JP2003261547A - Method of producing 4-alkyl-5-formylthiazole derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a simple and general method for producing 4-alkyl-5- formylthiazole derivative in high yield by overcoming problems in the conventional production process. <P>SOLUTION: In the production process for 4-alkyl-5-formylthiazole derivative represented by general formula (2) (R<SP>1</SP>is a 1-4C alkyl; R<SP>2</SP>is H or an amino group which may be substituted), 4-alkyl-5-hydroxymethylthiazole derivative represented by general formula (1) [R<SP>1</SP>and R<SP>2</SP>are each identical in the formula (2)] is subjected to the oxidation reaction in a two-phase solvent system of a high water-solubility carboxylic ester or ketone solvent and an aqueous solution in the presence of an N-oxyl compound. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 4-alkyl-5
-A process for the production of formyl thiazole derivatives. The 4-alkyl-5-formylthiazole of the present invention is useful, for example, as a synthetic intermediate for thiamine (vitamin B1) [J. Am. Chem. Soc. , 61, 891 (19
39)], and also useful as a raw material for agricultural chemicals and pharmaceuticals [Organic Synthetic Chemistry, Vol. 60, No. 2, p15].
5-161 (2002)].

[0002]

2. Description of the Related Art Conventionally, as a method for producing a 4-alkyl-5-formylthiazole derivative represented by the formula (2),
Japanese Examined Patent Publication 7-107052, Appl. Catal. ，
88, 149 (1992), Stud. Surf. Sc
i. Catal. , 90, 47 (1994) and others, a method by a reduction reaction of an ester compound (3) is known. However, in the catalytic hydrogenation reaction using these metal catalysts, the conversion rate and selectivity are still low, and high temperature is required, so it cannot be said that the method can be practically used.

[0003]

[Chemical 3]

Similarly, a method for producing a 5-formyl-4-methylthiazole derivative starting from the ester compound 3 is described in J. Am. Chem. Soc. , 61, 89
1 (1939), a method via a hydrazide compound is known. However, the total yield was 2
It is as low as 3% and cannot be said to be a method for practical use.

[0005]

[Chemical 4]

Further, a decarboxylation formylation reaction by oxidation of naturally occurring compound (6) is also known [J. A
m. Chem. Soc. , 4943 (1982)].

[0007]

[Chemical 5]

In this method, pyridinium dichromate (PDC), which is a chromium reagent, must be used in a stoichiometric amount in the oxidation reaction, so that industrial production is impossible. Besides this, a method using 4,5-dimethylthiazole (7) as a starting material [Eur. J. Org. C
hem. , 593 (1998)], but the total yield is low and the number of steps is large, so that the method cannot be put to practical use. NBS is N-bromosuccinimide, C ₆
H ₁₂ N ₄ is hexamethylenetetramine.

[0009]

[Chemical 6]

As described above, although various synthetic methods have been developed, there is no synthetic method that enables industrial production, and the creation of a practical synthetic method has been strongly desired.

Although a method for synthesizing aldehydes by oxidation of alcohols has been performed for a long time and many methods are known, no special equipment is required, inexpensive reagents are used, and a high yield is obtained. Little is known about how it can be manufactured. For example, P. L. Anelli et al. Torii
Et al. Report that the corresponding aldehyde can be obtained from alcohol by a method using N-oxyl compound as a catalyst in a mixed solvent system of methylene chloride-water. [J. Org.
Chem. 52, 2559 (1987), J. Am. Or
g. Chem. 54, 2970 (1989), J. Am. O
rg. Chem. 55, 462 (1990), J. O
rg. Chem. , 56, 2416 (1991), B
all. Chem. Soc. Jpn. , 64,796
(1991), etc.]. Oxidation of alcohols using these N-oxyl compounds as catalysts is generally carried out in a two-phase system of a hydrophobic organic solvent such as methylene chloride and an aqueous solution containing an oxidant and the like (JP-A-2-200653; See Kaihei 5-25078 and JP-A-6-212827). However, each of these methods has various problems.

For example, JP-A-2-200653 describes a method for producing an aldehyde by oxidizing a primary alcohol such as undecanol, octanol or an alcohol having a cyclohexane ring in the presence of an N-oxyl compound. There are problems (molecules, peroxide, sodium hypochlorite, etc.) in each case (publication publication, page 2, upper left to upper right column), and a specific compound called alkali metal bromate should be used as an oxidizing agent. There is a limitation that it must be.

