WO2003006442A1

WO2003006442A1 - Novel preparation process of 1,3-oxazole-2-thiol

Info

Publication number: WO2003006442A1
Application number: PCT/EP2002/006882
Authority: WO
Inventors: Yukiyoshi Watanabe
Original assignee: Bayer Cropscience Ag
Priority date: 2001-07-04
Filing date: 2002-06-21
Publication date: 2003-01-23
Also published as: JP2003081949A

Abstract

A process for the preparation of 1,3-oxazole-2-thiol characterized in that glycolaldehyde dimer or a glycolaldehyde di(C1-2 alkyl)acetal is reacted with a thiocyanate in a C3-4 alcohol or an aprotic polar solvent as a diluent in the presence of a mineral acid.

Description

NOVEL PREPARATION PROCESS OF -OXAZOLE-2-THIOL

The present invention relates to a novel process for the preparation of known 1,3- oxazole-2-thiol.

l,3-Oxazole-2-thiol is useful as an intermediate for the preparation of active substances which can be used in identical, agricultural or pharmaceutical applications. For example, 2-(3,4,4-trifluoro-3-butenylthio)oxazoles, described in Japanese Patent Application No. 2000-240855, are used as nematicides.

A preparation process for l,3-oxazole-2-thiol has been described in Canadian Journal of Chemistry, vol. 50, p. 3082-3083 (1972), consisting of the reaction of glycolaldehyde, formed by decarboxylation of dihydroxymaleic acid, with potassium thiocyanate in the presence of hydrochloric acid. The process, however, is not suitable for the synthesis at an industrial level due to a low yield of the obtained 1,3-oxazole-

2-thiol (35%) and a long reaction time (16 hours).

It has been found that l,3-oxazole-2-thiol can be obtained by a process in which glycolaldehyde dimer or glycolaldehyde di(Cι_-2alkyl)acetal is reacted with a thiocynate in a C₃-₄ alcohol or an aprotic polar solvent as a diluent, in the presence of a mineral acid.

According to the above-mentioned preparation process of the present invention, surprisingly, the aimed l,3-oxazole-2-thiol can be obtained with a shorter reaction time and well higher yield than the aforementioned known preparation process.

Thus, the process of the present invention is very suitable for the preparation of 1,3- oxazole-2-thiol on an industrial scale.

Below, the process of the present invention is described in more detail. In the preparation process of the present invention, in case of using, for example, glycolaldehyde diethylacetal and potassium thiocyanate as the starting materials, using, for example, hydrochloric acid as a mineral acid, and using, for example, acetonitrile as a diluent, the preparation process of the present invention can be illustrated by the following reaction equation.

^C ₂H₅0 OC₂H₅

Glycolaldehyde dimer or glycolaldehyde di(Cι_-4 alkyl)acetals used as the starting materials in the preparation process of the present invention are well known compounds in the field of organic chemistry. As glycolaldehyde di(Cι_-4 alkyl) acetal there can be mentioned glycolaldehyde-dimethylacetal, -diethylacetal,-di(n-propyl)- acetal, -di(i-propyl)-acetal, ,-di(n-butyl)-acetal, -di(i-butyl)-acetal, -di(t-butyl)-acetal. Glycolaldehyde-dimethylacetal and -diethylacetal are preferably used. Glycol- aldehyde-diethylacetal is particular preferably used. In an other preferred embdiment

Glycolaldehyde dimer is used.

Thiocyanates to be reacted with the above-mentioned glycolaldehyde dimer or a glycolaldehyde di(Cι-₄ alkyl)acetal according to the present invention are per se known compounds, too. As their specific examples there can be mentioned, for example, sodium thiocyanate, potassium thiocyanate, ammonium thiocyanate and thio- cyanic acid. Potassium thiocyanate is preferably used.

In the preparation process of the present invention it is preferable to use a thiocyanate in the range of generally about 2 moles to about 4 moles, particularly about 2.2 moles to about 3.6 moles for 1 mole of the starting material glycolaldehyde dimer, or in the range of about 1 mole to about 2 moles, particularly about 1.1 moles to about 1.8 moles for 1 mole of the starting material glycolaldehyde di(Cι_-4 alkyl)acetal. As acids may be used organic acids and mineral acids. As mineral acids can be mentioned, for example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid. Hydrochloric acid is preferably used.

In the preparation process it is preferable to use such a mineral acid in the range of generally about 1 mole to about 2 moles, particularly about 1.1 to about 1.8 moles for 1 mole of the starting material glycolaldehyde di(C_1-4 alkyl)acetal, or in the range of about 2 moles to about 4 moles, particularly about 2.2 moles to about 3.6 moles for 1 mole of the starting material glycolaldehyde dimer.

