JP2011207800A - Method for producing 2-fluoroisobutyrate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrial production method for 2-fluoroisobutyrate.SOLUTION: A reaction of 2-hydroxybutyrate and sulfuryl fluoride (SOF) is carried out in the presence of an organic base to synthesize a 2-fluoroisobutyrate-containing composition (dehydroxy fluorination reaction step); the resulting 2-fluoroisobutyrate-containing composition is subjected to distillation purification while being brought into contact with air or oxygen (aeration distillation step); whereby a 2-fluoroisobutyrate at high purity is produced in a good yield. In this production method, it is not necessary to use a largely excessive amount of a fluorine source, and by-product methacrylate can be purified and removed suitably even in a large scale. This preferable embodiment can solve problems of the prior art in a production method of 2-fluoroisobutyrate.

Description

  The present invention relates to a method for producing 2-fluoroisobutyric acid ester.

2-Fluoroisobutyric acid ester is important as a pharmaceutical and agrochemical intermediate. As a conventional technique related to the present invention, a dehydroxyfluorination reaction in which 2-hydroxyisobutyric acid ester is used as a raw material to replace a hydroxyl group with a fluorine atom is general. Representative examples thereof include Patent Documents 1 to 6. These are anhydrous hydrogen fluoride (HF) or pyridine-fluoride in the presence of boron trifluoride (BF ₃ ), sulfuric anhydride (SO ₃ ), fluorosulfuric acid (FSO ₃ H) or chlorosulfuric acid (ClSO ₃ H). It reacts with hydrogen (Py · HF). Among these, there is one in which a hydroxyl group (—OH) is derived into a leaving group (—OSO ₂ CH ₃ , —OSO ₂ CF ₃ or —OSOCl) and then reacted with anhydrous hydrogen fluoride.

On the other hand, the present patent applicant discloses a dehydroxyfluorination reaction of alcohols by a combination of sulfuryl fluoride (SO ₂ F ₂ ) and an organic base (Patent Document 7).

JP 2004-059466 A JP 2003-221360 A International Publication No. 1998/001416 JP-A-8-127555 International Publication No. 1994/024086 JP-A-5-085987 JP 2006-290870 A

An object of the present invention is to provide an industrial production method of 2-fluoroisobutyric acid ester. In the production research of this compound, how to suppress the by-product of the methacrylic acid ester or how to purify and remove the by-product methacrylic acid ester is an important issue. In the conventional manufacturing method, the by-production of methacrylic acid ester was suppressed by using a fluorine source (F < ^- >) in large excess. For this reason, it takes time and labor to post-process and recover the excessively used fluorine source, and it is also necessary to use hastelloy, tetrafluoroethylene resin, or the like, which has higher corrosion resistance, as the material of the manufacturing equipment. As a result, the manufacturing method is expensive. In addition, since the boiling points of the 2-fluoroisobutyric acid ester of the target product and the methacrylic acid ester of the by-product are extremely close (in the case of methyl ester, 106 ° C. and 100 ° C., respectively) It was necessary to increase the reflux ratio (return rate) using a high distillation apparatus and perform fractional distillation over a long period of time. However, when such fractional distillation was carried out on a large scale, the by-product methacrylate ester self-polymerized in the distillation apparatus, which was newly found to be problematic in operation. On the other hand, as shown in Scheme 1, by-product methacrylic acid ester is reacted with bromine (Br ₂ ) to induce self-polymerization to a dibromide having an extremely high boiling point, thereby simplifying fractional distillation. Are also disclosed (CN 1944388, JP 2001-226318 A, JP 9-12508 A). However, this method additionally requires a complicated operation, and dibromide becomes a new problem as a halogen-based waste in purification on a large scale.

  On the other hand, in Patent Document 7, an olefin body is easily produced as a by-product in the dehydroxyfluorination reaction of a tertiary alcohol as compared with a primary alcohol or a secondary alcohol. Must be used in large excess.