Japanese Unexamined Patent Publication (Kokai) No. 5-25078 discloses that (isobutylphenyl) butyl alcohol and the like are added to N-
A method for producing an aldehyde by oxidation in the presence of an oxyl compound is described, but it is described that hypochlorite or hypobromite is used as an oxidizing agent.

JP-A-6-212827 describes a method for producing an oxygen-containing heterocyclic aldehyde by oxidizing an oxygen-containing heterocyclic alcohol in a solvent such as methylene chloride in the presence of an N-oxyl compound. Because of its high water solubility, the carboxylic acid is further oxidized in the aqueous layer and the yield of aldehyde is reduced. Therefore, by changing the ratio of the amount of the organic solvent and water and adding an inorganic salt to the water, the residual amount of the aldehyde in the aqueous layer is reduced to improve the yield. Further, WO 01/66495 describes a method in which an alcohol compound and an N-oxyl compound are supported on silica gel and then oxidized to obtain an aldehyde, a ketone, a carboxylic acid or the like.

[0015]

However, the above-mentioned publicly known documents do not mention the production of aldehydes of thiazole compounds containing nitrogen and sulfur as hetero atoms. In the present invention, a method for producing an aldehyde derivative of a thiazole compound such as 5-formyl-4-methylthiazole from an alcohol derivative of a thiazole compound containing nitrogen and sulfur as hetero atoms such as 5-hydroxymethyl-4-methylthiazole As a result of intensive studies, 5-formyl-4-methylthiazole was used in a two-phase reaction with water using methylene chloride or carbon tetrachloride as an organic solvent, which is often used in an oxidation reaction using an N-oxyl compound as a catalyst. It has been found that it cannot be obtained in a satisfactory yield.

As a result of further intensive research, the aldehyde derivative of a thiazole compound such as 5-formyl-4-methylthiazole was treated with a specific solvent in the oxidation reaction catalyzed by the N-oxyl compound from the corresponding alcohol derivative. The present invention has been completed by finding that it is extremely important to select and use.

The object of the present invention is to overcome the drawbacks found in the above-mentioned conventional production methods and to produce a desired 4-alkyl-5-formylthiazole derivative in a high yield by a simple and practical production method. It is to provide a general-purpose manufacturing method to obtain.

[0018]

The present invention uses a 4-alkyl-5-hydroxymethylthiazole derivative represented by the general formula (1) as a main solvent of carboxylic acid esters or ketones having high water solubility. Then, the 4-alkyl-5-formylthiazole derivative represented by the general formula (2) is characterized in that the oxidation reaction is carried out in the presence of an N-oxyl compound by a two-phase reaction with an aqueous solution. Pertaining to the law.

[0019]

[Chemical 7]

(R ¹ represents an alkyl group having 1 to 4 carbon atoms, and R ² represents a hydrogen atom or an amino group which may have a substituent.)

[0021]

[Chemical 8] (R ¹ and R ² are the same as above.)

That is, the present inventors have found that 5-formyl-4-
In developing a method for producing an aldehyde compound having a thiazole ring such as methylthiazole, various production routes were investigated, and as a result, a 4-alkyl-5-hydroxymethyl-thiazole compound which can be easily synthesized as a starting material was identified. When an oxidation reaction is carried out in the presence of an N-oxyl compound using an alcohol having a thiazole ring, by using a carboxylic acid ester or ketone having high water solubility as a main solvent, the target thiazole ring can be obtained. It has been found that an aldehyde compound having a can be produced with high purity and high yield, and can be carried out industrially simply and inexpensively.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, the alkyl group having 1 to 4 carbon atoms includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-
Examples thereof include linear or branched alkyl groups such as butyl and tert-butyl. One or two substituents can be substituted on the amino group, and examples of the substituent include triphenylmethyl, diphenylmethyl, tert-butyloxycarbonyl, formyl, acetyl, and chloroacetyl groups.

