Preparation method of perfluorohexyl octane

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of perfluorohexyl octane. The preparation method comprises the following steps: by taking perfluorohexyl ethyl iodide as a raw material, firstly carrying out Grignard reagent exchange with a reagent A, and then carrying out nucleophilic addition reaction with n-hexanal to obtain a compound III; carrying out esterification and substitution on the compound III to prepare a compound V, or carrying out an Apple substitution reaction to prepare the compound V; and carrying out reduction reaction on the compound V, rectifying and purifying to obtain a target product. The reagent A comprises an isopropyl magnesium chloride tetrahydrofuran solution, a methyl magnesium chloride tetrahydrofuran solution, a methyl magnesium bromide tetrahydrofuran solution, an ethyl magnesium chloride tetrahydrofuran solution, an ethyl magnesium bromide tetrahydrofuran solution and / or a phenyl magnesium bromide tetrahydrofuran solution. According to the method, the perfluorohexyl ethyl iodide and the n-hexanal are used as raw materials to prepare the perfluorohexyl octane, isomer impurities are fundamentally avoided, and the method has the advantages that purification is easy, the yield is high, the product purity is high, and industrial production is facilitated.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing perfluorohexyl octane. Background Art

[0002] Dry eye, also known as keratoconjunctivitis sicca, refers to a common and complex ophthalmic disease caused by insufficient tear secretion, excessive evaporation or abnormal tear composition. Dry eye can cause uncomfortable symptoms such as dry eyes, foreign body sensation, pain or itching, and can also cause visual impairment due to unstable tear film, which in turn has a negative impact on the patient's quality of life and even mental health. On May 18, 2023, perfluorohexyl octane eye drops developed by Bausch and Lomb and Novaliq were approved by the FDA for the treatment of ocular surface damage or dryness of the cornea. This product is also the first FDA-approved drug for dry eye that directly targets tear evaporation. As a common ophthalmic disease, with the increasing incidence of dry eye, the demand for drugs in the market will continue to increase.

[0003] The chemical name of perfluorohexyl octane is 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-tetradecane, and the structural formula is shown in Formula VI.

[0004]

[0005] At present, there are many reports on the synthesis methods of perfluorohexyl octane at home and abroad. For example, patents with publication numbers CN115703693A, US20190071376A1 or WO2018202835A1. However, the synthesis methods disclosed in CN115703693A and US20190071376A1 require expensive transition metal reagents, and the reaction process requires light, which is not suitable for industrial production. The method reported in WO2018202835A1 has a long reaction time of 3 days and a low yield, which is also not suitable for industrial production.

[0006] The reported synthesis methods of perfluorohexyl octane are summarized as follows: Route 1 and Route 2. Most existing synthesis methods use perfluorohexyl halogenated alkanes as starting materials, and react with 1-octene through free radical addition reaction, or then through reduction reaction to obtain the product. In this type of reaction, since free radical addition can be achieved at both ends of the double bond of the olefin, the selectivity of the addition product will be greatly affected, thereby producing 1-10% isomeric impurity perfluorohexyl halogenated alkanes, and then producing 2-perfluorohexyl octane isomeric impurities. Because its structure is similar to that of perfluorohexyl octane and the physical properties are not much different, it is difficult to remove, which ultimately leads to low product purity, as shown in Route 3. The original Novalik company described on page 9 of patent CN111867560B that the isomeric impurities (2-perfluorohexyl octane) produced in the synthesis of perfluorohexyl octane are not easy to remove during purification. However, the purity of perfluorohexyl octane used in the pharmaceutical field is required to be very high, so this type of synthesis method will result in the product not meeting the usage standards, greatly increasing the economic cost of industrial production.

[0007] Route 1:

[0008]

[0009] Route 2:

[0010]

[0011] Route 3:

[0012]

[0013] Therefore, in order to avoid the generation of isomeric impurities and solve the shortcomings of low product purity and difficulty in purification, it is urgent to develop a method for preparing perfluorohexyl octane with high yield and high purity. Summary of the invention

[0014] In view of this, in order to overcome the defects of the prior art such as easy generation of isomer impurities, low product purity, and difficulty in purification, the present invention proposes a new method for preparing perfluorohexyl octane.

