S3-1, adding water for extraction, and reserving an organic phase to obtain an organic phase II;
in step S4, diazotization deamination reaction is directly carried out in an organic phase II;
the chlorinating agent is any one of chlorine, sulfonyl chloride, trichloroisocyanuric acid and NCS, or a composition formed by any several of chlorine, sulfonyl chloride, trichloroisocyanuric acid and NCS.
The solvent II is any one of toluene, dichloromethane, chloroform, acetonitrile, isopropanol and ethanol, or a homogeneous system formed by mixing any several of the solvents.
In the technical scheme, the organic phase II is directly put into the next step for reaction, so that the post-treatment process between reactions is reduced, the reaction process steps are reduced, the reaction efficiency is improved, and the economic effect is further improved.
The present application may be further configured in a preferred example to: step S4 is specifically as follows:
s4-1, cooling the organic phase II obtained in the step S3-2 to-10-0 ℃, dropwise adding an acid II to acidify the organic phase II, and fully reacting to obtain an intermediate reaction liquid IV;
s4-2, adding a nitrous acid reagent solution into the intermediate reaction liquid IV, keeping the temperature lower than 0 ℃, and fully reacting to obtain an intermediate reaction liquid V;
s4-3, heating the intermediate reaction solution V to above 20 ℃, and adding hypophosphorous acid and a catalyst II to obtain an intermediate reaction solution VI;
s4-4, further purifying and separating the intermediate reaction solution V to obtain 3',5' -dichloro-2, 2, 2-trifluoro acetophenone;
wherein, the acid II is any one of hydrochloric acid, hydrobromic acid, hydrofluoric acid, phosphoric acid, acetic acid or sulfuric acid; the nitrous acid reagent is any one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite.
In the technical scheme, the organic phase II introduced in the step S3-2 is directly introduced into the step S4 for reaction, so that the separation process is reduced, the process steps are further reduced, and the production cost is reduced.
Detailed Description
The present application is further illustrated by the following examples.
Example 1
A preparation method of 3',5' -dichloro-2, 2, 2-trifluoro acetophenone comprises the following steps:
s1, carrying out nitration reaction on the compound I and a nitration reagent under the catalysis of acid I to obtain a composition of a compound II and a compound III;
s2, carrying out nitro reduction reaction on the compound II and compound III composition obtained in the step S1 to obtain a compound IV and compound V composition;
s3, performing chlorination reaction on the compound IV and compound V composition obtained in the step S2 through a chlorination reagent to obtain a compound VI and compound VII composition;
s4, carrying out diazotization elimination reaction on the compound VI and the compound VII obtained in the step S3 to obtain 3',5' -dichloro-2, 2, 2-trifluoroacetophenone;
step S1 specifically includes the following sub-steps:
s1-1, taking 104.5g (0.5mol) of the compound I, uniformly stirring and mixing with 200g of 98% concentrated sulfuric acid (acid I) by mass, heating to 60 ℃, uniformly dropwise adding 35.3g of fuming nitric acid as a nitrating reagent (0.55mol) within 10min after heating, and carrying out heat preservation reaction for 1.5h to obtain an intermediate reaction solution I;
s1-2, cooling the reacted intermediate reaction solution I to 0 ℃, dripping the reaction solution into ice-water mixed solution at 0 ℃, adding 1000mL of dichloromethane serving as an extracting agent I, fully stirring for 30min, standing and separating to obtain an organic phase I; s1-3, adding 500mL of 10% sodium bicarbonate solution into the organic phase I for washing, separating liquid again, and then removing the extracting agent I by reduced pressure distillation to obtain a composition of a compound II and a compound III.
Step S2 specifically includes the following sub-steps:
s2-1, taking 122.8g (0.484mol) of the compound II and compound III composition obtained in the step S1-3, adding 300mL of absolute ethyl alcohol as a solvent I, adding 5% of platinum carbon catalyst as a catalyst I, replacing three times with nitrogen to remove air, replacing three times with hydrogen to remove the nitrogen, introducing hydrogen, starting stirring and reacting, wherein the hydrogen pressure is 0.1MPa, the temperature is controlled at 50 +/-10 ℃ in the reaction process, and reacting for 1.5 hours to obtain an intermediate reaction liquid II;
s2-2, cooling the intermediate reaction liquid II to room temperature, filtering to remove the platinum-carbon catalyst, evaporating ethanol, adding 150mL of toluene after evaporation, heating to 40 ℃, stirring to dissolve and clarify, cooling to-20 ℃, standing overnight, filtering, and drying to obtain the composition of the compound IV and the compound V.
