CN1307165C - 4-methyl-5-formylthiazole preparation method - Google Patents
4-methyl-5-formylthiazole preparation method Download PDFInfo
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Abstract
This method for producing the 4-methyl-5-formylthiazole expressed by general formula (2) comprises reacting 4-methyl-5-(2-hydroxyethyl)thiazole expressed by general formula (1) with at least one kind of oxidizing agent selected from chromium oxide (CrO<SB>3</SB>) and an inorganic bichromate salt in the presence of an acid in a two-phase system composed of water and an organic solvent.
Description
Technical Field
The invention belongs to the field of synthesis of organic compounds, and relates to a novel preparation method of 4-methyl-5-formylthiazole.
Background
By the following general formula (2)
The 4-methyl-5-formylthiazole shown in the above is an important synthon for synthesizing modern drugs cephalosporin (for example, refer to patent document 1) and neuroprotective agent (for example, refer to patent document 2). However, its synthesis has been very difficult so far.
Processes for the preparation of 4-methyl-5-formylthiazole are known from the main literature.
The method for producing 4-methyl-5-formylthiazole uses two starting materials: that is to say that the first and second electrodes,
1) 4-methyl-5-methoxycarbonylthiazole (the following general formula (3), hereinafter abbreviated as "MT-COOMe") and
2) 4-methyl-5- (2-hydroxyethyl) thiazole (the following general formula (1), hereinafter abbreviated as "MT-CH2CH2OH”)
The first synthesis of 4-methyl-5-formylthiazole (hereinafter abbreviated as "MT-CHO") was carried out in 1939 from MT-COOMe (see, for example, non-patent document 1), and it includes the following steps.
The overall MT-CHO yield under these conditions was 23%.
A method for directly producing MT-CHO by vapor-phase hydrogenation of molecular hydrogen in the presence of a specific catalyst using MT-COOMe as a starting material was filed in 1989 (see patent document 3).
The reaction was carried out under stringent temperature conditions (315 ℃ C.) at which the conversion of MT-COOMe to MT-CHO was 74% and the selectivity to aldehyde (MT-CHO) was about 80%.
In addition, it is known that: with NaHSO3Decomposing vitamin B1 to obtain approximately quantitative 4-methyl-5- (2-hydroxyethyl) thiazole (MT-CH)2CH2OH) (see non-patent document 2). From the 4-methyl-5- (2-hydroxyethyl) thiazole (MT-CH)2CH2OH) was attempted since 1982 (see, for example, non-patent document 3), and the present inventors attempted to use the synthesis method of non-patent document 3, but only a few mg of the target 4-methyl-5-formylthiazole (MT-CHO) was obtained.
Because of the starting material MT-CH2CH2OH is readily synthesized from vitamin B1, so this process is a very attractive process. However, the method described in non-patent document 3, i.e., the method using pyridinium dichromate as an oxidizing agent, has the following disadvantages in industrialization.
1) Complicated reaction, special equipment and high-valence oxidant.
2) The use of an excessive amount of the oxidizing agent (6 moles of the oxidizing agent per 1 mole of the substrate) causes environmental pollution problems such as a large amount of solid waste.
3) The target compound is difficult to separate and recover from the resulting tarry mixture at the end of the reaction.
