KR20160117684A - New process for the production of 1-hydroxyalkane phosphonic esters - Google Patents

Abstract

The present invention relates to a process for preparing a 1-hydroxyalkane phosphonic ester derivative which is useful as a phosphorus flame retardant intermediate and which is known to be useful as an antiviral drug or the like. It has been found that the conventional processes can produce an excessive amount of solid by- In order to solve the problem of limitation of the reaction which can be caused only by the activated aromatic ketone, the phosphite compound is mixed with calcium fluoride and hydroxide Potassium in the presence of a mixed catalyst and reacting the compound with a general carbonyl compound in the presence of a mixed catalyst of potassium and potassium.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparing 1-hydroxyalkane phosphonic ester derivatives,

The present invention relates to a novel process for the preparation of 1-hydroxyalkane phosphonic ester derivatives which are useful as intermediates for organophosphorus flame retardants and which act as enzyme inhibitors, antiviral agents and anti-HIV agents.

Compounds containing phosphorus (P) are known to exhibit various functions. Among them, the performance as a flame retardant has attracted attention. In general, a flame retardant which has been mainly applied to a polymer resin has been mainly used as a halogen-based flame retardant including bromine (Br). Although their flame retardancy was satisfactory, there were environmental problems such as toxic gas generation and generation of harmful substances such as dioxin and benzofuran, and the necessity of a non-halogen flame retardant agent was required due to poor compatibility with resin Research in this area has been actively developed in many fields. Examples of the non-halogen flame retardant include an inorganic hydrate, a nitrogen compound, a phosphorus flame retardant, and an organic phosphorus flame retardant. In the case of an inorganic hydrate, a disadvantage is that a too large amount of inorganic hydrate is used in order to obtain a desirable flame retardant effect, It is pointed out. When nitrogen oxides are used as the flame retardant, the flame retarding effect is not sufficient and the toxic gas at the time of combustion is also a problem. In addition, the phosphorus flame retardant, which mainly uses phosphorus, lowers the basic physical properties of the resin, Is susceptible to heat or friction shocks, and thus, handling, storage, mixing, etc. are dangerous and the working environment is not good. Organophosphorus flame retardants have been recognized as the most desirable alternative to halogen flame retardants, though some improvements still need to be made.

In the present invention, not only is it useful as an intermediate for synthesizing an organophosphorus flame retardant, but also an enzyme inhibitor, an antiviral agent, a 1-hydroxyalkanephosphine represented by the following general formula (I) known to act as an anti- Lt; / RTI > derivatives of the present invention.

In the formula, R ¹ and R ² each independently represent an alkyl group having 1 to 12 carbon atoms, and R ³ and R ⁴ each independently represent hydrogen or an alkyl group having 1 to 4 carbon atoms or a phenyl group.

F. Texier-Boullet et al., 1986, Tetrahedron Letters , Vol. 27, No. 30, pp. 3515 discloses a process in which a dialkyl phosphite and a ketone are reacted in the presence of a mixed solid of gamma alumina and potassium fluoride in the presence of a mixed solid, and after completion of the reaction, dichloromethane is added in an excess amount to extract the 1- To obtain an alkane phosphonic ester derivative. This method succeeded to react with excess of mixed solids without solvent, but the product was obtained by further adding a solvent which can dissolve the product after completion of reaction by using too much mixed solid as a catalyst, It is necessary to treat the solid by-products of the solvent and excess use of the solvent.

Fujimoto Kazuo et al. Disclosed a method of using a mixed catalyst of magnesium chloride and triethylamine to obtain a 1-hydroxyalkanephosphonic ester in 2007 patent published in Korean Patent Publication No. 10-2007-0084573. Although this method is a useful method which does not use a reaction solvent, the mixed catalyst acts on the reactant to increase the viscosity of the whole reaction mixture, which makes it difficult to stir in the reaction. If stirring is performed for a long time to complete the reaction, Decomposed and returned to the reactant.

Chubei Wang, Ph.D., Phosphorus , Sulfur , and In a paper published in Silicon 188, p. 1334, a phosphite and an aromatic ketone were reacted with triethylamine catalyst without a solvent to obtain a 1-hydroxyalkanephosphonic ester. This reaction can be used only for a compound having an activated carbonyl group such as an aromatic ketone. The amount of triethylamine to be used as a catalyst is 50 mol% (0.5 molar) or more, and depending on the compound, 100 mol% And the distillation process is required to remove excess triethylamine after completion of the reaction.