[0015] One of the purposes of the present invention is to provide a method for preparing perfluorohexyl octane.

[0016] To achieve the above object, the present invention adopts the following technical solutions:

[0017] The preparation method of perfluorohexyl octane comprises the following steps:

[0018] S1: Using perfluorohexylethyl iodide as a raw material, first add reagent A to undergo a Grignard exchange reaction, and then add n-hexanal to undergo a nucleophilic addition reaction to obtain compound III;

[0019] S2: Compound III obtained in S1 is subjected to two-step reactions of esterification and substitution to prepare Compound V; or Compound III is subjected to one-step Apple substitution reaction to prepare Compound V;

[0020] S3: Compound V obtained in S2 is subjected to a reduction reaction under the action of an acid-binding agent and a reducing agent to obtain perfluorohexyl octane;

[0021] The reagent A comprises any one or more of isopropylmagnesium chloride tetrahydrofuran solution, methylmagnesium chloride tetrahydrofuran solution, methylmagnesium bromide tetrahydrofuran solution, ethylmagnesium chloride tetrahydrofuran solution, ethylmagnesium bromide tetrahydrofuran solution and phenylmagnesium bromide tetrahydrofuran solution;

[0022] The structural formulas of the compounds are shown below:

[0023]

[0024] Preferably, the reagent A is isopropylmagnesium chloride tetrahydrofuran solution.

[0025] Most preferably, the reagent A is a 2M isopropylmagnesium chloride tetrahydrofuran solution.

[0026] Furthermore, in S1, the mass ratio of the perfluorohexylethyl iodide, the n-hexanal and the reagent A is 4-6:0.5-2:5; and / or the reaction temperature of the Grignard exchange reaction is 0-10°C, and the reaction time is 0.5-2h; and / or the reaction temperature of the nucleophilic addition reaction is 10-20°C, and the reaction time is 2-5h.

[0027] Preferably, in S1, the mass ratio of the perfluorohexylethyl iodide, the n-hexanal and the reagent A is 4.83:0.85:5.

[0028] Further, in S1, the reagent A is stirred and cooled to 0-5° C. under nitrogen protection, and then the perfluorohexylethyl iodide is added dropwise to react.

[0029] Further, in S1, the reaction is monitored by GC, and after the reaction is completed, a dilute HCl solution is added to quench the reaction.

[0030] Further, the reaction product of S1 is extracted, washed, dried, concentrated and recrystallized to obtain a pure compound III; the extractant is methyl tert-butyl ether, and the extraction times are two; the washing is to wash the organic phase obtained by extraction with sodium bicarbonate solution and brine; the recrystallization solvent is n-hexane.

[0031] Furthermore, the two-step reaction of esterification and substitution includes: the compound III obtained in S1 undergoes an esterification reaction with a reagent B to obtain a compound IV; the compound IV undergoes a substitution reaction with a substitution reagent to obtain a compound V; the reagent B includes any one or more of methylsulfonyl chloride and methylsulfonic anhydride; the substitution reagent includes any one or more of anhydrous sodium iodide, potassium iodide, lithium iodide and tetrabutylammonium iodide; the structural formula of the compound IV is as follows:

[0032]

[0033] Preferably, the reagent B is methanesulfonyl chloride.

[0034] Preferably, the substitution reagent is anhydrous sodium iodide.

[0035] Furthermore, the reaction solvent of the substitution reaction is solvent a, and the solvent a is any one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, tetrahydrofuran, and acetonitrile; and / or the mass ratio of the compound III to the reagent B is 150-200:50-70; and / or the amount ratio of the compound IV, the substitution reagent and the solvent a is 100-150g:65-85g:1-1.5L; and / or the reaction temperature of the esterification reaction is 0-10°C, and the reaction time is 1.5-3h; and / or the reaction temperature of the substitution reaction is 50-60°C, and the reaction time is 3.5-6h.

[0036] Preferably, the solvent a is N,N-dimethylacetamide.

[0037] Preferably, in the two-step reaction of esterification and substitution, the mass ratio of the compound III to the reagent B is 170:56.4.

[0038] Preferably, in the two-step reaction of esterification and substitution, the usage ratio of the compound IV, the substitution reagent and the solvent a is 110 g:78.3 g:1.1 L.