(patent document 1)
European patent application publication No. EP 236231;
(patent document 2)
International publication Nos. WO 95/01979;
(non-patent document 1)
E.R.Buchman，et al.“Thiamin analogs，I，B-(4-Methylthiazolyl-5)-alanine.”J.Am.Chem.Soc.1939，Vol.61，P.891-893；
(patent document 3)
European patent application publication No. EP 343640;
(non-patent document 2)
Robert L. White and Ian D.Spenser，“Thiamin Biosynthesis inSaccharomycescerevisiae”，Biochem.J.，1979，Vol.179，P.315-325；
(non-patent document 3)
R.L.White，et al.“Thiamin biosynthesis in yeast.Origin of thefive-carbon unit of the thiazole moiety.”，J.Am.Chem.Soc.1982，Vol.104，No.18，P.4934-4943；
Disclosure of Invention
In view of the above circumstances, the present inventors have made extensive studies on a method for obtaining 4-methyl-5-formylthiazole (MT-CHO) in high yield by a method advantageous for industrial use, and as a result, have found that 4-methyl-5- (2-hydroxyethyl) thiazole (MT-CH) can be used2CH2OH) as starting material, chromium oxide (CrO)3) Or an inorganic dichromate as an oxidizing agent, in the presence of an acid, in a 2-phase heterogeneous solvent composed of water and an organic solvent2CH2OH) can be obtained in a good yield, and the desired product, 4-methyl-5-formylthiazole (MT-CHO) can be obtained.
The present inventors have also found that, when the molar ratio of the respective raw materials and the reaction temperature are set within specific ranges in the above-mentioned reaction, the desired 4-methyl-5-formylthiazole (MT-CHO) can be obtained with high purity and high yield without side reactions, and have completed the present invention.
That is, an object of the present invention is to provide a method for producing 4-methyl-5-formylthiazole with high purity in good yield by an industrially advantageous method.
The present invention provides a method for producing 4-methyl-5-formylthiazole represented by the following general formula (2), which is characterized in that: in a 2-phase system composed of water and an organic solvent, 4-methyl-5- (2-hydroxyethyl) thiazole represented by the following general formula (1) and chromium oxide (CrO) are reacted in the presence of an acid3) Or inorganic dichromate.
Detailed Description
The present invention will be described in detail below.
The oxidizing agent which can be used in the present invention is chromium oxide (CrO)3) Or inorganic dichromate, and sodium dichromate (Na) can be used as the inorganic dichromate2Cr2O7) Potassium dichromate (K)2Cr2O7) And the like. One or more of these oxidizing agents may be used, and in addition, these oxidizing agentsThe agent may be either an aqueous or anhydrous substance.
The amount of the oxidizing agent used varies depending on the kind of the oxidizing agent used, and chromium oxide (CrO) is used3) Relative to MT-CH2CH2OH is 1.2-2.5 times of mol, preferably 1.8-2.2 times of mol; on the other hand, in the case of using an inorganic dichromate, it is preferable to use MT-CH2CH2OH is 0.6 to 1.2 times by mol, preferably 0.9 to 1.1 times by mol.
Examples of the acid that can be used include monovalent acids such as nitric acid and hydrochloric acid, and divalent acids such as sulfuric acid, and one kind or two or more kinds of these acids can be used.
The amount of the acid used varies depending on the kind of the acid used, andwhen a monovalent acid such as nitric acid or hydrochloric acid is used, the amount of the acid used is based on the amount of MT-CH2CH2OH is 5.0 to 7.0 times by mol, preferably5.4-6.6 times of mol; on the other hand, when a divalent acid such as sulfuric acid is used, it is preferable to use MT-CH2CH2OH is 2.0 to 4.0 times by mol, preferably 2.7 to 3.3 times by mol.
In the method for producing MT-CHO of the present invention, the intended product MT-CHO can be obtained with high purity and high yield by using the oxidizing agent and the acid in the above-mentioned ranges. On the other hand, when the amount of the oxidizing agent and the acid used exceeds the above range, further oxidation occurs and MT-COOH is produced as a by-product, whereas when the amount of the oxidizing agent and the acid used is less than the above range, the amount of the oxidizing agent necessary for the reaction is insufficient, and thus the yield of the desired product is lowered.
The reaction of the present invention uses the above-mentioned raw materials, and it is important to use a heterogeneous solvent composed of a two-phase system of water and an organic solvent as a reaction solvent.
