JP2003146911A - Method for producing acetylene derivative using strongly basic anion exchange resin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for industrially and advantageously producing an acetylene derivative useful as an intermediate for organic synthetic products such as a medicine or a polymer raw material at a low temperature in good yield. SOLUTION: This method for producing the acetylene derivative represented by general formula (II) (wherein, Ar denotes an aromatic ring or a heterocyclic ring group which may have a substituent; and n denotes 1 or 2) is carried out as follows. Deacetonation of a compound represented by general formula (I) (wherein, Ar denotes an aromatic ring or a heterocyclic ring group which may have a substituent; and n denotes 1 or 2) and having 3-hydroxy-3-methyl-1- butynyl group is carried out with a strongly basic anion exchange resin in an organic solvent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an acetylene derivative which is a compound useful as an intermediate for organic synthetic products such as medicines and a raw material for polymers, and more specifically, using a strongly basic anion exchange resin. Hydroxy-3-methyl-1
The present invention relates to an improved process for industrially producing an acetylene derivative from a compound having a butynyl group.

[0002]

2. Description of the Related Art A method for synthesizing an acetylene derivative includes a method for dehydrohalogenating a dihaloalkane or halogenated alkene obtained by halogenating a corresponding alkene, and 3-hydroxy. -3
A method of deacetonating a compound having a methyl-1-butynyl group with molten alkali or sodium hydride, methyl ketones such as acetophenone, DMF,
There is a method of reacting with phosphorus pentachloride and then dehydrochlorinating with alkali.

In the dehydrohalogenation method for dihaloalkanes or haloalkenes, products other than acetylene derivatives are likely to be produced, and the desired product is altered due to strong alkaline reaction conditions or high temperature reaction conditions, and the desired product is obtained. It is difficult to obtain with high purity.

The method of deacetonating a compound having a 3-hydroxy-3-methyl-1-butynyl group is characterized in that a highly pure target product can be easily obtained as compared with these methods.

In the method for synthesizing an acetylene derivative by deacetonation, sodium hydroxide or potassium hydroxide, which is hardly soluble in an organic solvent, or expensive sodium hydride is used as a base to react at a high temperature.

[0006] For example, Journal of Chemical Society
Perkin Trans. 1, Volume 5, Item 709 (1997) and J. Heterocy
cl. Chem. Volume 2, Item 607 (1984), Synthesis, Item 346 (1981)
In, 3-methyl-1-aryl-1-butyne-3
In the synthesis of aryl acetylene from ole, sodium hydroxide or potassium hydroxide is dissolved in a large amount of toluene and refluxed.

[0007] These require a large amount of solvent at a high temperature in order to sufficiently bring sodium hydroxide and potassium hydroxide into contact with the raw materials, and therefore scale-up is difficult.

On the other hand, J. Org. Chem. 10: 1763 (1985)
Then 2-methyl-4-phenyl-3-butyn-2-o-
Sodium hydride is added to reflux toluene to release acetone to form a terminal triple bond. Sodium hydride is a fire hazard and the reagents are expensive. Furthermore, it is difficult to handle because it is a powder.

Although all of these methods react at a high temperature of 110 ° C., the acetylene compound causes polymerization and decomposition due to heat, and damage to the reactor due to strong alkali and coloring of the contents are problems. Therefore, the reaction at a lower temperature has been desired.

[0010]

The present invention is a process for producing an acetylene derivative, characterized by deacetonating a compound having a 3-hydroxy-3-methyl-1-butynyl group with a strongly basic anion exchange resin. Is.

Further, the present invention provides the compound represented by the general formula (I):

[0012]

[Chemical 4]

(In the general formula (I), Ar represents an aromatic ring or a heterocyclic group which may have a substituent, and n represents 1 or 2), 3-hydroxy-3-methyl- A compound having a 1-butynyl group is deacetonized with a strongly basic anion exchange resin in an organic solvent, represented by the general formula (II):

[0014]

[Chemical 5]

(Wherein Ar represents an aromatic ring or a heterocyclic group which may have a substituent, and n represents 1 or 2), and a process for producing the acetylene derivative.