  Thus, there has been a strong demand for an industrial production method of 2-fluoroisobutyric acid ester that does not require the use of a large excess of a fluorine source and can suitably purify and remove the by-product methacrylic acid ester even on a large scale.

  As a result of intensive studies based on the above problems, the present inventors synthesized a composition containing 2-fluoroisobutyric acid ester by reacting 2-hydroxyisobutyric acid ester with sulfuryl fluoride in the presence of an organic base. (Dehydroxyfluorination reaction step), by carrying out distillation purification while bringing the resulting composition containing 2-fluoroisobutyric acid ester into contact with air or oxygen (aeration distillation step), so that it is not necessary to use a large excess of the fluorine source In addition, the present inventors have newly found a method for producing 2-fluoroisobutyric acid ester, which can suitably purify and remove by-product methacrylic acid ester even on a large scale. Moreover, it is preferable to perform a dehydroxyfluorination reaction process in presence of "the salt or complex which consists of an organic base and hydrogen fluoride", and the byproduct of a methacrylic acid ester can be suppressed effectively. Further, the aeration distillation step is preferably performed in the presence of a polymerization inhibitor, and the self-polymerization of the by-product methacrylate ester can be synergistically suppressed. The polymerization inhibitor is preferably phenothiazine, hydroquinone, 2,6-di-tert-butyl-4-methylphenol (BHT) or methoquinone (hydroquinone monomethyl ether), and is easily available on a large scale and is free from self-polymerization. Excellent suppression effect.

  Thus, the useful manufacturing method of 2-fluoroisobutyric acid ester was discovered and it reached | attained this invention.

  That is, the present invention includes [Invention 1] to [Invention 4] and provides an industrial production method of 2-fluoroisobutyric acid ester.

[Invention 1]
General formula [1]

Is reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base to give a general formula [2]

A dehydroxyfluorination reaction step for synthesizing a composition containing 2-fluoroisobutyric acid ester represented by the following, while contacting the composition containing 2-fluoroisobutyric acid ester obtained in the dehydroxyfluorination reaction step with air or oxygen The manufacturing method of 2-fluoroisobutyric acid ester including the aeration distillation process which performs distillation purification.

[Wherein, Me represents a methyl group and R represents an alkyl group having 1 to 6 carbon atoms]
[Invention 2]
The method for producing 2-fluoroisobutyric acid ester according to invention 1, wherein the dehydroxyfluorination reaction step is carried out in the presence of "a salt or complex comprising an organic base and hydrogen fluoride".

[Invention 3]
The method for producing 2-fluoroisobutyric acid ester according to Invention 1 or Invention 2, wherein the aeration distillation step is performed in the presence of a polymerization inhibitor.

[Invention 4]
The 2-fluoroisobutyric acid according to invention 3, wherein the polymerization inhibitor is phenothiazine, hydroquinone, 2,6-di-tert-butyl-4-methylphenol (BHT) or methoquinone (hydroquinone monomethyl ether). Ester production method.

  The advantages of the present invention over the prior art will be described below.

  In the production method of the present invention, the amount of the fluorine source used is remarkably small, and the organic base is used excessively with respect to hydrogen fluoride under more suitable reaction conditions, so that it is not necessary to use a material having strong corrosion resistance. Further, even when fractional distillation is carried out for a long time, self-polymerization of methacrylic acid ester does not occur due to aeration distillation, and high-purity 2-fluoroisobutyric acid ester can be recovered on a large scale with good yield. Furthermore, no pretreatment for distillation purification such as induction to dibromide is required.

  In addition, with respect to Patent Document 7, the desired reaction is good even if the amount of the fluorine source used is extremely small, although the 2-hydroxyisobutyric acid ester targeted in the present invention is a tertiary alcohol. Newly found to proceed. This finding is surprising, contrary to initial expectations.

  Thus, in the preferable aspect of this invention, the problem of the prior art in the manufacturing method of 2-fluoroisobutyric acid ester can be solved.

  The production method of 2-fluoroisobutyric acid ester of the present invention will be described in detail.

