A method for preparing 6-bromo-6,6-difluoro-1-hexanol

Abstract

This invention discloses a method for preparing 6-bromo-6,6-difluoro-1-hexanol, belonging to the field of organic synthesis. The method uses 4-penten-1-ol as a starting material, reacting it with dibromodifluoromethane via an addition reaction to prepare 4,6-dibromo-6,6-difluoro-1-hexanol; then, a dehalogenation reaction is carried out using a second metal reagent to obtain 6-bromo-6,6-difluoro-1-hexanol. In this method, the reactants and reagents are inexpensive and readily available, the reaction steps are short, and production control is convenient; the reaction conditions are mild, ensuring high safety; the process is simple, and the product has high purity.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and more specifically to methods for synthesizing fluorine-containing fine chemicals. Background Technology

[0002] Halogenated difluoroalkanols are an important class of fluorine-containing organic compounds, with the general structural formula R-CF2X-OH (where R is an alkyl or substituted alkyl group, and X is a halogen). These molecules simultaneously contain a geminal difluoro group (-CF2-), a halogen atom, and a hydroxyl group, exhibiting unique electronic effects, steric hindrance effects, and biological activity. The geminal difluoro structure (-CF2-) possesses strong electronegativity and low polarity, significantly enhancing the lipophilicity, metabolic stability, and bioavailability of drug molecules, while providing stable carbon-fluorine bonds. Halogen atoms (Cl, Br, I) can serve as reaction sites in coupling, substitution, and other transformations, and are also key functional groups for enhancing molecular biological activity. The hydroxyl group imparts hydrophilicity to the molecule, facilitating derivatization into ethers and esters or acting as a hydrogen bond donor, enhancing interactions with biological targets. Halogenated difluoroalkanols are widely used in pharmaceuticals, pesticide intermediates, and electronic chemicals. For example, 4-bromo-4,4-difluorobutanol is a key intermediate in the synthesis of chiral drugs. For example, short-chain difluorools (such as 2,2-difluoroethanol) are used to synthesize novel herbicides (such as penflusulfonamide) or as key intermediates in drug synthesis to build difluoroethoxy groups, which can further synthesize compounds used for analgesia, anti-inflammation, anticancer drugs, and highly active antibiotics. With the accelerated development of anticancer drugs and nervous system drugs, and the increasing demand for highly efficient and low-toxicity pesticides due to the green transformation of agriculture, the demand for high-end fluorinated intermediates continues to grow.

[0003] 6-Bromo-6,6-difluoro-1-hexanol is an important pesticide intermediate, commonly used in the synthesis of insecticides to control pests, and its market demand remains strong. However, its synthetic methods are rarely reported in the literature. In particular, process routes with the potential for large-scale industrial production (e.g., simple routes, mild conditions, and low production costs) are not reported and urgently need to be developed and researched. It is worth noting that although the synthesis of its homologues (such as 4-bromo-4,4-difluoro-1-butanol) is relatively mature, these methods are often difficult to directly and effectively extend to the synthesis of six-carbon chain target molecules. Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide a method for preparing 6-bromo-6,6-difluoro-1-hexanol, which can effectively reduce costs by using inexpensive and readily available compounds as starting materials. The synthetic route is simple, the reaction conditions are mild, the product obtained has high purity, and the economic benefits are good. It is expected to be used for industrial production.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] This invention provides a method for preparing 6-bromo-6,6-difluoro-1-hexanol, comprising:

[0007] Step S1: 4-Penten-1-ol and dibromodifluoromethane are reacted with a first metal reagent in the presence of a first reaction solvent at 50–90 °C to prepare 4,6-dibromo-6,6-difluoro-1-hexanol; wherein, the first reaction solvent is selected from at least one of ethanolamine, tert-butanol, ethanol, aniline, tetrahydrofuran, and ethylenediamine, and the first metal reagent is selected from one of cuprous iodide, ferrous chloride, and cuprous chloride;

[0008] Step S2: Under inert gas protection and continuous stirring, the 4,6-dibromo-6,6-difluoro-1-hexanol is subjected to a dehalogenation reaction with a second metal reagent in the presence of a second reaction solvent at 40°C to 90°C to obtain 6-bromo-6,6-difluoro-1-hexanol; wherein, the second reaction solvent is selected from one of acetonitrile, tetrahydrofuran, dimethyl sulfoxide and sulfolane, and the second metal reagent is sodium borohydride, sodium triacetylborohydride, or a combination of sodium borohydride and a calcium salt, wherein the calcium salt is selected from at least one of calcium chloride and calcium oxide.