Suitable diluents for the preparation process of the present invention are polar and aprotic. There can be mentioned, as C_3-4 alcohol, for example, n-propanol, isopropanol, tert-butanol and so on, and as aprotic polar solvent, for example, nitriles, for example, acetonitrile, propionitril and so on; ethers, for example, tetrahydrofuran (THF), dioxane and so on; and ketones, for example, acetone and so on. Above all, isopropanol, tert-butanol or acetonitrile are preferable. Particularly, in case of using glycolaldehyde dimer as starting material, it is preferable to use isopropanol, tert-butanol or acetonitrile as diluent and, on the other hand, in case of using a glycolaldehyde di(Cι_-4 alkyl)acetal as starting material, it is preferable to use acetonitrile as diluent.

The reaction in the preparation process of the present invention is conducted at a temperature in the range of generally about 20 to about 180°C, preferably about 50 to about 140°C. In another preferred embodiment of the invention, the reaction temperature is the reflux temperature of the reaction mixture. Reaction time is, depending on the used reaction temperature, usually about 1 hour to about 12 hours, preferably about 2 hours to about 8 hours. Said reaction can be conducted under normal pressure, but can be optionally conducted also under elevated or reduced pressure. The reaction pressure may be varied to a large extent, e.g. for adjusting the reaction temperature. Preferred reaction pressure is between 0.8 and 3 bar particular preferred is standard pressure.

Product isolation may be obtained by standard procedures, e.g. filtration, chromatography, distillation.

According to one of the preferable modes of the preparation process of the present invention, the aimed l,3~oxazole-2-thiol can be obtained by reacting 1 mole of glycolaldehyde diethylacetal with about 1 to about 2 moles of potassium thiocyanate in a diluent, for example, acetonitril, in the presence of about 1 to about 2 moles of concentrated hydrochloric acid for 4 hours under refluxing.

According to another preferable mode, the objective l,3-oxazole-2-thiol can be obtained by reacting 1 mole of glycolaldehyde dimer with about 2 to about 4 moles of potassium thiocyanate in a diluent, for example, isopropanol, in the presence of about 2 to about 4 moles of concentrated hydrochloric acid for 4 hours under refluxing.

In conducting the preparation process of the present invention glycolaldehyde dimer or a glycolaldehyde di(Cι_-4 alkyl)acetal can be reacted with a thiocyanate in a diluent in the presence of a mineral acid in one pot. Alternatively a thiocyanate can be first converted to thiocyanic acid, and then reacted with glycolaldehyde dimer or a glycolaldehyde di(Cι_-4 alkyl) acetal to yield l,3-oxazole-2-thiol.

The preparation process of the present invention will be described more specifically by examples, but the present invention shall not be restricted to these examples any way. Example 1

To a suspension of potassium thiocyanate (1.45 g, 15 mmoles) in isopropanol (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration. To the obtained solution of thiocyanic acid in isopropanol glycolaldehyde dimer (0.6 g, 5 mmoles) was added and refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate - 2 : 3) to obtain l,3-oxazole-2-thiol (0.99 g, yield 98%, mp 136 - 138°C).

Example 2

To a suspension of potassium thiocyanate (1.45 g, 15mmoles) in tert-butanol (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration. To the obtained solution of thiocyanic acid in tert- butanol glycolaldehyde dimer (0.6 g, 5 mmoles) was added and refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate = 2 : 3) to obtain l,3-oxazole-2-thiol (0.89 g, yield 88%, mp 136 - 138°C). Example 3

To a suspension of potassium thiocyanate (1.45 g, 15 mmoles) in acetonitrile (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration. To the obtained solution of thiocyanic acid in acetonitrile glycolaldehyde dimer (0.6 g, 5 mmoles) was added and refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate = 2 : 3) to obtain l,3-oxazole-2-thiol (0.96 g, yield 95%, mp 136 - 138°C).

Example 4

To a suspension of potassium thiocyanate (1.45 g, 15 mmoles) in acetonitrile (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration. To the obtained solution of thiocyanic acid in acetonitrile glycolaldehyde diethylacetal (1.34 g) was added and refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate = 2 : 3) to obtain l,3-oxazole-2-thiol (1 g, yield 99%, mp 136 - 138°C). Example 5

To a suspension of potassium thiocyanate (1.45 g, 15 mmoles) in acetonitrile (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration. To the obtained solution of thiocyanic acid in acetonitrile glycolaldehyde dimer (0.6g, 5mmoles) was added and stirred at 55 - 65°C for 4 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate - 2 : 3) to obtain l,3-oxazole-2-thiol (0.99 g, yield 98%, mp 136 - 138°C).

Example 6

To a suspension of potassium thiocyanate (1.45 g, 15 mmoles) in acetonitrile (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration. To the obtained solution of thiocyanic acid in acetonitrile glycolaldehyde dimer (0.6g, 5mmoles) was added and refluxed for 2 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate = 2 : 3) to obtain l,3-oxazole-2-thiol (0.93 g, yield 92%, mp 136 - 138°C). Example 7

To a suspension of potassium thiocyanate (1.45 g, 15 mmoles) in acetonitrile (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration. To the obtained solution of thiocyanic acid in acetonitrile glycolaldehyde dimer (0.6g, 5mmoles) was added and refluxed for 7 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate = 2 : 3) to obtain l,3-oxazole-2-thiol (0.99 g, yield 98%, mp 136 - 138°C).

