CN112110804A - Preparation method of 3, 5-dihalo-trifluoro-acetophenone and derivatives thereof - Google Patents
Preparation method of 3, 5-dihalo-trifluoro-acetophenone and derivatives thereof 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-dihalo-trifluoro-acetophenone and derivatives thereof, which takes 3-halogen-4-nitrotrifluoro-acetophenone as a raw material and finally obtains the derivatives of the 3, 5-dihalo-trifluoro-acetophenone through reduction reaction, halogenation reaction and amino substitution reaction.
Description
Technical Field
The application relates to the technical field of chemical pharmacy, in particular to a preparation method of 3, 5-dihalo-trifluoro-acetophenone and derivatives thereof.
Background
3, 5-dihalogen substituted trifluoroacetyl ketone compounds are important chemical pharmaceutical intermediates and are commonly used for preparing various medicaments for killing pests. For the purpose of drug modification and modification, modification of various groups at the para position of trifluoroacetyl group is often required.
Because the trifluoroacetyl group and the halogen atom are strong electron-withdrawing groups, the para-position reaction of the trifluoroacetyl group is difficult to occur, and a preparation method for preparing 4-substituted 3, 5-dihalo-trifluoro-acetophenone and derivatives thereof is lacked at present.
Disclosure of Invention
Aiming at the defects in the prior art, the application provides a preparation method of 3, 5-dihalo-trifluoro-acetophenone and derivatives thereof, which has higher yield and lower cost and has the prospect of large-scale application in industrial production.
In one embodiment, the present application provides a process for the preparation of 3, 5-dihalotrichloroacetophenone and its derivatives, comprising the steps of:
s1, carrying out reduction reaction on the compound I to obtain a compound II;
s2, performing halogenation reaction on the compound II to obtain a compound III;
s3, carrying out amino substitution reaction on the compound III to obtain a compound IV;
wherein R is1One selected from chlorine, bromine and iodine, R2One selected from chlorine and bromine, R3One selected from hydrogen, fluorine, chlorine, bromine and hydroxyl.
The compound I is a commonly used byproduct in the production of medicines, can be directly purchased and is also produced in the production process. And reducing the nitro group of the compound I to amino, halogenating the ortho position of the amino, and diazotizing the amino to substitute to obtain a compound IV. The reaction can form substituent on 4-position of benzene ring, and can prepare 3, 5-dihalo trifluoro acetophenone without substituent, and has wide application. In the process, harsh reaction conditions are not needed, and the dissolution and the catalyst used in each step are both conventional solvents and catalysts, so that the production cost is low, the conditions are mild, and the method can be applied to industrial production.
The present application may be further configured in a preferred example to: in step S1, compound i is dissolved in solvent i, and one of platinum carbon, palladium carbon, and Raney nickel is used as a catalyst to reduce the nitro group under the action of hydrogen. In one embodiment, the solvent I is selected from at least one or a homogeneously mixed system of two or more of the following: methanol, ethanol, ethyl acetate, n-butyl acetate, isopropyl acetate, isopropanol and toluene.
The present application may be further configured in a preferred example to: r1、R2In step S2, the halogenating agent is chlorine, and the halogenating agent is one selected from chlorine, sulfuryl chloride, trichloroisocyanuric acid, and NCS.
The present application may be further configured in a preferred example to: r3S3 specifically includes the following steps: s3-1-1, dissolving the compound III in a solvent III, cooling to-10-0 ℃, adding sulfuric acid for acidification, dropwise adding a nitrous acid reagent solution to diazotize amino, and fully reacting to obtain an intermediate reaction solution I;
s3-1-2, heating the intermediate reaction solution I to 20-30 ℃, adding a hypophosphorous acid solution and cuprous oxide, continuing to react until the reaction is complete, washing with an alkaline inorganic salt solution, preserving an organic phase, and drying to obtain a compound IV;
the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite, and the solvent III is selected from one of toluene, ethanol and isopropanol or a homogeneous system formed by any of toluene, ethanol and isopropanol.
In the technical scheme, the side reaction is less in the reaction process, the impurities generated in the system can be well dissolved in water, and the impurities can be quickly removed by adding water for extraction during subsequent separation, so that the production cost is low, the yield is high, and the economic effect is good.
The present application may be further configured in a preferred example to: r3Is a chlorine atom, S3 specifically comprises the following steps: s3-2-1, adding the compound III into hydrochloric acid for acidification, adding a nitrous acid reagent solution after acidification to diazotize amino, and obtaining an intermediate reaction solution II after complete reaction;
s3-2-2, preparing a hydrochloric acid solution of cuprous chloride, heating and fully mixing, adding the intermediate reaction liquid II prepared in the step S3-2-1 into the system, separating the system after full reaction, keeping an organic phase, drying and distilling under reduced pressure to obtain a compound IV; wherein the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite.
