A method for preparing heterocyclic fluorides

Abstract

This invention discloses a method for preparing heterocyclic fluorides. A heterocyclic compound of formula II-1 or II-2, and a mixture A of fluorine gas and inert gas are introduced into the first stage reactor of a microchannel reactor for a fluorination reaction. Then, the product from the fluorination reaction in the first stage reactor, the unreacted raw material, and a mixture B of fluorine gas and inert gas are introduced into the second stage reactor of the microchannel reactor for further fluorination to prepare the heterocyclic fluoride of formula III-1 or III-2. The fluorination method of this invention requires no catalyst, has a short reaction time, high product yield, few side reactions, is simple in process, and has low cost.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, and in particular to a method for preparing heterocyclic fluorides. Background Technology

[0002] Heterocyclic compounds with a structure of formula IV-1 or IV-2 are fluorinated chemicals.

[0003]

[0004] In Formula IV-1 or Formula IV-2, W is selected from CF2, N-perfluorinated straight-chain or branched alkenyl groups or O atoms, R2 is one or more fluorine atoms attached to any one or more atoms on the ring, trifluoromethyl groups, and R3 is a perfluorinated straight-chain or branched alkenyl group.

[0005] Due to the small radius and strong electronegativity of fluorine atoms, the introduction of fluorine atoms typically leads to significant changes in the polarity of the CF bond and the electron cloud distribution of the entire molecule. This endows fluorides with unique properties, playing important roles in pharmaceuticals, biology, surfactants, and novel materials. They can be introduced as crucial building blocks into drugs or biomolecules to improve their properties. Fluorine atoms also alter the dipole moment of the molecule, reducing its dielectric constant and significantly lowering the polarizability, thus reducing its dielectric constant. Perfluorinated or polyfluoroolefinic cyclic compounds possess excellent insulating properties and can be used as liquid cooling media in various fields such as data center immersion cooling, lithium battery thermal management systems, and semiconductor temperature control. They can also be used as foaming agents in polymer synthesis. Furthermore, due to their strained cyclic structure, they exhibit strong reactivity with -OH radicals and have a short atmospheric lifetime. Therefore, these compounds have a low global warming potential (GWP), making them environmentally friendly compounds with very high economic and environmental value.

[0006] The core step in synthesizing this type of fluorinated cyclic compound is the fluorination process that introduces fluorine atoms. Currently, fluorine atoms are mainly introduced into heterocyclic compounds through technologies or processes such as metal fluoride fluorination, electrochemical fluorination, and fluorine gas fluorination.

[0007] For example, the literature "Journal of Fluorine Chemistry, 1998, 87(1): 105-109" reported a method for fluorination of metal fluorides. Although the reaction conditions are relatively mild and the reaction is relatively stable, and there is no need to use dangerous materials such as fluorine gas or hydrofluoric acid, the fluorination reaction of metal fluorides has poor selectivity, making it difficult to achieve perfluorination. In addition, metal fluorides are expensive and have a limited range of applications.

[0008] The literature "J. Am. Chem. Soc. 1957, 79, 13, 3429–3432" reports an electrochemical fluorination method. Electrochemical fluorination has high reaction energy and can achieve the fluorination of inert compounds without the need for a catalyst. However, the electrochemical fluorination process inevitably produces a large amount of fluorination cracking products from the organic starting material, such as carbon tetrafluoride and nitrogen trifluoride, resulting in very low yields. Furthermore, it requires a large amount of hydrofluoric acid, placing high demands on the corrosion resistance of the equipment. Prolonged energization can lead to passivation of the anode surface, affecting the reaction yield. Currently, the application of this method is quite limited.

[0009] For the perfluorination of cyclic compounds, direct fluorination with fluorine gas has certain advantages, with higher yields and better selectivity. In 1990, Lagow et al. reported a series of fluorination reactions of cyclic compounds in the literature "Journal of Fluorine Chemistry, 1990(50):15-30". Using a specially designed multi-temperature zone reactor, fluorine gas with gradient concentrations of 5% to 100% was introduced sequentially. The four temperature conditions and six fluorine gas concentration conditions were combined to form 10-stage reaction conditions, realizing the perfluorination reaction of a series of heterocyclic compounds. However, this fluorination process cannot be continuously produced. It requires intermittent feeding of fluorinated substrates and long-term low-flow-rate fluorine gas introduction for the fluorination reaction. The gas introduction time is about 3 to 7 days. In addition, a large amount of fluorine gas is required in excess during the reaction process. The conversion rate of fluorine gas to the target product is low, and the value of large-scale production application is relatively limited. Further optimization of reaction conditions is needed. More importantly, straight-chain or branched perfluoroalkenyl fluorinated cyclic compounds contain unsaturated carbon-carbon double bonds. When they undergo a direct fluorination reaction with fluorine gas, the double bonds cannot be preserved. Instead, fluorine atoms are added to the C=C bond to form ortho-difluorinated compounds, and heterocyclic fluorinated compounds containing alkenyl groups cannot be obtained.

