A kind of preparation process of hexafluoroisopropanol

Abstract

The invention relates to a preparation process of hexafluoroisopropanol. The invention uses compound I as a raw material, and obtains hexafluoroisopropanol in two steps through hydrolysis reaction and trifluoromethylation reaction. The total yield of the two steps is as high as more than 74%, and the purity can reach 98%. The route has the advantages of no need to use heavy metal catalysts, low catalyst dosage, mild reaction conditions, high safety, low environmental pollution, etc.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a preparation process of hexafluoroisopropanol. Background Art

[0002] Hexafluoroisopropanol (1,1,1,3,3,3-hexafluoro-2-propanol, HFIP for short) is a highly polar solvent that is easily miscible with water and a variety of organic solvents, has good thermal stability, and has good permeability to ultraviolet light. In addition, it has excellent surface tension and can well disperse and dissolve certain dyes and organic pigments. It is an important fluorine-containing intermediate that can be used to prepare high-end fluorine-containing fine chemicals such as anesthetics (for example, see US 3,689,571), surfactants, etc. HFIP exhibits strong hydrogen bonds and will bind and dissolve most molecules with acceptance points such as oxygen, double bonds, or amine groups. Due to strong hydrogen bonds, it forms stable, distillable complexes with many ethers or amines. HFIP is soluble in water and most organic solvents. It is a volatile (boiling point 58.2°C) and polar substance with high density, low viscosity, and low surface tension.

[0003] The preparation methods of HFIP in the prior art are mainly as follows:

[0004] 1) Patent CN102557874A discloses a method for preparing hexafluoroisopropanol, which uses hexafluoroacetone as a raw material and undergoes a catalytic hydrogenation reaction in the presence of precious metal catalysts such as platinum, palladium, and rhodium. The reaction not only has a low yield, but also needs to be carried out under pressurized conditions, posing a high safety hazard.

[0005] 2) Patent CN100420661C also discloses a method for synthesizing 1,1,1,3,3,3-hexafluoroisopropanol, which also uses hexafluoroacetone as a raw material and undergoes a catalytic hydrogenation reaction in the presence of precious metal catalysts such as platinum, palladium, and rhodium, and needs to be carried out under acidic conditions. Although the reaction has a high yield, it needs to be carried out under acidic conditions and under pressurized conditions, which poses a high safety hazard.

[0006] 3) US4642386A and US4642386A also disclose a method for synthesizing hexafluoroisopropanol, which also uses hexafluoroisopropyl ketone as a raw material and utilizes the MPV reaction to prepare HFIP, but the conversion rate of this method is not high.

[0007] 4) Patent CN102274734B discloses a catalyst for preparing hexafluoroisopropanol by gas-phase catalytic hydrogenation of hexafluoroacetone hydrate, its preparation method and application. A good yield is obtained using a Pd-Cu-K / C catalyst, but it uses precious metals, which are relatively expensive, and the catalyst preparation is cumbersome and needs to be carried out under pressurized conditions, which is highly dangerous.

[0008] 5) In addition, the existing preparation methods of HFIP still have problems such as high reaction temperature, long reaction time, large amount of catalyst, high impurity content, etc., for example: CN112745194A, JP1301631, JP6184025.

[0009] In summary, the existing technologies generally have problems such as low yield, the use of precious metal catalysts, composite metal catalysts, etc. Therefore, there is an urgent need to provide a preparation process for hexafluoroisopropanol with high yield, no need to use precious metal catalysts, high purity, mild reaction conditions and short reaction time. Summary of the invention

[0010] The purpose of the present invention is to provide a preparation process of hexafluoroisopropanol to solve the technical problems existing in the prior art, such as low yield, need to use a noble metal catalyst, low purity, strict reaction conditions and long reaction time.

[0011] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0012] ;

[0013] The specific synthesis steps are as follows:

[0014] 1) Under nitrogen atmosphere, compound I is used as a raw material, mixed with concentrated sulfuric acid, and heated to 85°C. Nitrogen is continuously introduced during the reaction, and the generated trifluoroacetaldehyde gas is introduced into a cooled Dewar flask together with the nitrogen flow to condense to obtain a colorless liquid compound II;

[0015] 2) Under nitrogen protection, the compound II prepared in step 1) and TMSCF3 [(trifluoromethyl)trimethylsilane] are used as raw materials, and a trifluoromethylation reaction is carried out in anhydrous DMF solvent under the action of a carbene catalyst Cat, followed by the addition of 2N hydrochloric acid and continued stirring until the reaction is complete. After the reaction is completed, the target compound III is obtained by post-treatment.