Step S3 specifically includes the following sub-steps:
s3-1, taking 44.7g of the composition of the compound IV and the compound V obtained in the step S2-2, adding 200mL of toluene (solvent II), heating to 50 ℃, after full dissolution, uniformly dropwise adding 33.7g (0.25mol) of sulfonyl chloride as a chlorination reagent within 90min, and then carrying out heat preservation reaction for 8h to obtain an intermediate reaction solution III;
and S3-2, cooling the intermediate reaction solution III to room temperature, adding 200mL of water for rinsing, and standing for layering after rinsing to obtain an organic phase II.
Step S4 specifically includes the following sub-steps:
s4-1, cooling the organic phase II (containing 49.3g of the compound VI and the compound VII in total, and the total mole number of 0.191mol) obtained in the S3-2 to-10 ℃, dropwise adding 80g of sulfuric acid (acid II) with the mass fraction of 92.5% within 30min, and stirring for 1h under heat preservation after dropwise adding to obtain an intermediate reaction liquid IV;
s4-2, uniformly dropwise adding a sodium nitrite solution (containing 0.41mol of sodium nitrite) with the mass fraction of 33% into the intermediate reaction liquid IV within 1h to serve as a nitrous acid reagent solution, keeping the temperature below 0 ℃, and continuing to perform heat preservation reaction for 2h after dropwise adding is finished to obtain an intermediate reaction liquid V;
s4-3, heating the intermediate reaction solution V to 20 ℃, adding 83g of 50% hypophosphorous acid solution, adding 0.5g of cuprous oxide serving as a catalyst II, and carrying out heat preservation and stirring reaction for 2 hours to obtain an intermediate reaction solution VI;
s4-4, standing and layering the intermediate reaction solution VI, washing an organic layer by using a 5% sodium bicarbonate solution, drying by using sewage magnesium sulfate, and distilling the solvent under reduced pressure to obtain a clear transparent liquid, namely 41.2g of 3',5' -dichloro-2, 2, 2-trifluoro acetophenone, the purity is 99.3%, and the yield is 89.1%.
Example 2
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoro acetophenone, which is different from the method in example 1 in that: in step S1-1, fuming sulfuric acid (200g, 04mol) is used as acid I.
Examples 3 to 4
A process for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone which differs from that of example 1 in that: in step S1-1, 80% sulfuric acid is selected as acid I, and the reaction time is kept for 2h and 1h respectively.
Example 5
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoro acetophenone, which is different from the method in example 1 in that: in step S1-1, the acid I is trifluoromethanesulfonic acid in an equivalent amount.
Example 6
A process for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone which differs from that of example 1 in that: in step S1-1, acetic anhydride is used as acid I, and 100mL of dichloromethane is added as a solvent.
Example 7
A process for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone which differs from that of example 6 in that: in step S1-1, the solvent is carbon tetrachloride.
Examples 8 to 9
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoro acetophenone, which is different from the method in example 1 in that: in step S1-1, the nitrating reagent is selected from saturated sodium nitrate aqueous solution and nitrogen dioxide, and the amount of the nitrating reagent is kept unchanged.
Example 10
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, which differs from example 2 in that: in step S1-2, toluene was selected as extractant I.
Example 11
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, which differs from example 2 in that: step S1-2 and step S1-3 are replaced with step S1-2': and naturally cooling the intermediate reaction liquid I after the reaction to-5 +/-5 ℃, adding 500mL of toluene, stirring for 30min, standing for layering, retaining an organic layer, adding 500mL of 10% sodium carbonate aqueous solution, washing with 500mL of water, separating, and distilling under reduced pressure to remove toluene to obtain the composition of the compound II and the compound III.
Example 12
A preparation method of 3',5' -dichloro-2, 2, 2-trifluoro acetophenone is different from that of example 1 in that in step S1-1, after a compound I and 98% sulfuric acid are uniformly mixed, 35.3g of fuming nitric acid serving as a nitrating reagent (0.55mol) is uniformly dripped in 10min, the temperature is raised to 60 ℃, and the heat preservation reaction is carried out for 1.5h to obtain an intermediate reaction liquid I.