[0039] Furthermore, in the esterification reaction, the compound III is first mixed with triethylamine and dichloromethane, stirred and cooled to 0-5° C., and then the reagent B is added dropwise to carry out the esterification reaction to obtain compound IV.

[0040] Preferably, the usage ratio of the compound III, the triethylamine and the dichloromethane is 70-100 g:25-40 g:0.8-2 L, more preferably 85 g:30.7 g:1 L.

[0041] Preferably, the reaction time of the esterification reaction is 2 h.

[0042] Preferably, the reaction time of the substitution reaction is 4 h.

[0043] Furthermore, in the two-step reaction of esterification and substitution, GC is used to monitor the reaction, and water is added to quench the reaction after the reaction is completed.

[0044] Furthermore, in the two-step reaction of esterification and substitution, the esterification reaction product is extracted, washed, dried and concentrated to obtain a crude compound IV; the extractant is dichloromethane, and the extraction times are two; the washing is to combine the organic phases obtained by extraction and then wash them with dilute hydrochloric acid solution, sodium bicarbonate solution and brine in sequence.

[0045] Furthermore, in the two-step reaction of esterification and substitution, the substitution reaction product is extracted, washed, dried and concentrated to obtain compound V; the extractant is n-hexane, and the number of extractions is three times; the washing is to wash the organic phase obtained by extraction with sodium thiosulfate solution and brine in sequence.

[0046] Furthermore, the one-step Apple substitution reaction includes: adding reagent C, reagent D and solvent b to compound III obtained in S1 for reaction; then adding reagent E and continuing the reaction to obtain compound V; the reagent C includes any one or more of triphenylphosphine and tributylphosphine, the reagent D includes any one or more of imidazole, triethylamine, and pyridine, and the solvent b includes any one or more of tetrahydrofuran, dichloromethane, toluene, and acetonitrile; the reagent E includes any one or more of iodine, iodine in tetrahydrofuran solution, iodine in dichloromethane solution, and iodine in acetonitrile solution.

[0047] Preferably, reagent C is triphenylphosphine.

[0048] Preferably, reagent D is imidazole.

[0049] Preferably, solvent b is tetrahydrofuran.

[0050] Preferably, reagent E is a tetrahydrofuran solution of iodine.

[0051] Furthermore, in the one-step Apple substitution reaction, after adding reagent E, the temperature is controlled at 5-15°C and the reaction is carried out for 3-5 hours, more preferably 3.5 hours; and / or the amount ratio of iodine in the compound III, the reagent C, the reagent D, the solvent b and the reagent E is 70-100g:60-85g:15-30g:500-1000mL:60-90g.

[0052] Preferably, in the one-step Apple substitution reaction, the usage ratio of iodine in the compound III, the reagent C, the reagent D, the solvent b and the reagent E is 86.8 g: 71.1 g: 19.8 g: 608 mL: 73.7 g.

[0053] Furthermore, in the one-step Apple substitution reaction, after the reaction temperature is cooled to 0-5°C, reagent E is added dropwise.

[0054] Furthermore, in the one-step Apple substitution reaction, the compound III is mixed with reagent C, reagent D and solvent b, and then replaced with nitrogen for protection.

[0055] Furthermore, in the one-step Apple substitution reaction, GC is used to monitor the reaction, and water is added to quench the reaction after the reaction is completed.

[0056] Furthermore, the product of the one-step Apple substitution reaction was extracted, washed, filtered and concentrated to obtain compound V.

[0057] Preferably, the one-step Apple substitution reaction product is extracted twice with methyl tert-butyl ether; the organic phases are combined and washed with sodium bicarbonate solution, sodium thiosulfate solution and brine in sequence; anhydrous calcium chloride is then added, stirred for 2 hours, filtered and concentrated to obtain a crude product; n-hexane is then added to dissolve, filtered and concentrated to obtain compound V.

[0058] Further, in S3, the acid binding agent includes any one or more of anhydrous sodium acetate, sodium bicarbonate, and sodium carbonate; and / or the reducing agent includes any one or more of palladium carbon, palladium hydroxide carbon, and platinum carbon; and / or the reaction conditions include: controlling the pressure to be 1.1 to 1.3 MPa, the reaction temperature to be 20 to 30° C., and the reaction time to be 15 to 30 hours.