  The production method of the present invention comprises two steps of dehydroxyfluorination reaction and aeration distillation.

[1. Dehydroxyfluorination reaction process]
First, the dehydroxyfluorination reaction step will be described in detail.

  In the dehydroxyfluorination reaction step, the 2-hydroxyisobutyric acid ester represented by the general formula [1] is reacted with sulfuryl fluoride in the presence of an organic base, whereby the 2-fluoroisobutyric acid represented by the general formula [2] is obtained. An ester-containing composition can be synthesized. The contained composition contains a methacrylic acid ester as a by-product.

  Me of the 2-hydroxyisobutyric acid ester represented by the general formula [1] represents a methyl group.

  R of the 2-hydroxyisobutyric acid ester represented by the general formula [1] represents an alkyl group having 1 to 6 carbon atoms. The alkyl group can be linear or branched, or cyclic (when the number of carbon atoms is 3 or more). Of these, a methyl group and an ethyl group are preferable, and a methyl group is particularly preferable.

  The amount of sulfuryl fluoride used may be 0.7 mol or more, preferably 0.8 to 3 mol, preferably 0.9 to 1 mol of 2-hydroxyisobutyric acid ester represented by the general formula [1]. Two moles are particularly preferred.

  Organic bases include trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-amylamine, tri-n-hexylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2, 5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4 6-collidine, 3,4,5-collidine, 3,5,6-collidine, 4-dimethylaminopyridine (DMAP), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), N, N, N ′, N ′, N ″ -pentamethylguanidine, 1,5,7-triazabi Black [4.4.0] dec-5-ene (TBD), BEMP, include tert-Bu-P4, and the like. Among them, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3.0] non-5- Ene and 1,8-diazabicyclo [5.4.0] undec-7-ene are preferred, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine and 1, 8-Diazabicyclo [5.4.0] undec-7-ene is particularly preferred. These organic bases can be used alone or in combination.

  The organic base may be used in an amount of 0.7 mol or more per mol of 2-hydroxyisobutyric acid ester represented by the general formula [1], preferably 0.8 to 4 mol, and 0.9 to 3 Mole is particularly preferred.

  Examples of the organic base of the “salt or complex comprising an organic base and hydrogen fluoride” include the same organic bases as those described above (the organic base used in Invention 1), and the preferred organic bases and particularly preferred organic bases are also the same. . Therefore, it is one of the preferred embodiments that both organic bases are used together.

  The molar ratio of the organic base to hydrogen fluoride in the “salt or complex comprising an organic base and hydrogen fluoride” may be in the range of 100: 1 to 1: 100, preferably 50: 1 to 1:50, 25 1 to 1:25 is particularly preferred. The tri-n-butylamine · hydrogen trifluoride complex can be similarly prepared with reference to the method for preparing the triethylamine · hydrogen trifluoride complex. In addition, “complex consisting of 1 mol of triethylamine and 3 mol of hydrogen fluoride” and “pyridine 30% (-10 mol%) and hydrogen fluoride 70% (˜) commercially available from Aldrich (Aldrich 2009-2010 catalog). 90 mol%) ”can also be used.

When this step is carried out in the presence of “a salt or complex comprising an organic base and hydrogen fluoride”, the amount used is fluorine anion (1 mol of 2-hydroxyisobutyric acid ester represented by the general formula [1]). F ⁻ ) may be 0.1 mol or more, preferably 0.2 to 2 mol, particularly preferably 0.3 to 1 mol.

  Use of hydrogen fluoride in which the total amount (mol) of the organic base used in Invention 1 and the organic base of “a salt or complex comprising an organic base and hydrogen fluoride” is “a salt or complex comprising an organic base and hydrogen fluoride” When used in excess of the amount (mole), the corrosivity can be remarkably reduced, and materials such as stainless steel (SUS) or glass (glass lining) can be used. Therefore, the reaction conditions in which the organic base is used in excess with respect to hydrogen fluoride is one preferred embodiment.

