Preparation method of perfluorohexyloctane, product obtained by preparation method and detection method of perfluorohexyloctane

Abstract

The invention discloses a preparation method of perfluorohexyloctane and a product obtained by the preparation method. The preparation method is mild in reaction condition, convenient to operate and control, low in energy consumption, low in cost and suitable for industrial production, and the obtained product is high in yield and good in purity. Besides, the invention also discloses a gas chromatography detection method of the obtained perfluorohexyloctane product, the detection result is accurate and reliable, the related regulations and / or requirements of methodology verification such as accuracy and precision are met, and qualitative and / or quantitative detection can be conveniently realized, so that the gas chromatography detection method has very important economic and social values.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for preparing perfluorohexyloctane, the product obtained by the preparation method, and a method for detecting the product. Background Technology

[0002] Perfluorohexyloctane, usually referring to 1-perfluorohexyl-octane, has the CAS number 133331-77-8 and its structural formula is CF3(CF2)5(CH2)7CH3 or F(CF2)6(CH2)8H, which can be abbreviated as F6H8. It was first recorded in CN 1255065A (application date: March 6, 1998) and foreign literature (Zeana D, Becker J, Kuckelkorn R, et al. Perfluorohexyloctane as a long-term vitreous tamponade in the experimental animal[J]. International Ophthalmology, 1999, 23(1):17-24). It is mainly used as a liquid solvent and in ophthalmic preparations.

[0003] According to existing technologies such as CN 108349855A and CN 115703693A, 2-perfluorohexyl-octane usually exists as an isomer impurity. This is because both 1-perfluorohexyl-octane and 2-perfluorohexyl-octane can be synthesized by perfluorohexyl iodine and n-octene (also known as 1-octene) and then prepared by hydrogenation reduction. Depending on the process steps and / or process conditions, products mainly composed of 1-perfluorohexyl-octane or 2-perfluorohexyl-octane may be obtained.

[0004] 1-Perfluorohexyl-octane has a clear pharmaceutical use: it was approved by the U.S. Food and Drug Administration (FDA) in 2023 to be formulated as eye drops (solutions) for the treatment of dry eye syndrome; however, 2-perfluorohexyl-octane does not yet have a clear pharmaceutical use, and its toxic side effects and safety have not yet been fully investigated, which may pose potential risks.

[0005] Impurities are a critical quality attribute of pharmaceuticals, potentially affecting product safety and efficacy (see: 2020 Edition of the Chinese Pharmacopoeia, Part IV: 9102 Guidelines for Drug Impurity Analysis). Although my country has been continuously raising control requirements for the safety and efficacy of pharmaceuticals (including active pharmaceutical ingredients and formulations) in recent years, the reality remains unsatisfactory, with results falling short of expectations. For example, existing technologies such as CN 115703693A either completely omit the issue of purity and / or impurity limits for 1-perfluorohexyl-octane, or the 1-perfluorohexyl-octane prepared by these technologies suffers from low purity (e.g., purity <95%) and excessive impurity limits. This directly impacts and restricts the sustainable and healthy development of my country's active pharmaceutical ingredient and downstream formulation industries.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] To address the problems and / or shortcomings of existing technologies, one objective of this invention is to provide a method for preparing perfluorohexyloctane. This method features mild reaction conditions, ease of operation and control, low energy consumption, low cost, and suitability for industrial production, yielding a product with high yield and purity. Furthermore, this invention also provides the product obtained by this method and its gas chromatographic detection method. The detection results are accurate and reliable, meeting the relevant regulations and / or requirements for methodological validation such as accuracy and precision, and can conveniently achieve qualitative and / or quantitative detection.

[0008] A method for preparing perfluorohexyloctane according to the present invention includes the following steps:

[0009] S1: In the presence of an initiator, compound X undergoes an addition reaction with n-octene in the first solvent to prepare compound Y;

[0010]

[0011] S2: Under the condition of the presence of alkaline substances, the compound Y undergoes a dehalogenation reaction in the second solvent to obtain compound Z;

[0012]

[0013] S3: In the presence of a hydrogenation catalyst, the compound Z reacts with hydrogen in a third solvent to produce perfluorohexyloctane, which may then be further processed by distillation to obtain perfluorohexyloctane.

[0014]

[0015] Wherein, R is a halogen selected from chlorine, bromine, and iodine, the purity of the n-octene is ≥95.5% (e.g., ≥96%, ≥97%, ≥98%, etc.), and the content of any isomer impurity in the n-octene is ≤1.0% (e.g., 1.0%, ≤0.9%, ≤0.8%, etc.), and the isomer impurities include 2-octene and / or 3-octene.

[0016] Furthermore,

[0017] In any of the above technical solutions (method for preparing perfluorohexyloctane), R is iodine;

[0018] And / or, the purity of compound X is ≥96% or ≥99%; and / or, the maximum single impurity content in compound X is ≤0.6% or ≤0.4%;

[0019] And / or, the purity of the n-octene is ≥98%; and / or, the 2-octene content in the n-octene is ≤0.7%; and / or, the 3-octene content in the n-octene is ≤0.8%.

