阅读说明：本技术 邻位氨基三氟苯乙酮及其衍生物的制备方法 (Preparation method of ortho-amino trifluoro acetophenone and its derivative ) 是由 张凌霄 蔡刚华 于 2021-08-18 设计创作，主要内容包括：本申请涉及有机合成领域,更具体地说,它涉及邻位氨基三氟苯乙酮及其衍生物的制备方法,其中邻位氨基三氟苯乙酮的制备包括氨基保护、三氟乙酰基化和脱保护三个步骤,整体反应条件温和,产率较高,适用于大规模生产。另外,在上述制备的基础上,通过氨基重氮化后取代,进一步值得邻位氨基三氟苯乙酮的衍生物,具有较好的工业运用前景。(The application relates to the field of organic synthesis, in particular to a preparation method of ortho amino trifluoro acetophenone and derivatives thereof, wherein the preparation method of the ortho amino trifluoro acetophenone comprises three steps of amino protection, trifluoroacetylation and deprotection, the overall reaction condition is mild, the yield is high, and the method is suitable for large-scale production. In addition, on the basis of the preparation, the derivative of the o-amino trifluoroacetophenone is further worthy of substitution after amino diazotization, and the derivative has a good industrial application prospect.)

1. The preparation method of the ortho-amino trifluoro acetophenone is characterized by comprising the following steps:

s1, taking the compound I as a raw material, and under the action of alkali I, protecting amino with acyl chloride to obtain a compound II, wherein the reaction is shown as the formula I;

s2, under the action of n-butyllithium, performing acylation reaction on the compound II and a trifluoroacetyl compound to obtain a compound III, wherein the reaction formula is shown as a formula II;

s3, hydrolyzing the compound III, removing the protecting group on the amino group to obtain a compound IV, and specifically reacting as shown in the formula III;

wherein R is₁、R₂And R₃Can be independently driven-Cl、-F、-CF₃And is selected from-H, and R₁、R₂And R₃At least one of which is not-F or-CF₃，R₁、R₂And R₃At most one of the acyl chlorides is-H, and the acyl chloride can be any one of formyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride and pivaloyl chloride.

2. The method for preparing ortho-amino trifluoroacetophenone according to claim 1, wherein in step S1, a solution containing a compound i and a base i is prepared, and acid chloride is added in portions within 20 to 60min, followed by sufficient reaction and post-treatment to obtain a compound ii; in the process of adding the acyl chloride, the temperature of the system is controlled to be lower than 5 ℃, and the mass ratio of the compound I to the acyl chloride is 1: 1-1.1.

3. The method for preparing ortho-amino trifluoroacetophenone according to claim 2, wherein in step S1, after the acid chloride is added to the system, the temperature is raised to 15 to 30 ℃ for reaction.

4. The method for preparing ortho-amino trifluoroacetophenone according to claim 2, wherein the base i is sodium hydroxide or potassium hydroxide in step S1, and in the preparation of the solution containing the compound i and the base i, the base i is first dissolved in water, the compound i is dissolved in ether, and then the two systems are mixed.

5. The method for preparing ortho-amino trifluoroacetophenone according to claim 1, wherein in step S2, TMEDA is added for catalysis during the reaction, and the amount of TMEDA is 1 to 1.1 times that of the compound ii.

6. The method for preparing ortho-amino trifluoroacetophenone according to claim 5, wherein the step S2 is as follows: dissolving a compound II in a solvent II, adding TMEDA, and reducing the temperature of the system to be less than 0 ℃ to obtain a mixed system I; uniformly adding a solution I formed by dissolving n-butyllithium in a solvent III into a mixed system I within 1-3 h, controlling the temperature to be 0-5 ℃ in the adding process to obtain a mixed system II, then completely reacting the mixed system II at 0-5 ℃, then cooling to be not higher than-10 ℃, adding a trifluoroacetyl compound for reaction, and continuously and fully reacting to obtain a mixed system III.

7. The method for preparing ortho-amino trifluoroacetophenone according to claim 6, wherein in step S2, the mass ratio of the compound II, n-butyl lithium and a trifluoroacetyl compound is 1: 2-5: 1.1-2, and the trifluoroacetyl compound is one of methyl trifluoroacetate, ethyl trifluoroacetate, propyl trifluoroacetate, isopropyl trifluoroacetate and tert-butyl trifluoroacetate.

8. The method for preparing ortho-amino trifluoroacetophenone according to claim 6, characterized in that in step S3, a mixed system III containing a compound III is directly taken, the temperature is controlled to be not higher than 10 ℃, the reaction is quenched, then the mixed system III is diluted to more than twice the volume of the mixed system III through a solvent II, then an aqueous solution of an acid I is added for hydrolysis reaction, the hydrolysis reaction temperature is 60-90 ℃, and after the reaction is finished, a base III is used for neutralization, and then the compound IV is further separated to obtain a compound IV.

9. The method for preparing o-amino trifluoroacetophenone according to claim 7, wherein the acid I is hydrochloric acid and the base III is sodium bicarbonate.

