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A kind of cleaning preparation method of 4-hydroxymethylthiazole and intermediate thereof

A technology of tetramethylpiperidine and alkyl, which is applied in the field of clean preparation of 4-hydroxymethylthiazole, can solve problems such as skin burns and dermatitis, irritating lachrymatory, strong irritation, etc., and achieves less side effects , The reaction is simple and easy to operate, and the effect of reducing production costs

Active Publication Date: 2021-07-09
博璞诺(上海)医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The problem to be solved by the present invention is that the raw material 1,3-dichloroacetone used in the existing preparation method of 4-hydroxymethylthiazole is highly toxic and highly irritating to the eyes, which can cause skin burns and dermatitis, and release Toxic chloride fumes are irritating and lachrymatory, and are likely to cause harm to operators. In addition, toxic and carcinogenic dichromic acid is used for oxidation in its own production process, which has relatively large environmental pollution and other defects. There is a clean preparation method of 4-hydroxymethylthiazole and its intermediates with completely different technologies. The raw materials used in the preparation method of the present invention are safe and non-toxic, the reaction is simple and easy to operate, and there are few side reactions. Water can be used as a solvent and after carrying out treatment, and vacuum distillation purification, which reduces the production cost, and the obtained product has high purity and is easy to industrialized large-scale production

Method used

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  • A kind of cleaning preparation method of 4-hydroxymethylthiazole and intermediate thereof
  • A kind of cleaning preparation method of 4-hydroxymethylthiazole and intermediate thereof
  • A kind of cleaning preparation method of 4-hydroxymethylthiazole and intermediate thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] The preparation of embodiment 1 acetate-3-chloro-2-hydroxyl propyl ester (compound IV)

[0073] In a 250mL three-necked flask, add epichlorohydrin (4.6g, 49.7mmol) and acetonitrile (50mL), then add acetic acid (3.9g, 64.9mmol) and tetrabutylammonium bromide (161mg, 0.5mmol), the system Heat to reflux. After the reaction was detected by TLC, the solvent was evaporated under reduced pressure, and the crude product was added to 50 mL of 5% potassium carbonate aqueous solution, and then added to 60 mL of ethyl acetate for extraction. After the organic phase was concentrated, the product was distilled under reduced pressure to obtain 6.1 g of a colorless liquid with a yield of 80.4% and a purity of 98.2% by HPLC. 1 H NMR (CDCl 3 ): δ4.22(d, J=8.0Hz, 2H), 4.10-4.06(m, 1H), 3.69-3.59(m, 2H), 2.78(d, J=8.0Hz, 1H), 2.12(s, 3H).

Embodiment 2

[0074] The preparation of embodiment 2 acetic acid-3-chloro-2-carbonyl propyl ester (compound III)

[0075] In a 250mL three-necked flask, add acetic acid-3-chloro-2-hydroxypropyl ester (5.0g, 32.8mmol), TEMPO (180mg, 1.2mmol), sodium bicarbonate (7.6g, 90.5mmol), ethyl acetate 50mL and water 20mL, the system was cooled to 4°C, and an aqueous solution (10mL) of sodium hypochlorite (3.6g, 48.3mmol) was added dropwise. After the dropwise addition, keep the system temperature and continue to stir for about half an hour, then add 20 mL of 5% sodium thiosulfate aqueous solution. Then the organic phase was separated, dried with anhydrous sodium sulfate, and the crude product was concentrated and distilled under reduced pressure to obtain 4.1 g of a colorless oily product with a yield of 83.0% and a purity of 99.2% by HPLC. 1 H NMR (CDCl 3 ), δ4.87(s,2H), 4.13(s,2H), 2.17(s,3H).

Embodiment 3

[0076] The preparation of embodiment 3 phenylacetic acid-3-bromo-2-carbonyl propyl ester (compound III)

[0077] In a 100mL three-necked flask, add phenylacetic acid-3-bromo-2-hydroxypropyl ester (5.0g, 18.3mmol), TEMPO (157.6mg, 0.9mmol), sodium bicarbonate (4.6g, 54.8mmol), bromide Potassium (3.4g, 28.6mmol), ethyl acetate 25mL and water 10mL, the system was cooled to 4°C, and sodium hypochlorite (2.1g, 28.2mmol) aqueous solution (5mL) was added dropwise. After the dropwise addition, keep the system temperature and continue to stir for about half an hour, then add 10 mL of 5% sodium thiosulfate aqueous solution. Then the organic phase was separated, dried with anhydrous sodium sulfate, and the crude product was concentrated and distilled under reduced pressure to obtain 4.7 g of a colorless oily product with a yield of 94.7% and an HPLC purity of 99.1%.

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Abstract

The invention discloses a clean preparation process of 4-hydroxymethylthiazole and its intermediate. The invention provides a process for cleanly producing 4-hydroxymethylthiazole. Taking compound I as an example, it includes the following steps: in a solvent, in the presence of a base and a catalytic amount of 2,2,6,6-tetramethylpiperidine-1-oxide, compound IV and hypohalogen The acid-alkali metal salt is oxidized to obtain compound III, which is then cyclized with N,N-dimethylthioacetamide to obtain II, and the ester group is hydrolyzed to obtain the target product I. The raw materials used in the preparation method of the present invention are safe and non-toxic, the reaction is simple and easy to operate, and there are few side reactions. Water can be used as a solvent and post-treatment, and vacuum distillation purification reduces production costs, and the obtained product has high purity. Easy to industrialized mass production.

Description

technical field [0001] The invention relates to a clean preparation method of 4-hydroxymethylthiazole and its intermediate. Background technique [0002] Nizatidine (English name: Nizatidine; CAS No.: 76963-41-2) is a gastric acid secretion inhibitor successfully developed by Eli Lilly and Company of the United States. It was first launched in the United States in 1987 under the trade name Axid. Nizatidine is a potent H2 receptor antagonist, acting on gastric acid secreting cells, blocking gastric acid formation and reducing basic gastric acid, and can also inhibit gastric acid secretion caused by food and chemical stimuli, such as gastrin and acetylcholine. It is suitable for the treatment of gastric and duodenal ulcers, gastroesophageal reflux disease and the prevention of recurrence of duodenal ulcers. The structure is as follows: [0003] [0004] The preparation method of nizatidine reported in existing literature (seeing J.O.C,1992,57,10,2869-2872 and US6069256) i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/29C07C69/14C07C69/614C07D277/28
CPCC07C67/26C07C67/29C07D277/28C07C69/16C07C69/14C07C69/614
Inventor 冯亚兵吴春原黄嘉慧朱文峰
Owner 博璞诺(上海)医药科技发展有限公司