JP5650031B2 - Purification method for Horner-Wadsworth-Emmons reagent - Google Patents

Description

  The present invention relates to a method for purifying an HWE reagent that selectively removes pyrophosphate esters contained in a Horner-Wadsworth-Emmons reagent (hereinafter also referred to as HWE reagent).

The Horner-Wadsworth-Emmons reaction (hereinafter also referred to as HWE reaction) is widely used as a reaction for generating a carbon-carbon double bond in the synthesis of organic compounds including pharmaceuticals and pharmaceutical intermediates. The HWE reagent represented by the general formula (I) used as a substrate for this HWE reaction is generally synthesized through an Arbuzov reaction.
(In the general formula (I), R ₁ is a linear or branched alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group, X is an oxygen atom or a carbon atom having one or more substituents, and Y is hydrogen. An atom, a carbon atom which may have a substituent, or an oxygen atom having a substituent.

In the Arbuzov reaction, conditions for reacting phosphite triesters and halides at high temperatures are common, and in this case, a very small amount of pyrophosphate esters represented by the following formula (II) may be formed. .
(In the general formula (II), R ₂ represents a linear or branched alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group.)

  Pyrophosphate esters have different toxicities depending on the substituent at the R site, but they are all toxic. For example, when R is tetraethyl pyrophosphate (TEPP) having an ethyl group, 1700 micrograms of human male oral LDLo / Kilogram is designated as a specific poison because of its extremely high toxicity, and it is not allowed to be mixed into the target compound, especially pharmaceuticals.

Distillation is a purification method that is generally considered to be industrially simple and economical, and has a high effect of removing impurities, but the boiling points of pyrophosphate esters and HWE reagents are close to each other, and pyrophosphate esters in distillation are used. Removal is difficult. For example, the boiling point of pyrophosphate ester is 125-130 ° C / 5 mmHg in the above-mentioned TEPP, whereas in the above general formula (I), X is CHCOOEt, Y is CH ₃ , and R ₁ is C ₂ H ₅ . The HWE reagent is 157 ° C./5 mmHg, and similarly, the HWE reagent in which X is O and Y is OEt is 130 ° C./5 mmHg. In general, in order to separate substances having boiling points close to each other by distillation, a high-stage distillation column and a large reflux ratio are required, which requires equipment costs and time. Further, when the boiling points are too close, separation itself is impossible.

  As another method, a removal method using the chemical properties of pyrophosphates can be considered. Although pyrophosphates have been reported to be hydrolyzed (Non-patent Document 1), pyrophosphates are used. Is only selective and effective in the state in which trace amounts are contained in organic compounds, especially in the state where trace amounts are contained in organic compounds having the same type of functional group as HWE reagent. There is no known removal method.

Toy, A.D.F.Journal of the American Chemical Society 1948, 70, 3882-3886

  As a result of intensive studies to solve the above problems, the present inventors have selectively and effectively selected pyrophosphate esters represented by the general formula (II) contained in the HWE reagent represented by the general formula (I). The present invention has been found to be able to be removed. That is, the present invention provides a method for purifying an HWE reagent that can selectively and effectively remove pyrophosphate esters contained in a trace amount in the HWE reagent without causing degradation or denaturation of the HWE reagent. It is intended.

The method for purifying the HWE reagent of the present invention comprises the following general formula (I):
(In the general formula (I), R ₁ is a linear or branched alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group, X is an oxygen atom or a carbon atom having one or more substituents, and Y is hydrogen. An atom, a carbon atom which may have a substituent, or an oxygen atom having a substituent is shown below.
The following general formula (II) contained in the HWE reagent represented by
(In the general formula (II), R ₂ represents a linear or branched alkyl group having 1 to 6 carbon atoms, a phenyl group, or a benzyl group. Hereinafter, this description is omitted.) It is characterized by being hydrolyzed with an acid.

The acid is preferably a mineral acid or a solid acid.
The solid acid is preferably a silicate mineral, and the silicate mineral is preferably smectite.
The mineral acid is preferably an aqueous solution of hydrogen chloride, sulfuric acid, phosphoric acid, or hydrofluoric acid.
The hydrolysis is preferably performed by heating.

As the general formula (I), for example, R ₁ is C ₂ H _5, X is CHCOOC ₂ H ₅ , Y is CH ₃ , and R ₂ is C ₂ H ₅ as the general formula (II). Are illustrated.
Further, there can be exemplified those in which R ₁ is CH _3, X is CHCOOC ₂ H ₅ , Y is CH ₃ in the general formula (I), and R ₂ is CH ₃ in the general formula (II).

