Process for Preparing Fluoro-1,3-Propanesultone

Method for preparing 3-fluoro-1,3-propanesultone {Process for Preparing Fluoro-1,3-Propanesultone}

<backgroundart><p> The present invention relates to a method for producing 3-fluoro-1,3-propanesultone, and more particularly, to a step of chlorinating 1,3-propanesultone; By carrying out a two-step reaction of substituting a fluorine group and performing the reaction under specific conditions in each step, difficult to handle fluorine gas is not used, and a high-yield, high-purity 3-fluoro- with high selectivity through a simple process It relates to a method for obtaining 1,3-propanesultone.</p><p> 3-Fluoro-1,3-propanesultone is a known compound used as an intermediate for pharmaceuticals, an organic solvent, a solvent or additive for an electrolyte solution of a lithium ion secondary battery, and the like. Japanese Patent Application Laid-Open No. 2004-47131 (Saito Midori et al.) reports the use of the above compounds and similar compounds as organic solvents or electrolyte additives for lithium ion secondary batteries, but the production of fluorinated 1,3-propanesultone There was no mention of how.</p><p> On the other hand, although a number of methods are known as a general method for fluorination of organic compounds, there has been no literature disclosed regarding the synthesis of derivatives of fluoro-1,3-propanesultone to date. In addition, the preparation method for the chlorinated 1,3-propanesultone used as a reaction intermediate in the present invention has also not been reported.</p><p> Therefore, there is a need for research on a synthesis method capable of obtaining 3-fluoro-1,3-propanesultone in high yield through a relatively simple process.</p></backgroundart><abstractproblem><p> Accordingly, it is an object of the present invention to provide a new method for preparing 3-fluoro-1,3-propanesultone whose production method is unknown as described above, and to provide a production method showing a practically usable yield and purification efficiency. will do</p><p> After continuing in-depth research and various experiments, the inventors of the present application proceed with the reaction in two stages, chlorination reaction and fluorine substitution reaction, using 1,3-propanesultone as a starting material, and apply appropriate reagents and reaction conditions to each. It was found that 3-fluoro-1,3-propanesultone having selectivity to a specific position can be prepared in high yield, and the present invention was completed by presenting purification conditions for obtaining high purity suitable for use. did it</p></abstractproblem>

<p> Therefore, the method for preparing 3-fluoro-1,3-propanesultone of Formula 1 according to the present invention includes a chlorination reaction for 1,3-propanesultone and a chlorine-substituted 1,3-propane obtained through the reaction. It consists of including a process of performing a fluorine substitution reaction on sultone.</p><p><img file="KR100908570B1_D0001.tif" /> (1)</p><p> The present invention provides a very effective method for synthesizing 3-fluoro-1,3-propanesultone because the reaction proceeds under mild conditions without directly using fluorine gas, and optionally mono-substituted conditions are formed.</p><p> Hereinafter, the present invention will be described in more detail for each reaction step as follows.</p><p> The chlorination reaction is a step of obtaining chloro-1,3-propanesultone as an intermediate for obtaining fluorinated 1,3-propanesultone, which is the final product desired by the present invention, and in the presence of a radical initiator, 1,3- as a starting material. It is achieved through the reaction of propanesultone with a chlorinating reagent.</p><p> Here, as the chlorination reagent, for example, chlorine gas, sulfuryl chloride (SO<sb>2</sb>Cl<sb>2</sb>) or thionyl chloride may be used, and among them, SO<sb>2</sb>Cl<sb>2</sb>can be used</p><p> As the radical initiator, for example, 2,2'-azoisobutyronitrile (AIBN), benzoyl peroxide, etc. may be used, and among them, AIBN may be preferably used.