Example 13
A process for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone is different from that of example 1 in that in step S1-2, 1000mL of methylene chloride as an extractant I is added to the intermediate reaction solution I after the reaction is completed, and after stirring thoroughly for 30min, the mixture is allowed to stand and separated to obtain an organic phase I.
Example 14
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, which is different from example 1 in that 5% palladium on carbon is selected as catalyst i and toluene is selected as solvent i in step S2-1.
Example 15
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone is different from that of example 1 in that Raney nickel is selected as a catalyst I in step S2-1, and ethanol and isopropanol are selected as solvents I and mixed in a volume ratio of 1:1 to obtain a homogeneous mixed system.
Example 16
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, which is different from example 1 in that, in step S2-1, the pressure of hydrogen is 1.0 MPa.
Example 17
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoro acetophenone, which is different from that in example 1, in step S2-2, the addition amount of toluene is 200mL, the temperature is raised to 50 ℃ after toluene is added, the temperature is reduced to-30 ℃ after the toluene is fully dissolved, the mixture is kept stand overnight, filtered and dried, and a composition of a compound iv and a compound v is obtained.
Example 18
A process for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone is different from that of example 1 in that in step S3-1, the solvent II is acetonitrile, the chlorinating agent is NCS in an amount equal to that of the solvent II, and the NCS is added directly to the system in the form of solid.
Example 19
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoro acetophenone, which is different from the method in example 18 in that chlorine gas is selected as a chlorinating agent in step S3, and the method comprises the following steps:
s3-1 ', taking 44.7g of the compound IV and compound V composition obtained in the step S2-2, adding 500mL of glacial acetic acid (solvent II), heating to 40 ℃, fully dissolving, slowly introducing 17.04g (0.24mol) of chlorine within 3h, simultaneously tracking and detecting the raw materials by using a time panel, introducing nitrogen after the reaction is finished, and blowing the generated hydrogen chloride and the redundant chlorine into an exhaust gas absorption device to obtain an intermediate reaction liquid III';
s3-2 ', cooling the intermediate reaction solution III' to room temperature, carrying out suction filtration, washing a filter cake twice by using 200mL of glacial acetic acid, and carrying out vacuum drying at 60 ℃ to obtain a composition of a compound IV and a compound V.
In step S4, the above-obtained composition of compound IV and compound V is added into toluene to prepare organic phase II for reaction.
Example 20
A preparation method of 3',5' -dichloro-2, 2, 2-trifluoroacetophenone is different from that of the embodiment 1 in that in the step S4, hydrochloric acid with the mass fraction of 30% is selected as acid II, the adding amount of the hydrochloric acid is 240g, and potassium nitrite saturated solution is selected as nitrous acid reagent.
Example 21
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, which is different from that in example 1, in step S4, acid ii is 150g of glacial acetic acid, and nitrous acid reagent is calcium nitrite saturated solution.
Example 22
A method for producing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, which is different from example 1 in that methyl nitrite is selected as the nitrous acid reagent in an amount equivalent to that in step S4.
Example 23
A method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, which is different from that of example 1, in step S1, further comprising the steps of:
s1-4, adding the compound II and compound III composition obtained in the step S1-3 into 330mL of toluene, heating to 40 ℃ to completely dissolve the compound II and compound III, cooling to-20 ℃, standing overnight, filtering to obtain a solid, namely compound III, and removing toluene from the residual liquid in a reduced pressure distillation mode to obtain compound II.
In the subsequent reaction, the compound II and the compound III are separately subjected to steps S2, S3 and S4, and the finally obtained products are combined to obtain the 3',5' -dichloro-2, 2, 2-trifluoroacetophenone.
Example 24
A process for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone was carried out in a manner similar to that of example 1 except that the experimental conditions of example 1 were enlarged and the amounts of the respective materials added were 10 times as much as those of example 1, and the reaction time and other reaction conditions were kept constant.
For the above examples, the following comparative examples were set up for comparison.
Comparative example 1
A preparation method of 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, which is synthesized by referring to a method in PCT application No. WO2018009751, and specifically comprises the following steps:
dissolving a compound VIII (25g, 110.6mmol) in 400mL THF at room temperature, dissolving 110.6mmol isopropyl magnesium chloride in 85mL THF, and uniformly dripping into the compound VIII in a THF solution system within 15min, and keeping the temperature at 20-25 ℃. After the addition was complete, the reaction was held at room temperature for a further 1.5 h.