  In the method for purifying the HWE reagent of the present invention, the pyrophosphate ester represented by the general formula (II) contained in the HWE reagent represented by the general formula (I) is hydrolyzed with an acid. Without causing denaturation, it is possible to selectively and effectively remove only pyrophosphate esters having the same type of functional group as the HWE reagent contained in a very small amount in the HWE reagent.

The method for purifying the HWE reagent of the present invention comprises the following general formula (I):
The following general formula (II) contained in the HWE reagent represented by
The pyrophosphate ester represented by is hydrolyzed with an acid.

In the general formula (I), the substituent when X is a carbon atom includes an alkyl group, an aryl group, a cyano group, an isocyano group, an alkoxyl group, an alkoxyalkane group, a carboxyl group, an alkylcarbonyl group, an alkoxycarbonyl group, and the like. Can be mentioned.
The substituent when Y is a carbon atom is the same as above.
Examples of the substituent when Y is an oxygen atom include an alkyl group, an aryl group, a carboxyl group, and an alkoxycarbonyl group.

  As the acid, a mineral acid or a solid acid can be used. As the mineral acid, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like can be preferably mentioned. Among them, hydrochloric acid or sulfuric acid is preferable from the viewpoint that pyrophosphates can be removed more selectively and efficiently. As the solid acid, silicate minerals and acidic ion exchange resins can be used, among which zeolite and smectite are preferable, and acidic clay and activated clay are more preferable.

  As a specific procedure for removing pyrophosphate esters, when a mineral acid is used as an acid with respect to 1 part by mass of HWE reagent containing 0.005 to 5 mass% of pyrophosphate esters, Add 0.5 to 2 parts by mass, preferably 0.7 to 1.2 parts by mass of an aqueous solution of 0.1 to 10% by mass, preferably 1 to 5% by mass, and stir for 1 to 20 hours. The temperature at that time is preferably adjusted to 30 to 100 ° C., and in order to suppress decomposition of the HWE reagent and effectively remove pyrophosphate esters, it is preferable to heat to 50 to 80 ° C.

  Whether or not the pyrophosphates have been removed can be confirmed by gas chromatography. After sufficiently removing pyrophosphates by heating, an organic solvent and sodium chloride are added to separate the aqueous acid layer, and sodium chloride is added until the pH of the organic layer is 3 to 9, preferably 4 to 8. Wash with alkaline aqueous solution.

As the organic solvent used in this case, any organic solvent can be used as long as it can dissolve the HWE reagent and has a relatively low solubility in water and can be separated. For example, ethyl acetate, diethyl ether, isopropyl ether , Heptane, pentane, isobutanol, xylene and the like are preferable.
After washing with an aqueous alkali solution, the HWE reagent from which pyrophosphates have been removed can be obtained by concentrating the organic solvent.

  Moreover, when using a solid acid as an acid, it replaces with said mineral acid, 0.001-0.1 mass part with respect to 1 mass part of HWE reagent, Preferably it is a solid of 0.01-0.05 mass part Add acid and stir for 1-20 hours. The temperature at that time is preferably adjusted to 30 to 100 ° C., and in order to suppress decomposition of the HWE reagent and effectively remove pyrophosphate esters, it is preferable to heat to 50 to 80 ° C. After removing pyrophosphates sufficiently by heating, the HWE reagent from which pyrophosphates have been removed can be obtained by removing the solid acid by filtration.

In particular, when this solid acid is used, compared with the case of using a mineral acid, first, the post-treatment is only filtration and simple, and second, the solid acid can be recovered and reused. This has the advantage that there is no discharge of the waste liquid accompanying the liquid separation operation, and is an industrially extremely advantageous means.
Hereinafter, the purification method of the HWE reagent of the present invention will be described in more detail using examples.

<Synthesis of HWE reagent>
The HWE reagent (A) (in the general formula (1), R ₁ is C ₂ H _5, X is CHCOOEt, and Y is CH ₃ ) was synthesized using a known technique of Arbuzov reaction.
According to analysis using gas chromatography, this HWE reagent contains 0.0527 GC area% tetraethyl pyrophosphate (hereinafter referred to as TEPP), and at the same time the purity of the HWE reagent is 88.61 GC area%. I understood. Furthermore, the appearance was light yellow.

(Comparative Example 1)
Water (100 g) was added to the HWE reagent (A) (100 g), and the mixture was heated and stirred at 80 ° C. for 10 hours. After completion of the heating, the solution was separated and water was removed by concentration under reduced pressure to obtain HWE reagent (98 g).

(Comparative Example 2)
To the HWE reagent (A) (100 g) was added 0.1 mass% aqueous sodium hydroxide solution (100 g), and the mixture was stirred at 25 ° C. for 1 hour. After completion of the stirring, isopropyl ether (100 g) and sodium chloride (20 g) were added, followed by liquid separation and washing with water, and the solvent was distilled off under reduced pressure to obtain an HWE reagent (90 g).

