JPH02279644A - Production of 4-methyl-4-hydroxy-1-octyne - Google Patents

Abstract

PURPOSE:To obtain the subject compound which is useful as an intermediate of medicines or agricultural chemicals, especially prostaglandin safely in high yield with industrial advantage by dehydrohalogenation of a specific alcohol with a base in a solvent. CONSTITUTION:The reaction of 2-hexenone with 2,3-dihalogeno-1-propene of formula I (X is halogen, Y is Cl, Br) is carried out in a solvent such as tetrahydrofuran in the presence of Zn powder or fine dust and water, when needed, in the coexistence of ammonium halide to give an alcohol of formula II. Then, the alcohol is allowed to react with a base such as caustic soda in an amount of usually 1 to 15 equivalents in a solvent such as dimethylformamide at -20 to 120 deg.C until the alcohol disappears. After completion of the dehydrohalogenation, the reaction mixture is filtered, combined with water poured, extracted, separated and the organic phase is concentrated to give the subject compound.

Description

Detailed Description of the Invention <Industrial Utilization Public Funds> The present invention provides a method for producing 4-methyl-4-hydroxy-1-octyne, which is useful as an intermediate for pharmaceuticals or agricultural chemicals, especially as a pstaglandin intermediate. Regarding.

<Prior art and its problems> 4-Methyl-4-hydroxy-1-octyne has been produced from propargyl bromide or propargyl chloride and 2-hexanone in a Grignard reaction zone ζ. However, since propargyl bromide or propargyl chloride is self-degradable, there are problems such as the need for measures (safety measures) to suppress their self-degradability when used in large quantities industrially. However, the above production method is not necessarily an industrially advantageous method.

<Problems to be solved by the invention> The present inventors have solved these problems and achieved four industrial advantages.
- To produce methyl-4-hydroxy-1-octyne (As a result of intensive study, the present invention was completed.

Means for Solving the Problems> The present invention provides alcohols represented by the general formula (I) CHs-CCHtaka\/(1) (wherein, X represents a halogen atom). This is a method for producing 4-methyl-4-hydroxy-1-octyne, which is characterized by dehydrohalogenation by reaction with a base in a solvent.

Examples of the base used in the present invention include organic lithiums such as n-butyllithium, 8-butyllithium, t-butyllithium, benzyllithium, furyllithium, vinyllithium, phenyllithium, and methyllithium, lithium hydride, and hydrogenated lithium. Alkali metal hydrides such as sodium and potassium hydride, sodium methoxide, potassium t-
Alkali metal alcoholades such as butoxide, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or diazabicycloundecene (D
Examples include strong organic bases such as BU), diazabisciffournonene (DBN), and diazabicyclooctane (DBO).

Such a base is usually 1 to 16 with respect to the alcohol (I).
It is used in an equivalent amount, preferably 1 to 6 equivalent times.

The solvent depends on the base used. When using organolithiums or strong organic bases, hydrophilic aprotic solvents such as tetrahydrofuran or dioxane or hydrophobic hydrocarbons such as pentane, n-hexane, n-hebutane, benzene, toluene or xylene. A single solvent or a mixture of solvents that are inert to the reaction can be used, such as a system solvent.

When using an alkali metal hydride, -ζ is an aprotic polar solvent such as dimethylformamide or dimethyl sulfoxide, and when using an alkali metal alcoholade, ethyl ether, isopropyl ether, or tert-butanol is used. Alcohol-based solvents such as .

When using alkali metal hydroxides, water or mixtures of water and these exemplified solvents are used in addition to the exemplified solvents for the alkali metal alcoholades, water and toluene, xylene, pentane or Hydrophobic hydrocarbon solvents such as hexane or mixtures of water and hydrophobic halogenated hydrocarbon solvents such as monochlorobenzene or dichlorobenzene are also used.

゛The amount of solvents other than water to be used is not particularly limited, but is usually 0.1 to 20 times the weight of alcohol (I) ζ.

When water is used as a solvent, it is usually used in an amount of 1 to 6 times the weight of the alkali metal hydroxide 6r.

In the present invention 6ζ, a catalyst may be used, and the amount used is usually o,
o o s~6 times the weight.

Such catalysts include tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-pentylammonium bromide, tetra-n-
Organic quaternary ammonium salts such as pentylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltripropylammonium chloride, benzyltripropylammonium iodide or cetyltrimethylammonium chloride or higher alkylbenzene sulfonates, higher fatty acids Examples include surfactants such as salts, polyoxyethylene alkylphenol ethers, and higher aliphatic alcohols.