[0016] As a preferred embodiment of the present invention, the volume ratio of compound I to concentrated sulfuric acid in step 1) is 1:2-5; the reaction time in step 1) is 1-5 hours; the purity of compound I in step 1) is 90%;

[0017] As a preferred embodiment of the present invention, the molar ratio of compound II, Cat and TMSCF3 in step 2) is: 1: 0.005-0.1: 2-5; more preferably, the molar ratio of compound II, Cat and TMSCF3 is: 1: 0.005-0.01: 3;

[0018] As a preferred embodiment of the present invention, the structure of Cat in step 2) is: .

[0019] As a preferred embodiment of the present invention, the time of the trifluoromethylation reaction in step 2) is 0.5 hour to 2 hours; more preferably 0.75 hour.

[0020] As a preferred embodiment of the present invention, the post-treatment operation in step 2) is as follows: adding water and ether to the reaction mixture, extracting three times, combining the organic phases, washing the organic phases with saturated sodium bicarbonate and saturated brine, respectively, and then drying the organic phases with anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure. The residue is passed through a fast silica gel column, and the eluent is ethyl acetate / n-hexane in a volume ratio of 10%-30%. The eluents with a GC purity of more than 95% are combined, spin-dried, and vacuum-dried to obtain the target compound III.

[0021] Furthermore, the present invention also provides a method for preparing a carbene catalyst Cat1 (reference document: "Base-free transfer hydrogenation of aldehydes and ketones catalyzed by imidazolin-2-iminato actinide complexes", Deka, Hemanta et al., Catalysis Science & Technology, Vol. 13, No. 2, pp. 352-361, published on September 21, 2022), and the synthesis route thereof is as follows:

[0022]

[0023] The specific operations are as follows:

[0024] a) Add a THF solution containing tert-butanol to a THF solution of compound IV, stir and react for a certain period of time at room temperature, and after the reaction is completed, evaporate the solvent under reduced pressure, dissolve the residue in a hot toluene solution, filter with diatomaceous earth, and wash the filter cake with a small amount of hot toluene solution, remove the solvent under reduced pressure, add a certain amount of n-hexane for slurrying, heat to 60° C. and continue stirring for a period of time, cool in an ice bath, filter, and vacuum dry to obtain a carbene catalyst Cat1.

[0025] Furthermore, in step a), the molar ratio of compound IV to potassium tert-butoxide is 1:1-2, preferably 1:1.2-1.5.

[0026] The beneficial effects of the present invention are:

[0027] 1) The present invention provides a preparation process of hexafluoroisopropanol. Compound I is used as a raw material, and hexafluoroisopropanol is prepared in two steps through hydrolysis reaction and trifluoromethylation reaction. The total yield of the two steps is as high as more than 74%, and the purity can reach 98%. This route has the advantages of no need to use heavy metal catalysts, low catalyst dosage, mild reaction conditions, high safety, and low environmental pollution. DETAILED DESCRIPTION

[0028] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] The present invention is further explained below in conjunction with specific implementation modes. Example 1

[0030] Preparation of carbene catalyst Cat1:

[0031]

[0032] Synthesis steps:

[0033] 7.14 g of compound IV (20 mmol) was weighed into 100 mL of tetrahydrofuran solution, and 2.69 g of potassium tert-butoxide (24 mmol) was added to the above solution. The mixture was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in 100 mL of hot toluene solution and filtered with diatomaceous earth. The filter cake was washed with 20 mL*2 hot toluene solution, and the solvent was removed under reduced pressure. 50 mL of n-hexane was added to the residue, and the temperature was raised to 60°C and then slurried. Stirring was continued for half an hour, cooled to room temperature, and then placed in an ice bath for cooling, quickly filtered, and vacuum dried to obtain 5.77 g of carbene catalyst Cat1 (18 mmol) with a yield of 90%. 1 H-NMR (400 MHz, C6D6): δ(ppm): 6.86 (d, 1H), 6.80-6.77(m, 2H), 6.51(d,1H), 2.27 (d, 6H), 2.13 (s, 3H), 2.10(s, 6H), 2.01-1.93 (m, 3H),1.63-1.51(m,6H). Example 2

[0034] 1) Under nitrogen atmosphere, 50 mL of compound I (purity 90%, 0.47 mol) was measured and mixed with 100 mL of concentrated sulfuric acid (1.81 mol), and the mixture was heated to 85°C and reacted for 1 hour. During the reaction, nitrogen was continuously introduced, and the generated trifluoroacetaldehyde gas was introduced into a cooled Dewar flask together with the nitrogen flow to condense to obtain 36.8 g of colorless liquid compound II (0.376 mol), with a yield of 80%;