[0020] Furthermore,

[0021] In any of the above technical solutions (method for preparing perfluorohexyloctane), in step S1, the molar ratio of compound X to n-octene is 1:1 to 2 (e.g., molar ratios of 1:1.01, 1:1.02, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.5, 1:2, etc.); preferably, the molar ratio of compound X to n-octene is 1:1 to 1.2.

[0022] And / or, the amount of initiator used per gram of compound X is 0.005 g to 0.05 g (e.g., 0.005 g, 0.008 g, 0.01 g, 0.015 g, 0.02 g, 0.03 g, 0.04 g, etc.); preferably, the amount of initiator used per gram of compound X is 0.008 g to 0.015 g;

[0023] And / or, the amount of the first solvent used per gram of compound X is 0.4 ml to 15 ml (e.g., 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml, 1.0 ml, 2 ml, 3 ml, 5 ml, 10 ml, 12 ml, 15 ml, etc.); preferably, the amount of the first solvent used per gram of compound X is 0.5 ml to 1 ml;

[0024] And / or, the temperature of the addition reaction is 60°C to 90°C (e.g., 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc.); preferably, the temperature of the addition reaction is 75°C to 85°C.

[0025] And / or, the addition reaction time is 1.5 hours to 24 hours (e.g., 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 15h, 20h, etc.); preferably, the addition reaction time is 3.5 hours to 5 hours;

[0026] And / or, the initiator is azobisisobutyronitrile, azobisisoheptanenitrile, or benzoyl peroxide; preferably, the initiator is azobisisobutyronitrile or azobisisoheptanenitrile.

[0027] And / or, the first solvent is a nitrogen-containing solvent; preferably, the nitrogen-containing solvent is acetonitrile.

[0028] Furthermore,

[0029] In any of the above technical solutions (method for preparing perfluorohexyloctane), step S1 further includes a post-processing step: after the addition reaction is completed, the temperature is lowered to 45℃±2℃ and vacuum distilled until no fraction is produced, then lowered to room temperature, washed with water, and heated to 110℃±2℃ for vacuum distillation, collecting the fraction with an outlet temperature of 85℃~95℃, which is the final product; wherein, the pressure of the vacuum distillation is ≤-0.09MPa (for example, -0.1MPa~-0.09MPa).

[0030] Furthermore,

[0031] In any of the above technical solutions (the method for preparing perfluorohexyloctane), in step S2, the amount of base substance used per mole of compound Y is 1.5 moles to 3 moles (e.g., 1.5 moles, 1.6 moles, 1.7 moles, 1.8 moles, 1.9 moles, 2 moles, 2.1 moles, 2.2 moles, 2.5 moles, etc.); preferably, the amount of base substance used per mole of compound Y is 1.8 moles to 2.2 moles.

[0032] And / or, the amount of the second solvent used per gram of compound Y is 5 ml to 15 ml (e.g., 5 ml, 8 ml, 10 ml, 12 ml, 15 ml, etc.); preferably, the amount of the second solvent used per gram of compound Y is 5 ml to 8 ml;

[0033] And / or, the temperature of the dehalogenation reaction is 60°C to 90°C (e.g., 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, etc.); preferably, the temperature of the dehalogenation reaction is 80°C to 90°C.

[0034] And / or, the dehalogenation reaction time is 1.5 hours to 24 hours (e.g., 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 15h, 20h, etc.); preferably, the dehalogenation reaction time is 7.5 hours to 10 hours;

[0035] And / or, the alkaline substance is sodium hydroxide or its hydrate, potassium hydroxide or its hydrate, lithium hydroxide or its hydrate; preferably, the alkaline substance is potassium hydroxide or its hydrate;

[0036] And / or, the second solvent comprises water and an alcohol solvent, wherein the volume ratio of water to alcohol solvent in the second solvent is 1:1 to 5 (e.g., volume ratios of 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, etc.); wherein, the alcohol solvent is selected from alcohol solvents with 1 to 4 carbon atoms; preferably, the volume ratio of water to alcohol solvent in the second solvent is 1:1 to 2; and / or, the alcohol solvent is ethanol;

[0037] And / or, it also includes a post-processing step: after the dehalogenation reaction is completed, cool to room temperature, stir, let stand, separate the liquids, take the organic phase, wash with water, and obtain the final product.

[0038] Furthermore,

[0039] In any of the above technical solutions (method for preparing perfluorohexyl octane), in step S3, the amount of hydrogenation catalyst used per gram of compound Z is 0.005 g to 0.05 g (e.g., 0.005 g, 0.008 g, 0.01 g, 0.015 g, 0.02 g, 0.03 g, 0.04 g, etc.); preferably, the amount of hydrogenation catalyst used per gram of compound Z is 0.015 g to 0.025 g.