[0059] Preferably, the acid binding agent is anhydrous sodium acetate.

[0060] Preferably, the reducing agent is palladium carbon, and most preferably palladium carbon with a content of 10%.

[0061] Preferably, in S3, the reaction time is 20 hours.

[0062] Further, in S3, the reaction solvent is solvent c, and the solvent c includes any one or more of isopropanol, n-propanol, ethanol, methanol, tetrahydrofuran, and ethyl acetate; the dosage ratio of the compound V, the acid binding agent, the reducing agent, and the solvent c is 30-60 g: 5-8 g: 3-6 g: 100-800 mL.

[0063] Preferably, the solvent c is isopropanol.

[0064] Preferably, in S3, the usage ratio of the compound V, the acid binding agent, the reducing agent and the solvent c is 35-50 g:5.4-7.7 g:3.5-4.9 g:150-500 mL, and most preferably 35 g:5.4 g:3.5 g:150 mL or 50 g:7.7 g:4.9 g:500 mL.

[0065] Further, in S3, GC is used to monitor the reaction until it is complete.

[0066] Further, the S3 reaction product is filtered, extracted, washed, dried, concentrated, and distilled under reduced pressure to obtain perfluorohexyl octane; the extractant is water and n-hexane, and the number of extractions is three times; the washing is to combine the organic phases obtained by extraction and then wash them with sodium bicarbonate solution, sodium thiosulfate solution and brine in sequence; the pressure of the reduced pressure distillation is -0.097 to -0.099 MPa, and the 85 to 90°C fraction is collected to obtain pure perfluorohexyl octane.

[0067] Furthermore, the preparation method of perfluorohexyl octane specifically comprises the following steps:

[0068] S1: Preparation of Compound III

[0069] The reagent A is stirred and cooled to 0-5°C under nitrogen protection, and the perfluorohexylethyl iodide is added dropwise at 0-10°C for reaction for 1 hour; after the reaction, the n-hexanal is added dropwise, and the temperature is kept at 10-20°C for reaction for 3 hours. The reaction product is extracted, washed, dried, concentrated, and recrystallized to obtain the compound III;

[0070] S2: Preparation of Compound V

[0071] ① The compound III obtained in S1 is mixed with triethylamine and dichloromethane, and the mixture is stirred and cooled to 0-5°C, and the reagent B is then added dropwise, and the temperature is controlled at 0-10°C to react for 1.5-3h to obtain compound IV; the compound IV is mixed with the substitution reagent and the solvent a, and the mixture is stirred and heated to 50-60°C to react for 3.5-6h to obtain compound V;

[0072] or ② Compound III obtained in S1 is mixed with reagent C, reagent D and solvent b, replaced with nitrogen for protection, the reaction temperature is cooled to 0-5°C, reagent E is added dropwise, and the temperature is controlled at 5-15°C for 3.5 hours to obtain the compound V;

[0073] S3: Preparation of perfluorohexyl octane

[0074] The compound V obtained in S2 is mixed with an acid-binding agent, a reducing agent and a solvent c, and hydrogen is introduced after nitrogen replacement. The pressure is controlled at 1.1-1.3 MPa and the reaction is carried out at 20-30°C for 20 hours. The reaction product is filtered, extracted, washed, dried, concentrated and distilled under reduced pressure to obtain perfluorohexyl octane.

[0075] The second object of the present invention is to provide a compound III prepared by the above method.

[0076] The third object of the present invention is to provide a compound V prepared by the above method.