[0009] In some specific embodiments of the present invention, a method for preparing 6-bromo-6,6-difluoro-1-hexanol includes:

[0010] Step S1: Add 4-penten-1-ol, the first reaction solvent, the first metal reagent, and dibromodifluoromethane to the high-pressure reactor, and seal the reactor; under continuous stirring, raise the temperature to 50-90°C and react for 24-72 hours to obtain the first reaction solution; perform the first post-treatment on the first reaction solution to obtain 4,6-dibromo-6,6-difluoro-1-hexanol;

[0011] Step S2: The second reaction solvent and the 4,6-dibromo-6,6-difluoro-1-hexanol obtained in step S1 are added to a reaction vessel. Under inert gas protection and continuous stirring, the second metal reagent is added in several portions, and the temperature is slowly raised to 40℃~90℃. The reaction is carried out for 5~10 hours to obtain the second reaction solution. The second reaction solution is subjected to a second post-treatment to obtain 6-bromo-6,6-difluoro-1-hexanol.

[0012] Wherein, the first reaction solvent is selected from at least one of ethanolamine, ethanol, tert-butanol, aniline, tetrahydrofuran, and ethylenediamine; the first metal reagent is selected from one of cuprous iodide, ferrous chloride, and cuprous chloride; the second reaction solvent is selected from one of acetonitrile, tetrahydrofuran, dimethyl sulfoxide, and sulfolane; the second metal reagent is sodium borohydride, sodium triacetylborohydride, or a combination of sodium borohydride and a calcium salt, wherein the calcium salt is selected from at least one of calcium chloride and calcium oxide.

[0013] In some specific examples of the present invention, in step S1, the molar ratio of 4-penten-1-ol to the first reaction solvent, the first metal reagent, and dibromodifluoromethane is 1:(0.5-2.5):(0.005-0.025):(0.5-1.5).

[0014] In some specific examples of the present invention, in step S1, the molar ratio of 4-penten-1-ol, the first reaction solvent, the first metal reagent, and dibromodifluoromethane is 1:(1~1.5):(0.01~0.02):1.

[0015] In some specific examples of the present invention, in step S1, the first reaction solvent is ethanolamine and tert-butanol.

[0016] In some specific embodiments of the present invention, in step S1, the first reaction solvent is ethanolamine and ethanol.

[0017] In some specific embodiments of the present invention, in step S1, the first post-processing procedure is as follows:

[0018] After cooling, the first reaction solution was removed, dichloromethane was added to the first reaction solution, stirred, filtered under reduced pressure, and the resulting filtrate was retained. The filter cake was washed with dichloromethane and the washing liquid was collected. The washing liquid and filtrate were combined and concentrated under reduced pressure. Finally, the solution was distilled under reduced pressure to obtain 4,6-dibromo-6,6-difluoro-1-hexanol.

[0019] In some specific embodiments of the present invention, in the first post-processing, the stirring speed is 100~300 r / min, preferably 300 r / min.

[0020] In some specific embodiments of the present invention, in step S2, the molar ratio of 4,6-dibromo-6,6-difluoro-1-hexanol to the second metal reagent is 1:(0.5-5).

[0021] In some specific examples of the present invention, in step S2, the mass ratio of 4,6-dibromo-6,6-difluoro-1-hexanol to the second reaction solvent is 1:(3-8).

[0022] In some specific embodiments of the present invention, in step S2, the inert gas is nitrogen or argon.

[0023] In some specific embodiments of the present invention, in step S2, the stirring speed is 100~500 r / min, preferably 300 r / min.