[0010] In addition to direct fluorination of cyclic compounds, some chain compounds can be prepared into perfluorinated cyclic compounds through cyclization reactions in the presence of fluorine. For example, the literature "Journal of the American Chemical Society, 1962, 84(17):3409-3410" reported the cyclization process of perfluorosuccinate in the presence of fluorine. Although this reaction can prepare perfluorinated cyclic compounds, the reactant perfluorosuccinate is difficult to prepare and has a low yield, so its practical application value is small.

[0011] In summary, existing methods for preparing heterocyclic fluorides containing alkenyl groups either suffer from poor reaction selectivity, making it difficult to achieve perfluorination, and the high cost of metal fluorides limits their application scope; or they suffer from substrate breakage leading to numerous byproducts, low yields, and limited applications; or they involve batch reactions with long reaction times, numerous reaction steps, complex conditions, and complicated operations, making them unsuitable for the large-scale industrial production of fluorination processes for heterocyclic compounds, and direct fluorination of fluorine cannot yield heterocyclic fluorinated compounds containing straight-chain or branched perfluoroalkenyl groups; or they suffer from difficulties in preparing reaction raw materials, low yields, and limited practical application value. Summary of the Invention

[0012] To address the aforementioned technical problems, this invention proposes a method for preparing heterocyclic fluorides that utilizes readily available raw materials, achieves high raw material conversion rates, high product yields, low costs, and short fluorination reaction times, making it suitable for industrial production.

[0013] The objective of this invention is achieved through the following technical solution:

[0014] In a first aspect, the present invention provides a method for preparing heterocyclic fluorides. A heterocyclic compound of formula II-1 or II-2, and a mixture A of fluorine gas and an inert gas are introduced into the first stage reactor of a microchannel reactor for a fluorination reaction. Then, the product from the fluorination reaction in the first stage reactor, the unreacted raw material, and a mixture B of fluorine gas and an inert gas are introduced into the second stage reactor of the microchannel reactor for further fluorination to prepare the heterocyclic fluoride of formula III-1 or III-2.

[0015] The fluorination reaction temperature and the fluorine concentration in the mixed gas A in the first stage reactor satisfy the formula: T1 = -0.0271c1 2 -1.6296c1+4.9405, where T1 is the fluorination reaction temperature in the first stage reactor, and c1 is the fluorine concentration in mixed gas A with a value of 1% to 15%;

[0016] The fluorination reaction temperature and the fluorine concentration in the mixed gas B in the second stage reactor satisfy the formula: T2 = -0.004c2 2 -0.4412c2+44.79, where T2 is the fluorination reaction temperature in the second stage reactor, and c2 is the fluorine concentration in mixed gas B, ranging from 15% to 100%.

[0017] The molar ratio of the heterocyclic compound to the fluorine in gas mixture A is 1:0.5–35; the molar ratio of the product after the fluorination reaction in the first reactor to the fluorine in gas mixture B is 1:0.5–35.

[0018] The microchannel reactor consists of a first reactor section and a second reactor section.

[0019]

[0020] In formula II-1 or formula II-2, Y is selected from CH2, N-trifluoroacetyl or O atom, and R1 is one or more hydrogen atoms or methyl groups bonded to any one or more atoms on the ring;

[0021]

[0022] In Formula III-1 or Formula III-2, Z is selected from CF2, N-trifluoroacetyl or O atom, and R2 is one or more fluorine atoms or trifluoromethyl atoms bonded to any one or more atoms on the ring.

[0023] The fluorination reaction time of the first stage reactor in this invention is 15-90 s, and the fluorination reaction time of the second stage reactor is 15-90 s.

[0024] The inert gas described in this invention is selected from at least one of nitrogen, argon, and helium; preferably, the inert gas is nitrogen. The fluorine concentration described in this invention is the volume percentage of fluorine.

[0025] The fluorine concentration in gas mixture B of this invention is greater than the fluorine concentration in gas mixture A. This reduces the occurrence of side reactions and increases the reaction yield. The fluorine concentration c1 in gas mixture A is 1% to 15%; preferably 5% to 15%; the fluorine concentration c2 in gas mixture B is 15% to 100%; preferably 25% to 60%.

[0026] To better control the intensity of the reaction and reduce the occurrence of side reactions such as chain breakage, the fluorination reaction temperature T2 in the second stage reactor is greater than or equal to the fluorination reaction temperature T1 in the first stage reactor.

[0027] Furthermore, the fluorination reaction temperature T1 in the first stage reactor is -30 to 0°C; preferably, the fluorination reaction temperature T1 in the first stage reactor is -20 to 0°C.