As the organic solvent that can be used, for example, any organic solvent that does not mix with water under reaction conditions can be used. Examples of such an organic solvent include aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, and aliphatic ethers. Examples of the aliphatic hydrocarbon include pentane, hexane, heptane, octane, and the like. Examples of the aromatic hydrocarbon include benzene, toluene, and xylene. Examples of the halogenated hydrocarbon include chloroform, tribromomethane, dichloromethane, ethyl chloride, ethylene dichloride, chlorobenzene, and the like. Examples of the aliphatic ether include diethyl ether, dipropyl ether, dibutyl ether, ethyl propyl ether, and ethyl butyl ether. These organic solvents may be used alone or as a mixture of two or more thereof.
The mixing ratio of the organic solvent and water is not particularly limited, but is preferably 30 to 100 parts by weight based on 100 parts by weight of the organic solvent in many cases.
The reaction temperature is 20 to 50 ℃, preferably 25 to 30 ℃. The reason is that: when the reaction temperature exceeds 50 ℃, 4-methylthiazole-5-carboxylic acid (MT-COOH) is produced as a by-product, while when it is less than 20 ℃, the reaction rate may be lowered, which is not favorable for industrial application.
After the reaction is completed, MT-CHO remaining in the aqueous phase can be recovered from the aqueous phase by using an organic solvent as desired. Examples of the organic solvent usable in this case include the above-mentioned aromatic hydrocarbons, halogenated hydrocarbons, and aliphatic ethers, and among them, chloroform and methylene chloride are preferably used in the present invention because of a high ratio of the target product extracted from the acidic aqueous solution.
The invention uses chromium oxide (CrO)3) Or inorganic dichromate as an oxidizing agent, and a two-phase heterogeneous reaction solvent is used to obtain 4-methyl-5-formylthiazole by oxidizing 4-methyl-5- (2-hydroxyethyl) thiazole. In this reaction, the starting material MT-CH2CH2OH is contained in acidic aqueous phase, and the generated target MT-CHO moves to organic phase in sequence during reaction, so that the reaction can be preventedFurther oxidation of the desired product. Therefore, the object MT-CHO can be obtained in a high yield by the production method of the present invention.
(examples)
The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.
Example 1
10ml of water containing 1.60g (16 mmol) of CrO3And a solution of 1.77g (18 mmol) of sulfuric acid were added to 30ml of benzene with 1.15g (8 mmol) of MT-CH dissolved therein while mixing2CH2Solution of OH. After the oxidant was added in its entirety to the reaction mixture, it was mixed at a temperature of 35 ℃ for 4 hours. After 1 hour the organic phase was separated and benzene was added in the same volume. The organic phases were combined to one phase, dried over sodium sulfate and the solvent was removed in vacuo. 0.69g of MT-CHO was obtained. The yield thereof was found to be 68%. The product was purified by column chromatography. 0.55g of MT-CHO was obtained. The yield thereof was found to be 54%.
The melting point is 73-74 ℃,1H-NMR spectrum (delta, m.d.): 2.82s (Me, 3H), 9.02s (CHO, 1H), 10.15s (CHN, 1H).13C-NMR spectrum (delta, m.d.): 16.15 (CH)3) 132.74(CS), 158.89(NCS), 161.80(CN), 182.44 (CHO). The data by high-energy liquid chromatography show that: the purity of MT-CHO was 99.7%.
In addition, the first and second substrates are,1h and13CNMR spectra were in CDCl3And in DMSO-D6, recorded with an NMR spectrometer DPX-200(BRUKER) using TMS as the internal standard. The melting temperature was measured using the apparatus BOETIUS PHMK-05. The results of the high energy liquid chromatography were obtained from chromatography HP-1100 (Hewlett-Packard) using UF emission 254nm for the detector, 30% methanol + 70% water for the eluent and 70% methanol + 30% water. The reaction was controlled by thin layer chromatography using silica gel 60F254(Merck) on a 5X 10cm aluminum plate eluting with chloroform-methanol (10: 1). The column chromatography used was Wakogel C-200, 75-150mm, and the eluent used was chloroform and chloroform-methanol (10: 1). The oxidizing agent is a substance corresponding to the primary agent. All solvents used were those obtained by washing with concentrated sulfuric acid and water, drying with calcium chloride, and then distilling.
