JP3007984B1 - Method for producing unsaturated phosphonate ester - Google Patents

Abstract

Abstract: PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing an unsaturated phosphonate ester by efficiently adding a secondary phosphite to acetylene. SOLUTION: When reacting a secondary phosphite with an acetylene compound in the presence of a palladium complex catalyst,
Carrying out the reaction in the presence of a small amount of water,
An efficient method for producing an unsaturated phosphonate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing an unsaturated phosphonate, comprising reacting a secondary phosphite with an acetylene compound in the presence of a palladium complex catalyst.

[0002]

2. Description of the Related Art Unsaturated phosphonates have been found to have a basic skeleton in nature, and are known to exhibit their own physiological activity by acting with enzymes and the like. Also,
The Michael addition reaction of the compound with a nucleophile proceeds readily to give the corresponding phosphonate carbanion. Since the Horner-Emmons reaction is efficiently achieved by its addition reaction to a carbonyl compound, it is widely used as a method for synthesizing olefins. Therefore, unsaturated phosphonates are a group of compounds that are useful as carbon-carbon bond forming reagents, and particularly useful as synthetic intermediates of physiologically active substances such as pharmaceuticals and agricultural chemicals.

[0003] As a method of synthesizing an unsaturated phosphonate ester with formation of a carbon-phosphorus bond, generally,
It is known to replace the corresponding unsaturated halogen compound with a secondary phosphite. However, this method requires the addition of a base to capture the hydrogen halide formed simultaneously with the reaction, thereby producing a large amount of a hydrogen halide salt. Further, the unsaturated halogen compound as the starting material is not always easily available industrially, and generally has toxicity. For this reason, the method
It is not considered an industrially advantageous method. Recently,
A method of adding a secondary phosphite to an acetylene compound has been found (American Chemical Society, Vol. 118, 1571).
(Page, 1996, JP-A-9-136895), the efficiency of which is low in terms of reaction rate, and is not necessarily an industrially advantageous method.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a process for efficiently adding secondary phosphite to acetylene and producing an unsaturated phosphonate ester industrially and advantageously. Is what you do.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies on the reactivity between secondary phosphites and acetylene compounds in order to solve the above-mentioned problems. As a result, the present reaction was carried out in the presence of water. It has been found that the present invention has enhanced properties, and based on this fact, the present invention has been completed.

That is, according to the present invention, when a secondary phosphite is reacted with an acetylene compound in the presence of a palladium complex catalyst, the reaction is carried out in the presence of a small amount of water. An efficient method for producing a saturated phosphonate is provided.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION A secondary phosphite used as a reaction raw material in the present invention is represented by the following general formula (II). HP (＝ O) (OR ³ ) ₂ (II) In the above formula, R ³ represents an alkyl group, a cycloalkyl group, an aralkyl group, or an aryl. The alkyl group has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Specific examples thereof include methyl, ethyl, propyl, hexyl and the like. The cycloalkyl group has 3 to 12, preferably 5 to 6, carbon atoms. Specific examples thereof include cyclohexyl, cyclooctyl, cyclododecyl and the like. The aralkyl group has 7 to 13 carbon atoms, preferably 7 to 9 carbon atoms. Specific examples thereof include benzyl, phenethyl, phenylbenzyl, naphthylmethyl and the like. The aryl group has 6 to 14 carbon atoms, preferably 6 carbon atoms.
~ 12. Specific examples thereof include phenyl, naphthyl, and their substituted products (tolyl, naphthyl, benzylphenyl, etc.).