[0024] In some specific embodiments of the present invention, in step S2, the temperature is slowly increased to 70°C to 90°C.

[0025] In some specific embodiments of the present invention, in step S2, slow heating means raising the internal temperature to 70-90°C in 1 hour.

[0026] In some specific embodiments of the present invention, in step S2, the second metal reagent is sodium borohydride and anhydrous calcium chloride, and the molar ratio of sodium borohydride and anhydrous calcium chloride is 1:2.

[0027] In some specific embodiments of the present invention, in step S2, the second metal reagent is mixed under dry conditions.

[0028] In some specific embodiments of the present invention, in step S2, the second post-processing procedure is as follows:

[0029] The second reaction solution was poured into ice water, stirred, and the pH was adjusted to 3-5. Dichloromethane was added for extraction and stirring. The mixture was allowed to stand and separated. The organic phase obtained from the separation was dried, concentrated, and finally distilled under reduced pressure to obtain 6-bromo-6,6-difluoro-1-hexanol.

[0030] In some specific embodiments of the present invention, in the second post-processing, the pH value is adjusted by adding hydrochloric acid with a concentration of 6 mol / L.

[0031] In some specific embodiments of the present invention, in the second post-processing, the stirring speed is 100~300 r / min, preferably 300 r / min.

[0032] The present invention also provides 6-bromo-6,6-difluoro-1-hexanol prepared by the above preparation method.

[0033] In the preparation method of this invention, 4-penten-1-ol is cleverly selected as the starting material. 4-penten-1-ol undergoes an addition reaction with dibromodifluoromethane to prepare 4,6-dibromo-6,6-difluoro-1-hexanol; then, a dehalogenation reaction is carried out using a second metal reagent to obtain 6-bromo-6,6-difluoro-1-hexanol. In this method, the reactants and reagents are inexpensive and readily available, the reaction steps are short, and production control is convenient; the reaction conditions are mild, ensuring high safety; the process is simple, and the product has high purity.

[0034] Compared with the prior art, the present invention has the following beneficial technical effects:

[0035] 1. This invention employs a two-step reaction method, which greatly shortens the process route, simplifies the reaction process, reduces production time, and saves production costs, making it of great significance for large-scale industrial production.

[0036] 2. The present invention has a short reaction route, few by-products, and a high purity and quality of final product. At the same time, the reaction conditions are mild and safe, requiring no special parameter control and having relatively relaxed requirements on synthesis equipment and other conditions, thus meeting the basic conditions for large-scale industrial production.

[0037] 3. The raw materials and reaction reagents used in this invention are inexpensive and readily available, resulting in low production costs and convenience, which can meet the needs of large-scale production. Attached Figure Description

[0038] Figure 1 The 1H NMR spectrum is that of 4,6-dibromo-6,6-difluoro-1-hexanol obtained in step S1 of Example 1.

[0039] Figure 2 The NMR fluorine spectrum is that of 4,6-dibromo-6,6-difluoro-1-hexanol obtained in step S1 of Example 1.

[0040] Figure 3 The gas chromatogram is of 4,6-dibromo-6,6-difluoro-1-hexanol obtained in step S1 of Example 1.

[0041] Figure 4 The 1H NMR spectrum of 6-bromo-6,6-difluoro-1-hexanol obtained in step S2 of Example 1 is shown.

[0042] Figure 5 The NMR fluorine spectrum is that of 6-bromo-6,6-difluoro-1-hexanol obtained in step S2 of Example 1.

[0043] Figure 6 The gas chromatogram is of 6-bromo-6,6-difluoro-1-hexanol obtained in step S2 of Example 1. Detailed Implementation

[0044] To better illustrate the present invention and facilitate understanding of its technical solutions, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be understood that the following embodiments are for illustrative purposes only and do not represent or limit the scope of protection of the present invention; the scope of protection of the present invention is defined by the claims.

[0045] Unless otherwise specified, all reagents or instruments used in the following examples and comparative examples are commercially available products.