The present invention will be described in detail below.
Highly water-soluble carboxylic acid esters used in the present invention include linear or branched C ₁ -C ₄ lower aliphatic carboxylic acid linear or branched C ₁ -C ₄ lower C ₄ -which may have an alkyl ester or a substituent
It is a C ₇ lower lactone. Further, ketones having high water solubility are linear or branched lower aliphatic (C ₁ -C ₄ ).
The ketones or C _{5 to} C ₇ cyclic ketones that may have a substituent are shown. The water solubility of the main solvent used in the present invention is 0.5% (wt%) or more, preferably 0.6%.
As described above, those having a solubility of 2% or more are more preferable.

Specific examples of the organic solvent that can be used as the main solvent include methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate,
Lower alkyl esters of lower carboxylic acids such as sec-butyl acetate, tert-butyl acetate, methyl propionate, ethyl propionate, acetone, methyl ethyl ketone, methyl propyl ketone, methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone, s
chain or cyclic lower alkyl ketones such as ec-butyl methyl ketone, pinacolone (tert-butyl methyl ketone), ethyl butyl ketone, diethyl ketone, butyrone (dipropyl ketone), and lower cyclic ketones such as cyclohexanone be able to.

Of these, ethyl acetate, propyl acetate, butyl acetate, methyl ethyl ketone, methyl propyl ketone, methyl isopropyl ketone, methyl butyl ketone and methyl isobutyl ketone are preferable, and methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone are particularly preferable. These may be used alone or in combination of two or more. Further, these organic solvents may contain water as needed. These solvents are usually 2 to 20 per 1 kg of the compound of the general formula (1).
It is recommended to use about 0 L, preferably about 3 to 300 L.

Further, an organic solvent other than carboxylic acid esters and ketones may be added to these main solvents as an auxiliary solvent for the purpose of adjusting the water solubility. As this organic solvent, any organic solvent that is stable against oxidation performed in the presence of N-oxyl can be used.

Specific examples of the sub solvent include diethyl ether, ethyl propyl ether, ethyl butyl ether,
Ethers such as dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, dimethoxyethane, nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, benzene, toluene, xylene, chlorobenzene, anisole, etc. A substituted or unsubstituted aromatic hydrocarbon, dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, halogenated hydrocarbons such as carbon tetrachloride,
Aliphatic hydrocarbons such as pentane, hexane, heptane and octane, cycloalkanes such as cyclopentane, cyclohexane, cycloheptane and cyclooctane, amides such as dimethylformamide, diethylformamide and dimethylacetamide, N-methylpyrrolidinone and the like Examples thereof include cyclic amides, cyclic ethers such as tetrahydrofuran, dioxane and dioxolane, and dimethyl sulfoxide.

These are used singly or as a mixture of two or more with respect to the main organic solvent. Further, these organic solvents may contain water as needed. The type and mixing ratio of the sub-solvent may be appropriately adjusted depending on the type, amount and concentration of the catalyst and oxidant described later. These subsolvents are
It is usually about 1 to 100 parts, preferably about 5 to 70 parts per 100 parts (volume part) of the main solvent.

Examples of the N-oxyl compound which can be used in this reaction include 4-benzoyloxy-2,6-tetramethylpiperidine-N-oxyl and 4- (4-tert.
-Butylbenzoyloxy) -2,6-tetramethylpiperidine-N-oxyl, 4-cyano-2,6-tetramethylpiperidine-N-oxyl, 4-methoxy-2,
6-tetramethylpiperidine-N-oxyl, 2,6-
Piperidine-N-oxyl compounds such as tetramethylpiperidine-N-oxyl, 3-benzoyloxymethyl-
2,5-tetramethylpyrrolidine-N-oxyl, 3-
Pyrrolidine-N-oxyl compounds such as methoxycarbonyl-2,5-tetramethylpyrrolidine-N-oxyl,
Di (2,6-tetramethylpiperidine-N-oxyl)
Examples include N-oxyl polymolecular bonding compounds such as -yl-1,10-decanoic acid diester.

The amount of these N-oxyl compounds used is 0.001 to 1 mol of the compound of the general formula (1).
It is used in the range of 100 mol, preferably in the range of 0.01 to 10 mol. Moreover, since the N-oxyl compound can be prepared in the reaction system, it is also possible to use a corresponding reductant.