  Examples of the reaction solvent include aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene and mesitylene, methylene chloride, chloroform, 1,2-dichloroethane and the like. Halogen series, diethyl ether, tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran and other ether series, ethyl acetate, n-butyl acetate ester series, N, N-dimethylformamide, N, N-dimethylacetamide, N- Examples thereof include amides such as methylpyrrolidone and 1,3-dimethyl-2-imidazolidinone, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide. Among them, n-hexane, n-heptane, toluene, xylene, mesitylene, methylene chloride, tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, pro Pionitrile and dimethyl sulfoxide are preferred, and toluene, xylene, methylene chloride, tert-butyl methyl ether, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide and acetonitrile are particularly preferred. These reaction solvents can be used alone or in combination. Since this step proceeds satisfactorily even if it is carried out without using a reaction solvent, the reaction without solvent (neat, in the absence of the reaction solvent) is one of the preferred embodiments.

  When using a reaction solvent, the amount used may be 0.01 L or more, preferably 0.02 to 2 L, preferably 0.03 to 1 mol of 2-hydroxyisobutyric acid ester represented by the general formula [1]. To 1 L are particularly preferred.

  The reaction temperature may be in the range of −30 to + 200 ° C., preferably −20 to + 175 ° C., particularly preferably −10 to + 150 ° C.

  The reaction time may be in the range of 120 hours or less, and varies depending on the raw materials and reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, and the raw materials are almost lost. Preferably, the end point is the end point.

The post-treatment is not particularly limited, but preferably the target composition containing 2-fluoroisobutyric acid ester represented by the general formula [2] is recovered with good yield by directly distilling the reaction end solution under reduced pressure. can do. Furthermore, by combining suitable reaction conditions in which the organic base is used in excess with respect to hydrogen fluoride, the fluorine ion concentration (F ⁻ ) in the contained composition can be significantly reduced (corresponding to 174 ppm in Example 1). ) Also newly found. This phenomenon (a phenomenon in which the fluorine ion concentration decreases by distillation in the presence of an organic base) was also observed in the subsequent fractional distillation of the containing composition (corresponding to 6 ppm in Example 1). This is the same as the phenomenon disclosed in Japanese Patent Application Laid-Open No. 2009-67776 for similar compounds. The production method of the present invention is advantageous in that the amount of the fluorine source used is remarkably small, and further, by adopting the above preferred reaction conditions and preferred post-treatment, the post-treatment is performed despite the fact that it is a fluorination reaction. It does not require the usual defluorination operation that is commonly used in processing. The present invention is also suitable as an industrial production method from such a viewpoint. Most of the residue remaining after direct vacuum distillation from the reaction end solution is “a salt or complex composed of an organic base and fluorosulfuric acid or hydrogen fluoride”, and the organic base contained is an aqueous solution of an inorganic base or the like. It can be reused by performing a regeneration operation such as neutralization by distillation, purification by distillation or the like, and dehydration by molecular sieves or the like as necessary. In this regeneration operation, tri-n-butylamine having high fat solubility and an appropriate boiling point in distillation purification is preferable.

[2. Aeration distillation process]
Next, the aeration distillation process will be described in detail.

  In the aeration distillation step, the composition containing 2-fluoroisobutyric acid ester represented by the general formula [2] obtained in the dehydroxyfluorination reaction step (containing methacrylic acid ester as a by-product) is contacted with air or oxygen. By performing distillation purification, the purified product that contains almost no by-product methacrylic acid ester can be recovered.

  Aeration distillation can effectively suppress the self-polymerization of the by-product methacrylate ester in the gas phase. Furthermore, since the polymerization inhibitor can effectively suppress the self-polymerization of the by-product methacrylic acid ester in the liquid phase state, by combining these, the self-polymerization in distillation purification can be controlled synergistically. Can do.

  Since aeration distillation can also be suitably applied to direct distillation under reduced pressure directly from the reaction end solution, which is a preferable post-treatment of the dehydroxyfluorination reaction step, the “distillation purification” in the claims includes this vacuum distillation. Is also included.

