阅读说明：本技术 一种4-甲基噻唑-5-甲醛的新型合成方法 (Novel synthesis method of 4-methylthiazole-5-formaldehyde ) 是由 韩津 蓝艳 于 2021-01-29 设计创作，主要内容包括：本发明提出了一种4-甲基噻唑-5-甲醛的新型合成方法,包括如下步骤：以4-甲基噻唑-5-甲醇为原料,进行催化氧化反应得到4-甲基噻唑-5-甲醛；所述催化氧化反应中,氧化剂为分子氧(氧气或空气),催化体系由催化剂A、催化剂B、催化剂C组成；催化剂A为哌啶类氮氧自由基及其衍生物,催化剂B为氮氧化物及其等价物,催化剂C为质子酸、溴化物或三价铁盐。本发明所述反应原料绿色、廉价,催化体系高效、环保,整个反应过程清洁、安全,从经济或环保角度考虑都极具优势。(The invention provides a novel synthesis method of 4-methylthiazole-5-formaldehyde, which comprises the following steps: 4-methylthiazole-5-methanol is taken as a raw material to carry out catalytic oxidation reaction to obtain 4-methylthiazole-5-formaldehyde; in the catalytic oxidation reaction, an oxidant is molecular oxygen (oxygen or air), and a catalytic system consists of a catalyst A, a catalyst B and a catalyst C; catalyst A is piperidine nitroxide free radical and its derivative, catalyst B is nitrogen oxide and its equivalent, and catalyst C is protonic acid, bromide or ferric salt. The reaction raw materials are green and cheap, the catalytic system is efficient and environment-friendly, and the whole reaction process is clean and safe, so that the method has great advantages from the economic or environment-friendly perspective.)

1. A novel synthesis method of 4-methylthiazole-5-formaldehyde, which is characterized by comprising the following steps: 4-methylthiazole-5-methanol is taken as a raw material to carry out catalytic oxidation reaction to obtain 4-methylthiazole-5-formaldehyde; in the catalytic oxidation reaction, an oxidant is oxygen or air, and a catalytic system consists of a catalyst A, a catalyst B and a catalyst C; catalyst A is piperidine nitroxide free radical and its derivative, catalyst B is nitrogen oxide and its equivalent, and catalyst C is protonic acid, bromide or ferric salt.

2. The novel synthesis method of 4-methylthiazole-5-carbaldehyde according to claim 1, wherein the piperidine nitroxide radical and its derivatives are one or more combinations of compounds of the following structures:

3. a novel synthesis method of 4-methylthiazole-5-carbaldehyde according to claim 1 or 2, characterized in that said nitrogen oxides and their equivalents are one or more of sodium nitrite, potassium nitrite, methyl nitrite, ethyl nitrite, tert-butyl nitrite, isoamyl nitrite.

4. A novel process for the synthesis of 4-methylthiazole-5-carbaldehyde according to any of claims 1 to 3, wherein said protic acid is hydrochloric acid.

5. A novel synthesis method of 4-methylthiazole-5-carbaldehyde according to any one of claims 1 to 4, wherein said bromide is one or more of hydrogen bromide, sodium bromide and potassium bromide.

6. A novel synthesis method of 4-methylthiazole-5-carbaldehyde according to any one of claims 1 to 5, wherein said ferric salt is one or more selected from ferric chloride, ferric bromide, ferric sulfate, ferric nitrate and potassium ferricyanide.

7. A novel synthesis method of 4-methylthiazole-5-carbaldehyde according to any one of claims 1 to 6, wherein the solvent for catalytic oxidation reaction is one or more of dichloromethane, chloroform, 1, 2-dichloroethane, chlorobenzene, fluorobenzene, trifluorotoluene, acetonitrile and acetic acid.

8. A novel synthesis method of 4-methylthiazole-5-carbaldehyde according to any one of claims 1 to 7, wherein the temperature of the catalytic oxidation reaction is 0 to 120 ℃.

