JPH02204486A - Production of 2,4-dialkylthiazole - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an intermediate for medicines, etc., by regulating pH of a mixture containing a halomethyl alkyl ketone and reacting the regulated mixture with a thioalkanoic acid amide. CONSTITUTION:(A) A methyl alkyl ketone expressed by formula I (R<1> is 2-5C alkyl) is halogenated in the presence of a reaction initiator in a hydrophilic inert organic solvent to provide a mixture containing a halomethyl alkyl ketone expressed by formula II (X is Cl<-> or Br<->). The resultant mixture is then reacted with (B) a thioalkanoic acid amide expressed by formula III (R<2> is 1-4C alkyl). In the process, the component (A) is previously regulated to pH5-8 with an alkali and then reacted with the component (B) to afford the objective thiazole expressed by formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing co,+-sialgylthiazole, which is useful as a pharmaceutical intermediate, in high yield.

(The problems that the prior art and the invention are trying to solve 1)
A commonly known method for producing goudialkylthiazoles is a method in which a halomethylalkyl ketone and a thioalkanoic acid amide are reacted (Hump reaction).

CII:l (III:)
[:IV:1 (in the formula, R1 represents an alkyl group of q~, X represents a chlorine atom or a bromine atom, R represents an alkyl group of q~) For example, JAC8 (Journal of the American Chemical Society) 2J, One in 377
5'? ? ? For (/Y,!2), bromomethylalkyl ketone and thioacetamide are reacted in a benzene solvent under reflux, the mixture after one reaction is treated with dilute hydrochloric acid, a small amount of the solvent is removed by steam distillation, and then There is a description that the target compound was obtained in a yield of 76% by decomposing the hydrochloride of the target thiazole compound with caustic alkali.

and.

, 1゜Agr-Food Chem-(Journal Op Agri-Food Chem-)L, /3141-/Jt6(/9g,?)
It is reported that, as a result of repeated trials in the same manner as in all of the above methods, the yield of the target compound was 5o11j. Also,
J-IndianChem-8oc- (Journal of the Indian Chemical Noise) Part 3
．． AJl'J-4 (/-97G) K dissolves thioacetamide in an equimolar amount of caustic alkaline water bath solution, adds an ethanol solution of bromomethylalkyl quatone, stirs overnight, and then dissolves the product in a solvent. It is stated that the target compound was obtained in a yield of 5OCS by extraction. However, when the present inventors retested this method, the pH in the reaction system was ~7.2, and the yield was 57%.

- On the other hand, the halomethylalkylketone used as a raw material here is usually easily obtained by halogenating methyl alkylketone in a hydrophilic inert organic solvent in the presence of a known reaction initiator. Because halomethylalkylketones are thermally unstable and difficult to release immediately, and exhibit strong lachrymatory and skin irritation properties, it is best to handle the reaction mixture under sealed conditions while keeping it as low as possible. desirable. However, in the mixture obtained by this halogenation reaction,
Since it contains acidic by-products such as hydrohalic acid and various other by-products, the reaction mixture is usually washed with water before being subjected to the subsequent reaction, but in the case of the reaction with Thioa A/canoic acid amide. Even if you use a mixture sound washed with water,
Aim for 41. - The yield of dialkylthiazole was not high.

(Means for Solving the Problem) In view of the above-mentioned circumstances, the present inventors used a reaction mixture containing a noromethylalkylketone obtained by a halogenation reaction of a methylalkylketone, and converted it into a thioalkanoic acid amide. As a result of various studies on the reaction method that can obtain J, 4tL dialkylthiazole in high yield, an alkali was added to the mixture obtained by the halogenation reaction to adjust the pH in the system to J''~g. They then discovered that by reacting with thioalkanoic acid amide, halomethylalkylketones can be handled under sealed conditions and the target compound can be obtained in high yield, thus completing the present invention.

That is, 1. The gist of the present invention is as follows:
Hs...CI) (In the above formula, π is C
In the presence of a reaction initiator, in a hydrophilic inert organic solvent, a methyl alkyl ketone represented by an alkyl group of 2 to S is converted into the following compound [■] (the above formula where 5R' is as defined in the above-mentioned CI), and X represents a chlorine atom or a bromine atom. (In the above formula, R represents an alkyl group of C8~) By reacting with a thioalkanoic acid amide, the following -incorporation [■] \ (in the above formula, % R' and R2 are as defined in [I] and [■] above) In the method for producing 23-cudi alkylthiazole, an alkali is added in advance to a mixture containing a halomethylalkyl ketone, and the pH is adjusted to The present invention relates to a method for producing a co-dialkylthiazole, which is characterized in that it is reacted with a thioalkanoic acid amide after adjusting it to 5.--ffK.