The acetylene compound used as a raw material in the present invention is represented by the following general formula (I). R ¹ C≡CR ² (I) In the above formula, R ¹ and R ² represent a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, an alkenyl group, an alkoxy group, an aryloxy group, It represents a monovalent group selected from silyl groups. The alkyl group has 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms. Specific examples thereof include methyl, ethyl, propyl, hexyl, decyl and the like. The cycloalkyl group has 5 to 18 carbon atoms, preferably 5 to 10 carbon atoms. Specific examples thereof include cyclohexyl, cyclooctyl, cyclododecyl and the like. The aryl group has 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Specific examples thereof include phenyl, naphthyl, and substitution thereof (tolyl, naphthyl, benzylphenyl, etc.). The heteroaryl group is derived from various cyclic compounds containing a hetero atom (enzyme, nitrogen, sulfur, etc.), and contains 4 to 12, preferably 4 to 8, atoms. Specific examples thereof include a thienyl group, a furyl group, a pyridyl group, and a pyrrolyl group. The aralkyl group has 7 to 13 carbon atoms, preferably 7 to 9 carbon atoms. Specific examples thereof include benzyl, phenethyl, phenylbenzyl, naphthylmethyl and the like. The alkenyl group has 2 to 18 carbon atoms, preferably 2 to 10 carbon atoms. Specific examples thereof include vinyl, allyl, 3-butenyl and the like. The alkoxy group has 1 to 1 carbon atoms.
8, preferably 1-4. Specific examples thereof include methoxy, ethoxy, butoxy and the like. The aryloxy group has 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms.
It is. Specific examples thereof include phenoxy and naphthyloxy. The silyl group includes those substituted with an alkyl group, an aryl group, an aralkyl group, and an alkoxy group. In this case, the alkyl group, the aryl group, and the aralkyl group include those described above. Specific examples thereof include trimethylsilyl, triethylsilyl, triphenylsilyl, tribenzenesilyl, phenyldimethyl, trimethoxy and the like. The above R ¹ and R ² are further functional groups inert to the reaction, for example, methoxy, methoxycarbonyl, cyano, dimethylamino,
It may be substituted with fluoro or the like. Examples of the acetylene compound preferably used in the present invention include, but are not limited to, unsubstituted acetylene, butyne, octyne, phenylacetylene, trimethylsilylacetylene, ethynylthiophene, hexinonitrile, cyclohexenylacetylene, and the like.

In order for the reaction of the present invention to occur, the use of a palladium catalyst is essential, and in the absence of a catalyst, no unsaturated phosphonate ester is formed. Although various structures can be used as the palladium catalyst,
Preferable ones are so-called low-valent palladium complexes, and particularly preferred are zero-valent complexes having tertiary phosphine or tertiary phosphite as a ligand. It is also a preferred embodiment to use an appropriate precursor complex which is easily converted to a zero-valent palladium complex in the reaction system. In the reaction system, a tertiary phosphine or a tertiary phosphite is not mixed with a complex containing a tertiary phosphine or a tertiary phosphite as a ligand. A method for generating a low-valent palladium complex as a ligand is also a preferred embodiment. Further, a tertiary phosphine or a tertiary phosphite is already mixed as a ligand and a tertiary phosphine or a tertiary phosphite is mixed in the reaction system. A method for generating another kind of low-valent palladium complex having phosphite as a ligand is also a preferred embodiment. As a ligand which exhibits advantageous performance by any of these methods, various tertiary phosphines and tertiary phosphites can be cited, and those having an extremely strong electron donating property in terms of reaction rate. Not always advantageous. Examples of suitable ligands include triphenylphosphine, diphenylmethylphosphine, phenyldimethylphosphine, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, , 1'-bis (diphenylphosphino) ferrocene, trimethylphosphite, triphenylphosphite and the like. Complexes that do not contain tertiary phosphine or tertiary phosphite used in combination with these ligands include bis (benzylideneacetone) palladium, palladium acetate, and the like. Tertiary phosphine and tertiary phosphite are already coordinated. Examples of the complex containing as a ligand include dimethylbis (triphenylphosphine) palladium, dimethylbis (diphenylmethylphosphine) palladium, (ethylene) bis (triphenylphosphine) palladium, and tetrakis (triphenylphosphine) palladium. However, the present invention is not limited to this. Palladium catalysts suitably used in the reaction include dimethylbis (triphenylphosphine) palladium itself, dimethylbis (diphenylmethylphosphine) palladium itself, (ethylene) bis (triphenylphosphine) palladium itself, dimethylbis (diphenylmethylphosphine) , Palladium itself, dimethylbis [1,3-bis (diphenylphosphino) propane] palladium itself, palladium acetate and 1,
A mixed system of 3-bis (diphenylphosphino) propane,
A mixed system of dimethylbis (diphenylmethylphosphine) palladium and 1,3-bis (diphenylphosphino) propane, tetrakis (triphenylphosphine) palladium and the like can be mentioned.