Example 2
5ml of water containing 0.55g (5.5 mmol) of CrO3And 0.65g (6.6 mmol) sulfuric acid solution while mixing, added dropwise to 15ml benzene dissolved with 0.36g (2.5 mmol) MT-CH2CH2Solution of OH. After the oxidant is added to the reaction mixture in its entirety, at warmMixing at 45-50 deg.C for 20 min. The aqueous phase was separated and extracted with chloroform (2X 10 ml). The organic phases were combined to one phase, washed with water, dried over sodium sulfate and the solvent was removed in vacuo. 0.19gMT-CHO was obtained. The yield thereof was found to be 58%.
Example 3
20ml of water containing 1.60g (16 mmol) of CrO at 40-45 deg.C3And a solution of 2.35g (24 mmol) of sulfuric acid was added dropwise to 30ml of benzene with 0.86g (6 mmol) of MT-CH dissolved therein2CH2Solution of OH. After the oxidant was added to the reaction mixture in its entirety, it was mixed at the same temperature for 2 hours. The aqueous phase was separated and extracted with chloroform (2X 15 ml). The organic phases were combined to one phase, washed with water, dried over sodium sulfate and the solvent was removed in vacuo. The product was purified by column chromatography using silica gel to give 0.50g of MT-CHO in 66% yield and 0.05gMT-CHOH in 6% yield.
Example 4
10ml of water containing 2.00g (20 mmol) of CrO3And a solution of 1.96g (20 mmol) of sulfuric acid was added dropwise to benzene containing 1.43g (10 mmol) of MT-CH in 4ml portions while mixing2CH2Solution of OH. The oxidizing agent was added quantitatively to the reaction mixture at each time and mixed at a temperature of 20 ℃ for 1 hour. The organic phase is separated and a certain amount of benzene is added again. After the reaction was complete, the organic phases were combined into one phase, dried over sodium sulfate and the solvent was removed in vacuo. 0.80gMT-CHO was obtained with a yield of 63%. The aqueous phase was neutralized with 1M KOH and extracted with chloroform (2X 10ml) to recover 0.30g (21%) of MT-CH2CH2OH。
Example 5
10ml of water containing 1.00g (10 mmol) of CrO3And a solution of 1.47g (15 mmol) of sulfuric acid were added to dichloromethane with mixing and 0.72g (5 mmol) of MT-CH dissolved therein2CH2Solution of OH. After the addition of the oxidant to the reaction mixture, it was mixed at a temperature of 20 ℃ for 3 hours. The organic phase was separated, washed with water, dried over sodium sulfate and the solvent was removed under vacuum. To obtain0.37g of MT-CHO in a yield of 58%. The aqueous phase was neutralized with 1M KOH and then extracted with chloroform (2X 10ml) to recover 0.07g (10%) of MT-CH2CH2OH。
Example 6
3ml of water containing 1.50g (15 mmol) of CrO3To 20ml of diethyl ether was added 1.08g (7.5 mmol) of MT-CH2CH2In solution in OH at a temperature of 20 deg.CMix at deg.C for 3 hours. During this time 2.21g (22.5 mmol) of sulfuric acid in 10ml of water were added in 3 equal portions to the reaction mixture. The organic phase is separated and fresh ether is added before the addition of sulfuric acid. After the reaction was complete, the organic phases were combined into one phase, dried over sodium sulfate and the solvent was removed in vacuo. 0.59g of MT-CHO was obtained with a yield of 63%. The aqueous phase was neutralized with 1M KOH and then extracted with chloroform (2X 10ml) to yield 0.29g (27%) of MT-CH2CH2OH。
Example 7
18ml of water containing 1.77g (6 mmol) of K2Cr2O7 and 2.36g (24 mmol) sulfuric acid solution while mixing, at 20 ℃ dropwise added to 30ml dichloromethane dissolved with 0.86g (6 mmol) MT-CH2CH2Solution of OH. And then mixed at the same temperature for 20 hours. The organic phase was separated, washed with water, dried over sodium sulfate and the solvent was removed under vacuum. 0.45g of MT-CHO was obtained with a yield of 59%.