10. A method for preparing an ortho-amino trifluoroacetophenone derivative, characterized in that an ortho-amino trifluoroacetophenone is prepared by the preparation method according to any one of claims 1 to 9, then diazotization is performed on an amino group to obtain an trifluoroacetophenone diazo compound, and then any one of the following treatment methods is performed to obtain the ortho-amino trifluoroacetophenone derivative:

(A) reducing the trifluoroacetophenone diazo compound to reduce the amino group to hydrogen, wherein the reaction formula is shown as a formula IV;

(B) carrying out diazo bromination reaction on the trifluoroacetophenone diazo compound, and substituting bromine for amino, wherein the reaction formula is shown as a formula V;

(C) carrying out diazo chlorination reaction on the trifluoro acetophenone diazo compound, and substituting chlorine for amino, wherein the reaction formula is shown as a formula VI;

(D) carrying out diazo chlorination on the trifluoro acetophenone diazo compound, and substituting fluorine for amino, wherein the reaction formula is shown as a formula VII;

(E) carrying out hydroxyl substitution reaction on diazo group of the trifluoro acetophenone diazo compound, wherein the reaction formula is shown as a formula VIII;

Technical Field

The application relates to the field of organic synthesis, in particular to a preparation method of ortho-amino trifluoro acetophenone and derivatives thereof.

Background

The trifluoro acetophenone compound and its ortho amino derivative are important medicine intermediate. By arranging amino substitution at the ortho position of the trifluoroacetyl group, different groups can be modified at the ortho position of the trifluoroacetyl group on a benzene ring, so that different effects are achieved.

At present, no good production process applicable to industrialization is available for the o-amino substituted trifluoroacetophenone and derivatives thereof. Generally, a benzene ring-substituted trifluoroacetophenone is used as a raw material, and the trifluoroacetophenone is subjected to nitration and reduction to obtain an ortho-amino trifluoroacetophenone, wherein the reaction formula is as follows:

in the above reaction, the nitrated site and the nitrated degree are difficult to control, and are affected by the substituent on the benzene ring, so that the yield of the reaction is affected, and the subsequent product is not easy to separate. In addition, the above raw materials are not readily available industrially. Therefore, the passage is difficult to industrially use.

Disclosure of Invention

In order to provide a preparation method of 3, 4, 5-trihalo-trifluoroacetophenone compound and ortho-amino derivatives thereof, which are suitable for industrial production, the application provides a preparation method of ortho-amino-trifluoroacetophenone and derivatives thereof.

Firstly, the application provides a preparation method of ortho-amino trifluoroacetophenone, which comprises the following steps:

s1, taking the compound I as a raw material, and under the action of alkali I, protecting amino with acyl chloride to obtain a compound II, wherein the reaction is shown as the formula I;

s2, under the action of n-butyllithium, performing acylation reaction on the compound II and a trifluoroacetyl compound to obtain a compound III, wherein the reaction formula is shown as a formula II;

s3, hydrolyzing the compound III, removing the protecting group on the amino group to obtain a compound IV, and specifically reacting as shown in the formula III;

wherein R is₁、R₂And R₃Can be independently selected from-Cl, -F, -CF₃And is selected from-H, and R₁、R₂And R₃At least one of which is not-F or-CF₃，R₁、R₂And R₃At most one of the acyl chlorides is-H, and the acyl chloride can be any one of formyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride and pivaloyl chloride.

In the technical scheme, the compound I is used as a raw material, and the trifluoro acetophenone compound with ortho-amino group is finally prepared through amino protection, acylation and tolerization.

In the reaction, the reaction of each step has better yield, the cost of raw materials is lower, the whole reaction is easy to carry out, and the generated three wastes are less, so that the method is suitable for the process of industrial production.

Wherein, when R1 and R3 are chlorine and R2 is F, the compound I can be obtained by the following reaction:

in the reaction, the starting material, 2, 6-dichlorofluorobenzene is a byproduct for producing 2, 4-dichlorofluorobenzene, 2, 4-dichlorofluorobenzene is a precursor for producing 2, 4-dichloro-5-fluoroacetophenone or 2, 4-dichloro-5-fluorobenzoyl chloride, and the method is widely applied to quinolone antibiotics such as ciprofloxacin, gatifloxacin, levofloxacin, norfloxacin and the like, the total energy is more than 2 ten thousand tons per year, the application of the byproduct, 2, 6-dichlorofluorobenzene is small, a large amount of stocks have large safety risks, the environmental cost is increased, and the scheme can effectively consume excessive materials and has high economic value.

Optionally, in step S1, preparing a solution containing the compound i and the base i, adding acyl chloride in batches within 20-60 min, then reacting sufficiently, and performing post-treatment to obtain a compound ii; in the process of adding the acyl chloride, the temperature of the system is controlled to be lower than 5 ℃, and the mass ratio of the compound I to the acyl chloride is 1: 1-1.1.

In the above technical scheme, the acyl chloride is added into the mixture in batches, and the reaction is controlled to be carried out at a lower temperature, so that the rearrangement reaction is not easy to occur, and the side reaction is not easy to cause, so that the step S1 has better yield and purity.

Since the final product is poorly water-soluble in step S1, after the reaction is completed, the raw material can be removed by washing with water or an aqueous methanol solution containing not more than 20% by volume, and the purification step can be completed.

Optionally, in step S1, after the acid chloride is added to the system, the temperature is raised to 15 to 30 ℃ for reaction.