[0046] Example 1

[0047]

[0048] Step S1: Preparation of 4,6-dibromo-6,6-difluoro-1-hexanol

[0049] 43 g (0.5 mol) of 4-penten-1-ol, 37 g (0.5 mol) of tert-butanol, 15.3 g (0.25 mol) of ethanolamine, 0.5 g (0.005 mol) of cuprous chloride, and 105 g (0.5 mol) of difluorodibromomethane were added to a high-pressure reactor, and the reactor was sealed. The mixture was stirred, heated to 80°C, and reacted for 48 hours to obtain the first reaction solution.

[0050] The mixture was then cooled, the vessel opened, and the first reaction solution was transferred to a single-necked flask. 200 ml of dichloromethane was added to the single-necked flask, and the mixture was stirred for 15 minutes. 50 g of silica gel was added to the vacuum filtration funnel for filtration under reduced pressure. The filtrate was retained, and the filter cake was washed with 50 ml of dichloromethane and the washing liquid was collected. The washing liquid and filtrate were combined and concentrated by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then subjected to vacuum distillation using an oil pump, and the fraction with a top temperature of 75-85℃ was collected to obtain product S1, which was a colorless and transparent liquid weighing 128 g.

[0051] The S1 product was analyzed by 1H NMR, 19F NMR, and gas chromatography (GC) to determine its structure and purity. The 1H NMR spectrum of the S1 product is shown below. Figure 1 As shown, the NMR fluorine spectrum (19F NMR) of the S1 product is as follows. Figure 2 As shown.

[0052] Figure 1 Medium, 1H-NMR (400 MHz, Chloroform-d)δ 4.36-4.25 (m, 1H), 3.78-3.61(m, 2H), 3.21-2.90 (m, 2H), 2.16-1.62 (m, 4H).

[0053] Figure 2 Medium, 19F-NMR (376 MHz, Chloroform-d) δ-42.79.

[0054] according to Figure 1 and Figure 2 The nuclear magnetic resonance spectrum confirmed that the S1 product was 4,6-dibromo-6,6-difluoro-1-hexanol.

[0055] The gas chromatography (GC) detection results of product S1 are as follows: Figure 3 As shown, the analysis results are presented in Table 1 below:

[0056] Table 1: Gas chromatographic analysis results of S1 product

[0057]

[0058] Based on the GC analysis results above, the purity of the product (4,6-dibromo-6,6-difluoro-1-hexanol) is 98.69%, and the molar yield is calculated to be 86%.

[0059] Step S2: Preparation of 6-bromo-6,6-difluoro-1-hexanol

[0060] Sodium borohydride and anhydrous calcium chloride (fine powder) are uniformly mixed in a molar ratio of 1:2 in a vacuum glove box to obtain a sodium borohydride mixture for later use.

[0061] Add 640 ml of dimethyl sulfoxide (DMSO) and 128 g (0.43 mol) of S1 product (colorless and transparent liquid) to a four-necked flask. Stir mechanically and under nitrogen protection, add 112 g of sodium borohydride mixture (containing 0.43 mol of NaBH4 and 0.86 mol of calcium chloride) to the flask in three portions. Control the mechanical stirring speed at 300 r / min, and slowly raise the temperature to 70-75 °C within 1 h. Maintain this temperature while stirring the reaction. Stop the reaction when the amount of S1 product remaining is <0.5% as monitored by GC (reaction time is about 6 h) to obtain the second reaction solution.

[0062] The second reaction solution was poured into 2L of ice water and stirred for 30 minutes. The pH was adjusted to approximately 4 with 6 mol / L hydrochloric acid. Then, 200 ml of dichloromethane (DCM) was added to the solution and stirred for 30 minutes for extraction. The solution was then allowed to stand and the organic phase was separated. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was then concentrated by rotary evaporation to obtain the crude product. The crude product was further subjected to vacuum distillation using an oil pump, and the fraction with a top temperature of 65–75°C was collected to obtain the final product, which weighed 71.6 g.

[0063] The final product was analyzed by 1H NMR, 19F NMR, and gas chromatography (GC) to determine its structure and purity. The 1H NMR spectrum of the final product is shown below. Figure 4 As shown, the final product's fluorine NMR spectrum (19F NMR) is as follows. Figure 5 As shown.