When R is3When the amino is chlorine, the amino is firstly acidified by hydrochloric acid to form salt, and the hydrochloric acid can be used for ensuring that the concentration of chloride ions in a system is higher, so that the amino is prevented from being separated and then being hydrolyzed into phenol or reduced into hydrogen on a benzene ring. And then, catalyzing by cuprous ions to enable chloride ions to replace diazo groups, thereby realizing the chlorination process of amino groups. In the process, in an acid system formed by hydrochloric acid and cuprous chloride solution, the method is favorable for improving the reaction rate and reaction balance, does not need harsh reaction conditions, is simple in three-waste treatment, is suitable for industrial large-scale production, and has a good economic effect.
The present application may be further configured in a preferred example to: r3Is fluorine atom, S3 specifically comprises the following steps: s3-3-1, dissolving a compound III in pyridine solution containing hydrogen fluoride, controlling the temperature to be-5 ℃, fully mixing, salifying amino and hydrogen fluoride, adding nitrous acid reagent solution to diazotize the amino, and obtaining intermediate reaction liquid III after complete reaction;
s3-3-2, heating the intermediate reaction liquid III to 60-90 ℃, continuing to react, adding a quenching agent after full reaction, washing, drying and further separating to obtain a compound IV;
wherein the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite.
After the temperature rise reaction is finished, the reaction system can be quickly cooled after the quenching agent is added, so that the reaction is stopped, the occurrence of side reactions is reduced, and the safety of the reaction is improved.
The present application may be further configured in a preferred example to: the quenching agent is a mixed solution formed by diethyl ether and water in a volume ratio of (0.8-2.5) to 1.
In the technical scheme, water and diethyl ether are selected as quenchers. The water has larger specific heat capacity, so that the system can be rapidly cooled, and the occurrence of side reaction is reduced. The ethyl ether has certain miscibility with water, which is helpful for more uniform dispersion of water in the organic solvent, so that the water can realize the process of rapid cooling, thereby rapidly stopping the reaction. In addition, the ethyl ether can also enable water to dissolve water-soluble impurities in the organic solvent more fully, thereby being beneficial to the subsequent separation step.
The present application may be further configured in a preferred example to: r3Is a bromine atom, S3 specifically comprises the following steps:
s3-4-1, dissolving a compound III in a solvent VI, heating, adding hydrobromic acid, fully reacting, cooling to-10-0 ℃, dropwise adding a nitrous acid reagent solution, fully reacting to diazotize an amino group, and obtaining an intermediate reaction liquid IV;
s3-4-2, adding the bromoidenone into the intermediate reaction liquid IV, then heating to 60-80 ℃, continuing to react fully, then extracting, retaining the organic phase and further separating to obtain a compound VI;
the nitrite reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite, and the solvent VI is selected from any one of toluene, ethanol and isopropanol, or a homogeneous mixed system formed by any more of the above.
The amino group is diazotized by hydrobromic acid, and other negative ions are not introduced into the system, thereby being beneficial to reducing the occurrence of side reactions. In the bromination process, the temperature is raised to 60-80 ℃, which is beneficial to the rapid and smooth reaction and the rapid discharge of nitrogen from the solution. In addition, side reactions are less in the temperature range, the purity and the yield of the obtained target product are high, impurities are water-soluble impurities, the removal is convenient, and the method has a good economic effect and an industrial application prospect.
The present application may be further configured in a preferred example to: r3Is hydroxyl, S3 specifically comprises the following steps:
s3-5-1, heating the sulfuric acid aqueous solution to 80 ℃, adding a compound III, fully reacting, cooling to 0 ℃, adding a nitrous acid reagent solution, and diazotizing amino to obtain an intermediate reaction solution V;
s3-5-2, preparing a copper sulfate solution, adding concentrated sulfuric acid for acidification, heating to 110 ℃, dropwise adding the intermediate reaction solution V into the solution, evaporating the product, purifying and drying to obtain a compound IV;
the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite.
In the technical scheme, the intermediate reaction liquid IV is dripped into acidified copper sulfate solution, amino is hydrated into hydroxyl under the catalysis of copper ions, and sulfuric acid is used for catalysis in the process, so that the side reaction is favorably reduced. In addition, in the above reaction, the use of concentrated sulfuric acid increases the concentration of hydrogen sulfate with a small amount of sulfate ions in the system, and contributes to further reducing the occurrence of a reaction between a carbocation and a group other than water after the separation of the diazo group, improving the yield of the reaction and the purity of the target product, and further improving the economic effect.