As the oxidizing agent, any compound having an oxidizing ability capable of oxidizing the reduced form of the N-oxyl compound can be used, but it is preferable to use the following compounds in consideration of solubility, reaction rate and the like. Preferred oxidizing agents include lithium hypochlorite, sodium hypochlorite, potassium hypochlorite, lithium hypobromite, sodium hypobromite, potassium hypobromite, lithium hypoiodite,
Sodium hypoiodite, alkali metal hypohalite such as potassium hypoiodite, calcium hypochlorite,
Calcium hypobromite, alkaline earth metal hypohalite such as calcium hypoiodite, lithium chlorite,
Alkali metal halous acid such as sodium chlorite, potassium chlorite, lithium bromate, sodium bromate, potassium bromate, etc., and subium such as calcium chlorite, calcium bromate, calcium iodate, etc. Alkaline earth metal halides such as alkaline earth metal salts, lithium chlorate, sodium chlorate, potassium chlorate, lithium bromate, sodium bromate, potassium bromate, lithium iodate, sodium iodate, potassium iodate, etc. With alkaline earth metal halides such as calcium chlorate, calcium bromate and calcium iodate, halogen molecules such as chlorine, bromine and iodine, and hydrogen peroxide derivatives such as hydrogen peroxide, sodium peroxide and potassium peroxide. Combination with tungstic acid, metal oxidation catalyst such as sodium tungstate, Carboxylic acid peroxides such as formic acid, peracetic acid and m-chloroperbenzoic acid, molecular oxygen, a combination of molecular oxygen and a metal catalyst, a combination of an oxidizing agent and an alkali metal halogen salt, an oxidizing agent and an alkaline earth metal halogen. Examples thereof include combinations of salts. Examples of the metal catalyst to be combined include cupric chloride, cupric bromide, cupric iodide and other halogenated copper, ruthenium chloride, ruthenium oxide,
It is possible to use various metal catalysts such as a ruthenium catalyst such as a ruthenium chloride triphenylphosphine complex.

These oxidizing agents can be used alone or in combination of two or more. The oxidizing agent can also be used by generating the compounds listed here with other compounds in the reaction system. The amount of the oxidizing agent used varies depending on the reaction product, the reaction conditions and the like, but it is preferable to carry out the reaction using 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of the compound of the general formula (1).

In the present invention, a halogen-containing salt may be added to the reaction system in order to carry out the oxidation reaction more efficiently. Known halogen-containing salts can be used, for example, lithium chloride, sodium chloride, potassium chloride,
Alkali metal halides such as lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, potassium iodide, beryllium chloride, magnesium chloride, calcium chloride, beryllium bromide, magnesium bromide, bromide Calcium, beryllium iodide, magnesium iodide, calcium iodide, and other alkaline earth metal halides, ammonium chloride, ammonium bromide, ammonium iodide, and other halogenated ammonium salts, tetramethylammonium chloride, tetramethylammonium bromide , Tetramethylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide And halogenated tetraalkylammonium and the like, and the like. 1 for halogen-containing salt
The seeds can be used alone or in combination of two or more. The amount of the halogen-containing salt to be used is usually about 0.01 to 20 molar equivalents, preferably 0.2 to 5 with respect to the compound of the general formula (1).
It may be about molar equivalent.

In this reaction, if the reaction is carried out in the presence of a neutral or alkaline aqueous solution, the reaction often proceeds efficiently. In this case, usable alkaline inorganic salts include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as beryllium carbonate, magnesium carbonate and calcium carbonate, lithium hydrogen carbonate and sodium hydrogen carbonate. , Alkali metal hydrogencarbonate such as potassium hydrogencarbonate, alkali metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxide such as magnesium hydroxide and calcium hydroxide, etc. it can. As long as the aqueous solution shows alkalinity, it is possible to use other than the above-mentioned examples. These alkaline inorganic salts are 1
They may be used alone or in combination of two or more. The amount of the alkaline inorganic salt used is usually 0.01 to saturated weight%, preferably 0.1 to saturated weight% with respect to water.

The reaction temperature of the above reaction depends on the composition of the solvent, but is usually about -20 to 60 ° C, preferably 0 to 15 ° C.
It is a degree. The obtained 4-alkyl-5-formylthiazole derivative represented by the general formula (2) is
Although it can be obtained as a substantially pure product by performing a usual extraction operation or distillation operation, it can be purified by other methods.