As described above, conventional techniques for synthesizing a 1-hydroxyalkane phosphonic ester derivative are problematic in that an excessive amount of solid byproduct must be treated and that a solvent capable of dissolving the product after the completion of the reaction is added in an excess amount and extracted to obtain a product When the reaction is carried out without a solvent, interaction with the used catalyst increases the viscosity of the entire reaction mixture, which makes it difficult to proceed with the desired reaction. When long stirring is attempted to complete the reaction, some products are decomposed And a relatively recently reported method using triethylamine as a catalyst is a limiting method applicable only when a compound containing an activated carbonyl group such as an aromatic ketone is reacted with a phosphite Not only is it a method, After completion of the reaction increases, so the amount of the Li ethylamine be excessive to apply the catalyst and the product in industrial applications such as with the difficulties have to remove via a distillation process that is not a preferred method hagieneun producing a 1-hydroxy-phosphonic alkane sulphonic ester derivative.

As described above, the synthesis methods of 1-hydroxyalkane phosphonic ester derivatives as described above have disadvantages that are not suitable for industrial production sites. The present inventors have found that the use of catalysts can be remarkably reduced to minimize the amount of solid byproducts produced, (F), potassium (K), and potassium (K) were used as a catalyst for the separation and purification of the used catalyst after the completion of the reaction without increasing the viscosity of the reaction mixture due to the interaction with the catalyst. And Ca (Ca) at the same time, thereby completing the present invention.

In the present invention, in order to overcome the disadvantages which are not suitable for industrial production sites, which have been known heretofore, in the synthesis methods of 1-hydroxyalkane phosphonic ester derivatives, the use amount of the catalyst is remarkably reduced to minimize the amount of solid by- (F) and potassium (K) in the course of investigating the easy separation method between the used catalyst and the target compound after completion of the reaction without increasing the viscosity of the reaction mixture due to the interaction with the catalyst, And calcium (Ca) at the same time.

That is, the present invention relates to a process for producing a phosphite compound represented by the following formula (II) by reacting a phosphite compound represented by the following formula (II) with a carbonyl compound represented by the following formula (III) in the presence of a mixed catalyst of calcium fluoride (CaF ₂ ) and potassium hydroxide There is provided a process for producing a 1-hydroxyalkane phosphonic ester derivative represented by the following general formula (I).

In the above formula, R ¹ and R ² each independently represent an alkyl group having 1 to 12 carbon atoms, and R ³ and R ⁴ each independently represent hydrogen or an alkyl group having 1 to 4 carbon atoms or a phenyl group.

The method of the present invention is a method capable of overcoming the problems of the prior methods. In this method, the generation of solid byproducts is minimized after completion of the reaction, and even if the reaction is proceeded without using a reaction solvent, There is no viscosity increase phenomenon and separation of the catalyst and the product after the completion of the reaction is easy, thereby providing a preferable production method.

The present invention provides a process for producing a 1-hydroxyalkane phosphonic ester derivative useful as an intermediate of an organic phosphorus flame retardant or known as an enzyme inhibitor, an antiviral agent or an anti-HIV agent, , The formation of solid byproducts is minimized after completion of the reaction, and even if the reaction is carried out without using a reaction solvent, the viscosity of the reaction mixture does not increase due to the interaction with the catalyst, and the separation of the catalyst and the product By utilizing the manufacturing method of the present invention, it is believed that the method can contribute greatly to the field of fine chemical and pharmaceutical raw material industry.

The present invention relates to a process for preparing a compound represented by the following formula (II) by reacting a compound represented by the following formula (II) with a carbonyl compound represented by the following formula (III) in the presence of a mixed catalyst of calcium fluoride (CaF ₂ ) and potassium hydroxide Hydroxyalkane phosphonic ester derivative represented by the formula (I).

In the formula, R ¹ and R ² each independently represent an alkyl group having 1 to 12 carbon atoms, and R ³ and R ⁴ each independently represent hydrogen or an alkyl group having 1 to 4 carbon atoms or a phenyl group.

In order for the target compound of formula (I) to be formed, two promoting actions must take place at the same time so that a favorable reaction proceeds. The carbonyl compound of formula (III) reacts with phosphorus compound phosphorus as shown in the following mechanism (P) of the phosphite of general formula (II) must be aggressively activated.

In the proposed mechanism, the carbonyl compounds already activated according to the structure of the carbonyl compound may undergo the reaction without the use of the catalyst containing M ¹ in the preceding figure. That is, the aromatic aldehyde and the aromatic ketone can be reacted with the general phosphite even if only the proper base catalyst is used. However, most of the non-activated carbonyl compounds can activate the desired reaction by simultaneously activating the phosphite and the carbonyl compound as in the previous mechanism. The metal M ¹ and M ² And the kind of the halogen X which is the counter ion of the metal M ¹ .