[0040] And / or, the amount of the third solvent used per gram of compound Z is 5 ml to 15 ml (e.g., 5 ml, 8 ml, 10 ml, 12 ml, 15 ml, etc.); preferably, the amount of the third solvent used per gram of compound Z is 7.5 ml to 10 ml.

[0041] And / or, the temperature of the hydrogenation reaction is 35°C to 65°C (e.g., 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, etc.); preferably, the temperature of the hydrogenation reaction is 45°C to 55°C;

[0042] And / or, the hydrogenation reaction time is 1.5 hours to 24 hours (e.g., 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 7h, 8h, 9h, 10h, 12h, 15h, 20h, etc.); preferably, the hydrogenation reaction time is 5.5 hours to 8 hours;

[0043] And / or, the hydrogenation catalyst is selected from one or more of palladium catalysts (including but not limited to Pd / C catalysts, Pd(OH)2 / C catalysts, etc.), platinum catalysts, and nickel catalysts (e.g., Raney nickel, etc.); preferably, the hydrogenation catalyst is a palladium catalyst, and the Pd content of the palladium catalyst is 1% to 10% (mass percentage); more preferably, the palladium catalyst is a palladium-carbon catalyst, and the Pd content of the palladium catalyst is 4.5% to 5.5% (mass percentage);

[0044] And / or, the third solvent is selected from alcohol solvents with 1 to 4 carbon atoms; preferably, the third solvent is ethanol;

[0045] And / or, it also includes a post-processing step: after the hydrogenation reaction is completed, the hydrogenation catalyst is removed, and the mixture is distilled at 50℃±2℃ to 40%±0.5% of the volume of the reaction liquid obtained from the hydrogenation reaction. Acetonitrile is added, and the mixture is distilled at 50℃±2℃ to 40%±0.5% of the volume of the reaction liquid obtained from the hydrogenation reaction. The mixture is then washed with water to obtain the final product.

[0046] Furthermore,

[0047] In any of the above technical solutions (method for preparing perfluorohexyloctane), the control parameters of the distillation process mainly include: feed temperature of 90℃~95℃, column top temperature of 45℃~50℃, reboiler temperature of 95℃~100℃, number of trays of 20~100 (e.g., number of trays of 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, etc.), reflux ratio of 1.2~2.5, and column pressure ≤-0.09MPa (e.g., -0.1MPa~-0.09MPa);

[0048] Preferably, the number of trays is 35 to 50; and / or, the number of distillations is 2 to 6.

[0049] More preferably, the number of trays is 40; and / or the number of distillations is 3 or 4.

[0050] Furthermore,

[0051] In any of the above-mentioned technical solutions (method for preparing perfluorohexyl octane), the amount of compound X (e.g., perfluorohexyl iodine) and n-octene used as starting materials is in the range of 0.1 kg to 1000 kg (e.g., 0.1 kg, 0.5 kg, 1 kg, 10 kg, 50 kg, 100 kg, 150 kg, 200 kg, 250 kg, 300 kg, 350 kg, 400 kg, 450 kg, 500 kg, 600 kg, 700 kg, 800 kg, 900 kg, 1000 kg, etc., with other reagents or raw materials varying accordingly), preferably in the range of 0.1 kg to 500 kg.

[0052] also,

[0053] The present invention also provides a perfluorohexyl octane product, wherein the GC purity of the perfluorohexyl octane product is ≥95% or ≥99.5%, and the content of 2-perfluorohexyl-octane in the perfluorohexyl octane product is ≤0.15% or ≤0.10%;

[0054] Preferably, the perfluorohexyloctane product is prepared by any one of the preparation methods described in the foregoing technical solutions.

[0055] This invention also provides a gas chromatographic detection method for perfluorohexyloctane products, wherein the chromatographic conditions of the gas chromatographic detection method include:

[0056] Chromatographic column: HP-1 gas chromatographic column or equivalent column;

[0057] Temperature program: The initial temperature is 40℃, held for 0 min, then increased to 130℃ at a rate of 10℃ / min, held for 18 min, then increased to 230℃ at a rate of 20℃ / min, held for 8 min, and finally increased to 280℃ at a rate of 30℃ / min, held for 3 min.

[0058] The injection port temperature is 200℃~350℃ (e.g., 210℃, 220℃, 230℃, 240℃, 250℃, 260℃, 270℃, 280℃, 290℃, 300℃, 310℃, 320℃, etc.);

[0059] The injection volume is 0.8 μl to 1.2 μl;

[0060] The split ratio is 10 to 30:1 (e.g., split ratios of 10:1, 12:1, 15:1, 18:1, 20:1, 22:1, 25:1, etc.);

[0061] The carrier gas is nitrogen;

[0062] The flow rate is 0.1 ml / min to 2 ml / min (e.g., 0.5 ml / min, 0.6 ml / min, 0.7 ml / min, 0.8 ml / min, 0.9 ml / min, 1.0 ml / min, 1.2 ml / min, 1.5 ml / min, etc.);

[0063] The detector is a flame ionization detector;

[0064] The detector temperature is 200℃~350℃ (e.g., 210℃, 220℃, 230℃, 240℃, 250℃, 260℃, 270℃, 280℃, 290℃, 300℃, 310℃, 320℃, etc.);

[0065] Preferably,

[0066] The chromatographic column has dimensions of 60m × 0.32mm and 1μm.