And cooling the solution after the reaction to below 0 ℃. Ethyl trifluoromethylacetate (12.23mL, 121.6mmol) was dissolved in 20mL of THF and added dropwise to the above reacted solution, the reaction was continued for 0.5h with incubation, after which time it was allowed to return to room temperature and stirring was continued for 1.5 h. Then, the system is cooled to-5 to-10 ℃, 73.7mL of 6M hydrochloric acid solution is diluted to 150mL by adding water, and the diluted solution is dripped into the cooled system. After the dropwise addition, the temperature is kept and the stirring is continued for 0.5h, and then the temperature is raised again to the room temperature.
Water was added to the above system and the layers were separated, the organic phase was retained and the aqueous phase was washed repeatedly three times with dichloromethane. And (3) combining the dichloromethane phase with the previous organic phase, drying by using anhydrous sodium sulfate, and then distilling under reduced pressure to remove the solvent to obtain the 3',5' -dichloro-2, 2, 2-trifluoroacetophenone.
The compound VIII is
19.9g of 3',5' -dichloro-2, 2, 2-trifluoro acetophenone was finally obtained in 74.2% yield and 95.9% purity.
Comparative example 2
A preparation method of 3',5' -dichloro-2, 2, 2-trifluoro acetophenone is carried out by referring to a method in Chinese invention with the publication number of CN107353189A, which comprises the following steps:
step 1, under the protection of nitrogen, n-butyllithium (23.2mmol dissolved in 14.5mL n-hexane to prepare 1.6M solution) is uniformly dropped into tetrahydrofuran solution (50mL) of compound VIII (5g, 22.1mmol) at-78 ℃ within 30min, stirring is kept for reaction for 1h, trifluoroacetic anhydride (2.56g, 23.2mmol) is dropped into the mixed solution, and reaction is kept at-78 ℃ for 2 h. Then warmed to room temperature and the reaction was continued at room temperature for 2.5 h. The reaction was terminated by adding 50mL of a saturated ammonium chloride solution, tetrahydrofuran was removed by distillation under reduced pressure and extracted with diethyl ether, the organic phase was retained, washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and after completion, the solvent was removed by distillation under reduced pressure to give 3',5' -dichloro-2, 2, 2-trifluoroacetophenone.
The compound VIII was identical to comparative example 1, giving 2.28g of 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, in 42.5% yield and 98.8% purity.
For the above examples and comparative examples, the yields of the respective steps, the total yields, and the purity ratios of the final objective compounds are shown in table 1.
The nuclear magnetic resonance hydrogen spectrum data of the compound V in deuterated chloroform is as follows: 1HNMR (500MHz, CDCl)3):d＝6.46(brs,2H),6.70(d,1H,J＝9.0Hz),7.32(dd,1H,J＝2.1Hz,9.0Hz),7.71(d, 1H,J＝2.1Hz)。
The nuclear magnetic resonance hydrogen spectrum data of the compound VI in the deuterated chloroform is as follows: 1HNMR (400MHz, CDC 1)3):7.95(s,2H),5.23(bs,2H)。
The 3',5' -dichloro-2, 2, 2-trifluoro acetophenone is deuteratedThe nuclear magnetic resonance hydrogen spectrum data in chloroform are as follows: 1H-NMR (360MHz, CDCl)3):δ＝7.7(s,1H),7.9(s,2H)。
By comparing the experimental data, it can be found that considerable yield and purity can be obtained by preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone by the method in examples 1 to 24 in the application. The purity of the final product is higher than that of the comparative example 1 and the comparative example 2, and the yield has obvious advantages compared with the comparative example 2 and is closer to that of the comparative example 1. However, in comparative example 2, tetrahydrofuran was used as a reaction system, and expensive, flammable and explosive isopropyl magnesium chloride was used, which greatly increased the production cost and the post-treatment cost compared to the preparation method in the above example. Therefore, the technical scheme provided in the application has good economic effect compared with the technical scheme in the comparative example 1.