In the present invention, calcium fluoride (CaF ₂ ) is used as the activator of the carbonyl compound and potassium hydroxide (KOH) is used as the phosphite activator, that is, in the catalyst configuration of M ¹ = Ca, M ² = K, The present invention has been accomplished by confirming reproducibly that the desired reaction proceeds like the proposed mechanism.

The most characteristic of the catalyst composition is that the reaction proceeds only when fluorine (F) is used as a constituent. For example, when calcium chloride having chlorine in place of fluorine is used, no reaction proceeds at all. When using metals other than calcium-potassium as a catalyst component even if fluorine is contained, some reaction proceeds but only a part of the reaction proceeds and stops because it is presumed that the mechanism of continuous catalysis is not satisfied. In addition to calcium fluoride (CaF ₂ ) as an activator of the carbonyl compound, some reactions such as NaF, KF, and MgF ₂ proceed, and in particular MgF ₂ The reaction proceeds relatively quickly but is partially decomposed in the vicinity of the reaction termination point and is partially returned to the phosphite and the carbonyl compound. Depending on the structure of the carbonyl compound used, it is one of the materials usable as a mixed catalyst with CaF ₂ . In addition to the KOH used in the present invention, NaOH or LiOH is also used as an activator of phosphite to promote a partial reaction. In this case, too, only a part of the reaction proceeds and stops, which is also because the mechanism of continuous catalytic action is not satisfied do. The use of organic bases such as triethylamine is not observed at all, suggesting that it is not possible to participate in the synthetic mechanisms presented above.

In the present invention in which a 1-hydroxyalkane phosphonic ester derivative is synthesized by the reaction of a phosphite and a carbonyl compound, the reaction can proceed in the absence of a reaction solvent during the progress of the reaction, and a solid , It is possible to carry out the reaction using an appropriate reaction solvent. As the usable solvent, most common solvents which do not contain a carbonyl or a hydroxyl group such as methylene chloride, chloroform, ethylene dichloride, benzene, toluene and chlorobenzene can be used. When the product is in a liquid form or is a relatively low substance with a melting point of not more than 45 degrees Celsius, the reaction is carried out by reacting a phosphite and a carbonyl compound in the presence of a mixed catalyst of the characteristic constitution of the present invention, that is, a mixed catalyst of CaF ₂ and KOH The desired reaction can be promoted and a small amount of solid by-product can be removed and the product can be easily separated by a simple filtration process after completion of the reaction.

The reaction may be carried out at a temperature of from 10 ° C to 80 ° C, preferably from 20 ° C to 60 ° C, to complete the reaction. Generally, when the reaction starts, an exothermic reaction is observed. The internal temperature can be controlled by adjusting the rate of the catalyst input. After the exothermic reaction is stopped, the reaction is completed by stirring at an appropriate temperature of 20 to 60 ° C.

The amount of CaF ₂ and KOH to be used as the catalyst is 5 mol% (0.05 molar) to 30 mol% (0.3 molar), preferably 10 mol% to 25 mol%, relative to the phosphite to be reacted. The carbonyl compound is reacted with 100 mol% (1.0 molar) to 130 mol% (1.3 molar equivalents) with respect to the phosphite used. When the melting point of the product is obtained as a solid form at 45 ° C or lower, 20 to 30% by weight, which is useful for filtering and removing solid by-products such as catalysts before the reaction product is solidified after completion of the reaction. The carbonyl compound partially mixed with the product is removed by vacuum or washed with water Can easily be removed.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to the methods specified in the embodiments.

30.642 g (0.10 mole) of di (2-ethylhexyl) phosphite and 7.932 g (0.11 mole) of ethylmethylketone are placed in a 100 ml 3-neck flask and 1.56 g (0.02 mole) of calcium fluoride is added while stirring. After stirring for 5 minutes to confirm that calcium fluoride is well dispersed, 1.12 g (0.02 mole) of KOH is added over about 10 minutes. At this time, you can check the heat, but adjust the KOH feed rate so that the internal temperature does not exceed 55 ℃. After the exothermic reaction is stopped, the internal temperature is adjusted to 45 ° C., and the reaction is completed by stirring at an internal temperature of 40 to 50 ° C. for 2 hours. The reaction can be confirmed by TLC. After confirming the completion of the reaction, the stirring is stopped, and the solid by-product is cooled to room temperature, and solid by-products can be removed by simple filtration.