</p><p> The reaction temperature of the chlorination reaction may be applied in the range of 40 ° C to 150 ° C. If the reaction temperature is too low, a lot of time is required for the chlorination reaction or the yield may be very low. It is undesirable because there is a problem of rapidly increasing. More preferably, the decomposition temperature of the radical initiator or higher for a stable reaction, for example, when using AIBN as a radical initiator, the reaction temperature may be adjusted to 70° C. or higher.</p><p> In this chlorination reaction, for example, since 1,3-propanesultone is liquid at the set reaction temperature of 80° C., AIBN (0.3 mol%) and SO as an initiator while stirring without a separate solvent<sb>2</sb>Cl<sb>2</sb>You can proceed by dropwise addition. At this time, SO<sb>2</sb>Cl<sb>2</sb>In order to minimize the non-reactive decomposition of , it is advantageous to increase the yield as the dropping rate is slowed, but in order to keep the radical reaction continuously proceeding, a dropping rate of about 1 volume%/min is preferable.</p><p> The completion of the reaction is based on the degree of disappearance of 1,3-propanesultone, a starting material, which can be checked by gas chromatography (GC). In the case of 3 hours of dropwise addition and stirring at 80°C, conversion proceeds at a conversion rate of 70% to 90% on GC.</p><p> According to the present inventors experimentally confirmed, <sp>1</sp>Through H-NMR and GC analysis, chloro-1,3-propanesultone is produced in a molar ratio of 2:5 for positions 2 and 3 of 1.3-propanesultone. Since the generated 2-position chlorine substituent tends to have extremely low reactivity with respect to the nucleophilic substitution reaction by the fluorine ion, it does not react in the next step, the fluorine substitution reaction, and remains there.</p><p> A mixture of two regioisomers produced by the chlorination reaction, ie, 2-chloro-1,3-propanesultone and 3-chloro-1,3-propanesultone, was reduced to HCl and SO dissolved in the reaction mixture.<sb>2</sb> After most of the gases are removed, a fluorine substitution reaction is performed without a separate separation process.</p><p> In the fluorine substitution reaction, chloro-1,3-propanesultone produced from the chlorination reaction is reacted with a fluorination reagent to produce 3-fluoro-1,3-propanesultone.</p><p> As the fluorination reagent, for example, ammonium bifluoride (NH<sb>4</sb>HF<sb>2</sb>), NR including alkyl ammonium bifluoride, etc.<sb>4</sb>F (HF)<sb>n </sb>(R = aliphatic hydrocarbon or H, n = 1 to 5) and the like, among others, ammonium bifluoride (NH<sb>4</sb>HF<sb>2</sb>) and alkyl ammonium bifluoride are more preferred.</p><p> The present inventors have known KF, NaF, CaF as common fluorination reagents<sb>2</sb> The reactivity was investigated by applying an alkali metal fluorine salt such as an alkali metal fluoride to the fluorine substitution reaction, but the reactivity did not appear in the reaction conditions below 120 ° C. Problems occurring were confirmed. Accordingly, the fluorination reagent in the present invention excludes metal alkylated fluorine salts.</p><p> On the other hand, NH<sb>4</sb>HF<sb>2</sb>As a result of investigating the fluorination reactivity, it was confirmed that fluorine substitution was completed for 3-chloro-1,3-propanesultone at 90° C. and reaction conditions for 3 hours. As mentioned above, in the case of 2-chloro-1,3-propanesultone, the fluorine substitution reaction does not proceed and remains in the reaction mixture.</p><p> In addition, hydrogen difluoride alkylammonium salt (NR<sb>4</sb>HF<sb>2</sb> R=methyl, ethyl, butyl, hexyl, nonyl, octyl, dodecyl) is also NH<sb>4</sb>HF<sb>2</sb>It was confirmed that the same or higher reactivity was compared with .</p><p> The fluorine substitution reaction may be preferably carried out in a solvent such as a carbonate compound, tetrahydrofuran, or acetonitrile, and among them, a carbonate compound is more preferable. The carbonate compound is largely classified into a linear carbonate and a cyclic carbonate, and among them, a linear carbonate such as dimethyl carbonate is more preferable. The dimethyl carbonate has excellent solubility in chloropropanesultone and serves to increase the reactivity of the ammonium bifluoride salt with high polarity. Therefore, it can be said that it is a suitable solvent instead of water or alcohol-based solvents, which have a problem of causing hydrolysis of sultone.</p><p> The product obtained as a result of the fluorine substitution reaction can be recrystallized from ethyl acetate to obtain 3-fluoro-1,3-propanesultone with high purity.