The present invention will be explained in detail below.

In the present invention, the methyl alkyl ketone represented by the above-mentioned entry [I] is first halogenated in a hydrophilic inert organic solvent in the presence of a reaction initiator, and the methyl alkyl ketone represented by the above-mentioned entry [I] is converted into a halogen represented by the above-mentioned entry (II). Methyl alkyl ketones are produced, and the methyl alkyl ketones used as raw materials include, for example, methyl ethyl ketone, methyl-n-propyl ketone, and methyl-n-propyl ketone.
Examples include ketones having a methyl group and an argyl group of C,=,, such as isobutyl ketone and methyl amyl ketone. On the other hand, molecular chlorine or molecular bromine is usually used as the chlorogenating agent, but molecular bromine is more desirable in view of the reactivity of the subsequent thiazolization.

The amount of halogenating agent used is usually θ relative to the methyl alkyl ketone. It may be about g~·7.2 times the mole.

The reaction initiator may be any known one, and typically includes hydrohalic acids such as hydrobromic acid, aliphatic carboxylic acids such as acetic acid and acetic anhydride, or their anhydrides, aluminum chloride, ferric chloride, etc. Lewis acids, iodine and mixtures thereof. The amount of these reaction initiators to be used is preferably 0.5 to 10% by weight, more preferably 5 to 3% by weight, based on the methyl alkyl ketone.

The halogenation reaction is carried out in a hydrophilic inert organic solvent, and specific examples of this solvent include methanol,
C, aliphatic monohydric or polyhydric alcohols such as ethanol, n-globanol, ibutanol, amyl alcohol, ethylene glycol, glycerin, or dimethyl ether, diethyl ether, methyl ethyl ether,
Examples include aliphatic or alicyclic ethers such as tetrahydrofuran and dioxane. The amount of these solvents used is usually o. r~koθ is the double weight of the image.

The temperature of the halogenation reaction is usually -is to QO℃, preferably 1/θ to -0℃, and the reaction time is usually 0.1-
/θ time. If the reaction temperature is too high, a large amount of by-products such as α-10 alkyl methyl ketone, which is an isomer of the target compound, will be produced; on the other hand, if the reaction temperature is too low, the halogenation reaction will not start. In addition, the reaction time depends on the conditions.
The initial reaction time may include any induction period.

In the present invention, it is necessary to mix the reaction mixture containing the no-romethylalkyl ketone obtained in the above-mentioned halogenation reaction with an alkali and adjust the 1iHf5~xFC of the mixture before reacting it with the thioalkanoic acid amide. Yes, and even 3! It is desirable to adjust it to f~ri・S. That is, by adjusting the pH within this range, the subsequent reaction with the thioalkanoic acid amide (5) proceeds favorably, making it possible to obtain co-,cudi-alkylthiazole in high yield. Furthermore, in the present invention, the produced halomethylalkyl ketone can be handled under sealed conditions, which is preferable in terms of industrial operations.

The alkali used here is usually a hydroxide or carbonate of an alkali metal or an alkaline earth metal, such as caustic soda, caustic potash, carbonate, potassium carbonate, magnesium carbonate, and the like. Alkali can be added in solid form, but it is usually preferable to add it as an aqueous solution. Addition of alkali is usually carried out at a temperature of -10 to -0°C. Addition of alkali After that, the mixture is stirred to become a homogeneous mixture, and then the subsequent thiazolization reaction is carried out.

The thioalkanoic acid amide used in the thiazolization reaction is the compound shown in the above-mentioned [■]64), and the amount used is usually 0.00% relative to the heromethylalkyl ketone. −/, 2 moles. This reaction method is usually carried out by supplying a powder or an aqueous or alcoholic solution of a thioalkanoic acid amide to a mixture containing the above-mentioned halomethylalkyl ketone. This thiazo
Since the oxidation reaction is an exothermic reaction, the thioalkanoic acid amide usually needs to be fed sequentially to account for the heat removal.

The reaction temperature for thiazolization is usually θ to 100°C, preferably 20 to 30°C. Further, the reaction time is usually about /% J hours after the completion of supply of thioate/canoic acid amide.

In the case of the present invention, the co-cudialkylthiazole represented by the GVI formula produced by this thiazolization reaction is a hydrohalide salt of a 2-helical dialkylthiazole. , and adjust the pH in the system to 11 or more to obtain F) the target compound. Then, the target compound can be recovered by extracting this mixture according to a conventional method.