In examples 1 to 13, the overall effect on the yield was not much influenced by the adjustment of step S1. In example 3, the reaction was carried out using 80% sulfuric acid, and the yield was still lowered under the condition of prolonged reaction time. Example 4 shortens the reaction time compared to example 3, further resulting in a decrease in the yield in step S1. Examples 5 and 6, respectively, using trifluoromethanesulfonic acid and acetic anhydride instead of 98% sulfuric acid, both resulted in a decrease in yield, demonstrating the superior reaction characteristics of 98% sulfuric acid and oleum in many acid reagents.
In example 8, the nitrating agent was saturated aqueous sodium nitrate solution, and in example 9, the reaction was carried out by introducing nitrogen dioxide. The aqueous sodium nitrate solution is less expensive to purchase, but the reaction performance is less effective than the solution of example 1 in which fuming nitric acid is used. The introduction of nitrogen dioxide needs additional equipment support, and the scheme can be selected according to conditions of an actual production line, and has good industrial application value.
The adjustment of the specific process steps in step S1 in examples 11-13 all resulted in a decrease in yield. In example 11, the intermediate reaction solution i was cooled by natural cooling, which takes a long time, and the temperature of the system is still high during cooling, so that partial side reactions are likely to occur, and the yield of step S1 is reduced. In example 12, fuming nitric acid was added dropwise and the system was subjected to temperature raising treatment, which also had a certain adverse effect on the yield in step S1. In example 13, the reacted material was not quenched by ice water, which caused difficulty in the separation process, and impurities could not be sufficiently separated from the organic phase during liquid separation, which further caused a decrease in the yield of step S1, and a decrease in the purity of the final product.
In examples 14 to 17, the process parameters in step S2 were adjusted compared to example 1. It can be seen that the increase in hydrogen pressure contributes to the improvement in the yield of step S2, and the substitution of Raney nickel and palladium on carbon for platinum on carbon contributes to the improvement in the yield of S2. Examples 18 and 19 adjusted some of the parameters in step S3, and had less effect on the final yield. In examples 20 to 22, the adjustment in step S4 was performed to some extent. From the above data, it can be seen that methyl nitrite is selected for a higher yield in the production process than other nitrous acid reagents.
In example 23, after completion of step S1, compound ii and compound iii were separated and subjected to the subsequent reaction. It can be seen that no matter whether the compound II and the compound III are separated or not, the subsequent reaction is basically not obviously influenced, so that in the actual production process, the working procedure of separating the compound II and the compound III can be completely omitted, and the aims of reducing the production cost and improving the economic effect can be fulfilled.
Example 24 is an experiment of performing amplification treatment on the scheme in example 1, and it can be seen that after ten times of equivalents are amplified, the technical scheme in example 1 can still realize production of 3',5' -dichloro-2, 2, 2-trifluoroacetophenone, and neither the yield nor the purity is significantly changed, which proves that the technical scheme in the application has a prospect of amplification reaction and application to large-scale production.
Claims (8)
1. A preparation method of 3',5' -dichloro-2, 2, 2-trifluoro acetophenone is characterized in that: the method comprises the following steps:
s1, carrying out nitration reaction on the compound I and a nitration reagent under the catalysis of acid I to obtain a composition of a compound II and a compound III;
s2, carrying out nitro reduction reaction on the compound II and compound III composition obtained in the step S1 to obtain a compound IV and compound V composition;
s3, performing chlorination reaction on the compound IV and compound V composition obtained in the step S2 through a chlorination reagent to obtain a compound VI and compound VII composition;
s4, carrying out diazotization elimination reaction on the compound VI and the compound VII obtained in the step S3 to obtain 3',5' -dichloro-2, 2, 2-trifluoroacetophenone;
in step S1, the acid i is one of phosphoric acid, polyphosphoric acid, methanesulfonic acid, chlorosulfonic acid, trifluoromethanesulfonic anhydride, acetic acid, acetic anhydride, boron trifluoride diethyl etherate, perchloric acid, phosphomolybdic acid, strong acid resin, fuming sulfuric acid, or 80% -98% sulfuric acid, or a stable mixed system formed by any two or more of the above acids; the nitrating reagent is any one or more of nitric acid, fuming nitric acid, sodium nitrate, potassium nitrate, ammonium nitrate, lead nitrate, aluminum nitrate, barium nitrate, nitrogen pentoxide and nitrogen dioxide;
in step S3, one or more of chlorine, sulfuryl chloride, trichloroisocyanuric acid, and NCS is/are selected for chlorination.