[0067] And / or, the injection port temperature is 280℃;

[0068] And / or, the injection volume is 1.0 μl;

[0069] And / or, the split ratio is 20:1;

[0070] And / or, at a flow rate of 1.0 ml / min;

[0071] And / or, the detector temperature is 300°C;

[0072] And / or, the perfluorohexyloctane product is prepared into a test solution with a concentration of 45 mg / ml to 55 mg / ml, wherein the solvent of the test solution is ethanol.

[0073] Furthermore,

[0074] In any of the above technical solutions (gas chromatography detection method for perfluorohexyloctane products), the gas chromatography detection method is a qualitative or quantitative detection method; preferably, the gas chromatography detection method is used for quantitative detection according to the internal standard method, the external standard method, or the peak area normalization method.

[0075] The purity and / or content of the raw materials (e.g., n-octene, compound X, etc.), intermediates, products (e.g., perfluorohexyloctane products) and their impurities (e.g., isomers of n-octene, 2-perfluorohexyl-octane impurities in products, etc.) described in this invention are all expressed as mass percentages.

[0076] The beneficial effects of this invention are mainly in the following aspects:

[0077] The preparation method provided by this invention can conveniently and efficiently produce perfluorohexyl octane. The reaction conditions are mild, easy to operate and control, with low energy consumption and low cost. The target product has a high yield and good purity. The 2-perfluorohexyl-octane isomer impurity can be controlled at a low level, which is conducive to expanding the production of perfluorohexyl octane and its application in multiple fields such as chemical and pharmaceutical industries. It also ensures the product supply capacity and market supply chain security, and better meets the market demand of downstream enterprises at home and abroad.

[0078] also,

[0079] The gas chromatography detection method provided by this invention has no obvious interference between the detected chromatographic peaks, has high resolution, and provides accurate and reliable detection results. It meets the relevant regulations and / or requirements for methodological validation such as accuracy and precision, and can achieve qualitative and / or quantitative detection, thereby more effectively monitoring and ensuring the quality of the product and its downstream products.

[0080] In summary, the preparation and detection methods for perfluorohexyloctane provided by this invention have good industrial applicability, providing strong support for its production and application, and thus have very important economic and social value. Attached Figure Description

[0081] Figure 1 The image shows the GC chromatogram of the crude 1-perfluorohexyl-octane obtained in Example 1.

[0082] Figure 2 This is a representative GC chromatogram of the 1-perfluorohexyl-octane product detected in Example 11. Detailed Implementation

[0083] The present invention will now be clearly and completely described in conjunction with specific embodiments. Those skilled in the art will understand that the embodiments described below are some, but not all, embodiments of the present invention, and are only used to illustrate the present invention, and should not be regarded as a limitation on the scope of protection of the present invention.

[0084] In the embodiments of the present invention, experiments without specific conditions are conducted according to conventional conditions in the art or conditions recommended by the manufacturer. The reagents and instruments used, unless otherwise specified, are all conventional products that can be purchased commercially.

[0085] in,

[0086] Perfluorohexyl iodine: CAS No. 355-43-1, liquid, purity ≥99%, maximum single impurity ≤0.4%, purchased from Fuxin Ruifeng Fluorochemical Co., Ltd.

[0087] 1-Octene: CAS No. 111-66-0, colorless and transparent liquid, purity ≥98%, of which the content of isomer impurities (2-octene ≤0.7%, 3-octene ≤0.8%) is a key / important indicator, purchased from Sasol Chemicals Ltd.

[0088] Example 1

[0089] (1) Preparation of compound A (addition reaction)

[0090]

[0091] References:

[0092] ①Davis CR, Burton DJ, Yang ZYTitanium-catalyzed addition ofperfluoroalkyl iodides to alkenes[J]. Journal of Fluorine Chemistry, 1995, 70(1):135-140.

[0093] ②Jaye JA, Sletten EMModular and Processable Fluoropolymers Prepared via a Safe, Mild, Iodo–Ene Polymerization[J].ACS Central Science, 2019, 5(6): 982-991. and its appendices Figure S22 and Figure S23, etc.

[0094] In the presence of 1 g azobisisobutyronitrile (initiator), 100 g (1 equivalent) of perfluorohexyl iodine and 27.68 g (approximately 1.1 equivalents) of n-octene were refluxed in 70 mL of acetonitrile at 80 °C for 4 h. The mixture was then cooled to 45 °C and distilled under reduced pressure (-0.095 MPa) until no fraction was produced. The mixture was then cooled to room temperature, washed with water (200 mL of purified water), and then heated to 110 °C and distilled under reduced pressure (-0.095 MPa). The fraction with an outlet temperature of 85 °C–95 °C was collected to obtain compound A, with a yield of 91.73% (based on perfluorohexyl iodine) and a purity ≥95%.