The reaction process is basically carried out at room temperature, the energy consumption is less, the reaction rate is higher, byproducts are not generated basically, and the economic effect is better.

Optionally, in step S1, the base i is sodium hydroxide or potassium hydroxide, and in the process of preparing a solution containing the compound i and the base i, the base i is dissolved in water, the compound i is dissolved in ether, and then the two systems are mixed.

In the reaction, diethyl ether and water are used as a mixed system, and the reaction is carried out under the catalysis of sodium hydroxide, so that fewer byproducts are generated in the process, and the impurity removal process can be completed through extraction, thereby being beneficial to further reducing the working procedures and lowering the cost in industrial production.

Optionally, in step S2, in the reaction process, TMEDA is added for catalysis, and the amount of the substance of TMEDA is 1 to 1.1 times of the amount of the substance of the compound ii.

In the technical scheme, TMEDA has special affinity to lithium ions, so that butyl lithium can be depolymerized and the activity is increased.

Optionally, step S2 is specifically as follows: dissolving a compound II in a solvent II, adding TMEDA, and reducing the temperature of the system to be less than 0 ℃ to obtain a mixed system I; uniformly adding a solution I formed by dissolving n-butyllithium in a solvent III into a mixed system I within 1-3 h, controlling the temperature to be 0-5 ℃ in the adding process to obtain a mixed system II, then completely reacting the mixed system II at 0-5 ℃, then cooling to be not higher than-10 ℃, adding a trifluoroacetyl compound for reaction, and continuously and fully reacting to obtain a mixed system III.

In the technical scheme, the whole reaction is carried out at a lower temperature, fewer byproducts are generated, the yield is higher, n-butyl lithium is not easy to generate danger, and the safety performance is improved. The solvent II and the solvent III can be any one of tetrahydrofuran, diethyl ether, cyclohexane and normal hexane independently. The concentration of the compound II in the solvent II is generally different within the range of 0.1-1M, and can be adjusted according to the actual process, preferably the compound II can be completely dissolved.

Optionally, in step S2, the mass ratio of the compound ii, n-butyl lithium and the trifluoroacetyl compound is 1: (2-5): (1.1-2), and the trifluoroacetyl compound is one of methyl trifluoroacetate, ethyl trifluoroacetate, propyl trifluoroacetate, isopropyl trifluoroacetate and tert-butyl trifluoroacetate.

Trifluoroacetic acid esters are selected for reaction, the first generated alcohol product has no influence on the subsequent reaction, the reaction can be directly continued in the system, and finally the separation is carried out, so that the separation steps are reduced. Meanwhile, the reaction process is mild and controllable, and the reaction rate is neither too fast nor too slow, so that the yield of the final product is improved.

Optionally, in step S3, directly taking a mixed system iii containing a compound iii, controlling the temperature to be not higher than 10 ℃, quenching the reaction, diluting the reaction mixture to be more than twice the volume of the mixed system iii by using a solvent ii, then adding an aqueous solution of an acid i to perform a hydrolysis reaction at a hydrolysis reaction temperature of 60 to 90 ℃, neutralizing the reaction mixture by using an alkali iii after the reaction is finished, and further separating the reaction mixture to obtain a compound iv.

In the technical scheme, the mixed system III is not separated, and the next reaction is directly carried out after primary quenching, so that the process flow is simplified, and the economic effect is improved. Quenching in the reaction can be carried out by some mineral acid (e.g., hydrochloric acid) which can be easily separated to render the residual t-butyllithium harmless. After quenching, the hydrolysis reaction is firstly diluted and then carried out under the acidic condition, so that the whole process is beneficial to reducing the occurrence of side reactions, the reaction condition is milder, the temperature runaway phenomenon caused by violent reaction is not easy to occur, and the safety of the production process is improved.

After the reaction is finished, the components in the reaction mixture can be separated by a chromatographic column separation mode, the components without the removal protection can be removed, and the components can also be separated by any other separable modes such as rectification and the like.

Optionally, the acid I is hydrochloric acid and the base III is sodium bicarbonate.

In the technical scheme, hydrochloric acid and sodium bicarbonate are selected, generated impurities are mainly inorganic salts, the impurities are easy to separate in an extraction mode, the whole system is not obviously influenced, and the purity of a final product is improved.

In addition, the application also provides a preparation method of the ortho-amino trifluoroacetophenone derivative, the preparation method is firstly used for preparing the ortho-amino trifluoroacetophenone, then diazotization reaction is carried out on amino to obtain a trifluoroacetophenone diazo compound, and then any one of the following treatment modes is carried out to obtain the ortho-amino trifluoroacetophenone derivative:

(A) reducing the trifluoroacetophenone diazo compound to reduce the amino group to hydrogen, wherein the reaction formula is shown as a formula IV;

(B) carrying out diazo bromination reaction on the trifluoroacetophenone diazo compound, and substituting bromine for amino, wherein the reaction formula is shown as a formula V;

(C) carrying out diazo chlorination reaction on the trifluoro acetophenone diazo compound, and substituting chlorine for amino, wherein the reaction formula is shown as a formula VI;

(D) carrying out diazo chlorination on the trifluoro acetophenone diazo compound, and substituting fluorine for amino, wherein the reaction formula is shown as a formula VII;

(E) carrying out hydroxyl substitution reaction on diazo group of the trifluoro acetophenone diazo compound, wherein the reaction formula is shown as a formula VIII;

by adopting the technical scheme, different substituent groups can be obtained at the ortho position of trifluoroacetyl group by firstly carrying out diazotization reaction and then carrying out substitution on amino, so that the trifluoroacetyl group has different properties, different subsequent modification capabilities and different properties.