[0028] Furthermore, the fluorination reaction temperature T2 in the second stage reactor is 0–50°C; preferably, the fluorination reaction temperature T2 in the second stage reactor is 0–30°C.

[0029] The fluorination reaction is carried out in a solvent-free environment or in a solvent. Preferably, the fluorination reaction is carried out in a solvent for better heat and mass transfer.

[0030] In one embodiment, the fluorination reaction is carried out in a solvent, in which the heterocyclic compound is dissolved, and the molar concentration is 0.1–6 mol / L; preferably, the molar concentration is 0.2–3 mol / L. The lower the content of the heterocyclic compound in the solution, the more uniform the dispersion and the higher the reaction selectivity; however, if the content of the heterocyclic compound in the solution is too low, it will result in a large amount of solvent separation / recovery required, making separation / recovery uneconomical.

[0031] The solvent is required to dissolve heterocyclic compounds or form a suspension with heterocyclic compounds without reacting with them. Preferably, the solvent is selected from at least one of haloalkanes, acids, and nitrogen-containing compounds; the haloalkane solvent is selected from at least one of 1,1,2-trifluoro-1,2,2-trichloroethane and perfluorohexane; the acid solvent is selected from at least one of formic acid, acetic acid, and trifluoroacetic acid; and the nitrogen-containing compound solvent is selected from at least one of acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0032] The total time for the fluorination reaction in this invention is 30–180 s, preferably 30–120 s.

[0033] In one specific embodiment, the heterocyclic fluoride shown in Formula III-1 or Formula III-2 is a fully fluorinated compound. The molar ratio of the heterocyclic compound shown in Formula II-1 or Formula II-2 to the fluorine gas in mixture A is 1:4 to 35, preferably 1:4.4 to 14. The molar ratio of the product after the fluorination reaction in the first reactor to the fluorine gas in mixture B is 1:4 to 35, preferably 1:4.4 to 14.

[0034] In one specific embodiment, the heterocyclic fluoride shown in Formula III-1 or Formula III-2 is a partially fluorinated compound. The molar ratio of the heterocyclic compound shown in Formula II-1 or Formula II-2 to the fluorine gas in the mixed gas A is 1:0.5 to 2, preferably 1:0.55 to 2. The molar ratio of the product after the fluorination reaction in the first reactor to the fluorine gas in the mixed gas B is 1:0.5 to 2, preferably 1:0.55 to 2.

[0035] This is because when the molar ratio of heterocyclic compound to fluorine gas is too low, the heterocyclic compound will be incompletely fluorinated, resulting in the formation of a large number of polyfluorinated substituted products and a low molar yield of perfluorinated heterocyclic compound; when the molar ratio of heterocyclic compound to fluorine gas is too high, it will cause partial chain scission and rearrangement reactions of the heterocyclic compound, producing more by-products and leading to a decrease in yield.

[0036] The fluorination reaction pressure described in this invention is 0.1–1.5 MPa; preferably, it is 0.3–1.0 MPa. If the reaction pressure is too high, it will increase operating costs and easily cause equipment damage; if the pressure is too low, the reaction efficiency between fluorine gas and the heterocyclic compound will be too low, and the designed material ratio may not even be achieved.

[0037] The microchannel reactor of the present invention has a channel shape that is cylindrical, heart-shaped, rhomboid, square, or spherical, and may or may not have a baffle structure inside. The cross-sectional size of the channel is 0.1 to 10 mm, preferably 0.1 to 3 mm.

[0038] Microchannel reactors can mix instantaneously and transfer heat efficiently. In order to balance reaction efficiency and product yield, the microchannel reactor of the present invention consists of a first reactor and a second reactor. The first reactor includes a first precooling unit, a first mixing unit and a first reaction unit; the second reactor includes a second mixing unit and a second reaction unit.

[0039] The first precooling unit includes one or more precooling modules.

[0040] The first mixing unit includes one or more mixing modules.

[0041] The first reaction unit includes one or more, or ten or fewer, reaction modules.

[0042] The second mixing unit includes one or more mixing modules.

[0043] The second stage reaction unit includes one or more, or six or fewer, reaction modules.

[0044] To better control the intensity of the reaction and reduce the occurrence of side reactions such as chain breakage, the temperature of the first precooling unit is ≤ the temperature of the first reaction unit, the temperature of the first mixing unit is the same as the temperature of the first reaction unit, and the temperature of the second mixing unit is the same as the temperature of the second reaction unit.

[0045] The heterocyclic compound of the present invention is subjected to a fluorination reaction to obtain a fluorinated heterocyclic compound, preferably a perfluorinated heterocyclic compound.