[0095] (2) Preparation of compound B (dehalogenation reaction)

[0096]

[0097] 100g of compound A obtained in step (1) and 22.11g (approximately 2.2 equivalents) of potassium hydroxide were added to water-ethanol (200ml purified water, 400ml ethanol) and refluxed at 85℃ for 8h. After that, the mixture was cooled to room temperature, stirred, allowed to stand, separated, and the organic phase was taken and washed with water (300ml purified water) to obtain compound B. The yield was 94.19% (based on compound A) and the purity was ≥95%.

[0098] (3) Preparation of 1-perfluorohexyl-octane (hydrogenation reaction)

[0099]

[0100] 100g of compound B obtained in step (2) and 2g of palladium on carbon (Pd content 5%) catalyst were added to a three-necked flask containing 750ml of ethanol. The mixture was continuously purged with hydrogen at 50℃ for 6 hours. After filtration, the mixture was distilled at 50℃ to 40% of the original reaction volume (approximately 300ml). 200ml of acetonitrile was added, and distillation was continued at 50℃ to 40% of the original reaction volume (approximately 300ml). After washing with water (300ml of purified water), crude 1-perfluorohexyl-octane was obtained, with a yield of 84.84% (based on compound B). The chromatographic (GC) purity was 97.68% (the retention time of 1-perfluorohexyl-octane was 26.807 min, calculated using peak area normalization). The content of isomer impurities (2-perfluorohexyl-octane) was 0.61%. Figure 1 As shown.

[0101] (4) Distillation process

[0102] The crude 1-perfluorohexyl-octane obtained in step (3) above is fed into a distillation column (feed temperature 90℃~95℃, top temperature 45℃~50℃, reboiler temperature 95℃~100℃, number of trays 40, reflux ratio 1.2~2.5, internal pressure ≤-0.09MPa) for multiple distillations (usually 3 or 4 times) to obtain the 1-perfluorohexyl-octane product with a yield of 61.77% (calculated based on the crude 1-perfluorohexyl-octane), a chromatographic (GC) purity of 99.81%, and an isomer impurity (2-perfluorohexyl-octane) content of 0.07% (calculated by peak area normalization).

[0103] Example 2

[0104] Preparation of compound A (addition reaction)

[0105] Screening test of n-octene dosage: Under the condition that other conditions remain unchanged, the dosage of n-octene was adjusted to 1 equivalent, 1.2 equivalent, etc. The results showed that there was no significant change in the reaction conditions, yield (in the range of 85% to 95%), purity (≥95%), etc. of compound A. The preferred dosage of n-octene is 1 to 2 equivalents, preferably 1 to 1.2 equivalents.

[0106] Example 3

[0107] Preparation of compound A (addition reaction)

[0108] Screening test for acetonitrile dosage: Under the condition that other conditions remain unchanged, the dosage of acetonitrile was adjusted; the results showed that the optimal dosage of acetonitrile per gram of perfluorohexyl iodine was 0.4 to 15 ml, preferably 0.5 to 1 ml.

[0109] Example 4

[0110] Preparation of compound A (addition reaction)

[0111] Screening test for reaction temperature: Under the condition that other conditions remain unchanged, the reaction temperature of the addition reaction was adjusted; the results showed that the optimal reaction temperature range for the addition reaction is 75℃~85℃; if it is below 45℃, the reaction rate will be severely reduced, and at a temperature of 35℃~45℃, there is almost no reaction after 12 hours.

[0112] Example 5

[0113] Preparation of compound B (dehalogenation reaction)

[0114] Screening test of potassium hydroxide dosage: Under the condition that other conditions remain unchanged, the dosage of potassium hydroxide was adjusted to 1.8 equivalents, 2 equivalents, etc.; the results showed that the optimal dosage of potassium hydroxide was 1.5 to 3 equivalents, and considering factors such as reaction rate and time cost, the preferred dosage was 1.8 to 2.2 equivalents.

[0115] Example 6

[0116] Preparation of compound B (dehalogenation reaction)

[0117] Screening test of reaction solvent: Under the condition that other conditions remain unchanged, the reaction solvent of the dehalogenation reaction was adjusted to purified water (without ethanol), etc. The results showed that purified water (without ethanol) as the reaction solvent rarely produces compound B or almost does not react. The optimal volume ratio of water to ethanol is 1:1 to 5.

[0118] Example 7

[0119] Preparation of compound B (dehalogenation reaction)

[0120] Screening test of reaction temperature: Under the condition that other conditions remain unchanged, the reaction temperature of the dehalogenation reaction was adjusted; the results showed that the optimal reaction temperature range of the dehalogenation reaction is 80℃~90℃; if it is lower than 45℃, the reaction rate will be severely reduced, and only 15%~20% of compound B is generated after 12 hours of reaction at 35℃~45℃.