The reaction is different for different amino substitutions, wherein the reduction of the amino group to hydrogen can be carried out in the following manner:

dissolving a compound V in a solvent at a concentration of 0.5-2 mol/L, heating to 40-80 ℃, clarifying the system, cooling to-10-0 ℃, dropwise adding sulfuric acid at the temperature like the system, wherein the amount of the sulfuric acid is 2-5 times of that of the compound V, continuing to perform heat preservation reaction for 40-80 min after acidification, and then adding a diazotization reagent into the system in batches within 1-2 h, wherein the amount of the diazotization reagent is preferably 2-2.4 times of that of the compound V, so that sufficient reaction and purification are facilitated.

After the nitrite is added, continuously keeping the temperature below 0 ℃ until the nitrite is fully reflected, then heating the system to room temperature, adding a hypophosphorous acid solution, wherein the amount of the hypophosphorous acid is preferably 3-4 times that of the compound V, simultaneously adding catalytic amount of cuprous oxide (generally 0.003-0.006 time of the compound V), continuously reacting for 1-3 hours at room temperature, cleaning several layers by using a sodium bicarbonate solution after the reaction is finished, drying by using anhydrous magnesium sulfate or other drying agents, and rectifying to obtain the deamination product.

The amino diazotization substitution can be carried out in the following way:

dissolving a compound V in a solvent at a concentration of 0.5-2 mol/L, heating to 40-80 ℃, adding hydrobromic acid and fully reacting, wherein the amount of the hydrobromic acid is 5-20 times of that of the compound V, cooling a system to-10-0 ℃ after fully reacting, and uniformly adding a diazotization reagent into the system within 40-80 min, wherein the amount of the diazotization reagent is preferably 1.2-1.5 times of that of the compound V. And in the dropping process, controlling the temperature to be lower than 0 ℃, and keeping the temperature until the reaction is fully performed after the dropping is finished.

And after the reaction is finished, adding cuprous bromide into the system, uniformly adding the cuprous bromide in batches within 10-60 min, wherein the ratio of the amount of the substance to the amount of the compound V is (1-1.2) to 1, heating to 50-80 ℃ after the addition is finished, continuing the reaction until the reaction is complete, then naturally cooling and extracting, drying after the extraction, and removing the solvent through reduced pressure distillation to obtain the amino diazotization bromination product.

The amino diazotization chlorine substitution can be carried out in the following way:

dissolving a compound V in concentrated hydrochloric acid at a concentration of 0.5-1M, heating to 60-70 ℃, fully reacting, then cooling to-10-0 ℃, uniformly adding a diazotization reagent within 0.5-1.5 h, wherein the amount of the added substance of the diazotization reagent is 1.2-1.5 times of that of a compound II, keeping the system temperature below 0 ℃ in the process of adding the diazotization reagent, preserving heat after the dropwise addition is finished, and continuing to fully react to obtain a diazotization compound solution I;

and preparing 1-1.2M solution from cuprous chloride and concentrated hydrochloric acid, heating to 60-80 ℃, uniformly mixing, dropwise adding the diazo compound solution I into the concentrated hydrochloric acid solution of cuprous chloride within 40-80 min, wherein the ratio of the amount of cuprous chloride to the amount of compound II is (1.3-1.8): 1, continuously preserving the temperature and fully reacting, cooling to normal temperature, extracting with an organic solvent, retaining the organic phase, drying and removing the solvent to obtain the diazotized chloro-product.

The amino diazotization fluorine substitution can be carried out in the following way:

dissolving a compound V in a pyridine hydrogen fluoride solution cooled to 0 +/-5 ℃ in a concentration of 0.5-1M, wherein the mass fraction of hydrogen fluoride is 65-70%, carrying out heat preservation and mixing for 40-60 min, then uniformly adding a diazotization reagent into the system within 0.5-1.5 h, wherein the amount of the added substance of the diazotization reagent is 1.2-1.5 times of that of a compound II, keeping the temperature of the system to be lower than 0 ℃ in the process of adding the diazotization reagent, carrying out heat preservation reaction for 20-30 min after dropwise addition is finished, then heating to 60-90 ℃, continuing carrying out heat preservation reaction for 2-4 h, then quenching with water and diethyl ether, separating an organic layer, washing with saline water, then carrying out reduced pressure concentration, and eluting with an organic solvent to obtain a diazotized fluorinated product.

Amino diazotization hydroxyl substitution can be carried out in the following way:

preparing a sulfuric acid solution with the mass fraction of 20-25%, heating to 70-80 ℃, adding a compound V into the sulfuric acid solution in batches within 20-30 min, keeping the temperature at 70-80 ℃ for sufficient reaction, cooling to-10-0 ℃, then uniformly adding a diazotization reagent into the system within 0.5-1.5 h, keeping the temperature of the system to be lower than 0 ℃ in the diazotization reagent adding process, adding the diazotization reagent in an amount which is 1.2-1.5 times of the amount of the substance of the compound II, and fully reacting for later use.