[0064] Figure 4 Medium, 1H-NMR (400 MHz, Acetone-d6) δ3.56 (t, J = 6.2 Hz, 2H), 2.56-2.39 (m, 2H), 1.71-1.59 (m, 2H), 1.59-1.44 (m, 4H).

[0065] Figure 5 Medium, 19F NMR (376 MHz, Acetone-d6) δ-43.93.

[0066] According to Figure 4 and Figure 5 Analysis of the nuclear magnetic resonance spectrum determined that the final product was 6-bromo-6,6-difluoro-1-hexanol.

[0067] The gas chromatography (GC) results of the final product are as follows: Figure 6 As shown, the analysis results are presented in Table 2 below:

[0068] Table 2: Gas Chromatography Analysis Results of the Final Product

[0069]

[0070] Based on the GC analysis results above, the purity of the product (6-bromo-6,6-difluoro-1-hexanol) is 98.48%, and the molar yield is calculated to be 76%.

[0071] Example 2

[0072]

[0073] Step S1: Preparation of 4,6-dibromo-6,6-difluoro-1-hexanol

[0074] 43 g (0.5 mol) of 4-penten-1-ol, 23 g (0.5 mol) of ethanol, 15.3 g (0.25 mol) of ethanolamine, 1 g (0.005 mol) of cuprous iodide, and 105 g (0.5 mol) of difluorodibromomethane were added to a high-pressure reactor, and the reactor was sealed. The mixture was stirred, heated to 80°C, and reacted for 48 hours to obtain the first reaction solution.

[0075] The mixture was then cooled, the vessel opened, and the first reaction solution was transferred to a single-necked flask. 200 ml of dichloromethane was added to the single-necked flask, and the mixture was stirred for 15 minutes. 50 g of silica gel was added to the vacuum filtration funnel for filtration under reduced pressure. The filtrate was retained, and the filter cake was washed with 50 ml of dichloromethane and the washing liquid was collected. The washing liquid and filtrate were combined and concentrated by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then subjected to vacuum distillation using an oil pump, and the fraction with a top temperature of 75-85℃ was collected to obtain product S1, which was a colorless and transparent liquid weighing 107 g.

[0076] Testing confirmed that the obtained product S1 was 4,6-dibromo-6,6-difluoro-1-hexanol, with a GC purity of ≥98% and a calculated molar yield of 72%.

[0077] Step S2: Preparation of 6-bromo-6,6-difluoro-1-hexanol

[0078] Add 535 ml of dimethyl sulfoxide (DMSO) and 107 g (0.36 mol) of S1 product (colorless and transparent liquid) to a four-necked flask. Stir mechanically and under nitrogen protection, add 76.6 g (0.36 mol) of sodium triacetylborohydride to the flask in three portions. Control the mechanical stirring speed at 300 r / min and slowly raise the temperature to 70-75 °C over 1 hour. Maintain this temperature while stirring the reaction. Stop the reaction when the amount of S1 product remaining is <0.5% as monitored by GC (reaction time is about 6 hours) to obtain the second reaction solution.

[0079] The second reaction solution was poured into 2L of ice water and stirred for 30 minutes. The pH was adjusted to approximately 4 with 6 mol / L hydrochloric acid. Then, 200 ml of dichloromethane (DCM) was added to the solution and stirred for 30 minutes for extraction. The solution was then allowed to stand and the organic phase was separated. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated by rotary evaporation to obtain the crude product. The crude product was further subjected to vacuum distillation using an oil pump, and the fraction with a top temperature of 65–75°C was collected to obtain the final product, which weighed 52 g.

[0080] Testing confirmed that the final product was 6-bromo-6,6-difluoro-1-hexanol with a GC purity of 98% and a calculated molar yield of 66%.