[0077] The beneficial effects of the present invention are:

[0078] The currently reported preparation methods of perfluorohexyl octane cannot avoid the generation of isomers, resulting in low product purity and difficulty in purification. The present invention avoids the free radical addition reaction type with poor reaction selectivity, and instead adopts the nucleophilic addition reaction type of Grignard reagent with a single reaction site and aldehyde. The reaction type adopted by the present invention is clear and has a single structure, which directly avoids the generation of isomers from the preparation method. Not only are the synthetic process conditions mild and controllable, and the operation is simple, but the obtained product has high purity and high yield, and is easy to distill and purify, has very high application value, and is more conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] Figure 1 For compound III 1 H NMR spectrum;

[0080] Figure 2 For compound III 13 C NMR spectrum;

[0081] Figure 3 For compound V 1 H NMR spectrum;

[0082] Figure 4 For compound V 13 C NMR spectrum;

[0083] Figure 5 Compound VI is perfluorohexyl octane 1 H NMR spectrum;

[0084] Figure 6 Compound VI is perfluorohexyl octane 13 C NMR spectrum;

[0085] Figure 7 This is the IR spectrum of compound VI perfluorohexyl octane;

[0086] Figure 8 This is the GC purity spectrum of perfluorohexyl octane of compound VI in Example 5;

[0087] Fig. 9 This is the GC purity spectrum of perfluorohexyl octane of compound VI in Example 6;

[0088] Fig.10 This is the GC purity spectrum of perfluorohexyl octane in Comparative Example 1. DETAILED DESCRIPTION

[0089] The technical solution of the present invention will be further described clearly and completely in conjunction with specific embodiments below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work belong to the protection scope of the present invention.

[0090] In the present invention, the structural formulas of the compounds involved are shown in Table 1.

[0091] Table 1

[0092]

[0093] The new preparation route of perfluorohexyl octane proposed by the present invention is as follows:

[0094] Overall reaction route A:

[0095]

[0096] Or overall reaction route B:

[0097]

[0098] Example 1. Synthesis of Compound III

[0099] (1) Synthesis route of compound III

[0100]

[0101] (2) Preparation method of compound III

[0102] Compound III was prepared according to the synthetic route of compound III. The specific steps include: adding 5.0 kg of 2M isopropyl magnesium chloride tetrahydrofuran solution to the reactor, stirring and cooling to 0-5°C under nitrogen protection, taking 4.83 kg of perfluorohexylethyl iodide (i.e. compound II) and dropping it into the system. After the addition is complete, keep the temperature at 0-10°C for 1 hour, then drop 850 g of n-hexanal (i.e. compound I), and keep the temperature at 10-20°C for 3 hours after the addition is complete. After the reaction is completed by GC monitoring, dilute HCl solution is added to quench the reaction, methyl tert-butyl ether is extracted twice, the organic phase is washed with sodium bicarbonate solution and brine, and dried and concentrated to obtain a crude product. Recrystallization from n-hexane gives 3.42 kg of pure compound III as a white solid.

[0103] After testing, the yield of compound III was 90.0% and the purity was 99.5%. 1 H NMR spectrum Figure 1 As shown, 1H NMR (500MHz, CDCl3): δ=3.60–3.70(m,1H),2.08-2.24(m,2H),1.59–1.85(m,2H) ,1.48(t,J=6.4Hz,2H),1.41(s,2H),1.30-1.33(m,4H),0.90(t,J=6.9Hz,3H); 13 C NMR spectrum Figure 2 As shown, 13 C NMR (150 MHz, CDCl3): δ = 70.92, 37.75, 31.79, 27.68, 27.43, 25.30, 22.63, 14.01; melting point: 60.5-61.5°C.

[0104] Example 2. Synthesis of Compound IV

[0105] (1) Synthesis route of compound IV

[0106]

[0107] (2) Preparation method of compound IV

[0108] Compound IV was prepared according to the synthetic route of compound IV, and the specific steps included: adding 170.0 g of compound III obtained in Example 1, 61.4 g of triethylamine and 2000 mL of dichloromethane to the reactor in sequence, stirring and cooling to 0-5°C. 56.4 g of methylsulfonyl chloride was dripped into the reaction system, and the temperature was controlled at 0-10°C for 2 hours after the dripping. After the reaction was completed by GC monitoring, water was added to quench the reaction, and dichloromethane was extracted twice, the organic phases were combined, washed with dilute hydrochloric acid solution, sodium bicarbonate solution and brine in sequence, and dried and concentrated to obtain 202.6 g of crude compound IV as an oily substance with a yield of 100%. This intermediate was not purified and was directly used in the next step.