(Effects of the Invention) According to the present invention, the reaction mixture containing halomethylalkylketone obtained in the halogenation reaction of methylalkylketone can be directly used in the next thiazolization reaction. This method allows handling of halomethylalkyl ketones in a sealed state, making it a highly desirable method for industrial operations. Furthermore, since the reaction mixture obtained in the )Sr3 generation reaction was adjusted to a specific pH, the yield of co,+-dialkylthiazole obtained in the thiazolization reaction was high. Furthermore, in the thiazolization reaction, malodorous components such as hydrogen sulfide and mercaptan may be produced due to the decomposition of reaction intermediates depending on the pH, and the present invention also exhibits such drawbacks.

(Example) Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to the following examples unless it exceeds the gist thereof.

Example 1 To methyl isopropyl ketone AF (/, 0 mol), add 62 g of a solution prepared by dissolving hydrogen bromide in methanol J7θml and acetic acid to a JOaJ concentration, and -j'
It was cooled to C. Bromine salt 2 was added to this solution, and the bromination reaction started after a 50-minute reaction induction period. After that, while keeping the reaction temperature at o-, t℃, the total amount of bromine ts, 2tc was 16
θ? Bromination was carried out by adding 1.0 mol of 21.0 mol). Based on the gas chromatography analysis results of the reaction solution, what is the reaction rate of the raw material ketone? 9.7, what is the selective production rate of bromomethyl ketone? ,6 I was disappointed.

While measuring the pH of this reaction solution, add anhydrous sodium carbonate? ? , JF and adjust the pH to 7. Adjusted to lI. The temperature of the reaction mixture was 6 fc at 5°C.

To this reaction solution, add thioacetamide 7j2 (h〇mol)
To prevent the temperature from i) rising above 5θ℃ due to heat generation,
Powder in several doses! ! , added.

After the total amount of ft was added, the reaction was continued for another 7 hours at Air°C. Add 25% caustic soda/A O' to this reaction solution.
? (/, 0 mol) was added to liberate the thiazole compound.

As a result of analyzing the reaction product by gas chromatography, the yield of methylisopropylketone KJt17 was 7% (7%).
zll, s%] for bromomethylketone. Note that hydrogen sulfide and mercaptan were not detected in the reaction product. .

Examples 2 to 1 In Example 1, the type of raw material ketone, the conditions of the pyrolysis reaction and the thiazolization reaction, and the pH of the bromination reaction mixture
As shown in Table 7, each reaction was carried out in the same manner as shown in Table 7, and the consistent yield for the starting ketone was the first.
It was as shown in the table.

In addition, in any case, during the thiazolization reaction, hydrogen sulfide, No mercaptan formation was observed. won.

Comparative Example/Example/Methyl isopropyl ketone was brominated in the same manner as in Example/, and then converted to sodium bicarbonate. After adding f (/, 0 mol) to make pl] and θ, thioacetamide was added to perform a -C thiazolization reaction.

A mixed gas of hydrogen sulfide and mercaptan is generated from the reactor, and the analysis results of the product show that the yield of comethyl-isoprobyl thiazole is 6 g% based on methyl impropyl ketone (7/7% based on bromomethyl ketone). ,!;q6)
Met.

Comparative Example In Example 1, after the bromination reaction, 1,2.5' sodium hydroxide (as NaOH) was added dropwise to adjust the pH/
/, after setting it to 1, add thioacetamide to make thiazo.
−・A reaction was carried out.

Although no hydrogen sulfide mercaptan was generated, the yield of the target product was 1] based on the raw material ketone (so, 3% based on bromomethyl ketone).

Claims (1)

[Claims] (1) Methyl alkyl ketone represented by the following general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] (In the above formula, R^1 represents an alkyl group of C_2 to_5) The following general formula [II] is obtained by halogenation in a hydrophilic inert organic solvent in the presence of a reaction initiator. There are mathematical formulas, chemical formulas, tables, etc.▼...[II] (In the above formula, R^ 1 is as defined in the above general formula [I], and X represents a chlorine atom or a bromine atom). etc.▼...[III] (In the above formula, R^2 represents an alkyl group of C_1 to_4) By reacting with a thioalkanoic acid amide, the following general formula [IV] ▲ Formula, There are chemical formulas, tables, etc.▼...[IV] (In the above formula, R^1 and R^2 are the above general formula [I]
and 2,4 as defined in [II])
- A method for producing a 2,4-dialkylthiazole, which comprises adding an alkali to a mixture containing a halomethylalkyl ketone in advance to adjust the pH to 5 to 8, and then reacting the mixture with a thioalkanoic acid amide. manufacturing method.