[0046] Secondly, the present invention provides a method for preparing perfluoroenylmorpholine, the method comprising the following steps:

[0047] S1: The compound shown in Formula I-1 or Formula I-2 reacts with trifluoroacetic anhydride to give the compound shown in Formula II-1 or Formula II-2;

[0048]

[0049] In Formula I-1 or Formula I-2, X is selected from CH2, NH or O atoms, and R1 is one or more hydrogen atoms or methyl groups bonded to any one or more atoms on the ring;

[0050]

[0051] In formula II-1 or formula II-2, Y is selected from CH2, N-trifluoroacetyl or O atom, and R1 is one or more hydrogen atoms or methyl groups bonded to any one or more atoms on the ring.

[0052] S2: Using the method for preparing heterocyclic fluorides described in the first aspect of the present invention, the compound shown in Formula II-1 or the compound shown in Formula II-2 is subjected to a fluorination reaction to obtain the compound shown in Formula III-1 or the compound shown in Formula III-2.

[0053]

[0054] In Formula III-1 or Formula III-2, Z is selected from CF2, N-trifluoroacetyl or O atom, and R2 is one or more fluorine atoms or trifluoromethyl atoms bonded to any one or more atoms on the ring.

[0055] S3: The compound shown in Formula III-1 or the compound shown in Formula III-2 is de-trifluoroacetyl group under alkaline conditions to obtain an amine compound;

[0056] S4: The amine compound reacts with a basic compound to generate a nitrogen anion intermediate, which then reacts with a perfluoroolefin compound to obtain a heterocyclic fluoride selected from the compounds shown in Formula IV-1 or Formula IV-2.

[0057]

[0058] In Formula IV-1 or Formula IV-2, W is selected from CF2, N-perfluorinated straight-chain or branched alkenyl groups or O atoms, R2 is one or more fluorine atoms attached to any one or more atoms on the ring, trifluoromethyl groups, and R3 is a perfluorinated straight-chain or branched alkenyl group.

[0059] Further, in step S1, the compound shown in Formula I-1 or the compound shown in Formula I-2 reacts with trifluoroacetic anhydride to introduce a trifluoroacetyl group by replacing the active hydrogen atom on the NH group, thus preventing it from being fluorinated by fluorine gas in subsequent reactions. Preferably, step S1 is carried out in a solvent selected from at least one of dichloromethane, dichloroethane, and ethylene glycol dimethyl ether.

[0060] In step S3, the alkaline conditions are provided by at least one of sodium hydroxide and potassium hydroxide.

[0061] Step S4 is carried out in a solvent selected from at least one of dichloromethane, dichloroethane, and ethylene glycol dimethyl ether. The perfluoroolefin is selected from at least one of perfluoro-2-methyl-2-pentene and perfluoro-4-methyl-2-pentene; the basic compound is selected from at least one of sodium bicarbonate and sodium carbonate.

[0062] The compounds shown in Formula I-1 and Formula I-2 of this invention can be selected from the following compounds:

[0063]

[0064] The compound represented by Formula II-1 or Formula II-2 of this invention may be selected from the following compounds:

[0065]

[0066] The compound shown in Formula III-1 or Formula III-2 of this invention may be selected from the following compounds:

[0067]

[0068] The amine compounds described in this invention may be selected from the following compounds:

[0069]

[0070] The compounds represented by Formula IV-1 or Formula IV-2 of this invention may be selected from the following compounds:

[0071]

[0072] As one embodiment, the present invention provides a method for preparing perfluoroenylmorpholine, the preparation method comprising the following steps:

[0073] S1: Morpholine reacts with trifluoroacetic anhydride in a solvent to give 2,2,2-trifluoro-1-morpholinoethyl-1-one;

[0074] S2: Fluoride 2,2,2-trifluoro-1-morpholinoethyl-1-one using the method for preparing heterocyclic fluorides described in the first aspect of the present invention to obtain 2,2,2-trifluoro-1-(perfluoromorpholino)ethyl-1-one;

[0075] S3: 2,2,2-trifluoro-1-(perfluoromorpholino)acet-1-one is detrifluoroacetylated under alkaline conditions to give 2,2,3,3,5,5,6,6-octafluoromorpholine;

[0076] S4: 2,2,3,3,5,5,6,6-octafluoromorpholine reacts with a basic compound to generate a nitrogen anion intermediate, which then reacts with perfluoro-2-methyl-2-pentene to give 2,2,3,3,5,5,6,6-octafluoro-4-(1,1,1,4,4,5,5,5-octafluoro-2-(trifluoromethyl)pent-2-en-3-yl)morpholine.

[0077] Furthermore, in step S4, the basic compound is selected from at least one of sodium bicarbonate and sodium carbonate.

[0078] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0079] 1. The method for preparing heterocyclic compounds described in this invention uses highly active fluorine gas, requires no catalyst, has a short reaction time, and is highly efficient.