  The amount of oxygen introduced in the aeration distillation is not particularly limited, but it may be set so that no explosion occurs in the entire distillation system including not only the distillation apparatus but also the decompression system and the exhaust system, and it is 90% or less of the critical oxygen concentration. Is preferable, and 80% or less of the critical oxygen concentration is particularly preferable. On the other hand, if the amount of oxygen introduced is extremely small, the desired effect cannot be obtained, so 0.0001% or more of the limiting oxygen concentration is preferable, and 0.001% or more of the limiting oxygen concentration is particularly preferable. When air is introduced, the oxygen concentration in the air may be calculated as 21%. The critical oxygen concentration varies depending on the R of the 2-fluoroisobutyric acid ester represented by the general formula [2] (alkyl group having 1 to 6 carbon atoms), the by-product amount of the methacrylic acid ester contained in the containing composition, and the like. About 10% should be considered as a guide. Finally, aeration distillation is preferably performed in contact with air, and can be performed safely with less equipment burden to obtain the same self-polymerization suppression effect as that in contact with oxygen.

  As polymerization inhibitors, phenothiazine, hydroquinone, 2,6-di-tert-butyl-4-methylphenol, methoquinone, tert-butylhydroquinone (TBH), 2,5-di-tert-butylhydroquinone, 1,2, 4-trihydroxybenzene, leucoquinizarin, nonflex F, nonflex H, nonflex DCD, nonflex MBP [2,2'-methylene-bis (4-methyl-6-tert-butylphenol)], ozonone 35, tetraethylthiuram Disulfide, Q-1300, Q-1301, chloranil, sulfur and the like can be mentioned. Among them, phenothiazine, hydroquinone, 2,6-di-tert-butyl-4-methylphenol, methoquinone, nonflex F, nonflex H, nonflex DCD, nonflex MBP, Q-1300 and Q-1301 are preferable, and phenothiazine Hydroquinone, 2,6-di-tert-butyl-4-methylphenol and methoquinone are particularly preferred. These polymerization inhibitors are commercially available and can be used alone or in combination.

  The amount of the polymerization inhibitor used may be 0.000001 mol or more, preferably 0.00001 to 0.05 mol, based on 1 mol of 2-hydroxyisobutyric acid ester represented by the general formula [1]. 0001 to 0.03 mol is particularly preferred. Polymerization inhibitors are not essential for aeration distillation, but are extremely effective for industrial production.

  The polymerization inhibitor is used in the steps of the dehydroxyfluorination reaction step [specifically, the step of charging the raw materials, the step of direct vacuum distillation (preferred post-treatment) from the reaction end solution, the distillate in the vacuum distillation ( It can also be added in advance from the containing composition) collection receiver, etc., and in some cases, a more preferable inhibitory effect can be obtained on the self-polymerization of the by-product methacrylate ester.

[Example]
Embodiments of the present invention will be specifically described by way of examples, but the present invention is not limited to these examples. Me represents a methyl group.

In the pressure-resistant reaction vessel made of 3L stainless steel, the following formula

429 g (3.63 mol, 1.00 eq) of methyl 2-hydroxyisobutyrate, 1029 g (5.55 mol, 1.53 eq) of tri-n-butylamine and 148 g (603 mmol, 0 of tri-n-butylamine trifluoride complex) .166 eq) was added, and sulfuryl fluoride was continuously blown from a cylinder while adjusting the internal pressure to be 1.0 MPa at room temperature, followed by stirring for 21 hours and 45 minutes. Further, sulfuryl fluoride was continuously blown from a cylinder while adjusting the internal pressure to 1.0 MPa at an internal temperature of 71 to 92 ° C., and stirred for 22 hours and 25 minutes. Finally, sulfuryl fluoride was continuously blown from the cylinder while adjusting the internal pressure to 1.0 MPa at an internal temperature of 100 to 105 ° C., and stirred for 3 hours and 55 minutes. The total amount of sulfuryl fluoride used was 441 g (4.32 mol, 1.19 eq). The reaction completed solution was cooled to room temperature, and the conversion rate of the reaction was measured by gas chromatography to be 99%. The reaction-terminated liquid is transferred to a distillation apparatus and subjected to simple distillation (flash distillation, boiling point to 83 ° C., reduced pressure to 4.2 kPa).