In addition, the present invention provides a strongly basic anion exchange resin having the general formula (III):

[0017]

[Chemical 6]

(In the formula, A represents a straight-chain alkylene group having 1 to 8 carbon atoms, and R ¹ , R ² and R ³ are each independently a carbon atom having 1 to 4 carbon atoms which may be substituted. A hydrogen group or an alkanol group is represented, X ⁻ represents a hydroxide ion, and the substituent A having an ammonium group may be substituted at any position of the benzene ring, and the benzene ring may further have an alkyl group and / or Or a quaternary ammonium hydroxide type anion exchange resin represented by (or may be substituted with a halogen atom), and a process for producing the above-mentioned acetylene derivative.

The present invention is characterized by using a strongly basic anion exchange resin as a base, and the reaction can proceed even at an extremely low temperature as compared with the conventional production method using alkali hydroxide or sodium hydride. found. Further, according to the present invention, it is possible to recover and reuse the reaction agent and the solvent, less by-products and coloring, and without damaging the reactor,
It is possible to obtain the target compound with a simple reaction operation under mild conditions and a high yield.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION The strongly basic anion exchange resin in the present invention comprises a quaternary ammonium group, a quaternary phosphonium group or a quaternary ammonium group on a polymer substrate having a three-dimensional network structure such as a styrene-polyvinylbenzene copolymer or an acrylic acid polymer. A tertiary sulfonium group is introduced with an ion exchange group, and examples thereof include those obtained by introducing a quaternized ammonium group using triethylamine or dimethylethanolamine after chloromethylating a polymer substrate. There are many commercially available products as such a strongly basic anion exchange resin.

The strongly basic anion exchange resin is a polymer insoluble in the reaction system of the present invention, and is styrene /
A gel-type or macro-crosslinked structure strong base anion exchange resin made of divinylbenzene polymer is preferable.

The strongly basic anion exchange resin used in the present invention is preferably a quaternary ammonium hydroxide type anion exchange resin containing the repeating unit represented by the general formula (III).

In the general formula (III), the A bonded to the ion exchange group is a linear alkylene group having 1 to 8 carbon atoms. Especially preferred of the alkylene chains are propylene chains, butylene chains, and pentylene chains. The alkylene group having an ion exchange group may be substituted at any position on the benzene ring.

In the general formula (III), the benzene ring is
It may be substituted with an alkyl group and / or a halogen atom. The alkyl group is C such as methyl group and ethyl group.
Examples of the halogen atom of the 1-C3 alkyl group include chlorine, bromine and iodine.

In the general formula (III), R ¹ , R ² and R ³ are hydrocarbon groups having 1 to 4 carbon atoms, particularly alkyl groups or alkanol groups having 1 to 4 carbon atoms such as hydroxylethyl. These groups may be different from each other, or some or all of them may be the same group,
It is particularly preferred that all are methyl groups.

In the general formula (III), X ⁻ represents a counter ion coordinated with an ammonium group, and in the present invention, an OH ⁻ type is used.

Specific examples of the strongly basic anion exchange resin represented by the general formula (III) include, for example, DIAION (registered trademark) PA316 and TSA120 manufactured by Mitsubishi Chemical Corporation.
0 is preferable, and TSA1200 is preferable.

Diaion PA316 (registered trademark) is
In the general formula (III), A is a methylene group, R ¹ , R ² ,
R ³ is a strongly basic anion exchange resin in which all are methyl groups, and Diaion TSA1200 (registered trademark) has a general formula (III) in which A is a butylene group, R ¹ , R ² and R ³
Is a strongly basic anion exchange resin in which all are methyl groups. Since these resins have a water content of 60 to 75% by weight, it is preferable to use them after rinsing and dehydrating with methanol.

The amount of the strongly basic anion exchange resin used is 3
A compound having a -hydroxy-3-methyl-1-butynyl group, particularly 10 to 500 g, and particularly 50 to 150 g per mol of the compound represented by the general formula (I) is preferable.