The present application may be further configured in a preferred example to: the nitrous acid reagent is sodium nitrite or potassium nitrite.
In the technical scheme, the sodium nitrite and the potassium nitrite have good water solubility, are less soluble in an organic phase during post-treatment, are easy to separate, and simplify the separation process.
Detailed Description
Embodiments 1 to 16 all relate to a method for preparing 3, 5-dihalo-trifluoroacetophenone, comprising the steps of:
s1, carrying out reduction reaction on the compound I to obtain a compound II;
s2, performing halogenation reaction on the compound II to obtain a compound III;
s3, carrying out amino substitution reaction on the compound III to obtain a compound IV;
example 1
Preparation method of 3, 5-dihalo-trifluoro acetophenone, R1And R2Are all chlorine.
Step S1 is specifically as follows: 0.5mol (127g) of the compound I is taken and dissolved in 300m of absolute ethyl alcohol (solvent I) in a reaction kettle, and 5.0g of 5 percent platinum carbon catalyst is added as a catalyst. And (3) fully replacing the reaction kettle with nitrogen to remove air, introducing hydrogen again, repeatedly replacing for three times, continuously introducing the hydrogen and starting stirring. The pressure of hydrogen gas is maintained at 0.1MPa in the reaction process, and the temperature is controlled at 40 ℃. After the reaction is finished, cooling the reaction solution to room temperature and filtering, evaporating ethanol to dryness in the filtrate, adding 150.0ml of toluene, heating to 40 ℃, fully stirring to dissolve the system into a clear transparent solution, cooling to-20 ℃, standing for crystallization, filtering and keeping a filter cake to be not dried to obtain a compound II.
Step S2 is specifically as follows, 0.2mol (44.7g) of the compound I obtained in step S1 is taken and dissolved in 200mL of toluene, the temperature is raised to 50 ℃, the mixture is fully stirred until the solution is clear, then 33.7g of sulfonyl chloride (0.25mol) is weighed and used as a halogenating reagent, the dropwise addition is completed within 90min, the reaction is continued to be carried out for 8h after the dropwise addition is completed, then the temperature is naturally reduced to 20 ℃, 200mL of water is added for rinsing, an organic phase is retained, and the compound III is obtained after the evaporation to dryness.
Step S3 specifically includes the following steps:
s3-1-1, dissolving 0.19mol (49.1g) of the compound III obtained in the step S2 in 150mL of toluene, cooling to-10 ℃, dropwise adding 80g of concentrated sulfuric acid with the concentration of 92.5% into the system within 30min, controlling the temperature of the system to be lower than 0 ℃ in the process, and continuing to react for 1h after dropwise adding is finished; after the reaction is finished, 87g (containing 0.41mol of sodium nitrite) of sodium nitrite solution with the mass fraction of 33 percent is dripped into the system within 30min as a nitration reagent, the temperature of the system is kept lower than 0 ℃ in the dripping process, and the heat preservation reaction is carried out for 2h after the dripping is finished, so as to obtain intermediate reaction liquid I;
s3-1-2, heating the intermediate reaction liquid to 20 ℃, adding 83.0g of 50% hypophosphorous acid and 0.5g of cuprous oxide, keeping the temperature for reaction for 2 hours, layering after the reaction is finished, cleaning an organic layer by using a 5% sodium bicarbonate aqueous solution, adjusting the pH value to be neutral, drying an organic phase by using anhydrous magnesium sulfate, and distilling under reduced pressure to obtain the compound 3, 5-dichloro-trifluoro acetophenone.
Example 2
A process for preparing 3, 5-dihalo-trifluoroacetophenone is different from that of example 1 in that 3-bromo-4-amino-trifluoroacetophenone is used in an amount equivalent to that of compound I.
Example 3
A process for preparing 3, 5-dihalo-trifluoroacetophenone is different from that of example 1 in that 3-iodo-4-amino-trifluoroacetophenone is used in an amount equivalent to that of compound I.
Example 4
A process for preparing 3, 5-dihalogentrifluoroacetophenone, which differs from example 1 in that R is2Is bromine. Step S2 is specifically as follows: dissolving 0.2mol (44.7g) of the compound I obtained in the step S1 in 150mL of chloroform, heating to 70 ℃, dissolving 0.22mol NBS (39.2g) and 0.02mol AIBN (3.3g) in 50mL of chloroform, adding the solution into the system within 30min, keeping the temperature for reaction for 2h after the dropwise addition is finished, adding 100mL of sodium hydroxide solution for quenching, cooling the system to room temperature, separating to obtain an organic phase, and evaporating the solvent to dryness to obtain a compound II.