The reaction is usually carried out at -20 to 120°C, preferably -10 to 11°C.
Perform at 0°C.

The reaction time is not particularly limited, and usually alcohol (I)
The end point of the reaction is the point at which ξ disappears from the reaction system.

After the reaction is complete, 4-methyl-4-hydroxy-1-octyne can be removed from the reaction mixture by, for example, filtration, water injection,
After extraction, liquid separation, etc., the organic layer is concentrated or distilled.

Alcohols that are raw material compounds (D is 2-hexanone and the general formula aI) (wherein, X represents a halogen atom and Y represents a chlorine atom or a bromine atom, respectively) 7 2,8-dihalogeno-1 - Produced from kerosene and heat ζ, which are reacted with propene in the presence of zinc and water.

As 2.8-dihalogeno-1-propene, 2.8-
Dichloro-1-propene, 2-chloro-8-bromo-1
-propene, 2-bromo-8-chloro-1-propene,
Examples include 2,8-dibromo-1-propene.

These 2,8-dihalogeno-1-propenes (■) are usually used in a molar range of 1 to 4 times the amount of 2-hexanone (ζ);
．． If 8-dihalogeno-1-propene is expensive, 2-hexanone can be used as m2 #8-dihalogeno-1-
It can also be called ξ, which is used in excess of propene.

Zinc is usually used in the form of powder or fine particles.

Zinc is usually used in an amount of 1 to 8 times, preferably 1 to 2 times, equivalent to 2,8-diherogeno-1-propene.

Water is usually used in an amount of 1 to 50 times the weight of 2-hexanone, but the amount used is not particularly limited.

In addition to water, an organic solvent may be present, and such organic solvents include aliphatic or aromatic hydrocarbons such as n-hexane, toluene, or xylene, ethers such as diethyl ether or tetrahydrofuran, or amines such as pyridine. Examples include solvents.

These organic solvents are usually 0.1 to 2-hexanone.
~80 times the weight is used, but the amount used is not limited to the special number ζ.

In the present invention, ammonium halides such as ammonium chloride or ammonium bromide may be coexisting, and the amount used is usually 0.06 to 1 times the weight of water, preferably 0.1 to 1 times the weight of water. be.

Moreover, an acid can also be used instead of heptammonium halide.ζ. As such an acid, a mineral acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or an organic acid such as acetic acid is used, and the amount used is not particularly limited, but is preferably 0.01 to 10 times mole based on 2-hexanone.

Furthermore, in the present invention, it is also possible to use organic quaternary ammonia and cum salt.

Such organic quaternary anthonium salts include tetra n-
Butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-pentylammonium bromide, tetra-n-pentylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltripropylammonium chloride, benzyltripropyl Examples include ammonium iodide, dodecyltrimethylammonium bromide, and cetyltrimethylammonium chloride.

The reaction is usually carried out at 6 to 96°C, preferably 10 to 80°C, more preferably 20 to 60°C, and the end point of the reaction is usually either 2-hexanone or 2°8-dihalogeno-1-propene. It is determined at the time when the substance disappears from the reaction system.

After completion of the reaction, the alcohol (I) can be removed from the reaction mixture by, for example, filtration, extraction, liquid separation, etc., and then concentrating or distilling the organic layer.

<Effects of the Invention> According to the present invention, 4-methyl-4-hydroxy-1-octyne can be produced safely and industrially advantageously.

<Example> The present invention will be explained below with reference to Examples.

Example 1 2-hexanone 40 t, tetrahydrofuran 1 00
t, zinc powder 62.8F, water 800F and acetic acid 17F
of 2.8-dichloro-1.- at 80-85°C.
Add Propene 66F over 8 hours. After the dropwise addition was completed, the mixture was stirred at the same temperature for 1 hour. After the reaction was completed, 50 g of ethyl acetate was added to the reaction solution. The organic layer of the Oki liquid was concentrated under reduced pressure to give 2-chloro-4-hydroxy-4-methyl-
55.5 t of 1-octene (yield yes) was obtained. nD
1.457g of 2-chloro-4-hydroxy-
A mixture of 85.8 f of 4-methyl-1-octene, 200 f of dimethylformamide and 82 f of caustic soda was
Stirred at ~50°C for 6 hours.

After the reaction was completed, the reaction mixture was poured into ice water, and then extracted with ethyl ether. After separation, the organic layer was concentrated and 25.2% of 4-methyl-4-hydroxy-1-octyne
F (yield 90%) was obtained.

Example 2 40 tons of 2-hexanone, 62.8 tons of zinc powder.