[0080] 2. The method for preparing heterocyclic compounds according to the present invention uses a microchannel reactor, which consists of a first-stage reactor and a second-stage reactor. The fluorination reaction temperature and fluorine concentration are specifically limited to reduce side reactions and improve the selectivity of the reaction. The fluorination yield can reach more than 96%.

[0081] 3. The method for preparing heterocyclic compounds described in this invention employs a continuous flow process, which involves fewer reaction steps, simpler conditions, and is easy to operate. The reaction time is significantly shortened, and automated production can be easily achieved.

[0082] 4. This invention uses fluorine gas as a fluorinating reagent in small amounts or in excess, and reacts quantitatively with compound II, which is protected active hydrogen. It produces few byproducts and generates virtually no waste. It is an economical, efficient, and green chemical synthesis process with prospects for industrial production. Attached Figure Description

[0083] Appendix Figure 1 This is a schematic diagram of the fluorination reaction process in Embodiment 1 of the present invention, wherein 1 is the first stage reactor, 11 is the first stage precooling unit, 12 is the first stage mixing unit, 13 is the first stage reaction unit, 2 is the second stage reactor, 21 is the second stage mixing unit, 22 is the second stage reaction unit, 31 is a mixed solution of trifluoroacetylmorpholine and perfluorohexane, 32 is a fluorine-nitrogen mixed gas with a fluorine content of 10%, 33 is a fluorine-nitrogen mixed gas with a fluorine content of 25%, and 34 is the fluorination reaction product. Detailed Implementation

[0084] The present invention will be further described below with reference to specific embodiments, but the invention is not limited to these specific embodiments. Those skilled in the art should recognize that the present invention covers all alternatives, improvements, and equivalents that may be included within the scope of the claims.

[0085] Example 1

[0086] S1. Protection: Install a three-necked flask equipped with a reflux condenser and a thermometer. Add morpholine (26.1 g, 0.3 mol), 150 mL of dichloromethane, and sodium bicarbonate (75.6 g, 0.9 mol) to the flask. Add trifluoroacetic anhydride (75.6 g, 0.36 mol) dropwise at 0 °C. After the addition is complete, slowly raise the temperature to 30 °C and react for 3 h. Then add 100 mL of saturated sodium bicarbonate aqueous solution and wash with water. Extract with dichloromethane (30 mL * 3 times). Dry with anhydrous magnesium sulfate. Vacuum rotary evaporation yields an oily product, which is identified by GC-MS as trifluoroacetylmorpholine (53.1 g, 0.29 mol).

[0087]

[0088] S2. Fluorination: The product synthesized in S1, trifluoroacetylmorpholine (55g, 0.3mol), was added to a dry polytetrafluoroethylene container, and 300mL of dry perfluorohexane liquid was added. The mixture was stirred until homogeneous to prepare a mixed solution of trifluoroacetylmorpholine and perfluorohexane with a trifluoroacetylmorpholine content of 1mol / L.

[0089] The mixed solution of trifluoroacetylmorpholine and perfluorohexane was pre-cooled to a pre-cooling temperature T0 of -15℃.

[0090] A pre-cooled mixed solution of trifluoroacetylmorpholine and perfluorohexane was pumped into the microchannel reactor. A gas-liquid phase microreactor was used, and there were 13 sets of microchannel reactors. advanced-Flow TMThe microchannel reactor is formed by combining G1 silicon carbide "heart-shaped" channel-shaped modular chips. The first stage reactor consists of 1 precooling module, 1 mixing module, and 5 reaction modules. The second stage reactor consists of 1 mixing module and 5 reaction modules. Each module holds 9 mL of liquid, the total liquid holding capacity of the precooling module is 9 mL, and the total liquid holding capacity of the reaction modules is 90 mL. First, a mixed solution of trifluoroacetylmorpholine and perfluorohexane enters the precooling unit of the first stage reactor of the microchannel reactor, and then enters the mixing unit. Simultaneously, a fluorine-nitrogen mixture with a fluorine content of 10% is introduced into the mixing unit. In the mixing unit, the trifluoroacetylmorpholine and perfluorohexane mixture and the fluorine-nitrogen mixture with a fluorine content of 10% are mixed before entering the reaction unit of the first stage reactor. The gas and liquid phases undergo a fluorination reaction in the reaction unit of the first stage reactor. The material after the fluorination reaction in the first stage reactor enters the second stage reactor, first entering the mixing unit of the second stage reactor, and simultaneously, a fluorine-nitrogen mixture with a fluorine content of 25% is introduced into the mixing unit of the second stage reactor. After mixing, it enters the reaction unit of the second stage reactor. The molar ratio of trifluoroacetylmorpholine to fluorine is 1:4.8. The temperature of the mixing and reaction units in the first stage reactor is -15℃, and the temperature of the mixing and reaction units in the second stage reactor is 0℃. The reaction pressure is 0.6 MPa, and the total reaction time for the fluorination reaction is 60 s.