[0121] Example 8

[0122] Preparation of 1-perfluorohexyl-octane (hydrogenation reaction)

[0123] Screening test of palladium-on-carbon catalyst dosage: Under the condition that other conditions remain unchanged, the dosage of palladium-on-carbon catalyst was adjusted; the results showed that the preferred dosage of palladium-on-carbon catalyst was 0.5% to 5% (based on the weight of compound B), preferably 1.5% to 2.5%.

[0124] Example 9

[0125] Preparation of 1-perfluorohexyl-octane (hydrogenation reaction)

[0126] Screening test of reaction solvent: Under the condition that other conditions remain unchanged, the amount of ethanol was adjusted; the results showed that the optimal amount of ethanol per gram of compound B was 5 to 15 ml, preferably 7.5 to 10 ml.

[0127] Example 10

[0128] Preparation of 1-perfluorohexyl-octane (hydrogenation reaction)

[0129] Screening test for reaction temperature: Under the condition that other conditions remain unchanged, the reaction temperature of the hydrogenation reaction was adjusted; the results showed that the optimal range of reaction temperature for the hydrogenation reaction is 35℃~65℃, preferably 45℃~55℃.

[0130] Example 11

[0131] The detection of crude 1-perfluorohexyl-octane and / or the finished 1-perfluorohexyl-octane product shall be performed by gas chromatography (GC) under the following chromatographic conditions:

[0132] Chromatographic column: HP-1 gas chromatographic column (size: 60m × 0.32mm, 1μm);

[0133] The temperature program is as follows: the starting temperature is 40℃, held for 0 min, then increased to 130℃ at a rate of 10℃ / min, held for 18 min, then increased to 230℃ at a rate of 20℃ / min, held for 8 min, and finally increased to 280℃ at a rate of 30℃ / min, held for 3 min.

[0134] The injection port temperature is 280℃;

[0135] The injection volume was 1 μl, and the split ratio was 20:1.

[0136] The carrier gas was nitrogen, and the flow rate was 1.0 ml / min;

[0137] Detector: Flame ionization detector (FID);

[0138] Detector temperature: 300℃.

[0139] Test solution: Weigh about 500 mg of the test sample (the crude or finished 1-perfluorohexyl-octane to be tested), add it to a 10 ml volumetric flask, dilute with ethanol and bring to volume, and shake well.

[0140] The aforementioned gas chromatography (GC) method has been verified to meet the requirements for method validation in the 2020 edition of the Chinese Pharmacopoeia, with a limit of detection (LOD) of 3.7590 μg / ml and a limit of quantitation (LOQ) of 12.5299 μg / ml.

[0141] A representative GC spectrum of a certain batch of 1-perfluorohexyl-octane products is shown below. Figure 2 As shown: the first large peak is the solvent (ethanol) peak and is not included in the calculation. The retention time of the isomer impurity (2-perfluorohexyl-octane) is 25.704 min, and the retention time of 1-perfluorohexyl-octane is 27.884 min.

[0142] Example 12

[0143] Scale-up production

[0144] (1) Preparation of compound A (addition reaction)

[0145] In the presence of 0.5 kg azobisisobutyronitrile (initiator), 50 kg perfluorohexyl iodine and 13.85 kg n-octene were refluxed in 35 L of acetonitrile at 80 °C for 5 h. The mixture was then cooled to 45 °C and distilled under reduced pressure (≤-0.09 MPa) until no fraction was produced. The mixture was then cooled to room temperature, washed with water (200 L of purified water), and then heated to 110 °C for reduced pressure distillation (≤-0.09 MPa). The fraction with an outlet temperature of 85 °C–95 °C was collected to obtain compound A, with a yield of 91.85% and a purity of ≥95%.

[0146] (2) Preparation of compound B (dehalogenation reaction)

[0147] 50 kg of compound A obtained in step (1) and 11.1 kg of potassium hydroxide were added to water-ethanol (100 L purified water, 200 L ethanol) and refluxed at 85 °C for 8 h. After that, the mixture was cooled to room temperature, stirred, allowed to stand, separated, and the organic phase was taken and washed with water (150 L purified water) to obtain compound B. The yield was 93.22% (based on compound A) and the purity was ≥95%.

[0148] (3) Preparation of 1-perfluorohexyl-octane (hydrogenation reaction)

[0149] 30 kg of compound B obtained in step (2) and 0.6 kg of palladium on carbon (Pd content 5%) catalyst were added to a three-necked flask containing 300 L of ethanol. The mixture was continuously purged with hydrogen at 50 °C for 6 h. After filtration, the mixture was distilled at 50 °C to 40% of the original reaction volume. 60 L of acetonitrile was added, and the mixture was distilled at 50 °C to 40% of the original reaction volume. After washing with water (90 L of purified water), crude 1-perfluorohexyl-octane was obtained with a yield of 84.93% (based on compound B) and a chromatographic (GC) purity of ≥95%.