[0081] Example 3

[0082]

[0083] Step S1: Preparation of 4,6-dibromo-6,6-difluoro-1-hexanol

[0084] 43 g (0.5 mol) of 4-penten-1-ol, 36.9 g (0.5 mol) of tert-butanol, 15.4 g (0.25 mol) of ethanolamine, 1.0 g (0.01 mol) of cuprous chloride, and 105 g (0.5 mol) of difluorodibromomethane were added to a high-pressure reactor, and the reactor was sealed. The mixture was stirred, heated to 90°C, and reacted for 48 hours to obtain the first reaction solution.

[0085] The mixture was then cooled, the vessel opened, and the first reaction solution was transferred to a single-necked flask. 200 ml of dichloromethane was added to the single-necked flask, and the mixture was stirred for 15 minutes. 50 g of silica gel was added to the vacuum filtration funnel for filtration under reduced pressure. The filtrate was retained, and the filter cake was washed with 50 ml of dichloromethane and the washing liquid was collected. The washing liquid and filtrate were combined and concentrated by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then subjected to vacuum distillation using an oil pump, and the fraction with a top temperature of 75-85℃ was collected to obtain product S1, which was a colorless and transparent liquid weighing 132 g.

[0086] Testing confirmed that the obtained product S1 was 4,6-dibromo-6,6-difluoro-1-hexanol, with a GC purity of ≥98% and a calculated molar yield of 89%.

[0087] Step S2: Preparation of 6-bromo-6,6-difluoro-1-hexanol

[0088] Sodium borohydride and anhydrous calcium chloride (fine powder) are uniformly mixed in a molar ratio of 1:2 in a vacuum glove box to obtain a sodium borohydride mixture for later use.

[0089] Add 800 ml of dimethyl sulfoxide (DMSO) and 132 g (0.44 mol) of S1 product (colorless and transparent liquid) to a four-necked flask. Stir mechanically and under nitrogen protection. Add 116 g of sodium borohydride mixture (containing 0.44 mol of NaBH4 and 0.88 mol of calcium chloride) to the four-necked flask in 5 batches. Control the mechanical stirring speed at 300 r / min. Slowly raise the temperature to 75-80℃ in 1 hour. Maintain this temperature while stirring the reaction. Stop the reaction when the amount of S1 product remaining is <0.5% as monitored by GC, and obtain the second reaction solution.

[0090] The second reaction solution was poured into 3L of ice water and stirred for 30 minutes. The pH was adjusted to approximately 4 using 6 mol / L hydrochloric acid. Then, 200 ml of dichloromethane (DCM) was added to the above liquid and stirred for 30 minutes for extraction. The mixture was then allowed to stand and the organic phase was separated. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was then concentrated by rotary evaporation to obtain a crude product. The crude product was further subjected to vacuum distillation using an oil pump, and the fraction with a top temperature of 65–75°C was collected to obtain the final product, weighing 77.5 g.

[0091] Testing confirmed that the final product was 6-bromo-6,6-difluoro-1-hexanol with a GC purity of 98% and a calculated molar yield of 80%.

[0092] Example 4

[0093]

[0094] Step S1: Preparation of 4,6-dibromo-6,6-difluoro-1-hexanol

[0095] 43 g (0.5 mol) of 4-penten-1-ol, 37 g (0.5 mol) of tert-butanol, 15.2 g (0.25 mol) of ethanolamine, 1.9 g (0.01 mol) of cuprous iodide, and 105 g (0.5 mol) of difluorodibromomethane were added to a high-pressure reactor, and the reactor was sealed. The mixture was stirred, heated to 90°C, and reacted for 72 hours to obtain the first reaction solution.

[0096] The mixture was then cooled, the vessel opened, and the first reaction solution was transferred to a single-necked flask. 200 ml of dichloromethane was added to the single-necked flask, and the mixture was stirred for 15 minutes. 50 g of silica gel was added to the vacuum filtration funnel for filtration under reduced pressure. The filtrate was retained, and the filter cake was washed with 50 ml of dichloromethane and the washing liquid was collected. The washing liquid and filtrate were combined and concentrated by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then subjected to vacuum distillation using an oil pump, and the fraction with a top temperature of 75-85℃ was collected to obtain product S1, which was a colorless and transparent liquid weighing 131 g.