9. The novel synthesis method of 4-methylthiazole-5-carbaldehyde according to any one of claims 1 to 8, wherein the amount of the piperidine nitroxide radical is 0.1 to 20% of the molar amount of 4-methylthiazole-5-methanol; the dosage of the nitrogen oxide and the equivalent thereof is 0.1 to 20 percent of the molar weight of the 4-methylthiazole-5-methanol; the dosage of the protonic acid is 0.1-20% of the molar weight of the 4-methylthiazole-5-methanol; the using amount of the bromide is 0.1-20% of the molar amount of the 4-methylthiazole-5-methanol; the dosage of the trivalent ferric salt is 0.1-20% of the molar weight of the 4-methylthiazole-5-methanol.

Technical Field

The invention relates to the technical field of synthesis of medical intermediates, in particular to a novel synthesis method of 4-methylthiazole-5-formaldehyde.

Background

4-methylthiazole-5-formaldehyde is an important intermediate for preparing cefditoren pivoxil tablets serving as third-generation cephalosporin antibacterial drugs, and has a chemical structureIn practice, 4-methyl is usedWhen 4-methylthiazole-5-formaldehyde is synthesized by taking thiazole-5-methanol as a starting material, expensive and toxic oxidants such as chromium reagents, manganese reagents, other transition metal oxides, high-valence iodine reagents and the like are mostly used, and the use amount of the oxidants is mostly excessive, so that a large amount of waste pollutants are generated, and great pressure is caused on environmental protection.

Currently, 2,2,6, 6-tetramethylpiperidine-nitrogen-oxygen free radical (TEMPO) and its derivatives show outstanding selectivity and catalytic activity in alcohol oxidation reactions. TEMPO as small organic molecule can avoid environmental pollution caused by toxic metal ion, and has mild reaction condition, easy recovery and wide application in practical production.

Two methods for preparing 4-methylthiazole-5-carbaldehyde from 4-methylthiazole-5-methanol are disclosed in patent CN 1628108A. One uses a TEMPO/KBr/NaClO oxidation system and the other uses pyridinium chlorochromate (PCC) as an oxidizing agent. The former method has higher yield, but the sodium hypochlorite is used at low temperature and has harsher conditions; the latter method has the disadvantages of high product purity, low yield, increased solid waste amount due to the use of heavy metal oxidant, environmental pollution, unstable product quality and the like.

In patent CN103030604A, TEMPO is used as a catalyst, and calcium hypochlorite or sodium hypobromite is used as an oxidant to oxidize 4-methylthiazole-5-methanol to obtain 4-methylthiazole-5-formaldehyde, although a cocatalyst such as potassium bromide is not required, the reaction yield is not high.

Disclosure of Invention

Based on the problems in the background art, the invention provides a green, efficient and economic synthesis method of 4-methylthiazole-5-formaldehyde by using 4-methylthiazole-5-methanol as a raw material.

The invention is realized by the following technical scheme:

4-methylthiazole-5-methanol is taken as a raw material, and one-step catalytic oxidation is carried out to prepare 4-methylthiazole-5-formaldehyde; in the catalytic oxidation reaction, an oxidant is molecular oxygen (oxygen or air), and a catalytic system consists of a catalyst A, a catalyst B and a catalyst C; catalyst A is piperidine nitroxide free radical and its derivative, catalyst B is nitrogen oxide and its equivalent, and catalyst C is protonic acid, bromide or ferric salt.

Wherein, the piperidine nitroxide free radical and the derivatives thereof are one or more combinations of the following structural compounds:

the nitrogen oxide and the equivalent thereof are one or a combination of more of sodium nitrite, potassium nitrite, methyl nitrite, ethyl nitrite, tert-butyl nitrite and isoamyl nitrite.

The protonic acid is hydrochloric acid. The bromide is one or more of hydrogen bromide, sodium bromide and potassium bromide. The ferric salt is one or more of ferric chloride, ferric bromide, ferric sulfate, ferric nitrate and potassium ferricyanide.

Wherein, the solvent of the catalytic oxidation reaction is one or a combination of more of dichloromethane, chloroform, 1, 2-dichloroethane, chlorobenzene, fluorobenzene, trifluorotoluene, acetonitrile and acetic acid.