Comparative Example 1 (Process according to Canadian Journal of Chemistry, vol. 50, p. 3082-3083 (1972)

To a suspension of potassium thiocyanate (1.45 g, 15 mmoles) in ethanol (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration to obtain a solution of thiocyanic acid in ethanol. In another flask dihydroxyfumaric acid (1.48 g, 10 mmoles) and water (22 ml) were placed and stirred at 60°C for 1 hour to obtain an aqueous solution of glycol- aldyhyde. These two reaction solutions were mixed and refluxed for 24 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate - gradiant elution from 3 : 2 to 2 : 3) to obtain l,3-oxazole-2-thiol (0.36 g, yield 36%, mp 136 - 138°C) and 4-ethoxy-4,5-dihydro-l,3-oxazole-2-thiol (0.1 g, yield 7%, mp 87 - 89°C).

Comparative Example 2 (Process according to Canadian Journal of Chemistry, vol. 50, p. 3082-3083 (1972)

To a suspension of potassium thiocyanate (1.45 g, 15 mmoles) in ethanol (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration to obtain a solution of thiocyanic acid in ethanol. In another flask dihydroxyfumaric acid (1.48 g, 10 mmoles) and water (22 ml) were placed and stirred at 60°C for 1 hour to obtain an aqueous solution of glycol- aldehyde. These two reaction solutions were mixed and refluxed for 43 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate = 2 : 3) to obtain l,3-oxazole-2-thiol (0.39 g, yield 39%, mp 136 - 138°C). Comparative Example 3 (Similar process to Synthesis Examples 1-3 of the present invention wherein the diluent is ethanol)

To a suspension of potassium thiocyanate (1.45 g, 15 mmoles) in ethanol (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration. To the obtained solution of thiocyanic acid in ethanol glycolaldehyde dimer (0.6 g, 5 mmoles) was added and refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate = 3 : 2) to obtain l,3-oxazole-2-thiol (0.09 g, yield 9%, mp 136 - 138°C) and 4-ethoxy-4,5- dihydro-l,3-oxazole-2-thiol (1.31 g, yield 89%, mp 87 - 89°C).

Comparative Example 4 (Similar process to Synthesis Examples 1-3 of the present invention wherein the diluent is ethanol and the reaction time is 61 hours)

To a suspension of potassium thiocyanate (1,45 g, 15 mmoles) in ethanol (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration. To the obtained solution of thiocyanic acid in ethanol glycolaldehyde dimer (0.6 g, 5 mmoles) was added and refluxed for 61 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate = 3 : 2) to obtain l,3-oxazole-2-thiol (0.72 g, yield 71%, mp 136 - 138°C) and 4-ethoxy-4,5- dihydro-l,3-oxazole-2-fhiol (0.13 g, yield 9%, mp 87 - 89°C).

Reference Example 5 (Similar process to Synthesis Example 4 of the present invention wherein the diluent is ethanol)

To a suspension of potassium thiocyanate (1.45 g, 15 mmoles) in ethanol (32 ml) concentrated hydrochloric acid (1.56 g) was added dropwise under stirring. After stirring the suspension at room temperature for 30 minutes, the deposited crystals were removed by filtration. To the obtained solution of thiocyanic acid in ethanol glycolaldehyde diethylacetal (1.34 g, 10 mmoles) was added and refluxed for 4 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated by silica gel column chromatography (eluent : n-hexane : ethyl acetate = 3 : 2) to obtain l,3-oxazole-2-thiol (0.25 g, yield 25%, mp 136 - 138°C) and 4-ethoxy-4,5-dihydro-l,3-oxazole-2-thiol (1.06 g, yield 72%, mp 87 - 89°C).

Claims

1. A process for the preparation of l,3-oxazole-2-thiol characterized in that glycolaldehyde dimer or a glycolaldehyde di(C_1-2 alkyl)acetal is reacted with a thiocyanate in a C_3-4 alcohol or an aprotic polar solvent as a diluent in the presence of a mineral acid.

2. The process set forth in Claim 1 wherein a thiocyanate is sodium thiocyanate, potassium thiocyanate or ammonium thiocyanate.

3. The process set forth in Claim 1 wherein a thiocyanate is potassium thiocyanate.

4. The process set forth in Claim 1 wherein a mineral acid is hydrochloric acid.

5. The process set forth in Claim 1 wherein a C₃.₄ alcohol as a diluent is isopropanol or tert-butanol.

6. The process set forth in Claim 1 wherein an aprotic polar solvent as a diluent is acetonitrile.