[0097] Testing confirmed that the obtained product S1 was 4,6-dibromo-6,6-difluoro-1-hexanol, with a GC purity of ≥98% and a calculated molar yield of 88%.

[0098] Step S2: Preparation of 6-bromo-6,6-difluoro-1-hexanol

[0099] Add 900 ml of dimethyl sulfoxide (DMSO) and 131 g (0.44 mol) of S1 product (colorless and transparent liquid) to a four-necked flask. Stir mechanically and under nitrogen protection, add 141 g (0.66 mol) of sodium triacetylborohydride to the flask in 5 portions. Control the mechanical stirring speed at 300 r / min and slowly raise the temperature to 75-80 °C in 1 h. Maintain this temperature while stirring the reaction. Stop the reaction when the amount of S1 product remaining is <0.5% as monitored by GC (reaction time is about 5 h) to obtain the second reaction solution.

[0100] The second reaction solution was poured into 3.2 L of ice water and stirred for 30 minutes. The pH was adjusted to approximately 4 with 6 mol / L hydrochloric acid. Then, 200 ml of dichloromethane (DCM) was added to the solution and stirred for 30 minutes for extraction. The solution was then allowed to stand and the organic phase was separated. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated by rotary evaporation to obtain the crude product. The crude product was further subjected to vacuum distillation using an oil pump, and the fraction with a top temperature of 65–75 °C was collected to obtain the final product, which weighed 65.5 g.

[0101] Testing confirmed that the final product was 6-bromo-6,6-difluoro-1-hexanol with a GC purity of 98% and a calculated molar yield of 68%.

[0102] In the above reaction, N2 protection is used to ensure the isolation of moisture. When adding materials in batches, the materials can be weighed in a vacuum glove box and loaded into multiple capped plastic tubes in batches. One tube is taken out each time the material is added and quickly added to the four-necked (reaction) flask.

[0103] In summary, in the above embodiments, 4-penten-1-ol was used as the starting material. The 4-penten-1-ol was reacted with dibromodifluoromethane via an addition reaction to prepare 4,6-dibromo-6,6-difluoro-1-hexanol; then, a dehalogenation reaction was carried out using a second metal reagent to obtain 6-bromo-6,6-difluoro-1-hexanol. In the above embodiments, the reaction materials and reagents used are inexpensive and readily available; the reaction steps are short, facilitating production control; the reaction conditions are mild, requiring no special parameter control, and the requirements for synthesis equipment are relatively relaxed; the process is simple, and the product purity is high.

[0104] Therefore, it is evident that the objective of this invention has been fully and effectively achieved. The function and structural principles of this invention have been demonstrated and explained in the embodiments. Any modifications can be made to the implementation methods without departing from these principles. Therefore, this invention includes all modified embodiments based on the spirit and scope of the claims.

Claims

1. A method for preparing 6-bromo-6,6-difluoro-1-hexanol, comprising: Step S1: 4-Penten-1-ol and dibromodifluoromethane are reacted with a first metal reagent in the presence of a first reaction solvent at 50–90 °C to prepare 4,6-dibromo-6,6-difluoro-1-hexanol; wherein, the first reaction solvent is selected from at least one of ethanolamine, tert-butanol, ethanol, aniline, tetrahydrofuran, and ethylenediamine, and the first metal reagent is selected from one of cuprous iodide, ferrous chloride, and cuprous chloride; Step S2: Under inert gas protection and continuous stirring, the 4,6-dibromo-6,6-difluoro-1-hexanol is subjected to a dehalogenation reaction with a second metal reagent in the presence of a second reaction solvent at 40°C to 90°C to obtain 6-bromo-6,6-difluoro-1-hexanol; wherein, the second reaction solvent is selected from one of acetonitrile, tetrahydrofuran, dimethyl sulfoxide and sulfolane, and the second metal reagent is sodium borohydride, sodium triacetylborohydride, or a combination of sodium borohydride and a calcium salt, wherein the calcium salt is selected from at least one of calcium chloride and calcium oxide.