In a mixture of 40f ammonium chloride and 800f water,
66t of 2,8-dichloro-1-propene at 80-40℃
A mixture of 50 f of tetrahydrofuran and 50 f of tetrahydrofuran is added over 1 hour.

After completion of the dropwise addition, the mixture was stirred at the same temperature for 2 hours. After the reaction was completed, the reaction solution was extracted with 800 ml of ethyl acetate.

The organic layer was concentrated under reduced pressure, and the resulting residue was distilled to 2
-Chloro-4-hydroxy-4-methyl-1-octene 45.6f (yield 65%') was obtained.

2-chloro-4-hydroxy-4-methyl- obtained here
1-octene 86.8F and diethyl ether 200
A n-butyllithium-hexane solution (1,6M concentration) 126- was added dropwise to the mixture of F over 2 hours at -20°C.

After stirring at the same temperature for 2 hours, the reaction mixture was poured into ice water,
Afterwards, it was overtreated. After separating the Oki liquid, the organic layer was concentrated under reduced pressure to obtain 4-hydroxy-4-methyl-1-octyne 18.7F (49% yield).

Example 8 2-hexanone 40t1 zinc powder 89t, cetyltrimethylammonium chloride 6f, toluene 60t, water 800t
and 2,8-dibromo-1-propene 108F, 6% hydrochloric acid 800F was added at 40 to 45'C over 8 hours while maintaining the pH Hlk in the reaction system at 4.0 to 4.6. . After the addition was completed, the mixture was stirred at the same temperature for 1 hour.

After the reaction was completed, the reaction solution was separated and the organic layer was concentrated under reduced pressure to obtain 2-bromo-4-hydroxy-4-methyl-1-octene 68F (yield 72%).

n IJO12 C1' Add 45% to a mixture of 44.2F of the obtained 2-bromo-4-hydroxy-4-methyl-1-octene, 176t of toluene and 82f of tetrabutylammonium bromide.
96 caustic potassium aqueous solution was added dropwise at 60 to 60°C over 4 hours. After the dropwise addition was completed, the mixture was stirred at the same temperature for 2 hours. The reaction mixture was separated and the organic layer was washed with water. Thereafter, the organic layer was concentrated under reduced pressure to give 4-hydroxy-4-methyl-
1-octyne 17.6? (yield: 68%).

Example 4 2-hexanone 40t, tetrahydrofuran 100t
sZinc powder 52.8F% water 800t.

Tetrabutylammonium bromide 52 and acetic acid 17
t mixed pasture ζ, 2°8-dichlor-1 at 80-85°C
- Propene 66F was added over 8R. After finishing dropping,
It was kept at the same temperature for 80 minutes.

Hereinafter, 2-chloro-4-
Hydroxy-4-methyl-1-octene 56.9, t
(yield 81%).

2-chloro-4-hydroxy-4-methyl- obtained here
A mixture of 1-octene 86f1 dioxane 10F, benzyltrimethylammonium chloride IP, N-methylpyrrolidone 100t and caustic potassium 16.8F was added to 60
Stirred at ~60°C for 4 hours. After the reaction was completed, the reaction mixture was poured into ice water and extracted twice with ethyl acetate IQ Oml. The organic layer after separation was washed with water. Thereafter, the organic layer was concentrated under reduced pressure to obtain 4-hydroxy-4-methyl-1-octyne 26f (yield: 9296).

Example 6 2-hexanone 40f, toluene 50v.

Zinc powder52. Of, 2,8-dibromo-
1-propene 108f was added over 2 hours. After the dropwise addition was completed, the mixture was stirred at the same temperature for 8 hours.

Thereafter, the same post-treatment as in Example 1 was carried out to obtain 59.8f of 2-bromo-4-hydroxy-4-methyl-1-octene (yield 68%).

2-bromo-4-hydroxy-4-methyl- obtained here
1-Octene was reacted and post-ripened in the same manner as in Example 1 except that sodium chloride methylate 16.2f was used instead of caustic soda to give 4-hydroxy-4-methyl-1.
-Octyne is obtained.

Example 6 2-iodo-4-hydroxy-4-methyl- instead of 2-chloro-4-hydroxy-4-methyl-1-octene
4-hydroxy-4-
Methyl-1-octyne is obtained.

Claims (2)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, X represents a halogen atom.) It is characterized by dehydrohalogenation by reacting alcohols with a base in a solvent. 4-methyl-4-
Method for producing hydroxy-1-octyne. (2) 2-Hexanone and 2,8-dihalogeno-, which is represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. 2. The method for producing 4-methyl-4-hydroxy-1-octyne according to claim 1, wherein the alcohol is obtained by reacting 1-propene in the presence of zinc and water.