[0150] (4) Distillation process

[0151] The crude 1-perfluorohexyl-octane obtained in step (3) above is fed into a distillation column (feed temperature 90℃~95℃, top temperature 45℃~50℃, reboiler temperature 95℃~100℃, number of trays 40, reflux ratio 1.2~2.5, internal pressure ≤-0.09MPa) for multiple distillations (usually 3 or 4 times) to obtain the 1-perfluorohexyl-octane product with a yield of 63.05% (calculated based on the crude 1-perfluorohexyl-octane), chromatographic (GC) purity ≥99.5%, and isomer impurity (2-perfluorohexyl-octane) content ≤0.15% (calculated by peak area normalization).

[0152] Example 13

[0153] Based on Example 12, production was scaled up 2 to 5 times. After addition reaction, dehalogenation reaction, hydrogenation reaction and distillation, 1-perfluorohexyl-octane product was obtained with a yield of 55 to 65% (calculated based on crude 1-perfluorohexyl-octane). The chromatographic (GC) purity was ≥99.5%, and the content of isomer impurities (2-perfluorohexyl-octane) was ≤0.15% (calculated by peak area normalization).

[0154] Of course, the present invention can also have other various embodiments. Without departing from the spirit and essence of the present invention, those skilled in the art can make various corresponding changes and / or modifications according to the present invention, and these corresponding changes and / or modifications should all fall within the protection scope of the appended claims.

Claims

1. A method for preparing perfluorohexyloctane, characterized in that, Includes the following steps: S1: In the presence of an initiator, compound X undergoes an addition reaction with n-octene in the first solvent to prepare compound Y; S2: Under the condition of the presence of alkaline substances, the compound Y undergoes a dehalogenation reaction in the second solvent to obtain compound Z; S3: In the presence of a hydrogenation catalyst, the compound Z reacts with hydrogen in a third solvent to produce perfluorohexyloctane, which may then be further processed by distillation to obtain perfluorohexyloctane. Wherein, R is a halogen selected from chlorine, bromine, and iodine, the purity of n-octene is ≥95.5%, and the content of any isomer impurity in n-octene is ≤1.0%, wherein the isomer impurities include 2-octene and / or 3-octene.

2. The preparation method according to claim 1, characterized in that, R stands for iodine; And / or, the purity of compound X is ≥96% or ≥99%; and / or, the maximum single impurity content in compound X is ≤0.6% or ≤0.4%; And / or, the purity of the n-octene is ≥98%; and / or, the 2-octene content in the n-octene is ≤0.7%; and / or, the 3-octene content in the n-octene is ≤0.8%.

3. The preparation method according to claim 1 or 2, characterized in that, In step S1, the molar ratio of compound X to n-octene is 1:1 to 2; preferably, the molar ratio of compound X to n-octene is 1:1 to 1.

2. And / or, the amount of initiator used per gram of compound X is 0.005 g to 0.05 g; preferably, the amount of initiator used per gram of compound X is 0.008 g to 0.015 g; And / or, the amount of the first solvent used per gram of compound X is 0.4 ml to 15 ml; preferably, the amount of the first solvent used per gram of compound X is 0.5 ml to 1 ml; And / or, the temperature of the addition reaction is 60°C to 90°C; preferably, the temperature of the addition reaction is 75°C to 85°C; And / or, the addition reaction takes 1.5 hours to 24 hours; preferably, the addition reaction takes 3.5 hours to 5 hours. And / or, the initiator is azobisisobutyronitrile, azobisisoheptanenitrile, or benzoyl peroxide; preferably, the initiator is azobisisobutyronitrile or azobisisoheptanenitrile. And / or, the first solvent is a nitrogen-containing solvent; preferably, the nitrogen-containing solvent is acetonitrile.

4. The preparation method according to claim 1 or 2, characterized in that, Step S1 further includes a post-processing step: after the addition reaction is completed, the temperature is lowered to 45℃±2℃ and vacuum distilled until no fraction is produced, then cooled to room temperature, washed with water, heated to 110℃±2℃ and vacuum distilled, and the fraction with an outlet temperature of 85℃~95℃ is collected to obtain the product; wherein, the pressure of the vacuum distillation is ≤-0.09MPa.