Example 5
A process for preparing 3, 5-dihalogentrifluoroacetophenone, which differs from example 2 in that R is2Is bromine. Step S2 is specifically as follows: dissolving 0.2mol (53.4g) of the compound I obtained in the step S1 in 150mL of chloroform, heating to 70 ℃, dissolving 0.22mol NBS (39.2g) and 0.02mol AIBN (3.3g) in 50mL of chloroform, adding the solution into the system within 30min, keeping the temperature for reaction for 2h after the dropwise addition is finished, adding 100mL of sodium hydroxide solution with the mass fraction of 5%, quenching, cooling the system to room temperature, separating to obtain an organic phase, and evaporating the solvent to obtain a compound II.
Example 6
A method for preparing 3, 5-dihalogentrifluoroacetophenone, which differs from example 1 in that step S2 is specifically as follows: s2, taking 0.2mol (44.7g) of the compound I obtained in the step S1, dissolving the compound I in 200mL of acetonitrile, stirring the solution at room temperature until the solution is clear, weighing 30.7g of NCS (0.23mol) as a halogenated reagent, adding the halogenated reagent, heating the mixture to reflux, reacting for 2 hours, concentrating the solvent after the reaction is finished, and drying the concentrated solvent to obtain a compound III.
Example 7
A method for preparing 3, 5-dihalogentrifluoroacetophenone, which differs from example 1 in that step S2 is specifically as follows:
taking 0.2mol (44.7g) of the compound I obtained in the step S1, dissolving the compound I in 500mL of glacial acetic acid, heating to 40 ℃, slowly introducing 17.04g of chlorine (0.24mol) in 3h for reaction, carrying out on-line monitoring until the raw material point disappears, continuously introducing nitrogen to remove redundant chlorine and hydrogen chloride, carrying out suction filtration, washing a filter cake twice by glacial acetic acid, and carrying out vacuum drying at 60 ℃ to obtain a compound III.
Example 8
A method for preparing 3, 5-dihalogentrifluoroacetophenone, which is different from example 1 in that 5% equivalent palladium on carbon is used as a catalyst in step S1.
Example 9
A method for preparing 3, 5-dihalogentrifluoroacetophenone, which differs from example 1 in that an equivalent amount of Raney nickel is used as a catalyst in step S1.
Example 10
A process for producing 3, 5-dihalogentrifluoroacetophenone, which differs from example 1 in that, in step S1, the hydrogen pressure is 1.0mPa and the reaction temperature is 50 ℃.
Example 11
A process for preparing 3, 5-dihalogentrifluoroacetophenone, which differs from example 1 in that in step S1, toluene is used as solvent I.
Example 12
A method for producing 3, 5-dihalogentrifluoroacetophenone, which is different from example 1 in that, in step S3, the solvent iii is a mixed solvent of ethanol and isopropanol in a volume ratio of 1: 1.
Example 13
A method for preparing 3, 5-dihalogentrifluoroacetophenone, which is different from example 1 in that in step S3, an aqueous solution with a mass fraction of 30% is prepared from potassium nitrite in an amount equal to the amount of a nitrite reagent.
Example 14
A method for producing 3, 5-dihalogentrifluoroacetophenone differs from example 1 in that methyl nitrite is used as a nitrous acid reagent in an amount equivalent to that used in step S3.
Example 15
A method for preparing 3, 5-dihalogentrifluoroacetophenone, which is different from example 1 in that calcium nitrite and calcium nitrite in equal amounts are prepared into an aqueous solution with a mass fraction of 35% and added in step S3.
Example 16
A process for the preparation of 3, 5-dihalotrichloroacetophenone by up-scaling the procedure in example 8 using 10 times the amount of each of the materials used in example 8, otherwise the conditions were otherwise identical to those in example 8.
Example 17
A preparation method of 3, 5-dihalo trifluoro acetophenone, which is a scale-up treatment of the method in example 5, wherein the use amount of each material is 10 times of that in example 5, and other conditions are consistent with example 5.
3, 5-dihalo-trifluoroacetophenone was produced by the methods in examples 1 to 17 in the yields and purities shown in Table 1.