[0091] The reaction liquid material was collected, and gaseous nitrogen and other gases were removed. The mixture was then rotary evaporated, and the content of each component was determined by GC-MS. 96.8 g (0.296 mol) of the target product, perfluoro-N-trifluoroacetylmorpholine, was obtained. The molar yield of the target product, perfluorotrifluoroacetylmorpholine, was 98.7% (based on trifluoroacetylmorpholine) or 82.2% (based on fluorine gas).

[0092]

[0093] S3. Deprotection: Perfluoro-N-trifluoroacetylmorpholine (65.4 g, 0.2 mol) was added to a mixed solution of 180 mL methanol and 20 mL water, followed by the addition of potassium carbonate (27.6 g, 0.2 mol). The reaction was carried out at 30 °C for 2 h. After the reaction was completed, the system was concentrated by vacuum rotary evaporation. The product was washed with 50 mL water, then extracted with dichloromethane (30 mL * 3 times), dried over anhydrous magnesium sulfate, and concentrated by vacuum rotary evaporation to obtain the target product.

[0094]

[0095] S4. Introduction of functional groups: Install a three-necked flask equipped with a reflux condenser and a thermometer, add the perfluoroamine compound (23.1 g, 0.1 mol) obtained in step S3, 20 mL of solvent and sodium bicarbonate (10.1 g, 0.12 mol) into the flask, add perfluoro-2-methyl-2-pentene dropwise at room temperature, react for 6 h, wash with 100 mL of water, separate the liquid and distill the lower layer to obtain the target compound perfluoroalkenylmorpholine.

[0096]

[0097] Examples 2 to 4

[0098] The operation steps of Examples 2 to 4 are the same as those of Example 1, except that the molar ratio of trifluoroacetylmorpholine to fluorine gas is changed in step S2, while other operations remain unchanged.

[0099] The yields of the target product, perfluoro-N-trifluoroacetylmorpholine, are shown in Table 1.

[0100] Table 1 Data from Examples 2 to 4

[0101]

[0102] Examples 1-4 show that the molar ratio of trifluoroacetylmorpholine to fluorine has a significant impact on the preparation method. A molar ratio of 1:4.4 to 8 allows for the preparation of perfluoro-N-trifluoroacetylmorpholine in relatively high yields. When the molar ratio is below 1:4, the molar yield of the target product, perfluoro-N-trifluoroacetylmorpholine, is low because the substrate, trifluoroacetylmorpholine, is not completely fluorinated. As the molar ratio increases, the substrate undergoes partial chain scission and rearrangement reactions, generating more byproducts, leading to a decrease in yield. However, while the molar ratio increases, the reaction time shortens, and the timely removal of the substrate and fluorine from the reactor terminates the reaction, resulting in fewer byproducts than theoretically possible. Therefore, the yield does not decrease rapidly, but excessive fluorine will increase costs.

[0103] Examples 5 to 8

[0104] The operation steps of Examples 5 to 8 are the same as those of Example 1, except that the solvent in step S2 is changed, while other operations remain the same.

[0105] The molar yields of the target product perfluoro-N-trifluoroacetylmorpholine in Examples 5 to 8 are shown in Table 2 below.

[0106] Table 2 Data from Examples 5 to 8

[0107]

[0108] As shown in Table 2, the target product can be obtained in high yield by using halogenated alkanes, acids, and nitrogen-containing compounds as solvents.

[0109] Examples 9 to 14

[0110] The operation steps of Examples 9 to 14 are the same as those of Example 1, except that the fluorination reaction temperature in step S2 is changed, while other operations remain unchanged.

[0111] The molar yields of the target product, perfluoro-N-trifluoroacetylmorpholine, are shown in Table 3.

[0112] Table 3 Data from Examples 9 to 14

[0113]

[0114] Examples 15 to 20

[0115] The operation steps of Examples 15 to 20 are the same as those of Example 1, except that the concentration of fluorine gas c1 (fluorine-nitrogen mixture) in the first reactor and the concentration of fluorine gas c2 (fluorine-nitrogen mixture) in the second reactor are changed in step S2. Other operations remain unchanged.

[0116] The molar yields of the target product, perfluoro-N-trifluoroacetylmorpholine, are shown in Table 4.

[0117] Table 4 Data from Examples 15 to 20

[0118]

[0119] Comparative Examples 1 to 4

[0120] The operating steps of Comparative Examples 1 to 4 are the same as those of Example 1, except that the fluorination reaction temperature in step S2 is changed, while other operations remain unchanged.