5. The preparation method according to claim 1 or 2, characterized in that, In step S2, the amount of base substance used per mole of compound Y is 1.5 moles to 3 moles; preferably, the amount of base substance used per mole of compound Y is 1.8 moles to 2.2 moles. And / or, the amount of the second solvent used per gram of compound Y is 5 ml to 15 ml; preferably, the amount of the second solvent used per gram of compound Y is 5 ml to 8 ml. And / or, the temperature of the dehalogenation reaction is 60℃~90℃; preferably, the temperature of the dehalogenation reaction is 80℃~90℃; And / or, the dehalogenation reaction takes 1.5 hours to 24 hours; preferably, the dehalogenation reaction takes 7.5 hours to 10 hours. And / or, the alkaline substance is sodium hydroxide or its hydrate, potassium hydroxide or its hydrate, lithium hydroxide or its hydrate; preferably, the alkaline substance is potassium hydroxide or its hydrate; And / or, the second solvent comprises water and an alcohol solvent, wherein the volume ratio of water to alcohol solvent in the second solvent is 1:1 to 5; wherein the alcohol solvent is selected from alcohol solvents with 1 to 4 carbon atoms; preferably, the volume ratio of water to alcohol solvent in the second solvent is 1:1 to 2; and / or, the alcohol solvent is ethanol; And / or, it also includes a post-processing step: after the dehalogenation reaction is completed, cool to room temperature, stir, let stand, separate the liquids, take the organic phase, wash with water, and obtain the final product.

6. The preparation method according to claim 1 or 2, characterized in that, In step S3, the amount of hydrogenation catalyst used per gram of compound Z is 0.005 g to 0.05 g; preferably, the amount of hydrogenation catalyst used per gram of compound Z is 0.015 g to 0.025 g. And / or, the amount of the third solvent used per gram of compound Z is 5 ml to 15 ml; preferably, the amount of the third solvent used per gram of compound Z is 7.5 ml to 10 ml. And / or, the temperature of the hydrogenation reaction is 35°C to 65°C; preferably, the temperature of the hydrogenation reaction is 45°C to 55°C; And / or, the hydrogenation reaction takes 1.5 hours to 24 hours; preferably, the hydrogenation reaction takes 5.5 hours to 8 hours. And / or, the hydrogenation catalyst is selected from one or more of palladium catalysts, platinum catalysts, and nickel catalysts; preferably, the hydrogenation catalyst is a palladium catalyst, and the Pd content of the palladium catalyst is 1% to 10%; more preferably, the palladium catalyst is a palladium-carbon catalyst, and the Pd content of the palladium catalyst is 4.5% to 5.5%. And / or, the third solvent is selected from alcohol solvents with 1 to 4 carbon atoms; preferably, the third solvent is ethanol; And / or, it also includes a post-processing step: after the hydrogenation reaction is completed, the hydrogenation catalyst is removed, and the mixture is distilled at 50℃±2℃ to 40%±0.5% of the volume of the reaction liquid obtained from the hydrogenation reaction. Acetonitrile is added, and the mixture is distilled at 50℃±2℃ to 40%±0.5% of the volume of the reaction liquid obtained from the hydrogenation reaction. The mixture is then washed with water to obtain the final product.

7. The preparation method according to claim 1 or 2, characterized in that, The control parameters of the distillation process mainly include: feed temperature of 90℃~95℃, column top temperature of 45℃~50℃, reboiler temperature of 95℃~100℃, number of trays of 20~100, reflux ratio of 1.2~2.5, and column pressure ≤-0.09MPa. Preferably, the number of trays is 35 to 50; and / or, the number of distillations is 2 to 6. More preferably, the number of trays is 40; and / or the number of distillations is 3 or 4.

8. A perfluorohexyloctane product, characterized in that, The GC purity of the perfluorohexyl octane product is ≥95% or ≥99.5%, and the content of 2-perfluorohexyl-octane in the perfluorohexyl octane product is ≤0.15% or ≤0.10%. Preferably, the perfluorohexyloctane product is prepared by the preparation method according to any one of claims 1 to 7.

9. The gas chromatographic detection method for perfluorohexyloctane products according to claim 8, characterized in that, The chromatographic conditions of the gas chromatography detection method include: Chromatographic column: HP-1 gas chromatographic column or equivalent column; Temperature program: The initial temperature is 40℃, held for 0 min, then increased to 130℃ at a rate of 10℃ / min, held for 18 min, then increased to 230℃ at a rate of 20℃ / min, held for 8 min, and finally increased to 280℃ at a rate of 30℃ / min, held for 3 min. The injection port temperature is 200℃~350℃; The injection volume is 0.8 μl to 1.2 μl; The split ratio is 10 to 30:1; The carrier gas is nitrogen; The flow rate is 0.1 ml / min to 2 ml / min; The detector is a flame ionization detector; The detector temperature is 200℃~350℃; Preferably, The chromatographic column has dimensions of 60m × 0.32mm and 1μm. And / or, the injection port temperature is 280℃; And / or, the injection volume is 1.0 μl; And / or, the split ratio is 20:1; And / or, at a flow rate of 1.0 ml / min; And / or, the detector temperature is 300°C; And / or, the perfluorohexyloctane product is prepared into a test solution with a concentration of 45 mg / ml to 55 mg / ml, wherein the solvent of the test solution is ethanol.

10. The gas chromatography detection method according to claim 9, characterized in that, The gas chromatography detection method is a qualitative or quantitative detection method; preferably, the gas chromatography detection method is used for quantitative detection according to the internal standard method, the external standard method, or the peak area normalization method.

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