Wherein, taking example 1 as an example, the nuclear magnetic data of the final obtained product is 1H-NMR (360MHz, CDCl)3):＝7.7(s,1H),7.9(s,2H)。
As can be seen from the above experimental data, the preparation of 3, 5-dihalo-trifluoroacetophenone can be realized by the method of the present application, wherein in step S1, the use of palladium carbon and Raney nickel can increase the conversion rate of the raw material, and increasing the pressure of hydrogen also helps to increase the conversion rate of the raw material. R1And R2Can be reasonably selected from halogen, and when R is1、R2When the electron donating ability of (1) is enhanced, there is an effect of improving the yield of steps S1, S2, and S3.
In step S3, when calcium nitrite is selected as the nitroso agent, the yield of step S3 is slightly reduced, and the use of methyl nitrite helps to increase the yield of S3. However, methyl nitrite is oil-soluble and tends to remain in the system during the final separation, thus resulting in a decrease in the purity of the final product.
The reaction of amplified amount is carried out in the example 16 and the example 17, and the reaction yield and the purity are not obviously changed, which proves that the method has the potential of industrial production and has better industrial application prospect.
Example 18
A method for preparing a 3, 5-dihalo-trifluoroacetophenone derivative, which is different from example 8 in that the step S3 is embodied as follows: s3-2-1, taking 51.6g (0.2mol) of a compound III, adding 300mL of concentrated hydrochloric acid, heating to 60 ℃, stirring for 1h, then cooling to-10 ℃, uniformly dropwise adding 50.3g (containing 0.24mol of sodium nitrite) of a sodium nitrite (nitrous acid reagent) solution with the content of 33% within one hour, and continuing to react for 30min after dropwise adding is finished to obtain an intermediate reaction solution II;
s3-2-2, weighing 29.7g of cuprous chloride, dissolving the cuprous chloride in 300mL of hydrochloric acid to prepare a hydrochloric acid solution of cuprous chloride, heating to 60 ℃, stirring for 1h, and then carrying out the stepsUniformly dropwise adding the intermediate reaction liquid II prepared in the step S3-2-1 into the cuprous chloride hydrochloric acid solution within 1h, continuously carrying out heat preservation reaction for 1h after dropwise adding is finished, cooling to room temperature, extracting with dichloromethane twice, combining organic phases, drying with sewage magnesium chloride, and distilling the solvent under reduced pressure to obtain a compound IV, wherein R in the compound IV is3Is chlorine.
Example 19
A method for preparing a 3, 5-dihalo-trifluoroacetophenone derivative, which is different from example 5 in that the step S3 is specifically as follows: s3-2-1, taking 69.4g (0.2mol) of a compound III, adding 300mL of concentrated hydrochloric acid, heating to 60 ℃, stirring for 1h, then cooling to-10 ℃, uniformly dropwise adding 50.3g (containing 0.24mol of sodium nitrite) of a sodium nitrite (nitrous acid reagent) solution with the content of 33% within one hour, and continuing to react for 30min after dropwise adding is finished to obtain an intermediate reaction solution II;
s3-2-2, weighing 29.7g of cuprous chloride, dissolving the cuprous chloride in 300mL of hydrochloric acid to prepare a hydrochloric acid solution of cuprous chloride, heating to 60 ℃, stirring for 1h, then uniformly dropwise adding the intermediate reaction liquid II prepared in the step S3-2-1 into the cuprous chloride hydrochloric acid solution within 1h, continuing to perform heat preservation reaction for 1h after dropwise adding is finished, cooling to room temperature, extracting twice with dichloromethane, combining organic phases, drying with polluted magnesium chloride, distilling the solvent under reduced pressure to obtain a compound IV, wherein R in the compound IV is3Is chlorine.
Example 20
A method for producing a 3, 5-dihalo-trifluoroacetophenone derivative, which is different from example 18 in that methyl nitrite is used as the nitrous acid reagent in an amount equivalent to that used in step S3 and step S3.
Example 21
A method for preparing a 3, 5-dihalo-trifluoroacetophenone derivative, which is different from that of example 18 in that a nitrite reagent is calcium nitrite in an amount equivalent to that of the above-mentioned substance, and calcium nitrite is added as an aqueous solution having a mass fraction of 35%.
Example 22
A process for producing a 3, 5-dihalo-trifluoroacetophenone derivative, which is different from example 18 in that the process in step S18 is subjected to an amplification treatment, wherein steps S1 and S2 are the same as steps S1 and S2 in example 16, each material in step S3 is used in an amount 10 times the amount used in step S3 in example 18, and the rest of the conditions are the same as in example 18.