2. The process for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone according to claim 1, wherein: step S1 is specifically as follows:
s1-1, mixing the compound I with acid I, then dropwise adding a nitration reagent, and fully reacting to obtain an intermediate reaction liquid I;
s1-2, adding water and an extracting agent I into the intermediate reaction liquid I after the reaction is finished, and keeping an organic phase I;
s1-3, washing the organic phase I obtained in the step S1-2 and removing the solvent to obtain a composition of a compound II and a compound III;
wherein, the acid I is one of 80-98% sulfuric acid or fuming sulfuric acid, and the nitrating reagent is fuming nitric acid.
3. The method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone according to claim 2, wherein: in step S1-1, after the compound I and the acid I are mixed, heating to 40-60 ℃, and then dropwise adding a nitration reagent for reaction; in step S1-2, the intermediate reaction solution I is cooled to 0-10 ℃, the intermediate reaction solution I is dripped into ice water, and then the extracting agent I is added.
4. The method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone according to claim 1, wherein: in step S2, the nitro group is reduced by hydrogenation reduction under the action of catalyst i, which is any one of platinum carbon, palladium carbon or Raney nickel.
5. The method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone according to claim 4, wherein: step S2 is specifically as follows:
s2-1, dissolving the compound II and compound III composition obtained in the step S1 in a solvent I, adding a catalyst, removing air, heating to 40-60 ℃, introducing hydrogen, and fully reacting to obtain an intermediate reaction liquid II;
s2-2, cooling, filtering and concentrating the intermediate reaction liquid II obtained in the step S2-1, further purifying and drying by a recrystallization method to obtain a composition of a compound IV and a compound V;
wherein, the solvent I is any one of the following substances or a homogeneous mixed system formed by any more of the following substances: methanol, ethanol, ethyl acetate, n-butyl acetate, isopropyl acetate, isopropanol, and toluene.
6. The method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone according to claim 5, wherein: the step S2-2 is specifically as follows: and (2) cooling and filtering the intermediate reaction liquid II obtained in the step S2-1, adding toluene, heating to 40-50 ℃, fully dissolving, cooling to-30-20 ℃, standing to precipitate solids, filtering and drying to obtain the composition of the compound IV and the compound V.
7. The method for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone according to claim 1, wherein: step S3 is specifically as follows:
s3-1, dissolving a compound IV and a compound V in a solvent II, heating to 50-60 ℃, uniformly adding a chlorination reagent within 90min after full dissolution, and then carrying out heat preservation and full reaction to obtain an intermediate reaction solution III;
s3-2, cooling the intermediate reaction liquid obtained in the step S3-1, adding water for extraction, and reserving an organic phase to obtain an organic phase II;
in step S4, diazotization deamination reaction is directly carried out in an organic phase II;
the chlorination reagent is any one of chlorine, sulfonyl chloride, trichloroisocyanuric acid and NCS, or a composition formed by any several of chlorine, sulfonyl chloride, trichloroisocyanuric acid and NCS;
the solvent II is any one of toluene, dichloromethane, chloroform, acetonitrile, isopropanol and ethanol, or a homogeneous system formed by mixing any several of the solvents.
8. The process for preparing 3',5' -dichloro-2, 2, 2-trifluoroacetophenone according to claim 7, wherein: step S4 is specifically as follows:
s4-1, cooling the organic phase II obtained in the step S3-2 to-10-0 ℃, dropwise adding an acid II to acidify the organic phase II, and fully reacting to obtain an intermediate reaction liquid IV;
s4-2, adding a nitrous acid reagent solution into the intermediate reaction liquid IV, keeping the temperature lower than 0 ℃, and fully reacting to obtain an intermediate reaction liquid V;
s4-3, heating the intermediate reaction solution V to above 20 ℃, and adding hypophosphorous acid and a catalyst II to obtain an intermediate reaction solution VI;
s4-4, further purifying and separating the intermediate reaction solution V to obtain 3',5' -dichloro-2, 2, 2-trifluoro acetophenone;
wherein, the acid II is any one of hydrochloric acid, hydrobromic acid, hydrofluoric acid, phosphoric acid, acetic acid or sulfuric acid; the nitrous acid reagent is any one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite.
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