2. The method for preparing 6-bromo-6,6-difluoro-1-hexanol according to claim 1, characterized in that, include: Step S1: Add 4-penten-1-ol, the first reaction solvent, the first metal reagent, and dibromodifluoromethane to the high-pressure reactor, and seal the reactor; With continuous stirring, the temperature is raised to 50-90℃ and the reaction is carried out for 24-72 hours to obtain the first reaction solution; the first reaction solution is subjected to a first post-treatment to obtain 4,6-dibromo-6,6-difluoro-1-hexanol. Step S2: The second reaction solvent and the 4,6-dibromo-6,6-difluoro-1-hexanol obtained in step S1 are added to a reaction vessel. Under inert gas protection and continuous stirring, the second metal reagent is added in several portions, and the temperature is slowly raised to 40℃~90℃. The reaction is carried out for 5~10 hours to obtain the second reaction solution. The second reaction solution is subjected to a second post-treatment to obtain 6-bromo-6,6-difluoro-1-hexanol. Wherein, the first reaction solvent is selected from at least one of ethanolamine, ethanol, tert-butanol, aniline, tetrahydrofuran, and ethylenediamine; the first metal reagent is selected from one of cuprous iodide, ferrous chloride, and cuprous chloride; the second reaction solvent is selected from one of acetonitrile, tetrahydrofuran, dimethyl sulfoxide, and sulfolane; the second metal reagent is sodium borohydride, sodium triacetylborohydride, or a combination of sodium borohydride and a calcium salt, wherein the calcium salt is selected from at least one of calcium chloride and calcium oxide.

3. The method for preparing 6-bromo-6,6-difluoro-1-hexanol as described in claim 1 or 2, characterized in that, In step S1, the molar ratio of 4-penten-1-ol to the first reaction solvent, the first metal reagent, and dibromodifluoromethane is 1:(0.5-2.5):(0.005-0.025):(0.5-1.5).

4. The method for preparing 6-bromo-6,6-difluoro-1-hexanol as described in claim 1 or 2, characterized in that, In step S1, the molar ratio of 4-penten-1-ol, the first reaction solvent, the first metal reagent, and dibromodifluoromethane is 1:(1~1.5):(0.01~0.02):

1.

5. The method for preparing 6-bromo-6,6-difluoro-1-hexanol as described in claim 1 or 2, characterized in that, In step S1, the first post-processing procedure is as follows: After cooling, the first reaction solution was removed, dichloromethane was added to the first reaction solution, stirred, filtered under reduced pressure, and the resulting filtrate was retained. The filter cake was washed with dichloromethane and the washing liquid was collected. The washing liquid and filtrate were combined and concentrated under reduced pressure. Finally, the solution was distilled under reduced pressure to obtain 4,6-dibromo-6,6-difluoro-1-hexanol.

6. The method for preparing 6-bromo-6,6-difluoro-1-hexanol as described in claim 1 or 2, characterized in that, In step S2, the molar ratio of 4,6-dibromo-6,6-difluoro-1-hexanol to the second metal reagent is 1:(0.5-5).

7. The method for preparing 6-bromo-6,6-difluoro-1-hexanol as described in claim 1 or 2, characterized in that, In step S2, the mass ratio of 4,6-dibromo-6,6-difluoro-1-hexanol to the second reaction solvent is 1:(3-8).

8. The method for preparing 6-bromo-6,6-difluoro-1-hexanol as described in claim 1 or 2, characterized in that, In step S2, the inert gas is nitrogen or argon.

9. The method for preparing 6-bromo-6,6-difluoro-1-hexanol as described in claim 1 or 2, characterized in that, In step S2, the second post-processing procedure is as follows: The second reaction solution was poured into ice water, stirred, and the pH was adjusted to 3-5. Dichloromethane was added for extraction and stirring. The mixture was allowed to stand and separated. The organic phase obtained from the separation was dried, concentrated, and finally distilled under reduced pressure to obtain 6-bromo-6,6-difluoro-1-hexanol.

10. 6-bromo-6,6-difluoro-1-hexanol prepared by any one of claims 1 to 9.

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