Example 23
A process for producing a 3, 5-dihalo-trifluoroacetophenone derivative, which is different from example 19 in that the process in step S19 is subjected to an amplification treatment, wherein steps S1 and S2 are the same as steps S1 and S2 in example 17, the amount of each material used in step S3 is 10 times the amount used in step S3 in example 19, and the rest of the conditions are the same as example 19.
The yields and purities of examples 18 to 23 in the respective steps are shown in Table 2.
From the above experimental data, it can be seen that the method of examples 18 to 23, when the trifluoroacetyl group is substituted with chlorine at the para-position, also has a better yield and a higher purity of the final product. Examples 22 and 23 respectively carried out an experiment of synthesizing 3, 4, 5-trichloro-trifluoroacetophenone (nmr data is 1HNMR (300MHz, CDCl3): 8.05(d, J ═ 0.8Hz,2H)) and 3, 5-dibromo-4-chlorotrifluoroacetophenone (nmr data is 1HNMR (300MHz, CDCl3): 8.24(s,2H)), and proved that the above method has a good industrial application prospect.
Example 24
A method for preparing a 3, 5-dihalo-trifluoroacetophenone derivative, which is different from example 18 in that the step S3 is embodied as follows: s3-4-1, dissolving 51.6g (0.2mol) of a compound III in 300mL of acetonitrile (solvent IV), heating to 50 ℃, then adding 300mL of 47% hydrogen bromide, keeping the temperature for reaction for 1h, then cooling to-10 ℃, uniformly dropwise adding 50mL (containing 0.24mol of sodium nitrite) of 33% sodium nitrite solution within 1h, and continuing to react for 30min after dropwise addition is finished to obtain an intermediate reaction solution IV.
S3-4-2, adding 43.0g (0.3mol) of bromoidenone to the intermediate reaction liquid IV in batches uniformly within 30min, then heating to 60 ℃, stirring for reacting for 1h, extracting with dichloromethane after the reaction is finished, reserving an organic phase, drying with anhydrous magnesium sulfate, and carrying out reduced pressure distillation to obtain a compound IV.
In the process, the compound IV is 3, 5-dichloro-4-bromotrifluoroacetophenone.
Example 25
A process for producing a 3, 5-dihalo-trifluoroacetophenone derivative by mass production from the process of example 24, wherein step S1 and step S2 are the same as in example 22, the amount of each material used in step S3 is 10 times the amount used in step S3 in example 24, and the other conditions are the same as in example 24.
Example 26
A method for producing a 3, 5-dihalo-trifluoroacetophenone derivative, which is different from example 24 in that, in step S3-4-1, a mixed system of ethanol and isopropanol in a volume ratio of 0.4:1 is used as the solvent iv.
Example 27
A method for preparing a 3, 5-dihalo-trifluoroacetophenone derivative, which is different from example 18 in that the step S3 is embodied as follows:
s3-3-1, taking 51.6g of a compound III, adding the compound III into 300mL of hydrogen fluoride pyridine solution (the mass fraction of hydrogen fluoride is 70%) cooled to 0 ℃ within 30min, keeping the temperature at 0 +/-5 ℃, stirring for 1h, then dropwise adding 50.3g of sodium nitrite solution (containing 0.24mol of sodium nitrite) with the mass fraction of 33% within 1h, and continuing to react for 30min to obtain an intermediate reaction solution III;
and S3-3-2, heating the intermediate reaction liquid III to 60 ℃, continuing to react for 3 hours, adding 200mL of quenching agent which is mixed liquid formed by mixing diethyl ether and water according to the volume of 1.6:1, separating to obtain an organic layer, washing with saturated sodium chloride solution, eluting with 200mL of toluene, and drying to obtain a compound IV.
In the above process, R in the compound IV3The compound is fluorine, and the nuclear magnetic resonance hydrogen spectrum data of the compound is 1HNMR (400MHz, CDCl3) ═ 8.06(dd, J ═ 0.8,6.1Hz, 2H).
Examples 28 to 31
A method for producing a 3, 5-dihalo-trifluoroacetophenone derivative, which is different from example 27 in that in step S3-2-2, the quenching agents are: a mixed solution of diethyl ether and water in a volume ratio of 0.8:1, a mixed solution of diethyl ether and water in a volume ratio of 2.5:1, diethyl ether and water.
Example 32
A process for producing a 3, 5-dihalo-trifluoroacetophenone derivative by the up-scaling treatment of the process of example 27, wherein step S1 and step S2 are the same as in example 22, the amount of each material used in step S3 is 10 times the amount used in step S3 of example 33, and the other conditions are the same as in example 27.