</p><p> The fluorine substitution reaction may be carried out at a temperature range of 70° C. to 100° C. for 30 minutes to 6 hours. If the reaction temperature is too low or the reaction time is too short, the substitution reaction may take a lot of time or the yield may be very low. Conversely, if the reaction temperature is too high or the reaction time is too long, the reaction byproducts increase It is not preferable to have</p><p> After the fluorine substitution reaction, insoluble components are removed by filtration and the solvent is removed under reduced pressure. The reaction mixture still contains unreacted propanesultone and 2-chloro-1,3-propanesultone as impurities. </p><p> The present inventors tried various purification methods to obtain high-purity 3-fluoro-1,3-propanesultone from this reaction mixture. First, the most typical purification by distillation requires a high temperature of 90° C. or higher under reduced pressure, but there is a problem in that decomposition and denaturation of 3-fluoro-1,3-propanesultone are observed above this temperature. In addition, in purification by chromatography using silica gel or alumina as a stationary phase, a significant portion is mixed with unreacted 2-chloro-1,3-propanesultone, resulting in low separation yield.</p><p> On the other hand, it was confirmed that the recrystallization method using ethyl acetate as a solvent is very effective. Specifically, when the solvent-removed reaction mixture is completely dissolved in ethyl acetate and crystals are formed at a temperature of 0 to 18° C., a purity of 99.5% or more can be obtained. 3-fluoro-1,3-propanesultone separated by this recrystallization method is usually obtained in a yield of 30-50% compared to 1,3-propanesultone, which is a starting material.</p><p> Although 3-fluoro-1,3-propanesultone to be obtained in the present invention could be obtained by direct fluorination through the reaction of fluorine gas and 1,3-propanesultone, as shown in Comparative Example 1 to be described later, , the results showing low yield and selectivity were obtained. That is, it was observed that 2- or 3-fluoro-1,3-propanesultone was obtained in GC yields of 3% and 11%, respectively, when reacted at 50° C. by passing an equivalent amount of fluorine gas through the reactant. . Also, in this case, the starting material of 1,3-propanesultone is partially decomposed during the reaction to produce an unidentified compound. This side reaction seems to occur as fluoro-1,3-propanesultone is produced and they undergo an additional side reaction with fluorine gas. That is, 5 to 13% of fluoro-1,3-propanesultone is produced in the initial stage of the reaction, but the relative ratio decreases as the reaction proceeds. When the reaction temperature was raised to 80 °C or the equivalent of fluorine gas injected into the reactant was increased to 3 equivalents, the desired fluoro-1,3-propanesultone was rather reduced in production, and unidentified by-products only an increase was observed. Although the above method of using fluorine gas produces a small amount of the target compound, it is difficult to control the reactivity to the target compound, which shows a problem as a practical synthesis method.</p><p> The content of the present invention will be described in detail below with reference to Examples, but the scope of the present invention is not limited thereto.</p><p> The content of each component was expressed as area% of the peak on the detector (FID) of a gas chromatograph (Agilient Technologies, 6890N, column: J&amp;W Scientific HP-5).</p><p><u>Example</u><u> 1: 3-</u><u>fluoro</u><u>-1,3-</u><u>of propanesultone</u><u> Produce</u></p><p> 250 g of 1,3-propanesultone was placed in a 1000 ml reactor equipped with a stirrer and a condenser, and was charged with nitrogen at 80° C. for about 30 minutes. SO into a dropping funnel fitted to the reactor head.<sb>2</sb>Cl<sb>2</sb> 213 mL was added thereto, and it was added dropwise while stirring for 2 hours. 