[0109] Example 3. Synthesis of Compound V

[0110] (1) Synthesis route of compound V

[0111]

[0112] (2) Preparation method of compound V

[0113] Compound V was prepared according to the synthetic route of compound V, and the specific steps included: 110.0 g of compound IV prepared in Example 2, 78.3 g of anhydrous sodium iodide and 1.1 L of N,N-dimethylacetamide were added to the reactor in sequence. The mixture was stirred and heated to 50-60°C for 4 hours. After the reaction was completed by GC monitoring, water was added to quench the reaction, and the mixture was extracted three times with n-hexane. The organic phase was washed with sodium thiosulfate solution and brine in sequence, and dried and concentrated to obtain 110 g of liquid compound V product.

[0114] After testing, the yield of compound V was 94%. 1 HNMR spectrum Figure 3 As shown, 1 HNMR (500MHz, CDCl3): δ=4.05-4.10(m,1H),2.13–2.50(m,2H),2.02–2.10(m,2H),1 .65–1.97(m,2H),1.38–1.59(m,2H),1.33(t,J=8.1Hz,4H),0.91(t,J=7.0Hz,3H); 13 C NMR spectrum Figure 4 As shown, 13 C NMR (150MHz, CDCl3): δ=40.64, 36.20, 31.42, 31.09, 30.88, 29.11, 22.44, 13.90.

[0115] Example 4. Synthesis of Compound V

[0116] (1) Synthesis route of compound V

[0117]

[0118] (2) Preparation method of compound V

[0119] Compound V was prepared according to the synthetic route of compound V, and the specific steps included: adding 86.8 g of compound III, 71.1 g of triphenylphosphine, 19.8 g of imidazole and 608 mL of tetrahydrofuran prepared in Example 1 to the reactor in sequence, and replacing with nitrogen for protection. After the reaction temperature was cooled to 0-5 ° C, a tetrahydrofuran solution of 73.7 g of iodine was added dropwise, and the temperature was controlled to 5-15 ° C for 3.5 hours after the addition was complete. GC monitored the reaction, quenched the reaction with water, and extracted twice with methyl tert-butyl ether. The organic phases were combined and washed with sodium bicarbonate solution, sodium thiosulfate solution and brine in sequence. The organic phase was collected, 130 g of anhydrous calcium chloride powder was added, and the mixture was filtered and concentrated to obtain a crude product after stirring for 2 hours. Then n-hexane was added to dissolve and filter, and the filtrate was collected and concentrated to obtain 102.7 g of compound V product liquid with a yield of 95%. After testing, it was confirmed that the structure of the compound obtained in this example was consistent with the results of Example 3.

[0120] Example 5. Synthesis of perfluorohexyl octane (Compound VI)

[0121] (1) Synthesis route of compound VI

[0122]

[0123] (2) Preparation method of compound VI

[0124] Compound VI was prepared according to the synthetic route of compound VI, and the specific steps included: adding 50.0 g of compound V prepared in Example 3, 7.7 g of anhydrous sodium acetate, 4.9 g of 10% palladium carbon and 500 mL of isopropanol to a high-pressure hydrogenation kettle. After nitrogen replacement, hydrogen was introduced, the pressure was controlled at 1.1 to 1.3 MPa, and the reaction was carried out at 20 to 30 ° C for 20 hours. After the reaction was completed by GC monitoring, the filtrate was collected, water was added, and n-hexane was extracted three times, the organic phases were combined, and washed with sodium bicarbonate solution, sodium thiosulfate solution and brine in turn, and dried and concentrated to obtain a crude product. Vacuum distillation (pressure -0.097 to -0.099 MPa) was carried out, and the 85 to 90 ° C fraction was collected to obtain 35.4 g of pure perfluorohexyl octane as a colorless liquid.

[0125] After testing, the yield of perfluorohexyl octane is 91.5%, the purity is 99.95%, and the IR spectrum is as follows: Figure 7 As shown, the GC purity spectrum is as follows Figure 8 As shown, Figure 8 The integral results are shown in Table 2. 1 H NMR spectrum Figure 5 As shown, 1 HNMR (500MHz, CDCl3): δ=0.89(t, J=6.0Hz, 3H), 1.26-1.39(m, 10H), 1.56-1.63(m, 2H), 1.99-2.10(m, 2H); 13 C NMR spectrum Figure 6 As shown, 13 C NMR (150MHz, CDCl3): δ=108.37-122.55,31.84,30.91,29.18,22.69,20.12,14.10; IR(KBr ): 2959, 2929, 2860, 1469, 1365, 1240, 1206, 1145, 731, 707, 653; GC-MS: m / z=403.1, 432.1.