[0037]

EXAMPLES The present invention will be described below with reference to examples, but the invention is not limited thereto.

Example 1 Compound (1) 65 mg, 4-benzoyloxy-2,
A 6-tetramethylpiperidine-N-oxyl compound (6.7 mg, 4.8 mol%) is weighed out, and 2 ml of methyl ethyl ketone is added to form a uniform solution. Separately, an aqueous solution containing 20% by weight of sodium bromide and 7% by weight of sodium bicarbonate is prepared, 2 ml of this solution is added, and then the reaction solution is cooled to 0 ° C. To this, 4% of an 11 wt% aqueous solution of sodium hypochlorite (2.4 ml, 1.1 eq) cooled to 0 ° C was added.
Slowly drop in portions. After completion of dropping, the reaction solution was stirred at that temperature for 30 minutes. After completion of stirring, 20 ml of ethyl acetate was added to the reaction mixture to extract organic substances. Further, the aqueous layer was extracted twice with 20 ml of ethyl acetate, the organic layers were combined and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified on a silica gel column to give 5-formyl-4-methylthiazole (60 m
g, yield 94%) was obtained. 5-formyl-obtained
1H NMR of 4-methylthiazole is as follows. 1H NMR: d 2.79 (s, 3H), 8.97.
(S, 1H), 10.13 (s, 1H)

Examples 2 to 5 The results of the same reaction as in Example 1 except that the reaction solvent was changed to the following solvent are shown below.

[0040]

[Table 1]

Comparative Examples 1-2 The results of carrying out the same reaction as in Example 1 except that the reaction solvent was changed to the following solvent are shown below.

[0042]

[Table 2]

Examples 6 to 8 The results of carrying out the same reaction as in Example 1 except that the reaction temperature was changed as follows are shown.

[0044]

[Table 3]

Examples 9 to 16 The results of carrying out the same reaction as in Example 1 except that the following alkaline salts were added to the used hypochlorous acid aqueous solution are shown.

[0046]

[Table 4]

Examples 17 to 20 The results of carrying out the same reaction as in Example 1 except that the following halogen-containing salts were added to the used hypochlorous acid aqueous solution are shown.

[0048]

[Table 5]

Examples 21 to 27 The results of carrying out the same reaction as in Example 1 except that sodium hypochlorite used as an oxidizing agent was changed to the following oxidizing agent and saturated aqueous sodium hydrogen carbonate was used as a solvent are shown. .

[0050]

[Table 6]

Examples 28 to 35 The results of carrying out the same reaction as in Example 1 by changing the catalyst to a 4-benzoyloxy-2,6-tetramethylpiperidine-N-oxyl compound are shown below (the amount used is molar). The same amount as in Example 1).

[0052]

[Table 7]

[0053]

In the present invention, an oxidation reaction is carried out in the presence of an N-oxyl compound using an alcohol having a thiazole ring such as a 4-alkyl-5-hydroxymethyl-thiazole derivative which can be easily synthesized as a starting material. In this case, high water solubility, by using a carboxylic acid ester or ketone as a main solvent, the target aldehyde compound having a thiazole ring is highly pure, high yield, and industrially simple and inexpensive. It can be manufactured.

Continued front page    F-term (reference) 4C033 AD03 AD16 AD18                 4H039 CA62 CC20

Claims (4)

[Claims] 1. A 4-alkyl-represented by the general formula (1):
A 5-hydroxymethylthiazole derivative is used as a main solvent of carboxylic acid esters or ketones having high water solubility, and is reacted with an aqueous solution in a two-phase system to give N-
A method for producing a 4-alkyl-5-formylthiazole derivative represented by the general formula (2), which comprises performing an oxidation reaction in the presence of an oxyl compound. [Chemical 1] (R ¹ represents an alkyl group having 1 to 4 carbon atoms, and R ² represents a hydrogen atom or an amino group which may have a substituent.) (R ¹ and R ² are the same as above.) 2. The method according to claim 1, wherein R ¹ is a methyl group and R ² is a hydrogen atom. 3. The method according to claim 1, wherein the solubility of the carboxylic acid ester or ketone in water is 0.5 to 30%. 4. The production method according to claim 1, wherein the main solvent having high water solubility is methyl ethyl ketone, methyl isopropyl ketone, or methyl isobutyl ketone.