[0121] The molar yields of the target product, perfluoro-N-trifluoroacetylmorpholine, are shown in Table 5.

[0122] Table 5 Data from Comparative Examples 1 to 4

[0123]

[0124] Examples 9-14 and Comparative Examples 1-4 show that reaction temperature significantly affects product yield. A reaction temperature within the range of -20 to 30°C allows for high-yield preparation of the target product. In Comparative Example 1, the reaction temperature was too low, resulting in a slow reaction and low yield. In Comparative Example 4, the reaction temperature was too high, leading to vigorous reaction, increased byproducts, decreased selectivity, and a lower yield of the target product. The fluorination reaction temperature in the second reactor is higher than that in the first reactor, which is particularly beneficial for the fluorination reaction and can achieve a higher yield.

[0125] Comparative Examples 5 to 7

[0126] The operating steps of Comparative Examples 5 to 7 are the same as those of Example 1, except that the concentration of fluorine gas c1 (fluorine-nitrogen mixture) in the first reactor and the concentration of fluorine gas c2 (fluorine-nitrogen mixture) in the second reactor are changed in step S2. All other operations remain unchanged.

[0127] The molar yields of the target product, perfluoro-N-trifluoroacetylmorpholine, are shown in Table 6.

[0128] Table 6 Data from Comparative Examples 5 to 7

[0129]

[0130] Examples 15-20 and Comparative Examples 5-7 show that the fluorine content in the fluorine-nitrogen mixture significantly affects the product yield. A relatively high yield can be obtained when the fluorine concentration (c1) in the first reactor is 5%-15%, and the fluorine concentration (c2) in the second reactor is 25%-60%. A fluorine concentration (c1) less than or equal to the fluorine concentration (c2) in the second reactor is particularly favorable for the reaction, resulting in a higher yield. In Comparative Example 5, the fluorine content was too low, leading to poor mass transfer between the fluorine and the substrate, resulting in a low yield. In Comparative Example 7, the fluorine concentration (c1) in the first reactor was too high, and c1 was higher than c2, leading to a vigorous reaction, increased byproducts, decreased selectivity, and a lower yield of the target product.

[0131] Comparative Example 8

[0132] 10 mmol (3.67 g) of the N-perfluoroalkenylmorpholine compound of Formula 1 was added to a dry polytetrafluoroethylene reactor, followed by 10 mL of perfluorohexane, and stirred until homogeneous. The reactor was connected, purged with nitrogen for 30 min (flow rate 50 mL / min), and the reactor temperature was maintained at -15 °C. A fluorine-nitrogen mixture with a fluorine volume content of 10% was continuously introduced for 9 h (flow rate 10 mL / min, 24 mmol of fluorine gas). Then, the reactor temperature was maintained at 0 °C, and a fluorine-nitrogen mixture with a fluorine volume content of 25% was continuously introduced for 3.6 h (flow rate 10 mL / min, 24 mmol of fluorine gas), for a total of 48 mmol of fluorine gas. The reaction pressure was maintained at 0.6 MPa. Subsequently, the reactor was purged with nitrogen for 30 min, and the mixture was slowly restored to room temperature. The reactor was disassembled, the product was removed, and the product was rotary evaporated. The product content was analyzed by gas chromatography, and the content of each component was determined by GC-MS. The results showed that the main product was a perfluoroalkylmorpholine compound of Formula 2. The reason for this analysis is that the unsaturated carbon-carbon double bond on the perfluoroalkenyl group of the substrate undergoes a direct fluorination reaction with fluorine gas, resulting in the addition of fluorine atoms to the C=C bond to form perfluoroalkyl compounds. This does not yield perfluoro heterocyclic compounds containing straight-chain or branched perfluoroalkenyl groups.

[0133]

[0134] Comparative Example 9

[0135] The operating steps of Comparative Example 9 were the same as those of Example 1, except that the fluorination reaction process in step S2 was changed, while other operations remained unchanged. Referring to the heterocyclic compound fluorination process reported in the literature "Journal of Fluorine Chemistry, 1990(50):15-30", a four-temperature zone cryogenic reactor and six different concentrations of fluorine-nitrogen mixed gas were used, combined to form 10 gradient reaction conditions, with a total reaction time of 5.5 days. The reaction conditions are shown in Table 7. The molar yield of the target product, perfluorotrifluoroacetylmorpholine, was 56% (based on trifluoroacetylmorpholine) or 12% (based on fluorine gas).