[0035] 2) Under nitrogen protection, in a 1L three-necked flask, add 19.5g of compound II (0.2mol) prepared in step 1), 85.33g TMSCF3 (0.6 mol), 250 mL of anhydrous DMF and 0.32 g of carbene catalyst Cat (0.001 mol), the above mixture was stirred at room temperature for reaction for 45 minutes, then 200 mL of 2N hydrochloric acid was added, and stirring was continued until the reaction was complete. After the reaction was completed, 100 mL of water was added, extracted with 200 mL*3 ether, and the organic phases were combined. The organic phases were then washed with 150 mL of saturated sodium bicarbonate aqueous solution and 150 mL of saturated brine, respectively. After washing, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was dried by spin drying. The residue was subjected to rapid silica gel column chromatography, and the eluent was 10% by volume ethyl acetate / n-hexane. The eluents with a GC purity of more than 95% were combined, spin dried, and dried to obtain 30.9 g of compound III (0.184 mol), with a yield of 92% and a purity of 98%. Comparative Example 1

[0036] 1) Under nitrogen atmosphere, 50 mL of compound I (purity 90%, 0.47 mol) was measured and mixed with 100 mL of concentrated sulfuric acid (1.81 mol), and the mixture was heated to 85°C and reacted for 1 hour. During the reaction, nitrogen was continuously introduced, and the generated trifluoroacetaldehyde gas was introduced into a cooled Dewar flask together with the nitrogen flow to condense to obtain 36.4 g of colorless liquid compound II (0.371 mol), with a yield of 79%;

[0037] 2) Under nitrogen protection, in a 1L three-necked flask, add 19.5g of compound II (0.2mol) prepared in step 1), 85.35g TMSCF3 (0.6 mol), 250 mL of anhydrous DMF and 0.336 g of carbene catalyst Cat (0.001 mol), the above mixture was stirred at room temperature for reaction for 45 minutes, then 200 mL of 2N hydrochloric acid was added, and stirring was continued until the reaction was complete. After the reaction was completed, 100 mL of water was added, extracted with 200 mL*3 ether, and the organic phases were combined. The organic phases were then washed with 150 mL of saturated sodium bicarbonate aqueous solution and 150 mL of saturated brine, respectively. After washing, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was dried by spin drying. The residue was subjected to rapid silica gel column chromatography, and the eluent was 10% by volume ethyl acetate / n-hexane. The eluents with a GC purity of more than 95% were combined, spin dried, and dried to obtain 23.9 g of compound III (0.142 mol), with a yield of 71% and a purity of 96%.

[0038] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A process for preparing hexafluoroisopropanol, characterized in that: Its synthetic route is: The specific steps are: 1) Under a nitrogen atmosphere, compound I is used as a raw material, mixed with concentrated sulfuric acid, and heated to 85° C. Nitrogen is continuously introduced during the reaction, and the generated trifluoroacetaldehyde gas is introduced into a cooled Dewar flask together with the nitrogen flow to condense to obtain a colorless liquid compound II; 2) Under nitrogen protection, the compound II prepared in step 1) and TMSCF3 are used as raw materials, and a trifluoromethylation reaction is carried out in anhydrous DMF solvent under the action of a carbene catalyst Cat, followed by adding 2N hydrochloric acid and continuing to stir until the reaction is complete. After the reaction is completed, the target compound III is obtained by post-treatment; The purity of compound I in step 1) is 90%; The structure of Cat in step 2) is:

2. The preparation process according to claim 1, characterized in that: In the step 1), the volume ratio of compound I to concentrated sulfuric acid is 1:2-5; and the reaction time in the step 1) is 1-5 hours.

3. The preparation process according to claim 1 or 2, characterized in that: In the step 2), the molar ratio of compound II, Cat and TMSCF3 is: 1:0.005-0.1:2-5.

4. The preparation process according to claim 3, characterized in that: In the step 2), the molar ratio of compound II, Cat and TMSCF3 is 1:0.005-0.01:

3.

5. The preparation process according to claim 4, characterized in that: The time of the trifluoromethylation reaction in step 2) is 0.5 hour to 2 hours.

6. The preparation process according to claim 5, characterized in that: The post-processing operation in step 2) is: Water and ether were added to the reaction mixture, and the mixture was extracted three times. The organic phases were combined and washed with saturated sodium bicarbonate and saturated brine, respectively. The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was passed through a fast silica gel column with an eluent of ethyl acetate / n-hexane in a volume ratio of 10% to 30%. The eluates with a GC purity of more than 95% were combined, spin-dried, and vacuum-dried to obtain the target compound III.

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