Example 1
2% by mass hydrochloric acid (100 g) was added to the HWE reagent (A) (100 g), and the mixture was heated and stirred at 55 ° C. for 10 hours. After completion of the heating, isopropyl ether (100 g) and sodium chloride (20 g) were added for liquid separation, and the mixture was washed with an aqueous solution obtained by adding sodium chloride (20 g) to a 1% aqueous sodium carbonate solution (100 g). The solvent was removed by concentration under reduced pressure to obtain HWE reagent (95 g).

(Example 2)
Acid white clay (manufactured by Kanto Chemical Co., Inc.) (5 g) was added to HWE reagent (A) (100 g), and the mixture was heated and stirred at 80 ° C. for 10 hours. After heating, No. HWE reagent (95 g) was obtained by filtering using 5B filter paper.

Example 3
Activated clay (manufactured by Kanto Chemical Co., Inc.) (5 g) was added to HWE reagent (A) (100 g), and the mixture was heated and stirred at 80 ° C. for 10 hours. After heating, No. HWE reagent (95 g) was obtained by filtering using 5B filter paper.

The HWE reagents of Comparative Examples 1 and 2 and Examples 1 to 3 treated as described above were analyzed by gas chromatography, and how the GC area% and appearance of TEPP and HWE reagents changed before and after the treatment. The results are summarized in Table 1. In addition, the TEPP removal rate and the HWE reagent retention rate in Table 1 are obtained by the following equations, respectively.
TEPP removal rate = GC area% of TEPP after treatment / GC area% of TEPP before treatment
HWE reagent retention rate = GC area% of HWE reagent after treatment / GC area% of HWE reagent before treatment

  As shown in Table 1, in Comparative Example 1 in which TEPP was removed using only water, the TEPP removal rate by the treatment was 42.4%, and it could not be said that it was sufficiently removed. In Comparative Example 2 using sodium hydroxide, the TEPP removal rate was sufficient to be 95% or more, but the HWE reagent retention rate was 98.4%, and decomposition of the HWE reagent was observed. In addition, the appearance was light yellow before the treatment, but became dark yellow, and the modification was recognized.

  On the other hand, in Examples 1 to 3 according to the purification method of the HWE reagent of the present invention, the removal rate of TEPP is 95% or more, which is a sufficient value, and the decrease in the retention rate of HWE reagent and the appearance are not observed. It was.

  As is clear from the above examples, the method for purifying the HWE reagent of the present invention involves decomposing or modifying the HWE reagent by hydrolyzing the pyrophosphate ester contained in the HWE reagent with an acid. In addition, only pyrophosphate esters contained in a very small amount in the HWE reagent can be selectively and effectively removed.

Claims (8)

The following general formula (I)
(In the general formula (I), R ₁ is a linear or branched alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group, X is an oxygen atom or a carbon atom having one or more substituents, and Y is hydrogen. An atom, a carbon atom which may have a substituent, or an oxygen atom having a substituent.
The following general formula (II) contained in the Horner-Wadsworth-Emmons reagent represented by
(In the general formula (II), R ₂ represents a linear or branched alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group.)
A method for purifying a Horner-Wadsworth-Emmons reagent, which comprises hydrolyzing a pyrophosphate ester represented by the formula:   The method for purifying a Horner-Wadsworth-Emmons reagent according to claim 1, wherein the acid is a mineral acid or a solid acid.   The method for purifying a Horner-Wadsworth-Emmons reagent according to claim 2, wherein the solid acid is a silicate mineral.   The method for purifying a Horner-Wadsworth-Emmons reagent according to claim 3, wherein the silicate mineral is smectite.   The method for purifying a Horner-Wadsworth-Emmons reagent according to claim 2, wherein the mineral acid is an aqueous solution of hydrogen chloride, sulfuric acid, phosphoric acid, or hydrofluoric acid.   The method for purifying a Horner-Wadsworth-Emmons reagent according to any one of claims 1 to 5, wherein the hydrolysis is performed by heating. In the general formula (I), R ₁ is C ₂ H _5, X is CHCOOC ₂ H ₅ , Y is CH ₃ , and R ₂ is C ₂ H ₅ in the general formula (II), A method for purifying the Horner-Wadsworth-Emmons reagent according to any one of claims 1 to 6. 2. In the general formula (I), R ₁ is CH _3, X is CHCOOC ₂ H ₅ , Y is CH ₃ , and R ₂ is CH ₃ in the general formula (II). The purification method of Horner-Wadsworth-Emmons reagent of any one of -6.