[0126] Table 2. Figure 8 The integral result table

[0127]

[0128] Example 6. Synthesis of perfluorohexyl octane (Compound VI)

[0129] (1) Synthesis route of compound VI

[0130]

[0131] (2) Preparation method of compound VI

[0132] Compound VI was prepared according to the synthetic route of compound VI described above, and the specific steps included: adding 35.0 g of compound V prepared in Example 4, 5.4 g of anhydrous sodium acetate, 3.5 g of 10% palladium carbon and 150 mL of isopropanol to a high-pressure hydrogenation reactor. After nitrogen replacement, hydrogen was introduced, the pressure was controlled at 1.1-1.3 MPa, and the reaction was carried out at 20-30°C for 20 hours. After the reaction was completed by GC monitoring, suction was performed, the filtrate was collected, water was added, and n-hexane was extracted three times. The organic phases were combined, and washed with sodium bicarbonate solution, sodium thiosulfate solution and brine in turn, and dried and concentrated to obtain a crude product. Vacuum distillation (pressure -0.097 to -0.099 MPa) was performed, and the 85-90°C fraction was collected to obtain 25.1 g of pure perfluorohexyl octane as a colorless liquid. The yield was 93%, the purity was 99.97%, and the GC purity spectrum of perfluorohexyl octane was as shown below Fig. 9 As shown, Fig. 9 The integration results are shown in Table 3. After testing, it was confirmed that the structure of the compound obtained in this example was consistent with the results of Example 5.

[0133] Table 3. Fig. 9 The integral result table

[0134]

[0135] Comparative Example 1. Synthesis of perfluorohexyl octane

[0136] (1) Synthesis route of perfluorohexyl octane

[0137]

[0138] (2) Preparation method of perfluorohexyl octane

[0139] Perfluorohexyl octane is prepared according to the above-mentioned synthetic route of perfluorohexyl octane, and the specific steps include: adding 100g of perfluorohexyl iodide to the reactor, stirring and heating to 80-90°C under the protection of inert gas. Start to drop a toluene solution containing 23.6g of 1-octene and 0.74g of benzoyl peroxide. After the dropwise addition is completed, the temperature is maintained at 80-90°C for 3 hours, and the reaction is completed by GC monitoring. The reaction system is cooled to room temperature, water is added, and dichloromethane is extracted twice. The organic phases are combined, washed with sodium thiosulfate solution and brine in turn, and dried and concentrated to obtain 104g of crude intermediate. The obtained 104g crude intermediate is transferred to a high-pressure hydrogenation kettle, and then 1L of isopropanol, 16.0g of anhydrous sodium acetate and 10% palladium carbon 12.5g are added in turn. After nitrogen replacement, hydrogen is introduced, and the reaction pressure range is controlled to be 1.1-1.3MPa, and the reaction is carried out at 25-35°C for 20 hours. After the reaction is completed, the GC monitoring is performed, and the filtrate is collected. Water is added, and the filtrate is extracted three times with n-hexane. The organic phases are combined, and washed with sodium carbonate solution, sodium thiosulfate solution and brine in turn, and dried and concentrated to obtain a crude product. The vacuum distillation (pressure -0.097 to -0.099 MPa) is performed, and the 85 to 90 ° C fraction is collected to obtain 50.1 g of colorless liquid perfluorohexyl octane. After testing, the total yield of perfluorohexyl octane is 51.8%, and the purity is 97.11%; its GC purity spectrum is as follows Fig.10 As shown, Fig.10 The integration results are shown in Table 4.