1 g of 2,2'-azoisobutyronitrile (AIBN) was dissolved in 20 ml of dichloromethane, the first 4 ml was added, and then added dropwise over 5 times at 30 minute intervals. HCl gas generated in the reaction was neutralized in a base trap containing saturated aqueous NaOH solution connected to a condenser. After the dropwise addition was completed, the reaction temperature was set to 80° C. and stirred for 1 hour. After the dropwise addition was completed, the reactants showed no further change in the ratio of gas chromatography. After completion of the reaction, stirring was maintained for 1 hour after the dropwise addition, and then the temperature of the reactor was lowered to stop the reaction.</p><p> Next, 200 g of chloro-1,3-propanesultone produced in the previous step and NH as a fluorination reagent in a 1000 ml reactor equipped with a stirrer and a condenser for the fluorine substitution step<sb>4</sb>HF<sb>2 </sb>After pulverizing 1.5eq, 350 ml of dimethyl carbonate (DMC) was added as a reaction solvent, and then reacted at 90° C. for 5 hours while stirring using a stirrer. In the reaction, only 3-chloro-1,3-propanesultone was subjected to a fluorine substitution reaction and 100% conversion was performed to produce 3-fluoro-1,3-propanesultone.</p><p> The resulting mixture of 3-fluoro-1,3-propanesultone and the remaining reactant was filtered to remove salt, and DMC used as a reaction solvent was removed using a rotary evaporator. The reaction mixture was recrystallized from ethyl acetate to obtain 129 g of 3-fluoro-1,3-propanesultone as a white solid with a purity of 99.9%.</p><p> 3-fluoro-1,3-propanesultone and intermediate chloro-1,3-propanesultone were confirmed by NMR and mass spectroscopy.</p><p><u>3-Fluoro-1,3-propanesultone</u></p><p><sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 6.20 (dd, <i>J </i>= 58.4Hz, 3.6Hz, 1H), 3.44 - 3.40 (m, 2H), 2.94 - 2.76 (m, 2H)</p><p><sp>13</sp>C NMR (100 MHz, CDCl<sb>3</sb>) δ 109.0, 42.2, 31.2</p><p>MS (EI, 70 eV) m/z<i></i>140, 121, 108, 92, 84, 76, 65, 59, 48, 39, 28</p><p><u>3-Chloro-1,3-propanesultone</u></p><p><sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 6.46 (dd, <i>J </i>= 5.2Hz, 1H), 3.55 - 3.49 (m, 2H), 3.20 - 3.16 (m, 1H), 2.90 - 2.86 (m, 1H)</p><p><u>2-Chloro-1,3-propanesultone</u></p><p><sp>1</sp>H NMR (400 MHz, CDCl<sb>3</sb>) δ 4.91 (m, 1H), 4.78 - 4.74 (dd, 1H), 4.52 - 4.48 (dd, 1H), 3.82 - 3.80 (dd, 1H), 3.59 - 3.57 (m, 1H)</p><p><u>comparative example</u><u> 1: </u><u>Fluorine gas (F</u><u><sb>2</sb></u><u>)cast</u><u> used 3-</u><u>fluoro</u><u>-1,3-</u><u>of propanesultone</u><u> Produce</u></p><p> 250 g of 1,3-propanesultone was placed in a 1000 ml reactor equipped with a stirrer, and charged with nitrogen at 50° C. for about 30 minutes. Fluorine gas was passed through the reactants at a constant flow rate through a tube installed in the reactor head (1 g/min, total 80 g). After injecting fluorine gas over about 80 minutes, the mixture was further stirred for 1 hour. HF gas generated in the reaction was neutralized in a base trap containing saturated aqueous NaOH solution connected to a condenser. The temperature was lowered to room temperature and nitrogen gas was passed through the reactants for 30 minutes. When this reaction product was confirmed by GC and NMR, 11% of 3-fluoro-1,3-propanesultone and 3% of 2-fluoro-1,3-propanesultone were observed, and the remainder was unreacted 1,3-propanesultone. propanesultone and unidentified by-products. The recrystallization method and other purification methods presented in Example 1 were used to obtain 3-fluoro-1,3-propanesultone or 2-fluoro-1,3-propanesultone with increased purity from the reaction product. A pure compound from which the product was removed could not be obtained. </p><p> Those of ordinary skill in the art to which the present invention pertains will be able to make various applications and modifications within the scope of the present invention based on the above contents.</p>

<p> As described above, the method for preparing 3-fluoro-1,3-propanesultone according to the present invention does not use fluorine gas, which is difficult to handle, has a very simple reaction apparatus and process, and has high selectivity and high yield. % or more of high purity 3-fluoro-1,3-propanesultone can be obtained. Therefore, the manufacturing method of the present invention can be effectively applied to the preparation of 3-fluoro-1,3-propanesultone used for various purposes, such as an additive for an electrolyte of a lithium ion secondary battery, an organic solvent, and an intermediate for pharmaceuticals.</p>