Example 8
18ml of water containing 1.77g (6 mmol) of K2Cr2O7 and 2.36g (24 mmol) sulfuric acid solution were mixed together and added dropwise to 30ml benzene containing 0.86g (6 mmol) MT-CH at 50 deg.C2CH2Solution of OH. Followed by mixing at the same temperature for 1 hour. The aqueous phase was extracted with chloroform (2X 10 ml). The organic phases were combined, washed with water, dried over sodium sulfate and the solvent was removed under vacuum. 0.40g of MT-CHO was obtained with a yield of 53%.
Example 9
The solvent was slightly boiled and 18ml of water containing 1.77g (6 mmol) of K2Cr2O7 toAnd 2.36g (24 mmol) sulfuric acid solution while mixing, added dropwise to 30ml dibutyl ether dissolved with 0.86g (6 mmol) MT-CH2CH2Solution of OH. Then mixed at the same temperature for 2 hours. The aqueous phase was extracted with chloroform (2X 10ml), the organic phases were combined, washed with water, dried over sodium sulphate and the solvent was removed in vacuo. 0.44g of MT-CHO was obtained with a yield of 58%.
Example 10
18ml of water containing 1.77g (6 mmol) of K2Cr2A solution of O7 and 1.18g (12 mmol) sulfuric acid was added dropwise to 30ml of dichloromethane containing 0.86g (6 mmol) MT-CH, 3ml portions at 38 ℃ while mixing2CH2Solution of OH. After the oxidant was added to the reaction mixture, it was mixed for 30 minutes, the organic phase was separated and new solvent was added again. After the reaction was complete, the organic phases were combined into one phase, dried over sodium sulfate and then removed under vacuumA solvent. 0.42g of MT-CHO was obtained with a yield of 54%. The aqueous phase was neutralized with 1M KOH and extracted with chloroform (2X 10ml) to yield 0.31g (36%) of MT-CH2CH2OH。
Example 11
10ml of water containing 1.60g (16 mmol) of CrO3And a solution of 3.02g (48 mmol) of nitric acid were added to 30ml of chloroform while mixing, and 1.15g (8 mmol) of MT-CH was dissolved in the chloroform2CH2Solution of OH. After the oxidant was added in its entirety to the reaction mixture, it was mixed at a temperature of 35 ℃ for 4 hours. The organic phase was separated every 1 hour and chloroform was added in the same volume. The organic phases were combined to one phase, dried over sodium sulfate and the solvent was removed in vacuo. 0.65g of MT-CHO was obtained with a yield of 64%.
Example 12
10ml of water containing 1.60g (16 mmol) of CrO3And a solution of 1.70g (48 mmol) of hydrochloric acid were added to 30ml of chloroform while mixing, and 1.15g (8 mmol) of MT-CH was dissolved in the chloroform2CH2Solution of OH. After the oxidant was added in its entirety to the reaction mixture, it was mixed ata temperature of 35 ℃ for 4 hours. Every 1 hourThe organic phase was separated once and chloroform was added in the same amount. The organic phases were combined to one phase, dried over sodium sulfate and the solvent was removed in vacuo. 0.63g of MT-CHO was obtained with a yield of 62%.
Effects of the invention
As described above, according to the present invention, 4-methyl-5-formylthiazole can be produced in high yield and high purity from 4-methyl-5- (2-hydroxyethyl) thiazole in an industrially advantageous manner.