[0136] Table 7 Comparative Example 9 Step S2 Fluorination Reaction Conditions

[0137]

Claims

1. A process for the preparation of heterocyclic fluorides, characterized by: The heterocyclic compound shown in Formula II-1 or Formula II-2, along with a mixture A of fluorine and inert gas, is introduced into the first stage reactor of the microchannel reactor for fluorination. Then, the product from the fluorination reaction in the first stage reactor, the unreacted raw material, and a mixture B of fluorine and inert gas are introduced into the second stage reactor of the microchannel reactor for further fluorination to prepare the heterocyclic fluoride shown in Formula III-1 or Formula III-2. The fluorination reaction temperature in the first reactor and the fluorine concentration in the mixed gas A satisfy the formula: T1 = -0.0271c1 2 -1.6296c1+4.9405, wherein T1 is the fluorination reaction temperature in the first reactor, and c1 is the fluorine concentration in the mixed gas A and has a value of 1% to 15%. The temperature of fluorination reaction in the second reactor and the concentration of fluorine in the mixed gas B satisfy the formula: T2 = -0.004c2 2 -0.4412c2+44.79, wherein T2 is the temperature of fluorination reaction in the second reactor, c2 is the concentration of fluorine in the mixed gas B and the value is 15% to 100%. The molar ratio of the heterocyclic compound to the fluorine in gas mixture A is 1:0.5–35; the molar ratio of the product after the fluorination reaction in the first reactor to the fluorine in gas mixture B is 1:0.5–35. The microchannel reactor consists of a first reactor section and a second reactor section. In formula II-1 or formula II-2, Y is selected from CH2, N-trifluoroacetyl or O atom, and R1 is one or more hydrogen atoms or methyl groups bonded to any one or more atoms on the ring; In Formula III-1 or Formula III-2, Z is selected from CF2, N-trifluoroacetyl or O atom, and R2 is one or more fluorine atoms or trifluoromethyl atoms bonded to any one or more atoms on the ring.

2. The process for the preparation of heterocyclic fluorides according to claim 1, characterized in that: The fluorination reaction time in the first stage reactor is 15–90 s, and the fluorination reaction time in the second stage reactor is 15–90 s.

3. The process for the preparation of heterocyclic fluorides according to claim 1, characterized in that: The fluorine concentration in the mixed gas A is 5% to 15%; the fluorine concentration in the mixed gas B is 25% to 60%, and the inert gas is nitrogen.

4. The process for the preparation of heterocyclic fluorides according to claim 1, characterized in that: The fluorination reaction temperature T2 in the second stage reactor is greater than or equal to the fluorination reaction temperature T1 in the first stage reactor.

5. The process for the preparation of heterocyclic fluorides according to claim 4, characterized in that: The fluorination reaction temperature T1 in the first stage reactor is -20 to 0℃, and the fluorination reaction temperature T2 in the second stage reactor is 0 to 30℃.

6. The process for the preparation of heterocyclic fluorides according to claim 1, characterized in that: The heterocyclic compound is dissolved in a solvent and has a molar concentration of 0.1–6 mol / L.

7. The process for the preparation of heterocyclic fluorides according to claim 1, characterized in that: The pressure of the fluorination reaction is 0.1 to 1.5 MPa.

8. The process for the preparation of heterocyclic fluorides according to claim 1, characterized in that: The heterocyclic compound is fluorinated to obtain a perfluorinated heterocyclic compound, wherein the molar ratio of the heterocyclic compound shown in Formula II-1 or Formula II-2 to the fluorine in the mixed gas A is 1:4.4 to 14; the molar ratio of the product after fluorination in the first reactor to the fluorine in the mixed gas B is 1:4.4 to 14.

9. The process for the preparation of heterocyclic fluorides according to claim 1, characterized in that: The microchannel reactor has a channel cross-sectional dimension of 0.1 to 10 mm. The first stage reactor includes a first precooling unit, a first mixing unit, and a first reaction unit. The second stage reactor includes a second mixing unit and a second reaction unit.

10. A process for the preparation of a perfluoroalkenyl morpholine, characterized by: The preparation method includes the following steps: S1: Morpholine reacts with trifluoroacetic anhydride in a solvent to give 2,2,2-trifluoro-1-morpholinoethyl-1-one; S2: Fluoride 2,2,2-trifluoro-1-morpholinoethyl-1-one using the method for preparing heterocyclic fluorides according to any one of claims 1-8 to obtain 2,2,2-trifluoro-1-(perfluoromorpholino)ethyl-1-one; S3: 2,2,2-trifluoro-1-(perfluoromorpholino)acet-1-one is detrifluoroacetylated under alkaline conditions to give 2,2,3,3,5,5,6,6-octafluoromorpholine; S4: 2,2,3,3,5,5,6,6-octafluoromorpholine reacts with a basic compound to generate a nitrogen anion intermediate, which then reacts with perfluoro-2-methyl-2-pentene to give 2,2,3,3,5,5,6,6-octafluoro-4-(1,1,1,4,4,5,5,5-octafluoro-2-(trifluoromethyl)pent-2-en-3-yl)morpholine.

Images