And (2) additionally preparing a copper sulfate solution with the mass fraction of 30-40%, dropwise adding concentrated sulfuric acid into the copper sulfate solution for acidification, heating the mixture to a reflux state, dropwise adding the diazo compound solution III into the system, and distilling out the product while dropwise adding to obtain the diazo fluoro product. Wherein, the diazotization reagent can be sodium nitrite, potassium nitrite or other nitrite which can participate in the diazotization reaction.

In summary, the present application includes at least one of the following advantages:

1. in the application, a mode of amino protection-n-butyllithium trifluoroacetylation promotion-hydrolysis deprotection is adopted, so that the method has a good industrial application prospect on the whole, the reaction is easy to carry out, the raw material source is wide, and the method is suitable for industrial large-scale production.

2. In the further arrangement of the application, after the reaction in the step S2 is completed, the next process is carried out after the whole system is directly quenched, so that the process steps required by production can be effectively reduced, and the economic value of the reaction is improved.

3. In a further arrangement of the present application, the amino group can be modified to obtain the trifluoroacetophenone with different substituents.

Detailed Description

The present application will be described in further detail with reference to examples.

Example 1-15, a method for preparing ortho amino trifluoroacetophenone, comprising the steps of:

s1, taking the compound I as a raw material, and under the action of alkali I, protecting amino with acyl chloride to obtain a compound II, wherein the reaction is shown as the formula I;

the reaction of this step is specifically operated as follows:

weighing 5mol of a compound I, dissolving the compound I in 1.5L of diethyl ether, preparing 1L of an alkali I aqueous solution with the mass fraction of 40%, mixing the two solutions, cooling to 0 ℃, uniformly adding 1.65mol of acyl chloride within 0.5h, controlling the temperature of a reaction system to be lower than 5 ℃ in the adding process, heating the system to 20 ℃ after the acyl chloride is added, and continuing stirring until the reaction is carried out fully, wherein the reaction time is 2.5 h. After the reaction is finished, cooling to 0 ℃ and standing for 1.5h, then filtering, retaining filter residue, washing twice with a mixed solution formed by water and methanol in a volume ratio of 9:1, and drying to obtain a compound II.

S2, under the action of n-butyllithium, performing acylation reaction on the compound II and a trifluoroacetyl compound to obtain a compound III, wherein the reaction formula is shown as a formula II;

the specific operation of the step is as follows:

weighing 1mol of the compound II prepared in the step S1, dissolving the compound II in 500mL of anhydrous ether, adding 1mol of TMEDA (116g), fully mixing, cooling to 0 ℃, uniformly dropwise adding 0.88L of 2.5M n-butyllithium n-hexane solution within 2.5h, controlling the temperature to be not higher than 5 ℃ in the whole dropwise adding process, obtaining a mixed system II after dropwise adding is completed, reacting the mixed system II at 0-5 ℃ for 5h, then cooling to-20 ℃, adding 2.5mol of trifluoroacetyl compound, and continuously reacting for 8h to obtain a mixed system III, wherein the mixed system III contains the compound III.

S3, hydrolyzing the compound III, removing the protecting group on the amino group to obtain a compound IV, and specifically reacting as shown in the formula III;

the method comprises the following specific operations:

adding 200mL of hydrochloric acid with the mass fraction of 15% into a mixed system III for quenching, controlling the temperature of the system to be lower than 10 ℃ in the quenching process, then diluting the system with 500mL of diethyl ether, then adding 100mL of hydrochloric acid with the mass fraction of 37%, heating the system to 80 ℃, fully reacting for 5 hours, cooling to 20 ℃, adding 1L of ethyl acetate, then adjusting the pH value of the system to be higher than 7 by using a saturated sodium bicarbonate solution, extracting the system with ethyl acetate for three times, then combining organic phases, drying the organic phases by using anhydrous sodium sulfate, and purifying the organic phases by using a chromatographic column to obtain a compound II.

The chromatographic column adopts 200-300 mesh silicon dioxide, the mobile phase adopts a gradient elution method, petroleum ether is adopted for elution initially, and the final developing solvent is a mixed solvent formed by the petroleum ether and ethyl acetate in a volume ratio of 5: 1.

Examples 1 to 15, wherein R₁、R₂、R₃、R₄And the acid chlorides were selected as shown in table 1.