Claims (1)
1. A process for producing 4-methyl-5-formylthiazole represented by the general formula (2), which comprises: reacting 4-methyl-5- (2-hydroxyethyl) thiazole represented by the general formula (1) with one or more oxidizing agents selected from chromium oxide and inorganic dichromate in the presence of an acid in a 2-phase system composed of water and an organic solvent,
the reaction is carried out at a temperature of 20 to 50 ℃,
the amount of the oxidizing agent is 1.2 to 2.5 times by mole relative to 4-methyl-5- (2-hydroxyethyl) thiazole when chromium oxide is used; in the case of using an inorganic dichromate, the amount of the organic dichromate is 0.6 to 1.2 times by mol based on 4-methyl-5- (2-hydroxyethyl) thiazole,
the amount of the acid used is 5.0 to 7.0 times by mole relative to 4-methyl-5- (2-hydroxyethyl) thiazole when an inorganic monovalent acid is used; in the case of using an inorganic divalent acid, the amount of the inorganic divalent acid is 2.0 to 4.0 times by molewith respect to 4-methyl-5- (2-hydroxyethyl) thiazole.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2002124887/04A RU2228332C1 (en) | 2002-09-19 | 2002-09-19 | Method for preparing 4-methyl-5-formylthiazole |
| RU2002124887 | 2002-09-19 |
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| Publication Number | Publication Date |
|---|---|
| CN1495176A CN1495176A (en) | 2004-05-12 |
| CN1307165C true CN1307165C (en) | 2007-03-28 |
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| CNB031569889A Expired - Fee Related CN1307165C (en) | 2002-09-19 | 2003-09-17 | 4-methyl-5-formylthiazole preparation method |
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| Country | Link |
|---|---|
| JP (1) | JP4440585B2 (en) |
| CN (1) | CN1307165C (en) |
| RU (1) | RU2228332C1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100360511C (en) * | 2006-01-24 | 2008-01-09 | 浙江工业大学 | Method for synthesizing 4-methyl-5-methyol thiazole |
| CN104485998A (en) * | 2014-12-15 | 2015-04-01 | 北京理工大学 | Calibration device and method for response time of optical communication transmitting-receiving component |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU979344A1 (en) * | 1981-07-06 | 1982-12-07 | Болоховский химический комбинат синтетических полупродуктов и витаминов | Process for producing 4-methyl-5-beta-hydroethyl thiazole |
| WO1997022599A1 (en) * | 1995-12-18 | 1997-06-26 | Bayer Aktiengesellschaft | Improved process for producing 5-formylthiazol |
| US6372913B1 (en) * | 1997-08-14 | 2002-04-16 | Bayer Ag | Process for preparing 2-substituted 5-formylthiazoles |
-
2002
- 2002-09-19 RU RU2002124887/04A patent/RU2228332C1/en not_active IP Right Cessation
-
2003
- 2003-09-17 CN CNB031569889A patent/CN1307165C/en not_active Expired - Fee Related
- 2003-09-17 JP JP2003325125A patent/JP4440585B2/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU979344A1 (en) * | 1981-07-06 | 1982-12-07 | Болоховский химический комбинат синтетических полупродуктов и витаминов | Process for producing 4-methyl-5-beta-hydroethyl thiazole |
| WO1997022599A1 (en) * | 1995-12-18 | 1997-06-26 | Bayer Aktiengesellschaft | Improved process for producing 5-formylthiazol |
| US6372913B1 (en) * | 1997-08-14 | 2002-04-16 | Bayer Ag | Process for preparing 2-substituted 5-formylthiazoles |
Also Published As
| Publication number | Publication date |
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| JP4440585B2 (en) | 2010-03-24 |
| RU2002124887A (en) | 2004-03-20 |
| CN1495176A (en) | 2004-05-12 |
| JP2004107346A (en) | 2004-04-08 |
| RU2228332C1 (en) | 2004-05-10 |
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