453 g of a composition containing methyl 2-fluoroisobutyrate represented by the following formula was synthesized. The contained composition contained 344 g, 59 g, 6 g and 43 g of methyl 2-fluoroisobutyrate, methyl methacrylate, methyl 2-hydroxyisobutyrate and tri-n-butylamine, respectively, as determined by ¹ H-NMR (weight ratio). 76: 13: 1: 10). The yield was 79%. The fluorine ion concentration was 174 ppm.

The 453 g (total amount) of the composition containing methyl 2-fluoroisobutyrate obtained above was subjected to fractional distillation [theoretical plate number 30, air introduction amount 5 mL / min] over 6 hours 50 minutes, and the main distillation [boiling point 89 ° C. 292 g of a 50 kPa degree, reflux ratio (distillation: return) 1: 5] was recovered. The recovery rate was 85%, and the total yield was 67%. The gas chromatographic purity was 99.7% (the remaining 0.3% was methyl methacrylate). The fluorine ion concentration was 6 ppm. In addition, by employing aeration distillation, no self-polymerization of methyl methacrylate was observed at all locations in the fractional distillation apparatus. The ¹ H-NMR and ¹⁹ F-NMR of methyl 2-fluoroisobutyrate are shown below.

¹ H-NMR [reference material; (CH ₃ ) ₄ Si, deuterated solvent; CDCl ₃ ], δ ppm; 1.57 (d, 21.2 Hz, 6H), 3.77 (s, 3H).

¹⁹ F-NMR (reference material; C ₆ H ₅ CF ₃ , deuterated solvent; CDCl ₃ ), δ ppm; −84.29 (sep, 21.3 Hz, 1F).

The following formula synthesized in the same manner with reference to Example 1

A fractional distillation (aeration distillation) of a composition containing methyl 2-fluoroisobutyrate represented by the formula (methyl methacrylate as a by-product is also contained in the same degree as in Example 1) is obtained with respect to 1 mol of methoquinone (methyl 2-hydroxyisobutyrate). In the presence of 0.001 mol), the same results as in Example 1 were obtained. The fractional distillation of Example 2 was performed twice as long as the scale of Example 1. However, all of the fractional distillation apparatus in the fractional distillation apparatus can be scaled up by combining aeration distillation and a polymerization inhibitor. No self-polymerization of methyl methacrylate was observed at this location.

  The 2-fluoroisobutyric acid ester targeted in the present invention can be used as an intermediate for medical and agricultural chemicals.

Claims (4)

General formula [1]

Is reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base to give a general formula [2]
A dehydroxyfluorination reaction step for synthesizing a composition containing 2-fluoroisobutyric acid ester represented by the following, while contacting the composition containing 2-fluoroisobutyric acid ester obtained in the dehydroxyfluorination reaction step with air or oxygen The manufacturing method of 2-fluoroisobutyric acid ester including the aeration distillation process which performs distillation purification.
[Wherein, Me represents a methyl group and R represents an alkyl group having 1 to 6 carbon atoms] The method for producing 2-fluoroisobutyric acid ester according to claim 1, wherein the dehydroxyfluorination reaction step is carried out in the presence of "a salt or complex comprising an organic base and hydrogen fluoride". The method for producing 2-fluoroisobutyric acid ester according to claim 1 or 2, wherein the aeration distillation step is performed in the presence of a polymerization inhibitor. The 2-fluoroisoform according to claim 3, wherein the polymerization inhibitor is phenothiazine, hydroquinone, 2,6-di-tert-butyl-4-methylphenol (BHT) or methoquinone (hydroquinone monomethyl ether). A method for producing butyric acid esters.