Wherein the temperature of the catalytic oxidation reaction is 0-120 ℃, and preferably 20-80 ℃.

Wherein the dosage of the piperidine nitroxide radical is 0.1-20% of the molar weight of 4-methylthiazole-5-methanol; the dosage of the nitrogen oxide and the equivalent thereof is 0.1 to 20 percent of the molar weight of the 4-methylthiazole-5-methanol; the dosage of the protonic acid is 0.1-20% of the molar weight of the 4-methylthiazole-5-methanol; the using amount of the bromide is 0.1-20% of the molar amount of the 4-methylthiazole-5-methanol; the dosage of the trivalent ferric salt is 0.1-20% of the molar weight of the 4-methylthiazole-5-methanol.

The starting materials and reagents of the invention are commercially available.

The invention has the beneficial effects that:

the reaction raw materials are green and cheap, the catalytic system is efficient and environment-friendly, the whole reaction process is clean and safe, and the method has great advantages in both economic and environment-friendly aspects.

Drawings

FIG. 1 Synthesis route of 4-methylthiazole-5-carbaldehyde proposed by the present invention

FIG. 2 is a nuclear magnetic hydrogen spectrum of 4-methylthiazole-5-carbaldehyde prepared by the present invention

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the technical solutions of the present invention are further described in detail with reference to specific examples below.

Example 1

129.2g (1.0mol) of 4-methylthiazole-5-methanol, 3.44g (0.02mol) of 4-hydroxy-2, 2,6, 6-tetramethylpiperidine oxide, 8.1g (0.05mol) of ferric trichloride, 3.5g (0.05mol) of sodium nitrite and 400mL of 1, 2-dichloroethane are sequentially added into a 1L three-necked flask, and the mixture is stirred in the air at room temperature and normal pressure for reaction for 8 hours.

Sampling and detecting to the end point of the reaction; transferring the reaction solution to a separating funnel, washing twice with a saturated sodium thiosulfate solution, drying the organic phase overnight with anhydrous sodium sulfate after separating, distilling under reduced pressure to recover the solvent to obtain a light yellow solid, and recrystallizing with n-heptane to obtain light yellow crystal powder of 4-methylthiazole-5-formaldehyde with the content of 99% and the yield of 83%.

Example 2

129.2g (1mol) of 4-methylthiazole-5-methanol, 5.4g (0.03mol) of 2,2,6, 6-tetramethylpiperidine oxide, 12g (0.1mol) of 30% hydrochloric acid and 3.5g (0.05mol) of sodium nitrite were put into a 1L three-necked flask, 400mL of methylene chloride was added thereto, and after stirring, air was introduced thereinto to conduct a reaction at normal temperature for 10 hours.

After the reaction, the reaction solution was transferred to a separatory funnel, washed twice with a saturated sodium bicarbonate solution, the organic phase after separation was dried overnight with anhydrous sodium sulfate, and the solvent was recovered by distillation under reduced pressure to give a pale yellow solid, which was recrystallized from n-heptane to give a pale yellow crystalline powder having a 4-methylthiazole-5-carbaldehyde content of 99% and a yield of 96%.

Example 3

129.2g (1mol) of 4-methylthiazole-5-methanol, 18.6g (0.1mol) of 4-methoxy-2, 2,6, 6-tetramethylpiperidine oxide, 11.9g (0.1mol) of potassium bromide and 10.3g (0.1mol) of tert-butyl nitrite are put into a 1L pressure kettle, 400mL of dichloromethane is added, oxygen is introduced after uniform stirring, the temperature is raised to 80 ℃, and reflux reaction is carried out for 6 hours.

After the reaction, the reaction solution was cooled to room temperature, the pressure was carefully removed, the reaction solution was transferred to a separatory funnel, the organic phase after separation was dried overnight with anhydrous sodium sulfate, the solvent was recovered by distillation under reduced pressure to obtain a pale yellow solid, which was recrystallized from n-heptane to obtain pale yellow crystalline powder having a 4-methylthiazole-5-carbaldehyde content of 99% and a yield of 91%.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.