Selection of raw materials in Table 1 and examples 1 to 15

Numbering	R1	R2	R3	R4	Acyl chloride
						Example 1	-Cl	-F	-Cl	-OCH2CH3	Pivaloyl chloride
Example 2	-Cl	-Cl	-Cl	-OCH2CH3	Pivaloyl chloride
						Example 3	-H	-Cl	-Cl	-OCH2CH3	Pivaloyl chloride
Example 4	-Cl	-CF3	-Cl	-OCH2CH3	Pivaloyl chloride
						Example 5	-Cl	-H	-Cl	-OCH2CH3	Pivaloyl chloride
Example 6	-Cl	-H	-CF3	-OCH2CH3	Pivaloyl chloride
						Example 7	-Cl	-F	-Cl	-OCH3	Pivaloyl chloride
Example 8	-Cl	-F	-Cl	-Cl	Pivaloyl chloride
						Example 9	-Cl	-F	-Cl	-Br	Pivaloyl chloride
Example 10	-Cl	-F	-Cl	-OOCCF3	Pivaloyl chloride
						Example 11	-Cl	-F	-Cl	-OCH2CH3	Formyl chloride
Example 12	-Cl	-F	-Cl	-OCH2CH3	Acetyl chloride
						Example 13	-Cl	-F	-Cl	-OCH2CH3	Propionyl chloride
Example 14	-Cl	-F	-Cl	-OCH2CH3	N-butyryl chloride
						Example 15	-Cl	-F	-Cl	-OCH2CH3	Isobutyryl chloride

In addition, in step S1, the base i is sodium hydroxide.

In examples 1 to 15, the yield of step S1, the total yield of the compound IV three-step reaction, and the purity of the compound IV are shown in Table 2.

Table 2, examples 1 to 15

Numbering	Yield of Compound II	Yield of Compound IV	Purity of Compound IV
				Example 1	98.9％	85.0％	99.4％
Example 2	95.5％	84.8％	99.2％
				Example 3	96.2％	83.7％	99.5％
Example 4	97.0％	86.1％	99.6％
				Example 5	96.6％	82.8％	99.5％
Example 6	99.1％	83.4％	99.2％
				Example 7	98.3％	85.5％	99.3％
Example 8	90.4％	77.0％	99.5％
				Example 9	88.2％	80.2％	99.6％
Example 10	85.5％	73.9％	99.4％
				Example 11	94.4％	81.7％	99.5％
Example 12	96.7％	86.3％	99.4％
				Example 13	95.8％	82.0％	99.3％
Example 14	98.8％	81.3％	99.5％
				Example 15	98.6％	83.6％	99.1％

According to the experimental data, the method for preparing the compound IV has the advantages of good purity, high yield and less waste generation in the whole reaction process. Now, taking example 1 as an example, an amplification experiment was performed to obtain example 16.

Example 16, a method for preparing ortho amino trifluoroacetophenone includes the following steps:

s1, adding 30L of diethyl ether into a 100L reaction kettle, weighing 5.4kg (30mol) of the compound I (2, 4-dichloro-3-fluoroaniline), adding the compound I into the reaction kettle, driving n-propanol to cool by a cooling pump to reduce the temperature of the solution in the reaction kettle to 0 ℃, then adding 20L of a sodium hydroxide aqueous solution with the mass fraction of 40% which is prepared in advance, dropwise adding pivaloyl chloride into the reaction kettle while keeping stirring and the operation of a condensing pump, wherein the dropwise adding amount is 3.9L, the dropwise adding time is 0.5h, monitoring is kept during the dropwise adding process, the temperature is controlled to be not higher than 5 ℃, if the temperature is increased, the stirring speed is accelerated, and the temperature of the n-propanol in the cooling pump is reduced.

And after the dropwise addition is finished, stopping the cooling pump, recovering the system in the reaction kettle to room temperature, then continuing stirring and reacting for 4 hours, after the reaction is finished, opening the condensing pump again to control the temperature to 0 ℃, pumping the mixture into a filter throwing machine for filtering to obtain a mixed solution formed by mixing filter cake water and methanol in a volume ratio of 9:1, leaching, and then completely drying again to obtain a compound II.

S2, weighing 2.64kg (10mol) of compound II, placing in a 20L reaction kettle, adding 5L diethyl ether which is strictly dehydrated, keeping stirring, adding 1.16kg of TMEDA (1mol), controlling the temperature to be 0 ℃, and removing air in the system by nitrogen replacement (drying treatment when nitrogen is introduced). And then dropwise adding 8.8L of n-butyllithium n-hexane solution with the concentration of 2.5M, controlling the temperature to be lower than 5 ℃ in the dropwise adding process, controlling the temperature to be lower than 5 ℃ after the dropwise adding is finished, continuously stirring for 5 hours, then cooling to-20 ℃, adding 3.2L of ethyl trifluoroacetate (2.5mol) into the system, and continuously reacting for about 10 hours to obtain a mixed system III containing a compound III.

S3, adding 1L of hydrochloric acid with the mass fraction of 15% into the mixed system III, controlling the temperature of the system to be lower than 10 ℃, quenching residual n-butyllithium, then adding 5L of diethyl ether to dilute the system, adding 1L of concentrated hydrochloric acid with the mass fraction of 37% after the dilution is finished, and then heating to 80 ℃ for reaction. After 5h of reaction, cooling to room temperature, adding 10L of ethyl acetate, then adding 15L of saturated sodium carbonate solution, adjusting the pH value to be more than 7, then adding the mixture into an extraction tower, repeatedly extracting for three times by using ethyl acetate, mixing organic phases, drying, and then separating by using a chromatographic column, wherein a stationary phase is 200-300 meshes of silica gel, and a mobile phase is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 10: 1.