Example 33
A method for preparing a 3, 5-dihalo-trifluoroacetophenone derivative, which differs from example 27 in that step S3 is specifically as follows:
s3-5-1, dropwise adding 46.0g of concentrated sulfuric acid into 150mL of pure water, controlling the temperature at 80 ℃, adding 51.6g of the compound III into the system, stirring for 1h, cooling to 0 ℃, uniformly dropwise adding 50.3g of 33% sodium nitrite solution (containing 0.24mol of sodium nitrite) in 1h, and continuing to perform heat preservation reaction for 1h after dropwise adding is finished to obtain an intermediate reaction solution V;
s3-5-2, adding 71.5g of anhydrous copper sulfate (0.286mol) into 123.5g of pure water to prepare a copper sulfate solution, then dropwise adding 52.7g of concentrated sulfuric acid for acidification, uniformly stirring, heating to 110 ℃ to reflux the solution, dropwise adding the intermediate reaction solution V obtained in the step S3-5-1 into the solution, distilling out the product while dropwise adding the intermediate reaction solution V, keeping the volume unchanged, extracting the distilled product with dichloromethane, combining organic phases, and drying to obtain a compound IV.
In the process, the compound IV is 3, 5-dichloro-4-hydroxy trifluoro acetophenone.
Example 34, a process for the preparation of a 3, 5-dihalo-trifluoroacetophenone derivative by the scale-up procedure of example 33, wherein step S1 and step S2 were the same as in example 22, and step S3 was carried out using 10 times the amount of each material used in step S3 of example 33, under the same conditions as in example 33.
In examples 24 to 34, the yields and purities in the respective steps are shown in Table 3.
According to the experimental data, the preparation of the 3, 5-dichloro-trifluoro acetophenone and the derivatives thereof can be realized by the method, and the method has a good industrial application prospect. In the preparation process, the mixed system of ether and water is selected, so that the possibility of side reaction after the reaction is finished can be effectively reduced, and the yield and the purity of the step S3 are improved.
For the above examples, comparative examples are now set as follows.
Comparative example 1
A preparation method of 3, 5-dichloro-trifluoro acetophenone is characterized in that 3, 5-dichloro bromobenzene is used as a raw material, 5.0g of 3, 5-dichloro bromobenzene (22.1mmol) is dissolved in 50mL of tetrahydrofuran, 18.7mL of 1.3M tert-butyl lithium is dropwise added into the solution under the protection of nitrogen, dropwise addition is completed within 30min, after mixing reaction is completed for 2h, 3.30g of ethyl trifluoroacetate (23.2mmol) is dropwise added into the system, reaction is continued for 2h, and after the reaction is completed, the temperature is raised to room temperature for continuous heat preservation reaction for 4 h. After the reaction at room temperature, 50mL of saturated ammonium chloride solution was added to terminate the reaction, and the reaction was extracted with diethyl ether, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation to obtain a colorless liquid, i.e., 3, 5-dichloro-trifluoroacetophenone, in 38.4% yield and 99.4% purity.
When 3, 5-dihalo-trifluoroacetophenone is synthesized by the above comparative example, only a compound in which both the 3-position and the 5-position are chlorine can be synthesized due to the selectivity of the halogen atom, the applicability is narrow, a series of side reactions are liable to occur, and the yield is low. In the reaction process, an ultralow temperature state of-78 ℃ is needed, the production cost is high, and after the reaction is finished, the para-position of the trifluoromethyl is difficult to continue to react due to the strong electron withdrawing effect of the trifluoromethyl, so that the trifluoromethyl cannot be used for synthesizing the 4-substituted 3, 5-dihalo-trifluoroacetophenone derivative, and the application of the trifluoromethyl has great limitation in industrial application.
Claims (10)
1. A preparation method of 3, 5-dihalo trifluoro acetophenone and its derivatives is characterized in that: the method comprises the following steps:
s1, carrying out reduction reaction on the compound I to obtain a compound II;
s2, performing halogenation reaction on the compound II to obtain a compound III;
s3, carrying out amino substitution reaction on the compound III to obtain a compound IV;
wherein R is1One selected from chlorine, bromine and iodine, R2Is one of chlorine and bromine, R3One selected from hydrogen, fluorine, chlorine, bromine and hydroxyl.
2. The process for preparing 3, 5-dihalogentrifluoroacetophenone and its derivatives as claimed in claim 1, wherein: in step S1, dissolving compound i in solvent i, and reducing the nitro group under the action of hydrogen gas with one of platinum carbon, palladium carbon, and Raney nickel as a catalyst, where solvent i is selected from at least one or a homogeneous mixed system of two or more of the following substances: methanol, ethanol, ethyl acetate, n-butyl acetate, isopropyl acetate, isopropanol and toluene.