3-Hydroxy-3- that can be used in the present invention
The compound having a methyl-1-butynyl group is not particularly limited as long as it is a compound having one or a plurality of the groups, but preferably a cyclic hydrocarbon having one or a plurality of the groups (a monocyclic hydrocarbon, a condensed polycycle). Hydrocarbons, bridged cyclic hydrocarbons, cyclic spiro hydrocarbons, ring assembly hydrocarbons, etc., heterocyclic compounds (monocyclic compounds containing heteroatoms, polycyclic compounds, bridged cyclic compounds, cyclic spiro compounds) Etc.), ethers of the above cyclic hydrocarbons or heterocyclic compounds, etc., and particularly preferably
Aromatic and heterocyclic compounds represented by general formula (I) are preferred.

Specific examples of the Ar group of the general formula (I) include phenyl, naphthyl, anthryl, indenyl, azulenyl, fluorenyl, phenanthrenyl, acenaphthylenyl, biphenylenyl, naphthacenyl, pyrenyl, pentalenyl, heptanenyl, as-indacenyl, s-indacenyl. , Phenalenyl, fluoranthenyl, acephenanthrylenyl, aceanthrylenyl, triphenylenyl, chrysenyl, preyadenyl, picenyl, perylenyl, pentaphenyl, pentacenyl, tetraphenylenyl, hexaphenyl, hexacenyl, rubicenyl, coronenyl, trinaphthylenyl, hepta Phenyl, heptacenyl, pyrantrenyl, ovarenyl, pyridyl, pyrimidyl, furanyl, thienyl, piperidyl, quinolyl,
Isoquinolyl, pyrrolyl, 2H-pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, flazanyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolizinyl, chromenil, quinolidinyl, purinyl, 1H-indazolyl, quinazolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, pterazinyl, pterazinyl, pterazinyl, purazinyl, pterazinyl, pterazinyl, pterazinyl, pterazinyl. Examples include acridinyl, phenanthridinyl, xanthenyl, phenazinyl, phenothiazinyl, phenoxathiynyl, phenoxazinyl, thianthrenyl, chromanyl, isochromanil, ferrocenyl, and these groups are optionally substituted (e.g., alkyl groups, Even if it is substituted with an alkenyl group, aryl group, halogen group, amino group, carbonyl group, or alkoxy group There.

An organic solvent is used in the reaction of the present invention. Organic solvents include alkanes (pentane, hexane, heptane, octane) containing 5 to 8 carbon atoms, cycloalkanes (cyclopentane, cyclohexane, cycloheptane, cyclooctane) and isoalkanes (isopentane, isohexane, isoheptane, isooctane), It is preferably selected from the group of aprotic solvents such as benzene derivatives (eg benzene, toluene, xylene, chlorobenzene, or their mixtures or mixtures) and dioxane.

The amount of the organic solvent is usually 0.5 to 200 times by weight, preferably 0.5 to 200 times the weight of the compound having a 3-hydroxy-3-methyl-1-butynyl group, especially the compound represented by the general formula (I). It is used in the range of 2 to 10 times by weight, but it is not always necessary to use an amount such that all the raw materials are dissolved.

The temperature during the reaction in the present invention depends on the heat resistance of the strongly basic anion exchange resin used, but it is 50 ° C.
The range of -100 ° C is preferred.

The production method of the present invention can be carried out not only in a usual batch system but also in a continuous reaction by a flow type reactor.

[0036]

EXAMPLES Examples and preparation examples of the present invention are shown below.
The present invention is not limited to this. Preparation example 50.0 g of water-containing ion exchange resin Diaion (registered trademark) TSA1200 in 200 g of methanol at 25 ° C.
Stir at room temperature for 2 hours, filter, dry under reduced pressure at room temperature, and dehydrate Diaion (registered trademark) TSA1200 at 25.
3 g was obtained.