The amount of these palladium complexes to be used may be a so-called catalytic amount, which is generally 20 mol% or less based on the acetylene compound, and is usually 5 mol% or less, preferably 3 mol% or less. . Acetylene compounds and second
The use ratio of the primary phosphite is generally 1: 1:
Although 1 is preferred, a larger or smaller value does not inhibit the occurrence of the reaction.

The reaction of the present invention proceeds efficiently in the presence of a small amount of water. The amount of water added to reach the most efficient rate depends on the structure of the catalyst used for the reaction, particularly the structure of the ligand, but is generally 1 to 20 in a molar ratio to the amount of the palladium catalyst used. Is preferably within the range.
The concentration of water with respect to the volume of the whole reaction system is 10 to 1
In the range of 0.00000 ppm, preferably 100-5000
It is preferable to set in the range of ppm. The addition of this water to the reaction system shortens the reaction time,
The desired product can be obtained in an increased yield.

The reaction of the present invention does not require the use of a solvent, but can be carried out in a solvent if necessary. As the solvent, a hydrocarbon-based or ether-based solvent is generally used. If the reaction temperature is too low, the reaction does not proceed at an advantageous rate, and if the reaction temperature is too high, the catalyst decomposes. Is done. The intermediate of this reaction is sensitive to oxygen, and the reaction is preferably performed in an atmosphere of an inert gas such as nitrogen, argon, methane, or ethylene. Separation of the purified product from the reaction mixture is easily achieved by chromatography, distillation or recrystallization.

[0013]

The present invention will be described more specifically with reference to the following comparative examples and examples, but the embodiments are not limited to the examples.

Comparative Example 1 1 ml of benzene, 1 mmol of 1-octyne, 1 mmol of dimethyl phosphite, cis-PdMe as a catalyst
₂ (PPh ₃ ) ₂ (3 mol%) and add 6
The reaction was performed at 7 ° C. for 5 hours. By distilling the reaction solution, diethyl 1-octen-2-ylphosphonate (a) is obtained.
And diethyl 1-octen-1-ylphosphonate (b) were obtained in a ratio of 90:10 with a total yield of 51%.

Examples 1 to 5 The reaction was carried out in the same manner as in Comparative Example 1 except that various amounts of water were present in the reaction system. As a result, the results shown in Table 1 were obtained. This table shows that the reaction rate can be increased by adjusting the amount of water added, and that the selectivity of diethyl 1-octen-2-ylphosphonate (a) can be increased by adding water.

[0016]

[Table 1]

Example 6 In Example 3, unsubstituted acetylene was reacted instead of 1-octyne. In this case, dimethyl vinylphosphonate was formed in a yield of 87%.

Example 7 In Example 3, phenylacetylene was reacted instead of 1-octyne. In this case, α- and β-
Dimethyl phenylvinylphosphonate was produced in a 92% yield (α / β = 98/2).

[0019]

INDUSTRIAL APPLICABILITY According to the present invention, a novel unsaturated phosphonate ester useful for the synthesis of medicines and agricultural chemicals can be efficiently synthesized from acetylenes and secondary phosphites, and the separation and purification thereof can be performed. Easy. Therefore, the present invention has a great effect industrially.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-9-136895 (JP, A) JP-A-9-2955993 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07F 9/40

Claims (1)

(57) [Claims] 1. In the presence of a palladium complex catalyst, a compound represented by the following general formula (I): R ¹ C≡CR ² (I) wherein R ¹ and R ² are a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group , A heteroaryl group, an aralkyl group, an alkenyl group, an alkoxy group, an aryloxy group, and a silyl group, which are represented by the following general formula (II) HP (= O ) (OR ³ ) ₂ (II) (wherein, R ³ represents an alkyl group, a cycloalkyl group, an aralkyl group, or an aryl) when the secondary phosphite is reacted in the presence of water. Wherein R ¹ CH ＝ C (R ² ) P (＝ O) (OR ³ ) ₂ (III) wherein R ¹ , R ² and R ³ are Having the same meaning as described above). Manufacturing method of ether.