In example 16, the total yield of the three-step reaction was 82.2%, and the purity of the final compound III was 99.1%, which met the requirements of industrial production. The waste generated during the production process is as follows:

1. the solvents recovered after chromatographic column separation are mainly ethyl acetate and petroleum ether, and can be directly recovered and reused.

2. The residual solvent in step S1 is mainly diethyl ether and water, which contain a certain amount of inorganic base, diethyl ether can be directly used, and the residual components can be discharged after neutralization.

Therefore, in the whole reaction system, the final residual three wastes which need to be treated are less, and the raw material source is simple and easy to obtain, thereby having obvious significance in the industrial process.

Further, based on example 1, some parameters were adjusted to obtain the following examples.

Example 17, a method for preparing o-amino trifluoroacetophenone, different from example 1, in that acid chloride was uniformly added within 20min, the amount of the acid chloride was 1.5mol, and the yield of step S1 was 95.6%.

Example 18, a method for preparing o-amino trifluoroacetophenone, different from example 1 in that the acid chloride was uniformly added over 60min, the yield of step S1 was 97.9%.

Example 19, a method for preparing o-amino trifluoroacetophenone, different from example 1 in that the acid chloride was uniformly added within 10min, the yield of step S1 was 89.3%.

Example 20, a method for preparing o-amino trifluoroacetophenone, different from example 1, in that the reaction temperature of step S1 was 30 ℃, the yield of step S1 was 94.7%.

Example 21, a method for preparing o-amino trifluoroacetophenone, different from example 1, in that the reaction temperature of step S1 was 15 ℃, the yield of step S1 was 96.2%.

Example 22, a method for preparing o-amino trifluoroacetophenone, different from example 1, is that after the acid chloride was added in step S1, the reaction was continued at 5 ℃ and the yield in step S1 was 96.6%, but the reaction proceeded slowly and was monitored by a dot plate, and step S1 was completed after 7 hours.

Example 23, a method for preparing o-amino trifluoroacetophenone, differs from example 1 in that in step S2, the amount of TMEDA was 1.1mol, and the total yield of the final product in three steps was 85.8%.

Example 24, a method for preparing o-amino trifluoroacetophenone, different from example 1 in that, in step S2, a 0.25M n-butyllithium cyclohexane solution was added in a volume of 0.8L, the amount of trifluoroacetyl compound was 2mol, and the total yield of the final product in three steps was 82.0%.

Example 25 preparation of o-amino trifluoroacetophenone the difference from example 1 was that a 0.25M solution of n-butyllithium in cyclohexane was added in a volume of 2L and the amount of trifluoroacetyl compound was 5mol of the final product in a three-step overall yield of 88.5%.

Example 26, a method for preparing o-amino trifluoroacetophenone, different from example 1 in that the volume of a 0.25M n-butyllithium cyclohexane solution charged was 0.4L and the amount of trifluoroacetyl compound was 1mol of the final product, the three-step total yield was 71.3%.

Example 27, a method for preparing o-amino trifluoroacetophenone, different from example 1, is that in step S3, the hydrolysis temperature is 60 ℃, and the total yield of the final product in three steps is 83.9%.

Example 28, a method for preparing o-amino trifluoroacetophenone, different from example 1, is that in step S3, the hydrolysis temperature is 90 ℃, and the total yield of the final product in three steps is 87.0%.

According to the experimental data, the technical scheme in the application has better reaction performance in different parameter ranges when the ortho-amino trifluoroacetophenone is prepared. In examples 24 to 26, the amounts of the trifluoroacetyl compound and n-butyllithium in step S2 were adjusted, and both the trifluoroacetyl compound and n-butyllithium were used in excess, which is helpful for improving the reaction equilibrium and shifting the reaction equilibrium to the direction of the compound iii, and the excess trifluoroacetyl compound had a large difference in polarity from the compound iv as the final product, so that the subsequent separation solution was easy. The redundant trifluoroacetyl compound in the eluent can be reused after the solvent is evaporated to dryness through desalting treatment, and the overall yield is not obviously influenced.

Further, the following examples are set up, the derivatives being obtained on the basis of ortho amino trifluoroacetophenone as follows.

Example 29 preparation of 1- (3, 5-dichloro-4-fluorophenyl) -2,2, 2-trifluoroacetone, formula IV.

Wherein R1 and R3 are chlorine, R2 is fluorine, and the reaction is as follows:

weighing 0.3mol of a compound V, dissolving the compound V in 300mL of methylbenzene, heating to 50 ℃, cooling to below 0 ℃ after a system is clarified, dropwise adding 125g of sulfuric acid with the mass fraction of 92.5% into the system under the condition that the temperature is kept to be below 0 ℃ for acidification, continuously controlling the temperature of the system to be below 0 ℃ for heat preservation reaction for 1h after acidification, then uniformly dropwise adding 138.0g of sodium nitrite aqueous solution with the mass fraction of 33% (containing 0.66mol of diazotization reagent sodium nitrite) into the system within 1.5h, continuously keeping the temperature below 0 ℃ for reaction for 2h, heating the system to 20 ℃ after full reaction, adding 131g of hypophosphorous acid with the mass fraction of 50% and 0.8g of cuprous oxide, and carrying out heat preservation stirring reaction for 2 h.