3. The process for preparing 3, 5-dihalogentrifluoroacetophenone and its derivatives as claimed in claim 1, wherein: r1、R2In step S2, the halogenating agent is chlorine, and the halogenating agent is one selected from chlorine, sulfuryl chloride, trichloroisocyanuric acid, and NCS.
4. The process for preparing 3, 5-dihalogentrifluoroacetophenone and its derivatives as claimed in claim 1, wherein: r3S3 specifically includes the following steps:
s3-1-1, dissolving the compound III in a solvent III, cooling to-10-0 ℃, adding sulfuric acid for acidification, dropwise adding a nitrous acid reagent solution to diazotize amino, and fully reacting to obtain an intermediate reaction solution I;
s3-1-2, heating the intermediate reaction solution I to 20-30 ℃, adding a hypophosphorous acid solution and cuprous oxide, continuing to react until the reaction is complete, washing with an alkaline inorganic salt solution, preserving an organic phase, and drying to obtain a compound IV;
the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite, and the solvent III is selected from one of toluene, ethanol and isopropanol or a homogeneous system formed by any of toluene, ethanol and isopropanol.
5. The process for preparing 3, 5-dihalogentrifluoroacetophenone and its derivatives as claimed in claim 1, wherein: r3Is a chlorine atom, S3 specifically comprises the following steps:
s3-2-1, adding the compound III into hydrochloric acid for acidification, adding a nitrous acid reagent solution after acidification to diazotize amino, and obtaining an intermediate reaction solution II after complete reaction;
s3-2-2, preparing a hydrochloric acid solution of cuprous chloride, heating and fully mixing, adding the intermediate reaction liquid II prepared in the step S3-2-1 into the system, separating the system after full reaction, keeping an organic phase, drying and distilling under reduced pressure to obtain a compound IV;
wherein the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite.
6. The process for preparing 3, 5-dihalogentrifluoroacetophenone and its derivatives as claimed in claim 1, wherein: r3Is fluorine atom, S3 specifically comprises the following steps:
s3-3-1, dissolving a compound III in pyridine solution containing hydrogen fluoride, controlling the temperature to be-5 ℃, fully mixing, salifying amino and hydrogen fluoride, adding nitrous acid reagent solution to diazotize the amino, and obtaining intermediate reaction liquid III after complete reaction;
s3-3-2, heating the intermediate reaction liquid III to 60-90 ℃, continuing to react, adding a quenching agent after full reaction, washing, drying and further separating to obtain a compound IV;
wherein the nitrous acid reagent is one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite.
7. The process for preparing 3, 5-dihalogentrifluoroacetophenone and its derivatives as claimed in claim 6, wherein: the quenching agent is a mixed solution formed by diethyl ether and water in a volume ratio of (0.8-2.5) to 1.
8. The process for preparing 3, 5-dihalogentrifluoroacetophenone and its derivatives as claimed in claim 1, wherein: r3Is a bromine atom, S3 specifically comprises the following steps:
s3-4-1, dissolving a compound III in a solvent VI, heating, adding hydrobromic acid, fully reacting, cooling to-10-0 ℃, dropwise adding a nitrous acid reagent solution, fully reacting to diazotize an amino group, and obtaining an intermediate reaction liquid IV;
s3-4-2, adding the bromoidenone into the intermediate reaction liquid IV, then heating to 60-80 ℃, continuing to react fully, then extracting, retaining the organic phase and further separating to obtain a compound VI;
the nitrite reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite, and the solvent VI is selected from any one of toluene, ethanol and isopropanol, or a homogeneous mixed system formed by any more of the above.
9. The process for preparing 3, 5-dihalogentrifluoroacetophenone and its derivatives as claimed in claim 1, wherein: r3Is hydroxyl, S3 specifically comprises the following steps:
s3-5-1, heating the sulfuric acid aqueous solution to 80 ℃, adding a compound III, fully reacting, cooling to 0 ℃, adding a nitrous acid reagent solution, and diazotizing amino to obtain an intermediate reaction solution V;
s3-5-2, preparing a copper sulfate solution, adding concentrated sulfuric acid for acidification, heating to 110 ℃, dropwise adding the intermediate reaction solution V into the solution, evaporating the product, purifying and drying to obtain a compound IV;
the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite.
10. The method for preparing 3, 5-dihalogentrifluoroacetophenone and its derivative as claimed in any one of claims 4 to 9, characterized in that: the nitrous acid reagent is sodium nitrite or potassium nitrite.
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