To remove some dissolved KOH, 10 ml of water was added, and the mixture was neutralized with 1% HCl solution to a pH of about 4 to 6 to separate and remove the water layer. Further, 10 ml of water was added thereto to wash the organic layer, Was dried in vacuo at 60 ° C to remove ethylmethylketone and moisture to obtain 35.5 g of the target compound. (Yield: 92.5%)

Add 29,132 g (0.15 mole) of Di (n-butyl) phosphite and 10.454 g (0.18 mole) of acetone into a 100 ml 3-neck flask and add 2.34 g (0.03 mole) of calcium fluoride while stirring. After stirring for 5 minutes to confirm that calcium fluoride is well dispersed, 1.68 g (0.03 mole) of KOH is added over about 10 minutes. At this time, you can check the heat, but adjust the KOH feed rate so that the internal temperature does not exceed 55 ℃. After the exothermic reaction is stopped, the internal temperature is adjusted to 45 ° C., and the reaction is stirred at an internal temperature of 40 to 50 ° C. for 2 hours. Thus, the reaction can be confirmed by TLC. After confirming the completion of the reaction, the stirring is stopped, and the solid by-product is cooled to room temperature, and solid by-products can be removed by simple filtration.

Thereafter, the mixture was washed with water as in Example 1 and vacuum-dried to obtain 33.5 g of the target compound. (Yield: 88.5%)

33.015 g (0.30 mole) of dimethylphosphite and 22.651 g (0.39 mole) of acetone are placed in a 100 ml 3-neck flask and 4.685 g (0.06 mole) of calcium fluoride is added while stirring. After stirring for 5 minutes to confirm that calcium fluoride is well dispersed, 3.367 g (0.06 mole) of KOH is added over about 10 minutes. At this time, you can check the heat, but adjust the KOH feed rate so that the internal temperature does not exceed 55 ℃. After the exothermic reaction is stopped, the internal temperature is adjusted to 45 ° C., and the reaction is completed by stirring at an internal temperature of 40 to 50 ° C. for 5 hours. After confirming the completion of the reaction, stirring is stopped, and 30 ml of methylene chloride is added while cooling to room temperature. Solid byproducts are submerged on the bottom, and solid by-products can be removed by simple filtration.

Thereafter, as in Example 1, the organic layer was washed with water, and methylene chloride was distilled off, followed by vacuum drying to obtain 45.9 g of the desired compound. (Yield: 91.0%)

Add 30.642 g (0.10 mole) of Di (2-ethylhexyl) phosphite and 12.015 g (0.10 mole) of Benzophenone to a 100 ml 3-neck flask and add 1.56 g (0.02 mole) of calcium fluoride while stirring. After stirring for 5 minutes to confirm that calcium fluoride is well dispersed, 1.12 g (0.02 mole) of KOH is added over about 10 minutes. At this time, you can check the heat, but adjust the KOH feed rate so that the internal temperature does not exceed 55 ℃. After the exothermic reaction is stopped, the internal temperature is adjusted to 45 ° C., and the reaction is completed by stirring at an internal temperature of 40 to 50 ° C. for 2 hours. The reaction can be confirmed by TLC. After the completion of the reaction, stop stirring and cool to room temperature, solid byproducts will settle on the bottom, which can be filtered to remove solid byproducts. To remove some dissolved KOH, add 10 ml of water and stir with 1% HCl solution 4 to 6, and the water layer was separated and removed. Further, 10 ml of water was added thereto to wash the organic layer, and the organic layer obtained after washing with water was vacuum dried at 60 ° C to obtain the desired compound (30.5 g). (Yield: 97.0%)

Claims (2)

In the production of the 1-hydroxyalkane phosphonic ester derivative represented by the following general formula (I)
Characterized in that the phosphite compound represented by the following general formula (II) is reacted with a carbonyl compound represented by the following general formula (III) in the presence of a mixed catalyst of calcium fluoride (CaF ₂ ) and potassium hydroxide (KOH) A process for producing a 1-hydroxyalkane phosphonic ester derivative.

In the above formula, R ¹ and R ² each independently represent an alkyl group having 1 to 12 carbon atoms, and R ³ and R ⁴ each independently represent hydrogen or an alkyl group having 1 to 4 carbon atoms or a phenyl group.
(1), wherein the amount of calcium fluoride and potassium hydroxide to be used as a catalyst is 0.05 to 0.3 mol, relative to the amount of the phosphite compound represented by the general formula (II) A process for preparing a hydroxyalkane phosphonic ester derivative.