Example 1 3-Methyl-1-phenyl-1-butyne-3-in a reactor
5.04 g of ole, 20.2 g of hexane, Diaion TSA1200 (registered trademark) 2.52 prepared in Preparation Example
g, and stirred at 50 to 60 ° C. for 18 hours. The reaction mixture was filtered to remove insoluble ion exchange resin, and the filtrate was concentrated to obtain 2.80 g of ethynylbenzene (purity by liquid high performance chromatography: 94%). From the proton nuclear magnetic resonance spectrum and the retention time of high performance liquid chromatography, it was confirmed that the product structure was ethynylbenzene.

Example 2 1,4-bis (3-hydroxy-3-methyl-) was added to a reactor.
1-butynyl) benzene 4.64 g, toluene 15.0
g, 15.0 g of Diaion TSA1200 (registered trademark) prepared in Preparation Example was added, and the mixture was stirred at 55 to 65 ° C. for 12 hours. The reaction mixture was filtered to remove insoluble ion exchange resin, and the filtrate was concentrated to obtain 3.86 g of 1,4-diethynylbenzene (purity 79.7% by liquid high performance chromatography). Proton nuclear magnetic resonance spectrum,
From the retention time of liquid high performance chromatography, it was confirmed that the product structure was diethynylbenzene.

Example 3 5.12 g of 2- (3-hydroxy-3-methyl-1-butynyl) pyridine, 10.0 g of hexane, and Diaion TSA1200 (registered trademark) prepared in Preparation Example were placed in a reactor.
2.52 g was added, and the mixture was stirred at 55 to 65 ° C for 12 hours. The reaction mixture was filtered to remove insoluble ion exchange resin, and the filtrate was concentrated to give 2-ethynylpyridine (4.06 g).
(Purity 40.15 by liquid high performance chromatography
%) Was obtained. From the retention time of liquid high performance chromatography, it was confirmed that the structure of the product was 2-ethynylpyridine.

Example 4 Bis [4- (3-hydroxy-3-methyl-1) was added to a reactor.
-Butynyl) phenyl] ether 22.6 g, monochlorobenzene 89.5 g, and Diaion TSA1200 (registered trademark) 18.1 g prepared in the preparation example were added, and
Stir at 90 ° C. for 48 hours. The reaction mixture was filtered to remove insoluble ion exchange resin, and the organic layer was concentrated to obtain 16.8 g of bis (4-ethynylphenyl) ether (purity 71.2% by liquid high performance chromatography). From the proton nuclear magnetic resonance spectrum and the retention time of high performance liquid chromatography, the structure of the product was bis (4-
It was confirmed to be ethynylphenyl) ether.

[0041]

INDUSTRIAL APPLICABILITY According to the present invention, a method for producing acetylenes in good yield and industrially advantageous is provided.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 213/127 C07D 213/127 // C07B 61/00 300 C07B 61/00 300 F term (reference) 4C055 AA01 BA02 BA06 CA01 DA01 FA01 FA32 4H006 AA02 AC26 BA51 BA72 GP06 4H039 CA31 CG90

Claims (3)

[Claims] 1. A process for producing an acetylene derivative, which comprises deacetonating a compound having a 3-hydroxy-3-methyl-1-butynyl group with a strongly basic anion exchange resin. 2. General formula (I): (In the general formula (I), Ar represents an aromatic ring or a heterocyclic group which may have a substituent, and n represents 1 or 2), 3-hydroxy-3-methyl-1-butynyl A compound having a group is deacetonized with a strongly basic anion exchange resin in an organic solvent, represented by the general formula (II): (In the formula, Ar represents an aromatic ring or a heterocyclic group which may have a substituent, and n represents 1 or 2). 3. The strongly basic anion exchange resin has the general formula (III): (In the formula, A represents a linear alkylene group having 1 to 8 carbon atoms, R ¹ , R ² and R ³ are each independently a hydrocarbon group having 1 to 4 carbon atoms which may be substituted or Represents a alkanol group, X ⁻ represents a hydroxide ion, and the substituent A having an ammonium group may be substituted at any position of the benzene ring, and the benzene ring may further contain an alkyl group and / or
Or a quaternary ammonium hydroxide type anion exchange resin represented by (or may be substituted with a halogen atom), the process for producing an acetylene derivative according to claim 1 or 2.