[0140] Table 4. Fig.10 The integral result table

[0141]

Claims

1. A method for preparing perfluorohexyl octane, characterized in that: The steps include: S1: Using perfluorohexylethyl iodide as a raw material, first add reagent A to undergo a Grignard exchange reaction, and then add n-hexanal to undergo a nucleophilic addition reaction to obtain compound III; S2: Compound III obtained in S1 is subjected to two-step reactions of esterification and substitution to prepare Compound V; or Compound III is subjected to one-step Apple substitution reaction to prepare Compound V; S3: Compound V obtained in S2 is subjected to a reduction reaction under the action of an acid-binding agent and a reducing agent to obtain perfluorohexyl octane; the reagent A comprises any one or more of isopropyl magnesium chloride tetrahydrofuran solution, methyl magnesium chloride tetrahydrofuran solution, methyl magnesium bromide tetrahydrofuran solution, ethyl magnesium chloride tetrahydrofuran solution, ethyl magnesium bromide tetrahydrofuran solution and phenyl magnesium bromide tetrahydrofuran solution; The structural formulas of the compounds are shown below:

2. The method according to claim 1, characterized in that In S1, the mass ratio of the perfluorohexylethyl iodide, the n-hexanal and the reagent A is 4-6:0.5-2:5; and / or the reaction temperature of the Grignard exchange reaction is 0-10°C, and the reaction time is 0.5-2h; and / or the reaction temperature of the nucleophilic addition reaction is 10-20°C, and the reaction time is 2-5h.

3. The method according to claim 1, characterized in that The two-step reaction of esterification and substitution includes: the compound III obtained in S1 undergoes an esterification reaction with a reagent B to obtain a compound IV; the compound IV undergoes a substitution reaction with a substitution reagent to obtain a compound V; the reagent B includes any one or more of methylsulfonyl chloride and methylsulfonic anhydride; the substitution reagent includes any one or more of anhydrous sodium iodide, potassium iodide, lithium iodide and tetrabutylammonium iodide; the structural formula of the compound IV is as follows:

4. The method according to claim 3, characterized in that The reaction solvent of the substitution reaction is solvent a, and the solvent a is any one or more of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, tetrahydrofuran, and acetonitrile; and / or the mass ratio of the compound III to the reagent B is 150-200:50-70; and / or the amount ratio of the compound IV, the substitution reagent, and the solvent a is 100-150g:65-85g:1-1.5L; and / or the reaction temperature of the esterification reaction is 0-10°C, and the reaction time is 1.5-3h; And / or the reaction temperature of the substitution reaction is 50-60° C., and the reaction time is 3.5-6 hours.

5. The method according to claim 1, characterized in that The one-step Apple substitution reaction includes: adding reagent C, reagent D and solvent b to compound III obtained in S1 for reaction; then adding reagent E and continuing the reaction to obtain compound V; the reagent C includes any one or more of triphenylphosphine and tributylphosphine, the reagent D includes any one or more of imidazole, triethylamine, and pyridine, the solvent b includes any one or more of tetrahydrofuran, dichloromethane, toluene, and acetonitrile; the reagent E includes any one or more of iodine, iodine tetrahydrofuran solution, iodine dichloromethane solution, and iodine acetonitrile solution.

6. The method according to claim 5, characterized in that In the one-step Apple substitution reaction, after adding reagent E, the temperature is controlled at 5-15°C and the reaction is carried out for 3-5 hours; and / or the amount ratio of iodine in the compound III, the reagent C, the reagent D, the solvent b and the reagent E is 70-100g:60-85g:15-30g:500-1000mL:60-90g.

7. The method according to claim 1, characterized in that In S3, the acid binding agent includes any one or more of anhydrous sodium acetate, sodium bicarbonate, and sodium carbonate; and / or the reducing agent includes any one or more of palladium carbon, palladium hydroxide carbon, and platinum carbon; and / or the reaction conditions include: controlling the pressure to be 1.1 to 1.3 MPa, the reaction temperature to be 20 to 30° C., and the reaction time to be 15 to 30 hours.

8. The method according to claim 1, characterized in that In S3, the reaction solvent is solvent c, and the solvent c includes any one or more of isopropanol, n-propanol, ethanol, methanol, tetrahydrofuran, and ethyl acetate; the dosage ratio of the compound V, the acid binding agent, the reducing agent, and the solvent c is 30-60 g: 5-8 g: 3-6 g: 100-800 mL.

9. Compound III obtained by the method according to any one of claims 1 to 8.

10. Compound V obtained by the method according to any one of claims 1 to 8.

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