After the reaction is finished, standing for layering, washing an organic layer by using a 5% sodium bicarbonate aqueous solution, drying an organic phase by using anhydrous magnesium sulfate, and rectifying to obtain 63.5g of clear and transparent oily liquid 1- (3, 5-dichloro-4-fluorophenyl) -2,2, 2-trifluoroacetone with the purity of 99.1%, wherein the yield of the step is 81.1%.

The nuclear magnetic resonance hydrogen spectrum data of the target product are as follows: 1H NMR (400MHz, CHLOROFORM-d) δ 8.06(dd, J0.8, 6.1Hz, 2H).

Example 30 preparation of 1- (2-bromo-3, 5-dichloro-4-fluorophenyl) -2,2, 2-trifluoroacetone, formula V.

Wherein R1 and R3 are chlorine, R2 is fluorine, and the reaction is as follows:

taking 0.2mol of the compound V, adding the compound V into a reactor filled with 300ml of acetonitrile, heating to 50 ℃, adding 300ml of hydrobromic acid with the concentration of 47 percent, stirring for 1h to obtain uniform suspension, then cooling to-5 +/-5 ℃, uniformly dropwise adding 50.3g of sodium nitrite solution (containing 0.24mol of diazotization reagent sodium nitrite) with the mass fraction of 33 percent within 1h, controlling the temperature of the system to be lower than 0 ℃ in the dropwise adding process, keeping the temperature and stirring for 0.5h after the dropwise adding is finished, and preparing the diazotization solution for later use.

43.0g (0.3mol) of cuprous bromide is uniformly added into the diazo compound solution II within 30min, and after the addition is finished, the temperature is raised to 60 ℃, and the mixture is stirred for 1 h. After the reaction is finished, the temperature is reduced to normal temperature, the mixture is extracted by 300mL of dichloromethane, and the process is repeated for three times. The organic phases were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure to give 1- (2-bromo-3, 5-dichloro-4-fluorophenyl) -2,2, 2-trifluoroacetone as a pale yellow oily liquid (50.0 g, content 99.1%, yield 73.6%).

Example 31 preparation of 1, 1- (2,3, 5-trichloro-4-fluorophenyl) -2,2, 2-trifluoroacetone according to formula VI.

Wherein R1 and R3 are chlorine, R2 is fluorine, and the reaction is as follows:

weighing 0.2mol of a compound II, dissolving the compound II in 300mL of concentrated hydrochloric acid, heating to 60 ℃, cooling to below 0 ℃ after a system is clarified, uniformly dropwise adding 50.3g (containing 0.24mol of diazotization reagent sodium nitrite) of sodium nitrite solution with the mass fraction of 33% in 1h, controlling the temperature of the system to be lower than 0 ℃, and after dropwise adding is finished, keeping the temperature and stirring for 0.5h, thus preparing the diazotization solution for later use.

Adding 29.7g (0.3mol) of cuprous chloride into 300mL of hydrochloric acid with the mass fraction of 37%, heating to 60 ℃, stirring for 1h to uniformly mix, then uniformly dropwise adding the diazotization solution into the system within 1h, keeping the temperature and stirring for reaction for 1h after dropwise adding, naturally cooling, extracting with 300mL of dichloromethane, and repeating for three times. The organic phases were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure to give 1- (2,3, 5-trichloro-4-fluorophenyl) -2,2, 2-trifluoroacetone as a pale yellow oily liquid (50.9 g), purity 99.0%, yield in this step 86.2%.

Example 32, preparation of 1- (2-hydroxy-3, 5-dichloro-4-fluorophenyl) -2,2, 2-trifluoroacetone,

wherein R1 and R3 are chlorine, R2 is fluorine, and the reaction is as follows:

adding 46.0g of concentrated sulfuric acid into 150mL of water for dilution to prepare a sulfuric acid solution, heating to 80 ℃, adding the compound II (0.2mol) into the prepared sulfuric acid solution in batches within 30 minutes, keeping the system temperature at 60 ℃, and stirring for 1 hour. And then cooling to-10-0 ℃, uniformly dropwise adding 50.3g (containing 0.24mol of diazotization reagent sodium nitrite) of 33% sodium nitrite solution within 1 hour, controlling the temperature of the system to be lower than 0 ℃, and after dropwise adding, continuously stirring for 1 hour under heat preservation to obtain diazo compound solution III.

71.5g of anhydrous copper sulfate (0.286mol) was added to 123.5g of pure water, 52.7g of concentrated sulfuric acid was slowly dropped thereto, and after stirring uniformly, the solution was heated to 110 ℃ to reflux the solution. Slowly and dropwise adding the diazo compound solution III into the reflux system, distilling out the product while dropwise adding, keeping the volume of the system unchanged, firstly extracting the distilled product once by using 200mL of dichloromethane, then extracting twice by using 100mL of dichloromethane, combining organic phases, and drying to obtain 1- (2-hydroxy-3, 5-dichloro-4-fluorophenyl) -2,2, 2-trifluoroacetone, 40.6g of colorless to pale yellow liquid, the content of the colorless to pale yellow liquid is 99.2%, and the yield is 73.2%.

The derivatives prepared by the method have good yield and purity, are easy to react, separate and purify, and are suitable for the process of industrial production.

The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.